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WO2025040089A1 - Novel heterocyclic compound for selectively regulating cannabinoid cb1 function - Google Patents

Novel heterocyclic compound for selectively regulating cannabinoid cb1 function Download PDF

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Publication number
WO2025040089A1
WO2025040089A1 PCT/CN2024/113428 CN2024113428W WO2025040089A1 WO 2025040089 A1 WO2025040089 A1 WO 2025040089A1 CN 2024113428 W CN2024113428 W CN 2024113428W WO 2025040089 A1 WO2025040089 A1 WO 2025040089A1
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alkyl
saturated
cycloalkyl
hydrogen
halogen
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French (fr)
Chinese (zh)
Inventor
张龙
牛张明
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Mindrank Therapeutics Suzhou New Drug Research And Development Co Ltd
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Mindrank Therapeutics Suzhou New Drug Research And Development Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically includes novel heterocyclic compounds capable of selectively regulating CB1 function, compositions containing such compounds, and methods for applying such compounds to prepare drugs for treating or preventing diseases associated with abnormal CB1 genes/proteins or signal pathways (such as obesity, diabetes, metabolic syndrome, etc.).
  • CB1 and CB2 There are two subtypes of cannabinoid receptors: CB1 and CB2. It is generally believed that CB1 activation can increase appetite, promote fat synthesis and storage, inhibit the function of insulin and leptin, and promote inflammation and fibrosis. Studies have found that knocking out the CB1 receptor gene in mice can reduce the levels of insulin and leptin in their blood, and improve insulin and leptin resistance, indicating that the stimulation of CB1 receptors plays an important role in the development of diet-induced obesity. Inhibiting CB1 receptors can effectively reduce the body's food intake and increase energy consumption. Therefore, CB1 has become a hot target for the treatment of obesity and metabolic disorders. Some drugs have entered clinical trials or are on the market, such as Rimonabant.
  • the cannabinoid receptor CB 1 is one of the most highly expressed G protein-coupled receptors (GPCRs) in the human central nervous system. It is mainly located in the brain, spinal cord and peripheral nervous system. In addition, it is widely distributed in adipose tissue, liver, muscle, gastrointestinal tract, etc. Studies have found that most of the existing drugs under development have insufficient efficacy and high safety risks, especially central nervous system-related side effects, which limit the use of such drugs. Rimonabant was approved for marketing by the European Medical Committee (EMA) in 2006, but was soon banned due to potential psychiatric side effects such as anxiety, depression, and suicidal tendencies. Therefore, there is an urgent need to develop pure peripheral CB1 modulators that cannot penetrate the brain and do not act on the central nervous system in order to avoid CNS-related side effects.
  • GPCRs G protein-coupled receptors
  • heterocyclic new compounds of the formula (I) structure of the present invention not only have significant selective inhibition of CB1, but also are basically unable to penetrate the blood-brain barrier.
  • they also have higher efficacy and safety characteristics, better pharmacokinetic properties (including better permeability, lower clearance rate, longer T1/2 and higher exposure) and bioavailability.
  • representative compounds of the present invention such as MDR-001-305-3 not only have similar efficacy, but also have better PK (lower clearance rate, higher exposure, longer half-life and greater bioavailability), and more importantly, the brain penetration rate is much lower than INV-202, and it is expected that there will be no central nervous system toxicity or side effects, or the potential central nervous system toxicity and side effects will have a smaller risk. It is expected that MDR-001-305-3 will have better human PK characteristics and be more suitable as a candidate drug for the prevention or treatment of diseases related to CB1 targets and their signaling pathways.
  • the object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product thereof.
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • X 1 is independently selected from N or CR 1 ;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, sulfur pentafluoride, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 Cycloalkyl
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cyclo
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IA):
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cyclo
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer randomly selected from 0, 1, 2, 3, 4 and 5
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IB):
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R1-6 alkoxy is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl.
  • the hydrogen on R1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl ;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cyclo
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C2-50 alkenyl acyl, C10-50 alkenylalkyl acyl or C10-50 alkylalkenylalkyl acyl, C1-10 alkyl acyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl or M group; further Rd1, Rd2, Rd3, Rd4 , Rd5 , Rd
  • the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 2 groups selected from hydrogen, deuterium, halogen , oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups ;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer randomly selected from 0, 1, 2, 3, 4 and 5
  • r is an integer arbitrarily selected from 1, 1 and 2;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IC):
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxy
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen atoms
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (ID),
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • Y is arbitrarily and independently selected from O, S or NR;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cyclo
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IE):
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • R 0 is preferably selected from the M group; and the hydrogen on R 0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, sulfur pentafluoride, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 Cycloalkyl
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cyclo
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IF),
  • Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cyclo
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IE):
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycl
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2
  • R and A are not benzene rings at the same time, or when R and A are benzene rings at the same time, any two adjacent R1s together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IF):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • R d4 is not hydrogen, or R d4 is hydrogen, but R d1 is alkyl, haloalkyl, deuterated alkyl, cycloalkyl, alkylthio, or cycloalkylthio;
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IG):
  • Ring A arbitrarily and independently represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • R3 is independently selected from deuterium, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C2-10 heteroalkyl , haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino, -COOH, C3-10 saturated/partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocyclyl, aryl, heteroaryl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl , C1-10 alkyl substituted with carboxy
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IA):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • R 1 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl , sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl ; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalky
  • R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkyl
  • the C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IA):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxy
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycl
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio
  • R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkyl
  • the C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IB):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • the hydrogen on R1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl ;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl ; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalky
  • R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkyl
  • the C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IC):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl , C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthi
  • Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, s
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-ID):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and
  • the hydrogen of the group is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl , C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthi
  • R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkyl
  • the C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IE):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloal
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl ; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalky
  • R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkyl
  • the C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH , OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3, and 4.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IF):
  • Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • X1 and X2 are independently selected from N or CR1 ;
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycl
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl
  • Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10
  • R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl , C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthi
  • R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkyl
  • the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups . and a C 3-6 cycloalkyl group;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, and 3.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (7-ID):
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxy
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups;
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (7-IE):
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (7-IF):
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxy
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • M is arbitrarily and independently selected from
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from
  • R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alky
  • R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • r is an integer arbitrarily selected from 0, 1 and 2.
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (8-I):
  • Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalky
  • Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substitute
  • R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • Y is arbitrarily and independently selected from O, S or NR;
  • Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;
  • R 9 is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH 2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated, partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycl
  • Rd1 and Rd2 are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C2-50 alkenyl acyl, C10-50 alkenylalkyl acyl or C10-50 alkylalkenylalkyl acyl, C1-10 alkyl acyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl or M group; further Rd1 or R The hydrogen on d2 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphospho
  • R d3 and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; further, R d3 and R d4 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10
  • the halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, and 4;
  • n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;
  • t is arbitrarily selected from an integer among 0, 1 and 2.
  • R 9 is an alkyl group
  • at least one of R 1 or R 3 is a cyano group or a sulfur pentafluoride group, or R d4 , R d1 and R d2 are not hydrogen atoms at the same time.
  • Ring A arbitrarily and independently represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;
  • M is arbitrarily and independently selected from
  • the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (II):
  • A is selected from C 6-10 aryl, 5-10 membered heterocyclic group
  • E is selected from N or CH 2 ; when E is N, is a double bond; when E is CH 2 , is a single bond;
  • R is selected from C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl;
  • R 0 is selected from R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 91 : C 1-6 alkyl, C 2-6 alkenyl; each R 91 is the same or different and is independently selected from H, OH, -N + (C 1-6 alkyl); R 10 is selected from -C 1-6 alkyl-S(O) 2 NH 2 ;
  • R 1 is selected from H, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy; or two R 1 and the atoms to which they are attached form a 3-8 membered heterocyclic group;
  • R 2 is selected from H, halogen, pentafluorosulfur, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • R d1 and R d2 are the same or different and are independently selected from H, C 1-6 alkyl, and C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • w is selected from 0 or 1.
  • A is selected from phenyl, 5-6 membered heterocyclyl
  • A is selected from phenyl, piperidinyl (e.g. ).
  • R is selected from C 1-3 alkyl, phenyl, 5-6 membered heteroaryl
  • R is selected from methyl, phenyl, thienyl (e.g. ).
  • R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 91 : methyl, propyl, propenyl; each R 91 is the same or different and is independently selected from H, OH,
  • R 9 is selected from methyl
  • R 10 is selected from
  • R 1 is selected from H, CN, halogen; or two R 1 and the atoms to which they are attached form a 4-membered heterocyclic group;
  • R 1 is selected from H, Cl, CN; or two R 1 and their respective atoms form
  • R 2 is selected from H, halogen, pentafluorinated sulfur, halogenated C 1-3 alkyl;
  • R 2 is selected from H, F, trifluoromethyl, pentafluorosulfuryl.
  • R d1 and R d2 are the same or different and are independently selected from H, C 1-3 alkyl;
  • R d1 and R d2 are the same or different and are independently selected from H and methyl.
  • the above-mentioned compound, its pharmaceutically acceptable salt, corresponding isomer or isotope substitution is a new compound selected from the structure disclosed in the embodiments of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution.
  • the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
  • the oral dosage form is not particularly limited, and any oral dosage form known in the art may be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator.
  • a pharmaceutically acceptable excipient which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator.
  • excipients including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Another object of the present invention is to provide the use of the above-mentioned compound, its pharmaceutically acceptable salt, enantiomer or isotope substitution in the preparation of a drug for preventing and/or treating diseases related to abnormal CB1 signaling pathway.
  • the diseases related to the CB1 signaling pathway include but are not limited to various diabetes, obesity or overweight, metabolic syndrome and other diseases.
  • the present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, corresponding isomer or isotope substitution, and the use of the pharmaceutical composition in preventing and/or treating diseases related to abnormal CB1 signaling pathway.
  • the present invention also provides a method for preventing and/or treating diseases related to abnormal CB1 signaling pathway, comprising administering to a patient an effective amount of the compound represented by formula (I), a pharmaceutically acceptable salt, a corresponding isomer or an isotope substitute thereof, or administering to a patient an effective amount of the above-mentioned pharmaceutical composition.
  • the patient is a mammal, preferably a human.
  • C1-10 is selected from the group consisting of C1, C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;
  • C2-10 is selected from the group consisting of C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 and C10 ;
  • C3-10 is selected from the group consisting of C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;
  • alkyl means a straight or branched saturated hydrocarbon group, preferably a straight or branched saturated hydrocarbon group ( C1-10 alkyl) having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group includes a C1-3 alkyl group, a C1-6 alkyl group, a C3-6 alkyl group, a C1-10 alkyl group, etc.
  • C1-10 alkyl means a straight and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
  • C1-8 alkyl means a straight and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms
  • C1-6 alkyl means a straight and branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.
  • alkylene refers to a straight or branched chain divalent hydrocarbon group of the formula -(CH 2 ) n - Non-limiting examples include ethylene and propylene.
  • the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.
  • aliphatic ring refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group
  • the carbocycle can contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms.
  • the carbocycle can be monocyclic or polycyclic, it can be a saturated cycloalkyl or can optionally contain one, two or more double bonds and/or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl.
  • non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.
  • aryl or "aromatic ring” means: it should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic hydrocarbon ring with 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl”.
  • C 6-14 aryl is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring (“C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl When the C 6-20 aryl is substituted, it may be mono
  • spirocyclic ring refers to a ring system in which two rings share one ring-forming atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • paracyclic refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • bridged ring refers to a ring system in which two rings share three or more ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms or radicals selected from N, O, NH, S, S(O) or S(O) 2 , but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6).
  • the heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt).
  • the heterocyclic group can include fused or bridged rings and/or spirocyclic rings.
  • the non-limiting examples of monocyclic heterocyclic radical include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl.
  • Polycyclic heterocyclic radical includes the heterocyclic radical of spirocycle, condensed ring and bridge ring, and can also be the heterocyclic radical of benzo condensation such as dihydroisoquinolinyl.
  • the heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.
  • the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heteroaryl/heteroaromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus.
  • Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan.
  • heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc.
  • the heteroaryl/heteroaromatic ring may be optionally substituted or unsubstituted.
  • the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • heterocyclic groups, heteroaryls or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridin-2-yl may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene;
  • thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • pharmaceutically acceptable salts are derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali or organic salts of acid radicals such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, and the like.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic and organic bases selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid,
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • compounds provided by the present invention also exist in prodrug forms.
  • Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention.
  • prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Some compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally speaking, solvated form is suitable with non-solvated form, all included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form.
  • solvate refers to an association formed by one or more solvent molecules and the compounds of the present invention.
  • Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. Therefore, the term “hydrate” refers to an association formed by a solvent molecule that is water.
  • Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds.
  • radioactive isotope labeled compounds may be used, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to technicians in the field of cosmetics or topical drugs. For additional information about carriers, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents When a substituent can cross-link two atoms on a ring, the substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to a compound included in the chemical formula but not specifically mentioned, the substituent can be bonded through any atom thereof. Combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention is now further described by examples.
  • the examples given below are for illustrative purposes only and are not intended to limit the scope of this invention.
  • the compounds of the present invention can be prepared using many known methods in the field of organic synthesis.
  • the embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based thereon.
  • Preferred methods include, but are not limited to, the following description methods.
  • aq is aqueous solution
  • TLC thin layer chromatography
  • RT room temperature
  • MeOH is methanol
  • EtOH is ethanol
  • EtOAc is ethyl acetate
  • THF is tetrahydrofuran
  • equivalent is eq
  • CDI carbonyldiimidazole
  • DCM dichloromethane
  • PE petroleum ether
  • DIAD is diisopropyl azodicarboxylate
  • DMF is N,N-dimethylformamide
  • DMSO is dimethyl sulfoxide
  • CBz is benzyloxycarbonyl
  • BOC is tert-butyl ester.
  • 6-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)nicotinonitrile (3.28 g, 13.2 mmol) was added to a toluene (60 mmol) solution of methyl (4-chlorophenyl)sulfonyl)carbamate (3.0 g, 12 mmol).
  • the resulting mixed reaction solution was refluxed for 4 hours. Cooled to room temperature and waited for slow crystallization.
  • N-carbamoyl acetamide (782 mg, 7.75 mmol) was added to a solution of (E)-N-((4-chlorophenyl)sulfonyl)-3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-carbamoyl chloride (3.74 g, 7.75 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 hour.
  • LiHMDS (1M tetrahydrofuran, 88.4mL, 88.4mmol) was added to a solution of N,N-dimethylformamide (60mL) containing methyl 4-chlorobenzoate (5.00g, 29.4mmol) and 2-phenylacetic acid (4.0g, 29.4mmol) and stirred at 0°C for 2 hours.
  • the mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (50mL) and extracted with ethyl acetate (50mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.04 g, 3.7 mol) was added to a toluene (10 mL) solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (1.0 g, 3.7 mmol), and the mixture was heated to 110° C. and stirred for 4 hours.
  • PCl 5 (379 mg, 1.82 mmol) was added to a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1 -carboxamide (500 mg, 0.96 mmol) in chlorobenzene (8 mL) at room temperature, and the mixture was heated at 145°C and stirred for 3 hours.
  • Reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm) purification, when the content of mobile phase B reached 60%, the fractions containing the product were collected, and the compound N-(N′-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (180mg, 0.30mmol, yield: 32.14%) was concentrated under reduced pressure, LCMS m/z: 605[M+H] + .
  • N 2 H 4 .H 2 O (2.23 g, 69.68 mmol) was added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one (2.17 g, 8.71 mmol) in tetrahydrofuran (5 mL), and the mixture was heated at 80°C and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure.
  • Phosphorus pentachloride (649 mg, 3.12 mmol) was added to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (400 mg, 0.78 mmol) in chlorobenzene (8 mL) at room temperature, and the mixture was heated to 140°C and stirred for 2 hours.
  • the mixed reaction solution was purified by high performance liquid chromatography (chromatographic strip conditions: Waters 2767/Qda, Sunfire C18, 19 ⁇ 250 ⁇ 10um; mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 26% B-36%; retention time: 7.5-9.0 min of 16 min) to obtain compound N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (95 mg, 0.16 mmol, yield: 20.5%), LCMS m/z: 597 [M+H] + .
  • N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (95 mg) obtained above was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column: 250*30mm 10 ⁇ m; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol, A:B 60:40; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar, injection volume: 8mL; cycle time: 6.5min) was purified to obtain two isomers: MDR-001-304-1 and MDR-001-304-2:
  • lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 91 mL, 90.64 mmol) was added to a solution of methyl 4-chlorobenzoate (5.00 g, 29.24 mmol) and 2-(thiophene-2-yl)acetic acid (4.15 g, 29.24 mmol) in N,N-dimethylformamide (100 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL).
  • lithium hydroxide (1.86 g, 77.40 mmol) was added to a solution of ethyl 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoate (5.00 g, 15.48 mmol) in tetrahydrofuran (100 mL), water (50 mL) and ethanol (50 mL), and stirred at room temperature for 1 hour.
  • the mixed reaction solution was adjusted to pH 4-5 with hydrochloric acid (1 M) and diluted with ethyl acetate (200 mL).
  • hydrazine hydrate (651 mg, 20.34 mmol) was added to a solution of 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoic acid (4.00 g, 13.56 mmol) in ethanol (50 mL), and the mixture was heated to 80°C and stirred for 2 hours.
  • borane (1M tetrahydrofuran solution, 13.76 mL, 13.76 mmol) was added to a solution of 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazine-3(2H)-one (2.00 g, 6.88 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours.
  • the mixed reaction solution was quenched with methanol (40 mL), stirred at room temperature for 0.5 hours, and the mixed reaction solution was concentrated under reduced pressure.
  • 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine (1.05 g, 3.79 mmol) was added to a toluene solution (20 mL) containing methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.18 g, 4.17 mmol), and the mixture was heated to 110°C and stirred for 2 hours.
  • Phosphorus oxychloride 174 mg, 1.14 mmol
  • 4-dimethylaminopyridine 580 mg, 4.75 mmol
  • 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide 500 mg, 0.95 mmol
  • dichloromethane 20 mL
  • the mixture was heated at 50°C and stirred for 3 hours.
  • N-aminocarboxamidinoacetamide (949 mg, 9.40 mmol) and N,N-diisopropylethylamine (1.21 g, 9.40 mmol) were added to a solution of 1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (598 mg, 0.94 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 2 hours.
  • the mixed reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (5 mL ⁇ 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic column: spherical C18, 20-40um, 80g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 65mL/min; gradient: 5%B-80%B in 12min; detector: 254nm).
  • N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (80 mg, 0.13 mmol) obtained above was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*25mm 10 ⁇ m; mobile phase A; supercritical CO2 ; mobile phase B: acetonitrile (+0.1% 7.0M ammonia methanol), A:B 65:45; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 7.2min) was purified to obtain two isomers: MDR-001-302-1 and MDR-001-302-2.
  • n-BuLi (1.6M, 7.7mL, 12.35mmol) was added to a solution of 1,3-dibromo-2-(2-bromoethyl)benzene (4.2g, 1235mmol) in tetrahydrofuran (30mL), and stirred at -78°C for 2 hours.
  • the resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (10mL) and extracted with ethyl acetate (20mL ⁇ 3).
  • N-bromosuccinimide (1.08 g, 6.07 mmol) was added to a solution of tert-butyl bicyclo[4.2.0]oct-1(6),2,4-triene-2-ylcarbamate (1.33 g, 6.07 mmol) in acetonitrile (20 mL), and stirred at room temperature for 20 hours.
  • LCMS showed that the reaction was complete.
  • the resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3).
  • Potassium carbonate (790 mg, 5.7 mmol) and paraformaldehyde (1170 mg, 38.9 mmol) were added to a solution of 1-(5-chlorobicyclo[4.2.0]octan-1(6),2,4-trien-2-yl)-2-phenylethane-1-one (500 mg, 1.9 mmol) in tetrahydrofuran (20 mL), and the mixture was heated at 40°C and stirred for 5 hours.
  • the mixed reaction solution was concentrated under reduced pressure and passed through reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 min; detection wavelength: 254 nm).
  • Example 6 N-((E)-N′-((Z)-((S)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer and N-((E)-N′- Synthesis of ((Z)-((R)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomers (MDR-001-302-1 and MDR-001-302-2):
  • lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 91 mL, 90.64 mmol) was added to a solution of methyl 4-chlorobenzoate (5.00 g, 29.24 mmol) and 2-(thiophene-2-yl)acetic acid (4.15 g, 29.24 mmol) in N,N-dimethylformamide (100 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL).
  • lithium hydroxide (1.86 g, 77.40 mmol) was added to a solution of ethyl 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoate (5.00 g, 15.48 mmol) in tetrahydrofuran (100 mL), water (50 mL) and ethanol (50 mL), and stirred at room temperature for 1 hour.
  • the mixed reaction solution was adjusted to pH 4-5 with hydrochloric acid (1 M) and diluted with ethyl acetate (200 mL).
  • hydrazine hydrate (651 mg, 20.34 mmol) was added to a solution of 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butyric acid (4.00 g, 13.56 mmol) in ethanol (50 mL), and the mixture was heated at 80°C and stirred for 2 hours.
  • borane (1M tetrahydrofuran solution, 13.76 mL, 13.76 mmol) was added to a solution of 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazine-3(2H)-one (2.00 g, 6.88 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours.
  • the mixed reaction solution was quenched with methanol (40 mL), stirred at room temperature for 0.5 hours, and the mixed reaction solution was concentrated under reduced pressure.
  • 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine (1.05 g, 3.79 mmol) was added to a toluene solution (20 mL) containing methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.18 g, 4.17 mmol), and the mixture was heated to 110°C and stirred for 2 hours.
  • N-aminocarboxamidinoacetamide (949 mg, 9.40 mmol) and N,N-diisopropylethylamine (1.21 g, 9.40 mmol) were added to a solution of Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (598 mg, 0.94 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 2 hours.
  • the mixed reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (5 mL ⁇ 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic column: spherical C18, 20-40um, 80g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 65mL/min; gradient: 5%B-80%B in 12min; detector: 254nm).
  • N 2 H 4 .H 2 O (2.23 g, 69.68 mmol) was added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one (2.17 g, 8.71 mmol) in tetrahydrofuran (5 mL), and the mixture was heated at 80°C and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure.
  • Phosphorus pentachloride (649 mg, 3.12 mmol) was added to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (400 mg, 0.78 mmol) in chlorobenzene (8 mL) at room temperature, and the mixture was heated to 140°C and stirred for 2 hours.
  • the mixed reaction solution was purified by high performance liquid chromatography (chromatographic strip conditions: Waters 2767/Qda, Sunfire C18, 19 ⁇ 250 ⁇ 10um; mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 26% B-36%; retention time: 7.5-9.0 min of 16 min) to obtain compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (95 mg, 0.16 mmol, yield: 20.5%), LCMS m/z: 597 [M+H] + .
  • the mixed reaction solution was purified by reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40um, 40g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%B-50%B in 30 minutes; detector: 214nm).
  • MRANK-111-012A-1 Peak 1: Chiral HPLC: 2.561 min; (S, Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (9.21 mg, 0.014 mmol, yield: 30.7%), LCMS m/z: 643.1 [M+H] + .
  • MRANK-111-012A-2 Peak 2: Chiral HPLC: 3.747 min; (R, Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (4.67 mg, 0.0072 mmol, yield: 15.3%), LCMS m/z: 643.1 [M+H] + .
  • methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (198 mg, 0.70 mmol) was added to a toluene (5 mL) solution of 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazole (200 mg, 0.70 mmol), and the mixture was heated to 110° C. and stirred for 4 hours.
  • the mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm).
  • MDR-001-305A-1 Peak 1: Chiral HPLC: 0.565 min: 0.565 min; Compound MDR-001-305A-1 (64.11 mg, 0.10 mmol, yield: 45.79%), LCMS m/z: 619 [M+H] + .
  • MDR-001-305A-2 Peak 2: chiral HPLC: 0.986 min; compound MDR-001-305A-2 (73.26 mg, 0.11 mmol, yield: 52.32%), LCMS: m/z: 619.3 [m+H] + .
  • 2-(4-chlorophenyl)acetic acid (6.29 g, 36.76 mmol) and LiHMDS (1 M tetrahydrofuran solution, 114 mL, 113.96 mmol) were added to a solution of methyl benzoate (5.00 g, 36.76 mmol) in N,N-dimethylformamide (50 mL), and stirred at room temperature for 1 hour.
  • the mixed reaction solution was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (150 mL ⁇ 2).
  • Phosphorus pentachloride (285 mg, 1.37 mmol) was added to a solution of 4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (368 mg, 0.72 mmol) in chlorobenzene (10 mL) at room temperature, and the mixture was heated at 140°C and stirred for 2 hours under nitrogen protection.
  • the mixed reaction liquid was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-80%B in 20 minutes; detector: 214nm).
  • the mixed reaction liquid was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-80% B in 20 minutes; detector: 214 nm).
  • MDR-001-401A-1 Peak 1: chiral-HPLC: 2.855 min; N-((E)-N′-(Z)-((R)4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (26.56 mg, 0.045 mmol, yield: 27.1%), LCMS: m/z: 591 [M+H] + .
  • MDR-001-401A-2 Peak 2: chiral-HPLC: 3.244 min; N-((E)-N′-(Z)-((S)4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoimido)acetamide or enantiomer (25.81 mg, 0.044 mmol, yield: 26.3%), LCMS m/z: 591 [M+H] + .
  • the mixed reaction liquid was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm).
  • sodium hydride (60% w/w mineral oil dispersion, 951 mg, 23.78 mmol) was added to a solution of 1-(4-chlorophenyl)-2-phenylethane-1-one (5.00 g, 21.65 mmol) in dimethyl sulfoxide (100 mL), and then stirred at 5°C for 1 hour, and ethyl bromoacetate (3.97 g, 23.78 mmol) was added and stirred at room temperature for 2 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL).
  • sodium hydroxide (25% aqueous solution, 5.36 mL, 33.42 mmol) was added to a solution of ethyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate (3.53 g, 11.14 mmol) in tetrahydrofuran (100 mL), water (50 mL) and ethanol (50 mL), and stirred at room temperature for 16 hours.
  • the mixed reaction solution was adjusted to pH 4-5 with hydrochloric acid (1N) and extracted with ethyl acetate (200 mL).
  • hydrazine hydrate (545 mg, 17.03 mmol) was added to a solution of 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid (3.28 g, 11.35 mmol) in ethanol (50 mL), and the mixture was heated at 80°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure.
  • the mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (conditions are as follows: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 minutes; detector: 254 nm).
  • the mixed reaction solution was concentrated under reduced pressure and subjected to reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40um, 80g; mobile phase A: 0.1% TFA; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15min; detector: 254nm).
  • the fractions containing the desired product were collected at 60%B and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by preparative high performance liquid chromatography (system: Waters 2767/Qda; column: sunfire C18, 19*250*10um, 80g; mobile phase A: 0.1%TFA/ H2O ; mobile phase B: acetonitrile; flow rate: 20mL/min; gradient: 34-34%B; retention time 6.8-10.0min, 16min).

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Abstract

Provided is a novel heterocyclic compound having a regulatory effect on CB1 signaling pathway abnormalities. Specifically provided is a compound having a structure as shown in formula (I) or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotope substituent or an isomer thereof as a CB1 target regulator.

Description

用于选择性调节大麻素CB1功能的新型杂环类化合物Novel heterocyclic compounds for selective modulation of cannabinoid CB1 function

本申请要求享有申请人：This application requires the applicant to:

于2023年8月21日向中国国家知识产权局提交的，专利申请号为202311053936.6，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202311053936.6, filed with the State Intellectual Property Office of China on August 21, 2023, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”;

于2023年8月29日向中国国家知识产权局提交的，专利申请号为202311098622.8，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202311098622.8, filed with the State Intellectual Property Office of China on August 29, 2023, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”;

于2023年9月18日向中国国家知识产权局提交的，专利申请号为202311202822.3，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202311202822.3, filed with the State Intellectual Property Office of China on September 18, 2023, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”;

于2023年12月28日向中国国家知识产权局提交的，专利申请号为202311838739.5，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202311838739.5, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”, filed with the State Intellectual Property Office of China on December 28, 2023;

于2024年3月22日向中国国家知识产权局提交的，专利申请号为202410336861.0，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202410336861.0, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”, filed with the State Intellectual Property Office of China on March 22, 2024;

于2024年3月27日向中国国家知识产权局提交的，专利申请号为202410360934.X，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202410360934.X, filed with the State Intellectual Property Office of China on March 27, 2024, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”;

于2024年6月3日向中国国家知识产权局提交的，专利申请号为202410709443.1，名称为“用于选择性调节大麻素CB1功能的新型杂环类化合物”的在先申请的优先权权益；The priority benefit of the prior application for patent application number 202410709443.1, entitled “Novel heterocyclic compounds for selectively regulating the function of cannabinoid CB1”, filed with the State Intellectual Property Office of China on June 3, 2024;

所述在先申请的全文通过引用的方式结合于本公开中。The entirety of said prior application is incorporated into the present disclosure by reference.

技术领域Technical Field

本发明属于医药化学领域，具体包括能够选择性调节CB1功能的新型杂环类化合物，包含该类化合物的组合物及以及将该类化合物应用于制备治疗或预防与CB1基因/蛋白或信号通路异常相关的疾病(如肥胖、糖尿病、代谢综合征等病症)的药物的方法。The present invention belongs to the field of medicinal chemistry, and specifically includes novel heterocyclic compounds capable of selectively regulating CB1 function, compositions containing such compounds, and methods for applying such compounds to prepare drugs for treating or preventing diseases associated with abnormal CB1 genes/proteins or signal pathways (such as obesity, diabetes, metabolic syndrome, etc.).

背景技术Background Art

大麻素受体有两种亚型：CB1和CB2。通常认为CB1激活可以增加食欲、促进脂肪合成和储存，抑制胰岛素和瘦素的功能，并促进炎症和纤维化。研究发现，敲除小鼠CB1受体基因后，可使其血中胰岛素与瘦素水平降低，并改善胰岛素和瘦素抵抗，表明CB1受体的激动在饮食诱导的肥胖的发展中起重要作用。抑制CB1受体能够有效减少机体对食物的摄取，并增加能量的消耗。因此，CB1已经成为治疗肥胖和代谢紊乱相关疾病的热门靶点，有部分药物已经进入临床或上市如利莫纳班(Rimonabant)等。There are two subtypes of cannabinoid receptors: CB1 and CB2. It is generally believed that CB1 activation can increase appetite, promote fat synthesis and storage, inhibit the function of insulin and leptin, and promote inflammation and fibrosis. Studies have found that knocking out the CB1 receptor gene in mice can reduce the levels of insulin and leptin in their blood, and improve insulin and leptin resistance, indicating that the stimulation of CB1 receptors plays an important role in the development of diet-induced obesity. Inhibiting CB1 receptors can effectively reduce the body's food intake and increase energy consumption. Therefore, CB1 has become a hot target for the treatment of obesity and metabolic disorders. Some drugs have entered clinical trials or are on the market, such as Rimonabant.

然而大麻素受体CB 1是人类中枢神经系统表达量最高的G蛋白偶联受体(GPCR)之一，主要位于脑、脊髓与外周神经系统中，除此外，在脂肪组织、肝脏、肌肉、胃肠道等分布广泛。研究发现，已有的在研药物多数存在疗效不足、安全性风险高，尤其是中枢神经相关副作用，限制了这类药物的使用。利莫那班于2006年获得欧洲医学委员会(EMA)的上市批准，但却很快因潜在的焦虑、抑郁、自杀倾向等精神方面的副作用被禁止使用。因此迫切需要开发不能透脑，不做用于中枢神经的纯外周CB1调节剂，以便于避开CNS相关的副作用。However, the cannabinoid receptor CB 1 is one of the most highly expressed G protein-coupled receptors (GPCRs) in the human central nervous system. It is mainly located in the brain, spinal cord and peripheral nervous system. In addition, it is widely distributed in adipose tissue, liver, muscle, gastrointestinal tract, etc. Studies have found that most of the existing drugs under development have insufficient efficacy and high safety risks, especially central nervous system-related side effects, which limit the use of such drugs. Rimonabant was approved for marketing by the European Medical Committee (EMA) in 2006, but was soon banned due to potential psychiatric side effects such as anxiety, depression, and suicidal tendencies. Therefore, there is an urgent need to develop pure peripheral CB1 modulators that cannot penetrate the brain and do not act on the central nervous system in order to avoid CNS-related side effects.

技术效果Technical Effects

本发明人意外地发现部分本发明的式(I)结构的杂环新化合物不仅具有显著的选择性抑制CB1，而且基本不能透过血脑屏障。相比于结构已知的专利类似参照化合物还具有更高的疗效和安全特性，更好的药代(包括更好的渗透性、更低的清除率、更长的T1/2和更高的暴漏量)及生物利用度等特性。且与临床在研类似结构化合物INV-202比较，本发明代表性化合物如MDR-001-305-3不仅疗效接近，且PK更优(清除率更低、暴漏量更高、半衰期更长和生物利用更大)，更主要的是透脑率远低于INV-202，预期没有中枢神经毒副作用，或潜在中枢神经毒副作用风险更小。预期MDR-001-305-3将会有更优的人体PK特性以及更适合作为候选药物开发用于预防或治疗与CB1靶点及其信号通路相关的疾病。The inventors unexpectedly discovered that some of the heterocyclic new compounds of the formula (I) structure of the present invention not only have significant selective inhibition of CB1, but also are basically unable to penetrate the blood-brain barrier. Compared with similar reference compounds of patents with known structures, they also have higher efficacy and safety characteristics, better pharmacokinetic properties (including better permeability, lower clearance rate, longer T1/2 and higher exposure) and bioavailability. Compared with the clinically studied similar structure compound INV-202, representative compounds of the present invention such as MDR-001-305-3 not only have similar efficacy, but also have better PK (lower clearance rate, higher exposure, longer half-life and greater bioavailability), and more importantly, the brain penetration rate is much lower than INV-202, and it is expected that there will be no central nervous system toxicity or side effects, or the potential central nervous system toxicity and side effects will have a smaller risk. It is expected that MDR-001-305-3 will have better human PK characteristics and be more suitable as a candidate drug for the prevention or treatment of diseases related to CB1 targets and their signaling pathways.

发明内容Summary of the invention

本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物，

Figure PCTCN2024113428-ftappb-I100001
The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, enantiomer and isotope-substituted product thereof.
Figure PCTCN2024113428-ftappb-I100001

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100002
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C(Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100002
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1独立地选自N或CR1；X 1 is independently selected from N or CR 1 ;

R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3- 10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2- 10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10 环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, sulfur pentafluoride, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 Cycloalkyl acyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100003
Figure PCTCN2024113428-ftappb-I100004
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100003
Figure PCTCN2024113428-ftappb-I100004

L选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100005
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、 -S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L is selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100005
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(＝O)-, -S(＝O) 2- , -C( Rd1 )( Rd2 )C(＝O)-, -C( Rd1 )( Rd2 )C(＝S)-, -C( Rd1 )( Rd2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C 4-12 saturated or partially saturated heterocyclic aromatic groups; and the hydrogen on L is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100006
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100006
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、 饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , substituted with a saturated or partially saturated C 3-6 cycloalkyl group;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(IA)结构，

Figure PCTCN2024113428-ftappb-I100007
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IA):
Figure PCTCN2024113428-ftappb-I100007

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100008
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100008
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3- 10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2- 10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、 -NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 together with the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100009
Figure PCTCN2024113428-ftappb-I100010
Figure PCTCN2024113428-ftappb-I100011
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100009
Figure PCTCN2024113428-ftappb-I100010
Figure PCTCN2024113428-ftappb-I100011

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100012
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100012
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取 代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl. substituted, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数n is an integer randomly selected from 0, 1, 2, 3, 4 and 5

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(IB)结构，

Figure PCTCN2024113428-ftappb-I100013
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IB):
Figure PCTCN2024113428-ftappb-I100013

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100014
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100014
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3- 10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2- 10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环 烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成3-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally replaced by one or more selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated ring R 1 is substituted by a C 3-10 saturated or partially saturated heterocycloalkyl, a C 1-10 alkyl substituted by a C 3-10 cycloalkyl or a C 3-10 heterocycloalkyl, a C 2-10 heteroalkyl substituted by a C 3-10 cycloalkyl, or a C 3-10 heterocyclyl substituent; or any two adjacent R 1s together with the atoms to which they are attached form a 3-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkyl are substituted by a C 3-10 cycloalkyl or a C 3-10 heterocyclyl. R1-6 alkoxy is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl. And the hydrogen on R1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl ;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100015
Figure PCTCN2024113428-ftappb-I100016
Figure PCTCN2024113428-ftappb-I100017
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100015
Figure PCTCN2024113428-ftappb-I100016
Figure PCTCN2024113428-ftappb-I100017

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100018
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100018
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、 NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C2-50 alkenyl acyl, C10-50 alkenylalkyl acyl or C10-50 alkylalkenylalkyl acyl, C1-10 alkyl acyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl or M group; further Rd1, Rd2, Rd3, Rd4 , Rd5 , Rd6, Rd7 , Rd8 , Rd9 , Rd10, Rd11, Rd12, Rd13, Rd14 , Rd15, Rd16, Rd9 , Rd17 , Rd18, Rd19 , Rd110 , Rd111 The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl , saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 3-10 saturated or partially substituted cycloalkyl, or heterocyclic group. The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 2 groups selected from hydrogen, deuterium, halogen , oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups ;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数n is an integer randomly selected from 0, 1, 2, 3, 4 and 5

r任意的选自1、1和2中的整数；r is an integer arbitrarily selected from 1, 1 and 2;

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(IC)结构，

Figure PCTCN2024113428-ftappb-I100019
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IC):
Figure PCTCN2024113428-ftappb-I100019

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100020
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100020
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3- 10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2- 10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被 C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally replaced by 1 to more selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 1-10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by a substituent;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成3-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 3-30-membered heteroaryl, a 3-30-membered saturated or partially saturated cycloalkyl, or a 3-30-membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100021
Figure PCTCN2024113428-ftappb-I100022
Figure PCTCN2024113428-ftappb-I100023
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100021
Figure PCTCN2024113428-ftappb-I100022
Figure PCTCN2024113428-ftappb-I100023

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100024
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100024
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰 基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen atoms on Rd3, Rd4 , Rd5 , Rd6 and Rd7 are optionally replaced by one or more atoms selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(ID)结构，

Figure PCTCN2024113428-ftappb-I100025
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (ID),
Figure PCTCN2024113428-ftappb-I100025

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100026
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100026
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3- 10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2- 10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、 -COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or a carboxyl or carboxyl substitute or M group selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted; and the hydrogen on R 1 is optionally substituted with 1 to more substituted hydrogens selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C R 1 is substituted by a C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , or a C 3-10 heterocyclyl substituent; or any two adjacent R 1s together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C The R 1 is optionally substituted by 1 to 2 alkyl groups (i.e., 1-6 alkyl) 2 , =0, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 2 alkyl groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. The hydrogen on R 1 is optionally substituted by 1 to 2 alkyl groups (i.e., 1-6 alkyl) 2 , =0, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 2 alkyl groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100027
Figure PCTCN2024113428-ftappb-I100028
Figure PCTCN2024113428-ftappb-I100029
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100027
Figure PCTCN2024113428-ftappb-I100028
Figure PCTCN2024113428-ftappb-I100029

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100030
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100030
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素； The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

r任意选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(IE)结构，

Figure PCTCN2024113428-ftappb-I100031
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IE):
Figure PCTCN2024113428-ftappb-I100031

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100032
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100032
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

R0优先选自M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is preferably selected from the M group; and the hydrogen on R 0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10 环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, sulfur pentafluoride, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 Cycloalkyl acyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100033
Figure PCTCN2024113428-ftappb-I100034
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100033
Figure PCTCN2024113428-ftappb-I100034

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100035
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100035
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR； Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；优先为芳基、杂芳基、杂环基；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; preferably aryl, heteroaryl, heterocyclic group; and the hydrogen on R is further optionally substituted by 1 to more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(IF)结构，

Figure PCTCN2024113428-ftappb-I100036
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (IF),
Figure PCTCN2024113428-ftappb-I100036

其中，in,

环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X;

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100037
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100037
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自 氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atom to which it is attached, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by 1 to more selected from The hydrogen on R 2 is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo , haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100038
Figure PCTCN2024113428-ftappb-I100039
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100038
Figure PCTCN2024113428-ftappb-I100039

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100040
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代 基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100040
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2)-, -C(Rd1 ) ( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, said substituents being The radical is arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；优选为芳基、杂芳基、杂环基；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; preferably aryl, heteroaryl, heterocyclic group; and the hydrogen on R is further optionally substituted by 1 to more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

r任意选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(1-IE)结构，

Figure PCTCN2024113428-ftappb-I100041
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (1-IE):
Figure PCTCN2024113428-ftappb-I100041

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100042
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C (Rd1)( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1)＝C(Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100042
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100043
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100043

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100044
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100044
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(1-IF)结构，

Figure PCTCN2024113428-ftappb-I100045
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (1-IF),
Figure PCTCN2024113428-ftappb-I100045

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100046
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C (Rd1)( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1)＝C(Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100046
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、五氟化硫基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, sulfur pentafluoride, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100047
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100047

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100048
-OC(Rd1)(Rd2)-、-C(Rd1)(R12)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100048
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( R12 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IA)结构，

Figure PCTCN2024113428-ftappb-I100049
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IA):
Figure PCTCN2024113428-ftappb-I100049

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100050
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100050
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen atoms on L and X are further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1独立地选自N或CR1 X 1 is independently selected from N or CR 1

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100051
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100051

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100052
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100052
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IA)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IA):

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen atoms on L and X are further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、五氟化硫基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, sulfur pentafluoride, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自 M is arbitrarily and independently selected from

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IB)结构，

Figure PCTCN2024113428-ftappb-I100057
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IB):
Figure PCTCN2024113428-ftappb-I100057

其中，in,

环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100058
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100058
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen atoms on L and X are further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1任意独立地选自CR1或N；X 1 is arbitrarily and independently selected from CR 1 or N;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、 氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , Oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100059
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100059

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100060
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100060
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IC)结构，

Figure PCTCN2024113428-ftappb-I100061
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IC):
Figure PCTCN2024113428-ftappb-I100061

其中，in,

环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100062
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C (Rd1)( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1)＝C(Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100062
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1任意独立地选自CR1或N；X 1 is arbitrarily and independently selected from CR 1 or N;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、 氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , Oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100063
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100063

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100064
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100064
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC 1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3 , and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-ID)结构，

Figure PCTCN2024113428-ftappb-I100065
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-ID):
Figure PCTCN2024113428-ftappb-I100065

其中，in,

环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100066
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C (Rd1)( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1)＝C(Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100066
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 can form together with the atoms to which they are attached a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100067
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100067

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100068
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100068
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IE)结构，

Figure PCTCN2024113428-ftappb-I100069
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IE):
Figure PCTCN2024113428-ftappb-I100069

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100070
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100070
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100071
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100071

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100072
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100072
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

且R和A不同时为苯环，或者当R和A同时为苯环时，任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基；and R and A are not benzene rings at the same time, or when R and A are benzene rings at the same time, any two adjacent R1s together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group;

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IF)结构，

Figure PCTCN2024113428-ftappb-I100073
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IF):
Figure PCTCN2024113428-ftappb-I100073

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100074
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100074
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100075
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100075

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100076
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100076
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

前提是当任意两相邻的R1不与其附着的原子一起形成4-30元杂芳基，4-30元饱和或部分饱和环烷基、4-30元饱和或部分饱和杂环基时，或者Rd4不为氢，或者Rd4为氢，但Rd1为烷基、卤代烷基、氘代烷基、环烷基、烷硫基或环烷基硫基；Provided that when any two adjacent R 1's do not form together with the atoms to which they are attached a 4-30 membered heteroaryl, a 4-30 membered saturated or partially saturated cycloalkyl, or a 4-30 membered saturated or partially saturated heterocyclyl, or R d4 is not hydrogen, or R d4 is hydrogen, but R d1 is alkyl, haloalkyl, deuterated alkyl, cycloalkyl, alkylthio, or cycloalkylthio;

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(2-IG)结构，

Figure PCTCN2024113428-ftappb-I100077
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (2-IG):
Figure PCTCN2024113428-ftappb-I100077

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100078
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100078
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen atoms on L and X are further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100079
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100079

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100080
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100080
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

R3独立地选自氘、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C2-10杂烷基、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基、-COOH、C3-10饱和/部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、芳基、杂芳基、被C3- 10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基； R3 is independently selected from deuterium, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C2-10 heteroalkyl , haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino, -COOH, C3-10 saturated/partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocyclyl, aryl, heteroaryl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl , C1-10 alkyl substituted with carboxyl or carboxyl substitute; and R The hydrogen on 3 is further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1- 10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl , C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy , C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数； m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-IA)结构，

Figure PCTCN2024113428-ftappb-I100081
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IA):
Figure PCTCN2024113428-ftappb-I100081

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100082
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100082
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen atoms on L and X are further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

L0、L1、L2、L3、L4各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100083
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L0 , L1 , L2 , L3 , and L4 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100083
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部 分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on R 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; or any two adjacent R 1 together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, a 3-30 membered saturated or partially saturated heterocyclyl, and the aryl, heteroaryl, saturated or partially saturated The hydrogen on the partially saturated cycloalkyl and heterocyclyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100084
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100084

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100085
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100085
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl , sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经 C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或

Figure PCTCN2024113428-ftappb-I100086
更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl ;
Figure PCTCN2024113428-ftappb-I100086
Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3- 10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d5 , R d6 , R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 3-10 saturated or partially saturated cycloalkyl, or heterocyclic group. The C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-IA)结构，

Figure PCTCN2024113428-ftappb-I100087
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IA):
Figure PCTCN2024113428-ftappb-I100087

其中， in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100088
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100088
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)R(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100089
-OC(Rd1)(Rd2)-、-C(Rd 1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )R(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100089
-OC(R d1 )(R d2 )-, -C(R d 1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2 -, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100090
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100090

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100091
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代， 所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100091
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl; and the hydrogen on Z is further optionally substituted with 1 to more substituents, The substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或

Figure PCTCN2024113428-ftappb-I100092
更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or
Figure PCTCN2024113428-ftappb-I100092
Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3- 10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d5 , R d6 , R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 3-10 saturated or partially saturated cycloalkyl, or heterocyclic group. The C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素； The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3中的整数。t is an integer arbitrarily selected from 0, 1, 2, and 3.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-IB)结构，

Figure PCTCN2024113428-ftappb-I100093
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IB):
Figure PCTCN2024113428-ftappb-I100093

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100094
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100094
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl;

L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100095
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100095
-OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环 烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is preferably replaced by 1 to more selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated ring R 1 is substituted by a C 3-10 saturated or partially saturated heterocycloalkyl, a C 1-10 alkyl substituted by a C 3-10 cycloalkyl or a C 3-10 heterocycloalkyl, a C 2-10 heteroalkyl substituted by a C 3-10 cycloalkyl, or a C 3-10 heterocyclyl substituent; or any two adjacent R 1s together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C R1-6 alkoxy is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl. And the hydrogen on R1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl ;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自

Figure PCTCN2024113428-ftappb-I100096
M is arbitrarily and independently selected from
Figure PCTCN2024113428-ftappb-I100096

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、

Figure PCTCN2024113428-ftappb-I100097
-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-,
Figure PCTCN2024113428-ftappb-I100097
-OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经 C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或

Figure PCTCN2024113428-ftappb-I100098
更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl ;
Figure PCTCN2024113428-ftappb-I100098
Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3- 10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d5 , R d6 , R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 3-10 saturated or partially saturated cycloalkyl, or heterocyclic group. The C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3、4中的整数。t is an integer arbitrarily selected from 0, 1, 2, 3, and 4.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-IC)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IC):

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任 选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and any of the C 1-6 alkyl and C 1-6 alkoxy R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自 M is arbitrarily and independently selected from

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或 更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl , C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3中的整数。t is an integer arbitrarily selected from 0, 1, 2, and 3.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-ID)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-ID):

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1) -、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 ) -, -C(R d1 )(R d2 )C(R d1 )=C(R d1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl;

L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd5)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd5 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自 M is arbitrarily and independently selected from

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上 的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q represents any 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and The hydrogen of the group is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl , C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3- 10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d5 , R d6 , R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 3-10 saturated or partially saturated cycloalkyl, or heterocyclic group. The C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3、4中的整数。 t is an integer arbitrarily selected from 0, 1, 2, 3, and 4.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-IE)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IE):

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl;

L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2)C(Rd1 ) ＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部 分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on R 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; or any two adjacent R 1 together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, a 3-30 membered saturated or partially saturated heterocyclyl, and the aryl, heteroaryl, saturated or partially saturated The hydrogen on the partially saturated cycloalkyl and heterocyclyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自 M is arbitrarily and independently selected from

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经 C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl ; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3- 10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d5 , R d6 , R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 3-10 saturated or partially saturated cycloalkyl, or heterocyclic group. The C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH , OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3、4中的整数。t is an integer arbitrarily selected from 0, 1, 2, 3, and 4.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(3-IF)结构，

In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (3-IF):

其中，in,

环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2)C(Rd1 ) ＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclyl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自 M is arbitrarily and independently selected from

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、- C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-,- C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -N(R d7 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2- , or C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl; and the hydrogen on Z is further optionally substituted with 1 to more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl , C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3- 10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1- 6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱 和的C3-6环烷基的基团取代；Each of R d5 , R d6 , and R d7 may be the same or different and are independently selected from C 1-10 alkyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl , or C 3-10 heterocyclyl substituted with C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d5 , R d6 , and R d7 are The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d5 , R d6 , R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 3-10 saturated or partially saturated cycloalkyl, or heterocyclic group. The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more radicals selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups . and a C 3-6 cycloalkyl group;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3中的整数。t is an integer arbitrarily selected from 0, 1, 2, and 3.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(7-ID)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (7-ID):

其中，in,

X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基 团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30-membered heteroaryl, a 5-30-membered saturated or partially saturated cycloalkyl, or a 5-30-membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl and the hydrogen on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自 M is arbitrarily and independently selected from

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷 基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkane. and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(7-IE)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (7-IE):

其中，in,

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和 或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or a partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

M任意独立地选自 M is arbitrarily and independently selected from

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、- C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C(R d1 )(R d2 )S(＝O) 2 -, -C(＝O)C(R d1 )(R d2 )-, -C(＝S)C(R d1 )(R d2 )-, -S(＝O)C(R d1 )(R d2 )-,- C( Rd1 )( Rd2 )S(=O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with 1 to more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl;

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(7-IF)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (7-IF):

其中，in,

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

M任意独立地选自 M is arbitrarily and independently selected from

每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl;

Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl;

每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl or M group; further R d1 , R d2 The hydrogen on R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2.

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(8-I)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (8-I):

其中，in,

每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3- 10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2- 10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl , or C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 can form together with the atoms to which they are attached a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted;

每一个R3可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R3上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R3与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on R3 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl; or any two adjacent R 3 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR;

Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl;

R9独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R 9 is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH 2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated, partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy;

Rd1和Rd2任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1或Rd2上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Rd1和Rd2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Rd1 and Rd2 are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C2-50 alkenyl acyl, C10-50 alkenylalkyl acyl or C10-50 alkylalkenylalkyl acyl, C1-10 alkyl acyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl or M group; further Rd1 or R The hydrogen on d2 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or R d1 and R d2 and the atoms to which they are attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted with hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups;

每一个Rd3和Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3- 10杂环烷基取代的C3-10杂环基；更进一步地Rd3和Rd4上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Rd3和Rd及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d3 and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; further, R d3 and R d4 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d3 and R The hydrogen on d4 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or R d3 and R d and the atoms to which they are attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted with hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups;

所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof;

所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof;

m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4;

n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5;

t任意地选自0、1和2中的整数。t is arbitrarily selected from an integer among 0, 1 and 2.

前提是当R9为烷基时，R1或R3至少有一个为氰基或五氟化硫基，或者Rd4、Rd1和Rd2不同时为氢。Provided that when R 9 is an alkyl group, at least one of R 1 or R 3 is a cyano group or a sulfur pentafluoride group, or R d4 , R d1 and R d2 are not hydrogen atoms at the same time.

根据本发明的实施方案，环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；According to an embodiment of the present invention, Ring A arbitrarily and independently represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring;

根据本发明的实施方案，M任意独立地选自 According to an embodiment of the present invention, M is arbitrarily and independently selected from

本发明的一个方案中，所述化合物或其药学上可接受的盐、同位素取代物或其异构体，其具有式(II)结构，
In one embodiment of the present invention, the compound or its pharmaceutically acceptable salt, isotope-substituted product or isomer thereof has a structure of formula (II):

(II)其中，(II) Among them,

A选自C6-10芳基、5-10元杂环基；A is selected from C 6-10 aryl, 5-10 membered heterocyclic group;

E选自N或CH2；当E为N时，为双键；当E为CH2时，为单键；E is selected from N or CH 2 ; when E is N, is a double bond; when E is CH 2 , is a single bond;

R选自C1-6烷基、C6-10芳基、5-10元杂芳基；R is selected from C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl;

R0选自R9选自无取代或任选被一个、两个或更多个R91取代的下列基团：C1-6烷基、C2-6烯基；每个R91相同或不同，彼此独立地选自H、OH、-N+(C1-6烷基)；R10选自-C1-6烷基-S(O)2NH2；R 0 is selected from R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 91 : C 1-6 alkyl, C 2-6 alkenyl; each R 91 is the same or different and is independently selected from H, OH, -N + (C 1-6 alkyl); R 10 is selected from -C 1-6 alkyl-S(O) 2 NH 2 ;

R1选自H、CN、卤素、C1-6烷基、C1-6烷氧基；或者两个R1与其各自连接的原子形成3-8元杂环基；R 1 is selected from H, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy; or two R 1 and the atoms to which they are attached form a 3-8 membered heterocyclic group;

R2选自H、卤素、五氟化硫基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基；R 2 is selected from H, halogen, pentafluorosulfur, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;

Rd1、Rd2相同或不同，彼此独立地选自H、C1-6烷基、C1-6烷氧基；R d1 and R d2 are the same or different and are independently selected from H, C 1-6 alkyl, and C 1-6 alkoxy;

m选自0、1、2、3、4、5； m is selected from 0, 1, 2, 3, 4, 5;

n选自0、1、2、3、4、5；n is selected from 0, 1, 2, 3, 4, 5;

w选自0或1。w is selected from 0 or 1.

根据本发明的实施方案，A选自苯基、5-6元杂环基；According to an embodiment of the present invention, A is selected from phenyl, 5-6 membered heterocyclyl;

根据本发明的实施方案，A选自苯基、哌啶基(例如)。According to an embodiment of the present invention, A is selected from phenyl, piperidinyl (e.g. ).

根据本发明的实施方案，选自 According to an embodiment of the present invention, Selected from

根据本发明的实施方案，选自 According to an embodiment of the present invention, Selected from

根据本发明的实施方案，R选自C1-3烷基、苯基、5-6元杂芳基；According to an embodiment of the present invention, R is selected from C 1-3 alkyl, phenyl, 5-6 membered heteroaryl;

根据本发明的实施方案，R选自甲基、苯基、噻吩基(例如)。According to an embodiment of the present invention, R is selected from methyl, phenyl, thienyl (e.g. ).

根据本发明的实施方案，R9选自无取代或任选被一个、两个或更多个R91取代的下列基团：甲基、丙基、丙烯基；每个R91相同或不同，彼此独立地选自H、OH、 According to an embodiment of the present invention, R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 91 : methyl, propyl, propenyl; each R 91 is the same or different and is independently selected from H, OH,

根据本发明的实施方案，R9选自甲基、 According to an embodiment of the present invention, R 9 is selected from methyl,

根据本发明的实施方案，R10选自 According to an embodiment of the present invention, R 10 is selected from

根据本发明的实施方案，R1选自H、CN、卤素；或者两个R1与其各自连接的原子形成4元杂环基；According to an embodiment of the present invention, R 1 is selected from H, CN, halogen; or two R 1 and the atoms to which they are attached form a 4-membered heterocyclic group;

根据本发明的实施方案，R1选自H、Cl、CN；或者两个R1与其各自连接的原子形成 According to an embodiment of the present invention, R 1 is selected from H, Cl, CN; or two R 1 and their respective atoms form

根据本发明的实施方案，选自 According to an embodiment of the present invention, Selected from

根据本发明的实施方案，选自 According to an embodiment of the present invention, Selected from

根据本发明的实施方案，R2选自H、卤素、五氟化硫基、卤代C1-3烷基；According to an embodiment of the present invention, R 2 is selected from H, halogen, pentafluorinated sulfur, halogenated C 1-3 alkyl;

根据本发明的实施方案，R2选自H、F、三氟甲基、五氟化硫基。According to an embodiment of the present invention, R 2 is selected from H, F, trifluoromethyl, pentafluorosulfuryl.

根据本发明的实施方案，Rd1、Rd2相同或不同，彼此独立地选自H、C1-3烷基；According to an embodiment of the present invention, R d1 and R d2 are the same or different and are independently selected from H, C 1-3 alkyl;

根据本发明的实施方案，Rd1、Rd2相同或不同，彼此独立地选自H、甲基。According to an embodiment of the present invention, R d1 and R d2 are the same or different and are independently selected from H and methyl.

本发明的一些方案中，上述化合物、其药学上可接受的盐、对应异构体或同位素取代物为选自本发明实施例所公开结构的新化合物。In some embodiments of the present invention, the above-mentioned compound, its pharmaceutically acceptable salt, corresponding isomer or isotope substitution is a new compound selected from the structure disclosed in the embodiments of the present invention.

本发明还提供一种药物组合物，其包含治疗有效量的式(I)所示的化合物、其药学上可接受的盐、溶剂合物、对映异构体和同位素取代物中的至少一种。 The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution.

根据本发明的实施方案，所述药物组合物经配制而通过选自以下的途径给药：口服、注射、直肠、经鼻、经肺、局部、口腔和舌下、阴道、肠胃外、皮下、肌肉内、静脉内、皮内、鞘内和硬膜外。According to an embodiment of the present invention, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of oral, parenteral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.

所述口服剂型没有特别限定，可以采用本领域熟知的任意口服剂型，优选包括片剂、胶囊、混悬剂或者口服溶液等本领域已知的口服剂型。The oral dosage form is not particularly limited, and any oral dosage form known in the art may be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.

根据本发明的实施方案，所述药物组合物还可以包含药学上可接受的辅料，其选自包括但不限于下列辅料中的至少一种：填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、矫味剂、湿润剂、pH调节剂、增溶剂或助溶剂、渗透压调节剂。本领域技术人员根据具体剂型的需要，可以容易地确定如何选择相应的辅料及其相应用量。According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient, which is selected from at least one of the following excipients, including but not limited to: a filler, a disintegrant, a binder, a lubricant, a surfactant, a flavoring agent, a wetting agent, a pH regulator, a solubilizer or a cosolvent, and an osmotic pressure regulator. Those skilled in the art can easily determine how to select the corresponding excipient and its corresponding dosage according to the needs of the specific dosage form.

根据本发明的实施方案，所述药物组合物还可以进一步含有一种或多种额外的治疗剂。According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

本发明的另一目的在于提供上述化合物、其药学上可接受的盐、对应异构体或同位素取代物在制备用于预防和/或治疗CB1信号通路异常相关的疾病的药物中的应用。所述的CB1信号通路相关的疾病包括但不限于各种糖尿病、肥胖或超重、代谢综合征等病症。Another object of the present invention is to provide the use of the above-mentioned compound, its pharmaceutically acceptable salt, enantiomer or isotope substitution in the preparation of a drug for preventing and/or treating diseases related to abnormal CB1 signaling pathway. The diseases related to the CB1 signaling pathway include but are not limited to various diabetes, obesity or overweight, metabolic syndrome and other diseases.

本发明还提供所述式(I)所示的化合物、其药学上可接受的盐、对应异构体或同位素取代物，以及所述药物组合物在预防和/或治疗CB1信号通路异常相关的疾病中的用途。The present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salt, corresponding isomer or isotope substitution, and the use of the pharmaceutical composition in preventing and/or treating diseases related to abnormal CB1 signaling pathway.

本发明还提供一种预防和/或治疗CB1信号通路异常相关的疾病的方法，包括给予患者预防或治疗有效量的式(I)所示的化合物、其药学上可接受的盐、对应异构体或同位素取代物中的至少一种，或者给予患者预防或治疗有效量的上述药物组合物。The present invention also provides a method for preventing and/or treating diseases related to abnormal CB1 signaling pathway, comprising administering to a patient an effective amount of the compound represented by formula (I), a pharmaceutically acceptable salt, a corresponding isomer or an isotope substitute thereof, or administering to a patient an effective amount of the above-mentioned pharmaceutical composition.

在一些实施方案中，所述患者哺乳动物，优选是人。In some embodiments, the patient is a mammal, preferably a human.

定义和说明：Definition and Explanation:

C1-10选自C1、C2、C3、C4、C5、C6、C7、C8、C9和C10；C2-10选自C2、C3、C4、C5、C6、C7、C8、C9和C10；C3-10选自C3、C4、C5、C6、C7、C8、C9和C10； C1-10 is selected from the group consisting of C1, C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ; C2-10 is selected from the group consisting of C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 and C10 ; C3-10 is selected from the group consisting of C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 ;

术语“烷基”表示直链或支链的饱和烃基，优选具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链的饱和烃基(C1-10烷基)。所述烷基包括C1-3烷基、C1-6烷基、C3-6烷基、C1-10烷基等。“C1-10烷基”表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基，“C1-8烷基”表示具有1、2、3、4、5、6、7、或8个碳原子的直链和支链烷基，“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等或它们的异构体。The term "alkyl" means a straight or branched saturated hydrocarbon group, preferably a straight or branched saturated hydrocarbon group ( C1-10 alkyl) having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group includes a C1-3 alkyl group, a C1-6 alkyl group, a C3-6 alkyl group, a C1-10 alkyl group, etc. " C1-10 alkyl" means a straight and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, " C1-8 alkyl" means a straight and branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and " C1-6 alkyl" means a straight and branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.

本文所用术语“亚烷基”是指式-(CH2)n-的直链或支链二价烃基团。非限制性示例包括乙烯和丙烯。As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon group of the formula -(CH 2 ) n - Non-limiting examples include ethylene and propylene.

本文所用术语“1至多个”是指1个以上，例如1个、2个、3个、4个、5个或更多个。As used herein, the term "1 to a plurality of" means more than one, for example, 1, 2, 3, 4, 5 or more.

术语“脂肪环”、“碳环(基)”或“环烷基”指饱和或部分不饱和的单环或多环环状烃基，碳环可以包含3至20个碳原子，优选包含3至12个(例如3、4、5、6、7、8、9、10、11、12个)碳原子，更优选包含3至6个碳原子。碳环可以是单环或多环的，其可以是饱和的环烷基或者在其环上可以任选地包含一个、两个或更多个双键和/或三键，由此形成所谓的环烯基或环炔基。碳环在具有多个环的情况下，这些环可以形成螺环、稠环和桥环结构。例如，单环碳环的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基、环辛四烯基等；多环碳环的非限制性实例包括十氢化萘基或异冰片基。The term "aliphatic ring", "carbocycle (base)" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the carbocycle can contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The carbocycle can be monocyclic or polycyclic, it can be a saturated cycloalkyl or can optionally contain one, two or more double bonds and/or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl. In the case of a carbocycle having multiple rings, these rings can form spirocyclic, condensed and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.

术语“芳基”或“芳环”是指：应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、二环(如稠环、桥环、螺环)或三环烃环，其可以是单芳族环或稠合在一起的多芳族环，优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。当所述C6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。The term "aryl" or "aromatic ring" means: it should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) or tricyclic hydrocarbon ring with 6 to 20 carbon atoms, which can be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl". The term "C 6-14 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. When the C 6-20 aryl is substituted, it may be mono- or polysubstituted. Furthermore, there is no limitation on the substitution site, and for example, substitution may be at the ortho, para or meta position.

术语“螺环”是指两个环共用1个成环原子的环系，其可以含有如前所述的脂肪环、杂环、芳环或杂芳环。The term "spirocyclic ring" refers to a ring system in which two rings share one ring-forming atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

术语“并环”是指两个环共用2个成环原子的环系，其可以含有如前所述的脂肪环、杂环、芳环或杂芳环。The term "paracyclic" refers to a ring system in which two rings share two ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

术语“桥环”是指两个环共用3个以上成环原子的环系，其可以含有如前所述的脂肪环、杂环、芳环或杂芳环。 The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms, and may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

术语“杂环(基)”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自N、O、NH、S、S(O)或S(O)2的杂原子或原子团，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1-4个是杂原子(例如1、2、3和4个)；更优选包含3至6个环原子(例如3、4、5、6个)。杂环基可以通过所述碳原子中的任一个碳原子或氮原子(如果存在的话)或者氧或者硫原子(特别是在形成鎓盐的情况下)与分子的其余部分连接。所述杂环基可以包括稠合的或桥连的环和/或螺环的环。单环杂环基的非限制性实例包括氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、二氧杂环戊烯基、四氢吡喃基、吡咯啉基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二噻烷基、三噻烷基、高哌嗪基、二氮杂环庚烷基等，优选哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基，也可以是苯并稠合的杂环基例如二氢异喹啉基。所述杂环基可以是双环的，其非限制性实例包括六氢环戊并[c]吡咯-2(1H)-基，六氢吡咯并[1，2-a]吡嗪-2(1H)-基。杂环基也可以是部分不饱和的，即它可以包含一个或多个双键，其非限制性实例包括二氢呋喃基、二氢吡喃基、2，5-二氢-1H-吡咯基、4H-[1，3，4]噻二嗪基、4，5-二氢噁唑基或4H-[1，4]噻嗪基。The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms or radicals selected from N, O, NH, S, S(O) or S(O) 2 , but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt). The heterocyclic group can include fused or bridged rings and/or spirocyclic rings. The non-limiting examples of monocyclic heterocyclic radical include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl etc., preferably piperidinyl, pyrrolidinyl.Polycyclic heterocyclic radical includes the heterocyclic radical of spirocycle, condensed ring and bridge ring, and can also be the heterocyclic radical of benzo condensation such as dihydroisoquinolinyl.The heterocyclic radical can be bicyclic, and its non-limiting examples include hexahydrocyclopenta [c] pyrrole -2 (1H) -base, hexahydropyrrolo [1,2-a] pyrazine -2 (1H) -base. The heterocyclyl group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

本文中，术语“杂芳基/杂芳环”指包含1至4个杂原子、5至20个环原子的杂芳族体系，其中杂原子选自氧、硫、氮和磷。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元。杂芳基的非限制性实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基和/或吩噁嗪基等。Herein, the term "heteroaryl/heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl , isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and/or phenoxazinyl, etc.

杂芳基/杂芳环可以是任选取代的或未取代的，当被取代时，取代基优选为一个、两个或更多个彼此独立地选自下组的基团：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl/heteroaromatic ring may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

除非另有说明，否则杂环基、杂芳基或杂芳环包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式，包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基；吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。Unless otherwise specified, heterocyclic groups, heteroaryls or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at one, two or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present), may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.，″Pharmaceutical Salts″，Journal of Pharmaceutical Science 66：1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into either base or acid addition salts.

优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐如Na盐、钾盐、胺盐、母体化合物的季铵盐等。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸、无机碱和有机碱的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、 草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸等所述的无机碱和有机碱选自Na、钾、镁、钙等或胺、二乙胺、三乙胺、乙醇胺等。As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts such as sodium salts, potassium salts, amine salts, quaternary ammonium salts of the parent compound, and the like. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic and organic bases selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, The inorganic base and organic base described in oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid are selected from Na, potassium, magnesium, calcium, etc. or amines, diethylamine, triethylamine, ethanolamine, etc.

本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to the form of salts, compounds provided by the present invention also exist in prodrug forms. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。Some compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally speaking, solvated form is suitable with non-solvated form, all included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form.

在本文中，术语“溶剂合物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂合物的溶剂包括，但并不限于：水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。因此，术语“水合物”是指溶剂分子是水所形成的缔合物。As used herein, the term "solvate" refers to an association formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. Therefore, the term "hydrate" refers to an association formed by a solvent molecule that is water.

本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62：114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is represented by wedge-shaped bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are intended to be within the scope of the invention.

本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compounds. For example, radioactive isotope labeled compounds may be used, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington：The Science and Practice of Pharmacy，21st Ed.，Lippincott，Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to technicians in the field of cosmetics or topical drugs. For additional information about carriers, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When a substituent can cross-link two atoms on a ring, the substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to a compound included in the chemical formula but not specifically mentioned, the substituent can be bonded through any atom thereof. Combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.

术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

本发明现在进一步通过实施例描述。下面给出的实施例仅用于说明目的，而不是仅限于此发明的范围。本发明的化合物可以用有机合成领域中许多已知的方法来制备。本发明的实施例可以使用下面描述的方法来合成，以及有机合成化学领域中已知的合成方法，或在其基础上通过改进的方法。优选的方法包括，但不限于以下描述方法。 The present invention is now further described by examples. The examples given below are for illustrative purposes only and are not intended to limit the scope of this invention. The compounds of the present invention can be prepared using many known methods in the field of organic synthesis. The embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based thereon. Preferred methods include, but are not limited to, the following description methods.

未经特别说明，本发明所有使用的溶剂都是市售的，使用时无需进一步纯化。反应通常在氮气的惰性气氛下使用无水溶剂进行。核磁共振谱在Bruker-Avance-400(400mhz)谱仪测定，并以δ(ppm)形式报告化学位移。质谱用安捷伦1200系列(plus 6110/和1956A)LC/MS或岛津MS(DAD：SPD-M20A(LC))和岛津Micromass 2020检测仪。质谱仪配有一个正、负模式工作的电喷雾离子源(ESI)。Unless otherwise specified, all solvents used in the present invention are commercially available and do not require further purification when used. The reaction is usually carried out using anhydrous solvents under an inert atmosphere of nitrogen. The nuclear magnetic resonance spectrum is measured on a Bruker-Avance-400 (400 MHz) spectrometer, and the chemical shift is reported in the form of δ (ppm). Mass spectrometry is performed using an Agilent 1200 series (plus 6110/ and 1956A) LC/MS or Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) operating in positive and negative modes.

使用的缩写如下：aq为水溶液；TLC为薄层色谱法；RT为室温；MeOH为甲醇；EtOH为乙醇；EtOAc为乙酸乙酯；THF为四氢呋喃；当量为eq；CDI为羰基二咪唑；DCM为二氯甲烷；PE为石油醚；DIAD为偶氮二甲酸二异丙酯；DMF为N，N-二甲基甲酰胺；DMSO为二甲基亚砜；CBz为苄氧羰基；BOC为叔丁基羰基；HOAc为乙酸；Ms为甲磺酰基：NMP为N-甲基吡咯烷酮；DMAP为4-(二甲氨基)吡啶；Boc2O为二叔丁基二碳酸酯；TFA为三氟乙酸；DIPEA为二异丙基乙胺；SOCl2为亚硫酰氯；CS2为二硫化碳；TsOH为4-甲苯磺酸；MTBE为叔丁基甲醚；FA为甲酸；ACN为乙腈；i-PrOH为2-丙醇。The abbreviations used are as follows: aq is aqueous solution; TLC is thin layer chromatography; RT is room temperature; MeOH is methanol; EtOH is ethanol; EtOAc is ethyl acetate; THF is tetrahydrofuran; equivalent is eq; CDI is carbonyldiimidazole; DCM is dichloromethane; PE is petroleum ether; DIAD is diisopropyl azodicarboxylate; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; CBz is benzyloxycarbonyl; BOC is tert-butyl ester. Butyl carbonyl; HOAc is acetic acid; Ms is methanesulfonyl: NMP is N-methylpyrrolidone; DMAP is 4-(dimethylamino)pyridine; Boc2O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; DIPEA is diisopropylethylamine; SOCl2 is thionyl chloride; CS2 is carbon disulfide; TsOH is 4-toluenesulfonic acid; MTBE is tert-butyl methyl ether; FA is formic acid; ACN is acetonitrile; i-PrOH is 2-propanol.

化合物可以手动命名，也可以使用

Figure PCTCN2024113428-ftappb-I100164
进行命名，如果商业购买的，也可以使用供应商的目录名称。通常使用TLC或LC-MS来判断反应是否完成。Compounds can be named manually or using
Figure PCTCN2024113428-ftappb-I100164
Name the product, or use the supplier's catalog name if purchased commercially. TLC or LC-MS is usually used to determine whether the reaction is complete.

具体实施方式DETAILED DESCRIPTION

为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

实施例1、N-((E)-N′-(Z)-(((4-氯苯基)磺酰基)亚胺基)(3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)氨基甲酰亚胺基)乙酰胺(化合物1)的合成：Example 1. Synthesis of N-((E)-N′-(Z)-(((4-chlorophenyl)sulfonyl)imino)(3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)carbamoyl)acetamide (Compound 1):

1)、6-(2-苯基丙烯酰基)烟腈合成：

Figure PCTCN2024113428-ftappb-I100165
1) Synthesis of 6-(2-phenylacryloyl)nicotinonitrile:
Figure PCTCN2024113428-ftappb-I100165

向溶有6-(2-苯基乙酰基)烟腈(2.84g，128mmol)的甲醇(50mL)溶液中，依次加入哌啶(0.12mL，1.21mmol)，乙酸(0.12mL，2.08mmol)和福尔马林(4mL，37％水溶液，530mmol)，所得混合反应液回流4小时。冷却后，减压浓缩，并加水稀释，二氯甲烷萃取。合并的有机相，水洗三次，无水硫酸钠干燥，过滤、减压浓缩得到6-(2-苯基丙烯酰基)烟腈(3.0g，收率：＞99％)，LCMS m/z：235[M+H]+。To a solution of 6-(2-phenylacetyl)nicotinonitrile (2.84 g, 128 mmol) in methanol (50 mL), piperidine (0.12 mL, 1.21 mmol), acetic acid (0.12 mL, 2.08 mmol) and formalin (4 mL, 37% aqueous solution, 530 mmol) were added in sequence, and the resulting mixed reaction solution was refluxed for 4 hours. After cooling, it was concentrated under reduced pressure, diluted with water, and extracted with dichloromethane. The combined organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-(2-phenylacryloyl)nicotinonitrile (3.0 g, yield: >99%), LCMS m/z: 235 [M+H] + .

2)、6-(4-苯基-4，5-二氢-1H-吡唑-3-基)烟腈的合成：

Figure PCTCN2024113428-ftappb-I100166
2) Synthesis of 6-(4-phenyl-4,5-dihydro-1H-pyrazole-3-yl)nicotinonitrile:
Figure PCTCN2024113428-ftappb-I100166

将溶有6-(2-苯基丙烯酰基)烟腈(3.0g，128mmol)的水合肼(63mL)的乙醇(30mL)溶液，氮气保护保护下，回流3小时。冷却至室温后，将混合反应液减压浓缩，加水稀释，并用二氯甲烷萃取。合并的有机相用水洗涤两次，无水硫酸钠干燥，过滤、减压浓缩。残余物乙醇中结晶得到6-(4-苯基-4，5-二氢-1H-吡唑-3-基)烟腈(1.8g，收率：59％)，LCMS m/z：249[M+H]+。A solution of 6-(2-phenylacryloyl)nicotinonitrile (3.0 g, 128 mmol) in hydrazine hydrate (63 mL) in ethanol (30 mL) was refluxed for 3 hours under nitrogen protection. After cooling to room temperature, the mixed reaction solution was concentrated under reduced pressure, diluted with water, and extracted with dichloromethane. The combined organic phase was washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 6-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)nicotinonitrile (1.8 g, yield: 59%), LCMS m/z: 249 [M+H] + .

3)(4-氯苯基)磺酰基)氨基甲酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100167
3. Synthesis of Methyl (4-chlorophenyl)sulfonyl)carbamate
Figure PCTCN2024113428-ftappb-I100167

室温条件下，向溶有对氯苯磺酰胺(7.6g，40mmol)和三乙胺(10.12g，0.10mol)的无水乙腈(40mL)溶液中，缓慢加入氯甲酸甲酯(4.43mL，0.060mol)。所得混合反应液室温搅拌6小时。将混合反应 液乙酸乙酯(50mL)稀释，并用饱和碳酸氢钠水溶液(50mL)洗涤。有机相减压浓缩，并通过硅胶柱色谱纯化得到(4-氯苯基)磺酰基)氨基甲酸甲酯(4.5g，收率：45％)，LCMS m/z：250[M+H]+。At room temperature, methyl chloroformate (4.43 mL, 0.060 mol) was slowly added to a solution of p-chlorobenzenesulfonamide (7.6 g, 40 mmol) and triethylamine (10.12 g, 0.10 mol) in anhydrous acetonitrile (40 mL). The resulting mixed reaction solution was stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution (50 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give methyl (4-chlorophenyl)sulfonyl)carbamate (4.5 g, yield: 45%), LCMS m/z: 250 [M+H] + .

4)N-((4-氯苯基)磺酰基)-3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成

Figure PCTCN2024113428-ftappb-I100168
4) Synthesis of N-((4-chlorophenyl)sulfonyl)-3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
Figure PCTCN2024113428-ftappb-I100168

向溶有(4-氯苯基)磺酰基)氨基甲酸甲酯(3.0g，12mmol)的甲苯(60mmol)溶液中加入6-(4-苯基-4，5-二氢-1H-吡唑-3-基)烟腈(3.28g，13.2mmol)。所得混合反应液回流4小时。冷却至室温，等待缓慢结晶。过滤，滤饼用甲基叔丁醚洗涤洗涤，收集固体真空干燥得到N-((4-氯苯基)磺酰基)-3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(5.59g，收率：98％)，LCMS m/z：467[M+H]+。6-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)nicotinonitrile (3.28 g, 13.2 mmol) was added to a toluene (60 mmol) solution of methyl (4-chlorophenyl)sulfonyl)carbamate (3.0 g, 12 mmol). The resulting mixed reaction solution was refluxed for 4 hours. Cooled to room temperature and waited for slow crystallization. Filtered, the filter cake was washed with methyl tert-butyl ether, and the solid was collected and vacuum dried to obtain N-((4-chlorophenyl)sulfonyl)-3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (5.59 g, yield: 98%), LCMS m/z: 467 [M+H] + .

5)(E)-N-((4-氯苯基)磺酰基)-3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-碳杂亚胺酰氯的合成

Figure PCTCN2024113428-ftappb-I100169
5) Synthesis of (E)-N-((4-chlorophenyl)sulfonyl)-3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbamidyl chloride
Figure PCTCN2024113428-ftappb-I100169

将溶有N-((4-氯苯基)磺酰基)-3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(3.62，7.75mmol)和五氯化磷(1.69g，8.14mmol)的氯苯(40mL)溶液回流1小时。冷却后，将混合反应液减压浓缩得到粗产品，直接用于下一步反应。A solution of N-((4-chlorophenyl)sulfonyl)-3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (3.62 g, 7.75 mmol) and phosphorus pentachloride (1.69 g, 8.14 mmol) in chlorobenzene (40 mL) was refluxed for 1 hour. After cooling, the mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.

6)N-((E)-N′-(Z)-(((4-氯苯基)磺酰基)亚胺基)(3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)氨基甲酰亚胺基)乙酰胺的合成

Figure PCTCN2024113428-ftappb-I100170
6) Synthesis of N-((E)-N′-(Z)-(((4-chlorophenyl)sulfonyl)imino)(3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)carbamoylimido)acetamide
Figure PCTCN2024113428-ftappb-I100170

室温条件下，向溶有(E)-N-((4-氯苯基)磺酰基)-3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-碳杂亚胺酰氯(3.74g，7.75mmol)的二氯甲烷(15mL)溶液中，加入N-氨基甲酰乙酰胺(782mg，7.75mmol)，室温搅拌1小时。将混合反应液减压浓缩并通过乙醇重结晶得到N-((E)-N′-(Z)-(((4-氯苯基)磺酰基)亚胺基)(3-(5-氰基吡啶-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)氨基甲酰亚胺基)乙酰胺(2.59g，收率：61％)，LCMS m/z：549[M+H]+。At room temperature, N-carbamoyl acetamide (782 mg, 7.75 mmol) was added to a solution of (E)-N-((4-chlorophenyl)sulfonyl)-3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-carbamoyl chloride (3.74 g, 7.75 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and recrystallized from ethanol to obtain N-((E)-N′-(Z)-(((4-chlorophenyl)sulfonyl)imino)(3-(5-cyanopyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)carbamoyl)acetamide (2.59 g, yield: 61%), LCMS m/z: 549 [M+H] + .

实施例2、N-(N′-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚胺基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MDR-001-305-1、2、3和4)的合成： Example 2, Synthesis of N-(N′-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimido)acetamide and its isomers (MDR-001-305-1, 2, 3 and 4):

1)、化合物1-(4-氯苯基)-2-苯基乙烷-1-酮的合成：

Figure PCTCN2024113428-ftappb-I100171
1) Synthesis of compound 1-(4-chlorophenyl)-2-phenylethane-1-one:
Figure PCTCN2024113428-ftappb-I100171

在0℃和氮气保护下，向溶有4-氯苯甲酸甲酯(5.00g，29.4mmol)和2-苯基乙酸(4.0g，29.4mmol)溶液N，N-二甲基甲酰胺(60mL)溶液中，加入LiHMDS(1M的四氢呋喃，88.4mL，88.4mmol)，0℃搅拌2小时。将混合反应液用饱和氯化铵水溶液(50mL)淬灭，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯＝10/1)纯化得到化合物1-(4-氯苯基)-2-苯基乙烷-1-酮(6.0g，26.09mmol，收率：88.76％)。LCMS m/z：231[M+H]+ At 0°C and under nitrogen protection, LiHMDS (1M tetrahydrofuran, 88.4mL, 88.4mmol) was added to a solution of N,N-dimethylformamide (60mL) containing methyl 4-chlorobenzoate (5.00g, 29.4mmol) and 2-phenylacetic acid (4.0g, 29.4mmol) and stirred at 0°C for 2 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (50mL) and extracted with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1) to give compound 1-(4-chlorophenyl)-2-phenylethane-1-one (6.0g, 26.09mmol, yield: 88.76%). LCMS m/z: 231[M+H] +

2)、化合物1-(4-氯苯基)-3-羟基-2-苯基丁-1-酮的合成：

Figure PCTCN2024113428-ftappb-I100172
2) Synthesis of compound 1-(4-chlorophenyl)-3-hydroxy-2-phenylbutan-1-one:
Figure PCTCN2024113428-ftappb-I100172

向溶有1-(4-氯苯基)-2-苯基乙烷-1-酮(2.86g，12.43mmol)的四氢呋喃(30mL)中，加入碳酸钾(3.43g，24.86mmol，2.0eq)和乙醛(5.0M，24.9mL，124.3mmol)，室温搅拌16小时。将混合反应液过滤，并用四氢呋喃(20mL)洗涤滤饼。收集滤液减压浓缩得到化合物1-(4-氯苯基)-3-羟基-2-苯基丁-1-酮(3.4g，粗品)，直接用于下一步骤中，无需进一步纯化，LCMS m/z：275[M+H]+。Potassium carbonate (3.43 g, 24.86 mmol, 2.0 eq) and acetaldehyde (5.0 M, 24.9 mL, 124.3 mmol) were added to tetrahydrofuran (30 mL) containing 1-(4-chlorophenyl)-2-phenylethane-1-one (2.86 g, 12.43 mmol), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was filtered, and the filter cake was washed with tetrahydrofuran (20 mL). The filtrate was collected and concentrated under reduced pressure to give compound 1-(4-chlorophenyl)-3-hydroxy-2-phenylbutan-1-one (3.4 g, crude product), which was used directly in the next step without further purification, LCMS m/z: 275 [M+H] + .

3)、化合物1-(4-氯苯基)-2-苯基丁-2-烯-1-酮的合成：

Figure PCTCN2024113428-ftappb-I100173
3) Synthesis of compound 1-(4-chlorophenyl)-2-phenylbut-2-ene-1-one:
Figure PCTCN2024113428-ftappb-I100173

向溶有1-(4-氯苯基)-3-羟基-2-苯基丁-1-酮(3.4g，12.38mmol)的甲苯(30mL)溶液中，加入TsOH.H2O(4.7g，24.75mmol)，加热90℃搅拌3小时。将混合反应液通过硅胶柱色谱法(石油醚/乙酸乙酯＝10/1)纯化得到化合物1-(4-氯苯基)-2-苯基丁-2-烯-1-酮(2.9g，0.66mmol，收率：91.28％)。LCMS m/z：257[M+H]+。TsOH.H 2 O (4.7 g, 24.75 mmol) was added to a toluene (30 mL) solution of 1-(4-chlorophenyl)-3-hydroxy-2-phenylbutan-1-one (3.4 g, 12.38 mmol), and the mixture was heated at 90° C. and stirred for 3 hours. The mixed reaction liquid was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 1-(4-chlorophenyl)-2-phenylbut-2-ene-1-one (2.9 g, 0.66 mmol, yield: 91.28%). LCMS m/z: 257 [M+H] + .

4)、化合物3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑的合成：

Figure PCTCN2024113428-ftappb-I100174
4) Synthesis of compound 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole:
Figure PCTCN2024113428-ftappb-I100174

向溶有1-(4-氯苯基)-2-苯基丁-2-烯-1-酮(2.9g，11.3mmol)的乙醇(30mL)溶液中，加入NH2NH2.H2O (725mg，22.7mmol)，加热80℃搅拌5小时。将混合反应液减压浓缩并通过硅胶色谱法(石油醚/乙酸乙酯＝5/1)纯化得到化合物3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(2.5g，9.25mmol，收率：82％)，LCMS m/z：271[M+H]+。To a solution of 1-(4-chlorophenyl)-2-phenylbut-2-en-1-one (2.9 g, 11.3 mmol) in ethanol (30 mL) was added NH 2 NH 2 .H 2 O (725 mg, 22.7 mmol), heated at 80°C and stirred for 5 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (2.5 g, 9.25 mmol, yield: 82%), LCMS m/z: 271 [M+H] + .

5)、化合物3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成：

Figure PCTCN2024113428-ftappb-I100175
5) Synthesis of compound 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide:
Figure PCTCN2024113428-ftappb-I100175

在室温条件下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(1.0g，3.7mmol)的甲苯(10mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(1.04g，3.7mol)，加热110℃搅拌4小时。将混合反应液减压浓缩并通过硅胶柱色谱法(石油醚/乙酸乙酯＝3/1)纯化得到化合物3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(1.0g，1.91mmol，收率：51.92％)，LCMS m/z：522[M+H]+。At room temperature, methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.04 g, 3.7 mol) was added to a toluene (10 mL) solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (1.0 g, 3.7 mmol), and the mixture was heated to 110° C. and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.0 g, 1.91 mmol, yield: 51.92%), LCMS m/z: 522 [M+H] + .

6)、化合物3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯合成：

Figure PCTCN2024113428-ftappb-I100176
6) Synthesis of compound 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride:
Figure PCTCN2024113428-ftappb-I100176

在室温条件下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(500mg，0.96mmol)的氯苯(8mL)溶液中，加入PCl5(379mg，1.82mmol)，加热145℃搅拌3小时。将混合反应液减压浓缩得到3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(500mg，粗品)，直接用于下一步，无需进一步纯化，LCMSm/z：540[M+H]+。PCl 5 (379 mg, 1.82 mmol) was added to a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1 -carboxamide (500 mg, 0.96 mmol) in chlorobenzene (8 mL) at room temperature, and the mixture was heated at 145°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure to give 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (500 mg, crude product), which was used directly in the next step without further purification. LCMS m/z: 540 [M+H] + .

7)、化合物N-(N′-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚胺基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MDR-001-305-1、2、3、4)的合成：

Figure PCTCN2024113428-ftappb-I100177
7) Synthesis of compound N-(N′-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimino)acetamide and its isomers (MDR-001-305-1, 2, 3, 4):
Figure PCTCN2024113428-ftappb-I100177

室温条件下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(500mg，0.93mmol)的N，N-二甲基甲酰胺(3mL)溶液中，加入三乙胺(189mg，1.86mmol)和N-氨基甲酰亚胺乙酰胺(103mg，1.02mmol)，室温搅拌2小时。将混合反应液减压浓缩并通过 反相柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)纯化，当流动相B含量达到60％时，收集含产物的级分，减压浓缩化合物N-(N′-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚胺基)甲基)氨基甲酰亚胺基)乙酰胺(180mg，0.30mmol，收率：32.14％)，LCMS m/z：605[M+H]+.At room temperature, triethylamine (189 mg, 1.86 mmol) and N-carbamide imide acetamide (103 mg, 1.02 mmol) were added to a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (500 mg, 0.93 mmol) in N,N-dimethylformamide (3 mL), and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and filtered. Reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm) purification, when the content of mobile phase B reached 60%, the fractions containing the product were collected, and the compound N-(N′-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (180mg, 0.30mmol, yield: 32.14%) was concentrated under reduced pressure, LCMS m/z: 605[M+H] + .

将化合物N-(N′-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚胺基)甲基)氨基甲酰亚胺基)乙酰胺(120mg，0.198mmol)通过超临界流体色谱纯化(色谱条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100178
柱尺寸：250*25mm 10m流动相A：超临界CO2；流动相B：ACN，A：B＝75：25；波长：214nm；流量：100mL/min柱温：RT；柱亚：100bar，进样量：3.0mL；循环时间：8.0分钟)纯化得到两部分异构体，分别命名为：MDR-001-305-1/2和MDR-001-303-3/4：Compound N-(N′-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimido)acetamide (120 mg, 0.198 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100178
Column size: 250*25mm 10m mobile phase A: supercritical CO 2 ; mobile phase B: ACN, A:B=75:25; wavelength: 214nm; flow rate: 100mL/min column temperature: RT; column subpressure: 100bar, injection volume: 3.0mL; cycle time: 8.0min) was purified to obtain two isomers, named as: MDR-001-305-1/2 and MDR-001-303-3/4:

MDR-001-305-1/2：峰1：0.872-0.914min；(80mg，0.13mmol，收率：66.66％)，LCMSm/z：605[M+H]+。MDR-001-305-1/2: Peak 1: 0.872-0.914 min; (80 mg, 0.13 mmol, yield: 66.66%), LCMS m/z: 605 [M+H] + .

MDR-001-305-3/4：峰2：3.924分钟；(20mg，0.033mmol，16.67％产率)，LCMS：m/z：605[M+H]+。MDR-001-305-3/4: Peak 2: 3.924 min; (20 mg, 0.033 mmol, 16.67% yield), LCMS: m/z: 605 [M+H] + .

将上述所得异构体MDR-001-305-1/2(80mg，0.132mmol)再次通过超临界流体色谱(色谱条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100179
柱尺寸：250*30mm 10m流动相A：超临界CO2；流动相B：IPA，A：B＝60：40；检测波长：214nm；流量：120mL/min；柱温：RT；柱压：100bar，进样量：8.0mL；循环时间：5.45min)纯化得到两种异构体：MDR-001-305-1和MDR-001-305-2。The isomer MDR-001-305-1/2 (80 mg, 0.132 mmol) obtained above was again subjected to supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100179
Column size: 250*30mm 10m mobile phase A: supercritical CO 2 ; mobile phase B: IPA, A:B=60:40; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar, injection volume: 8.0mL; cycle time: 5.45min) was purified to obtain two isomers: MDR-001-305-1 and MDR-001-305-2.

MDR-001-305-1：峰1：0.789min；(25.89mg，0.042mmol，收率：32.36％)，LCMS m/z：605[M+H]+。MDR-001-305-1: Peak 1: 0.789 min; (25.89 mg, 0.042 mmol, yield: 32.36%), LCMS m/z: 605 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.61(s，1H)，7.99(d，J＝7.2Hz，2H)，7.84(d，J＝6.8Hz，2H)，7.55(d，J＝7.6Hz，2H)，7.41(d，J＝7.6Hz，2H)，7.35-7.19(m，5H)，4.63(s，1H)，4.42-4.24(m，1H)，2.10(s，3H)，1.47(d，J＝5.2Hz.3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.61 (s, 1H), 7.99 (d, J = 7.2Hz, 2H), 7.84 (d, J = 6.8Hz, 2H), 7.55 (d, J = 7.6Hz, 2H), 7.41 (d, J = 7 .6Hz, 2H), 7.35-7.19(m, 5H), 4.63(s, 1H), 4.42-4.24(m, 1H), 2.10(s, 3H), 1.47(d, J=5.2Hz.3H).

19F NMR(377MHz，DMSO-d6)δ61.300. 19 F NMR (377MHz, DMSO-d 6 ) δ61.300.

MDR-001-305-2：峰2：2.445分钟；(26.61mg，0.044mmol，收率：33.26％)，LCMS m/z：605[M+H]+。MDR-001-305-2: Peak 2: 2.445 min; (26.61 mg, 0.044 mmol, yield: 33.26%), LCMS m/z: 605 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.61(s，1H)，7.99(d，J＝7.2Hz，2H)，7.84(d，J＝6.8Hz，2H)，7.55(d，J＝7.6Hz，2H)，7.41(d，J＝7.6Hz，2H)，7.35-7.19(m，5H)，4.63(s，1H)，4.42-4.24(m，1H)，2.10(s，3H)，1.47(d，J＝5.2Hz.3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.61 (s, 1H), 7.99 (d, J = 7.2Hz, 2H), 7.84 (d, J = 6.8Hz, 2H), 7.55 (d, J = 7.6Hz, 2H), 7.41 (d, J = 7 .6Hz, 2H), 7.35-7.19(m, 5H), 4.63(s, 1H), 4.42-4.24(m, 1H), 2.10(s, 3H), 1.47(d, J=5.2Hz.3H).

19F NMR(377MHz，DMSO-d6)δ-61.300. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.300.

将上述所得异构体MDR-001-305-3/4(20mg，0.033mmol)通过SFC纯化(条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100180
柱尺寸：250*30mm 10m流动相A超临界CO2；流动相B：IPA，A：B＝70：30；波长：214nm；流量：120mL/min；柱温：RT；柱压：100bar，进样量：7.5mL；循环时间：6.0分钟)获得两种异构体：MDR-001-305-3和MDR-001-305-4：The isomer MDR-001-305-3/4 (20 mg, 0.033 mmol) obtained above was purified by SFC (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100180
Column size: 250*30mm 10m mobile phase A supercritical CO 2 ; mobile phase B: IPA, A:B=70:30; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar, injection volume: 7.5mL; cycle time: 6.0min) Two isomers were obtained: MDR-001-305-3 and MDR-001-305-4:

MDR-001-305-3：峰1：1.626min；(4.97mg，0.0082mmol，收率：24.85％)，LCMS m/z：605[M+H]+。MDR-001-305-3: Peak 1: 1.626 min; (4.97 mg, 0.0082 mmol, yield: 24.85%), LCMS m/z: 605 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.49(s，1H)，7.99(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.40-7.36(m，4H)，7.33-7.22(m，3H)，7.16-7.00(m，2H)，5.17(d，J＝10.8Hz，1H)，4.85-4.71(m，1H)，2.07(s，3H)，0.99(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.49 (s, 1H), 7.99 (d, J=8.0Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.40-7.36 (m, 4H), 7.33-7.22 (m, 3H) , 7.16-7.00 (m, 2H), 5.17 (d, J=10.8Hz, 1H), 4.85-4.71 (m, 1H), 2.07 (s, 3H), 0.99 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.293. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.293.

MDR-001-305-4：峰2：2.152分钟；(5.03mg，0.0083mmol，收率：25.15％)，LCMS m/z：605[M+H]+。MDR-001-305-4: Peak 2: 2.152 min; (5.03 mg, 0.0083 mmol, yield: 25.15%), LCMS m/z: 605 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.49(s，1H)，7.99(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.40-7.36(m，4H)，7.33-7.22(m，3H)，7.16-7.00(m，2H)，5.17(d，J＝10.8Hz，1H)，4.85-4.71(m，1H)，2.07(s，3H)，0.99(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.49 (s, 1H), 7.99 (d, J=8.0Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.40-7.36 (m, 4H), 7.33-7.22 (m, 3H) , 7.16-7.00 (m, 2H), 5.17 (d, J=10.8Hz, 1H), 4.85-4.71 (m, 1H), 2.07 (s, 3H), 0.99 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.293. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.293.

实施例3、N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(化合物MDR-001-304-1和2)的合成：Example 3. Synthesis of N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (compounds MDR-001-304-1 and 2):

1)、化合物1-(4-氯苯基)-2-(噻吩-2-基)丙-2-烯-1-酮的合成：

Figure PCTCN2024113428-ftappb-I100181
1) Synthesis of compound 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one:
Figure PCTCN2024113428-ftappb-I100181

室温条件下，向溶有1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(2.07g，8.73mmol)的干燥的四氢呋喃(40mL)溶液中，加入多聚甲醛(2.62g，87.30mmol)和碳酸钾(3.61g，26.19mmol)，加热40℃搅拌2小时。将混合反应液过滤、滤液用四氢呋喃(20mL)洗涤。收集滤液减压浓缩1-(4-氯苯基)-2-(噻 吩-2-基)丙-2-烯-1-酮(2.17g，粗品)，用于下一步，无需进一步纯化，LCMS m/z：249[M+H]+ At room temperature, paraformaldehyde (2.62 g, 87.30 mmol) and potassium carbonate (3.61 g, 26.19 mmol) were added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (2.07 g, 8.73 mmol) in dry tetrahydrofuran (40 mL), and the mixture was heated at 40°C and stirred for 2 hours. The mixed reaction solution was filtered and the filtrate was washed with tetrahydrofuran (20 mL). The filtrate was collected and concentrated under reduced pressure to obtain 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one. phen-2-yl)prop-2-en-1-one (2.17 g, crude), used in the next step without further purification, LCMS m/z: 249 [M+H] +

2)、化合物3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑的合成：

Figure PCTCN2024113428-ftappb-I100182
2) Synthesis of compound 3-(4-chlorophenyl)-4-(thiophene-2-yl)-4,5-dihydro-1H-pyrazole:
Figure PCTCN2024113428-ftappb-I100182

室温下，，向溶有1-(4-氯苯基)-2-(噻吩-2-基)丙-2-烯-1-酮(2.17g，8.71mmol)的四氢呋喃(5mL)溶液中，加入N2H4.H2O(2.23g，69.68mmol)，加热80℃搅拌4小时。将混合反应液减压浓缩。残余物通过硅胶(二氯甲烷/乙酸乙酯＝25/1)纯化得到3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(830mg，3.16mmol，收率：36.2％)，LCMS m/z：263[M+H]+.At room temperature, N 2 H 4 .H 2 O (2.23 g, 69.68 mmol) was added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one (2.17 g, 8.71 mmol) in tetrahydrofuran (5 mL), and the mixture was heated at 80°C and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel (dichloromethane/ethyl acetate = 25/1) to give 3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (830 mg, 3.16 mmol, yield: 36.2%), LCMS m/z: 263 [M+H] + .

3)、化合物3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成：

Figure PCTCN2024113428-ftappb-I100183
3) Synthesis of compound 3-(4-chlorophenyl)-4-(thiophene-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide:
Figure PCTCN2024113428-ftappb-I100183

室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(830mg，3.16mmol)的甲苯(10mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸酯(894mg，3.16mmol)，加热110℃搅拌3小时。将混合反应液减压浓缩。残余物用异丙醇(50mL)打浆，过滤。收集固体真空干燥得到3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(1.15g，2.24mmol，收率：70.9％)，LCMS m/z：514[M+H]+ At room temperature, to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (830 mg, 3.16 mmol) in toluene (10 mL), ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (894 mg, 3.16 mmol) was added, and the mixture was heated to 110° C. and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was slurried with isopropanol (50 mL) and filtered. The collected solid was dried in vacuo to give 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.15 g, 2.24 mmol, yield: 70.9%), LCMS m/z: 514 [M+H] +

4)、化合物3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯的合成：

Figure PCTCN2024113428-ftappb-I100184
4) Synthesis of compound 3-(4-chlorophenyl)-4-(thiophene-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride:
Figure PCTCN2024113428-ftappb-I100184

在室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(400mg，0.78mmol)的氯苯(8mL)溶液中，五氯化磷(649mg，3.12mmol)，加热140℃搅拌2小时。将混合反应液减压浓缩得到3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(1.15g，粗品)，直接用于下一步，无需进一步纯化。LCMS m/z：532[M+H]+ Phosphorus pentachloride (649 mg, 3.12 mmol) was added to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (400 mg, 0.78 mmol) in chlorobenzene (8 mL) at room temperature, and the mixture was heated to 140°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (1.15 g, crude product), which was used directly in the next step without further purification. LCMS m/z: 532 [M+H] +

5)、化合物N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(化合物MDR-001-304-1和2)的合成：

Figure PCTCN2024113428-ftappb-I100185
5) Synthesis of compound N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (compounds MDR-001-304-1 and 2):
Figure PCTCN2024113428-ftappb-I100185

在室温下，向3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(415mg，0.78mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入N-氨基甲酰亚胺乙酰胺(158mg，1.56mmol)，室温搅拌0.5小时，然后加入三乙胺(394mg，3.90mmol)，室温搅拌0.5小时。将混合反应液通过高效液相色谱(色谱条条件：Waters 2767/Qda，Sunfire C18，19×250×10um；流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：26％B-36％；保留时间：7.5-9.0min of 16min)纯化得到化合物N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺(95mg，0.16mmol，收率：20.5％)，LCMS m/z：597[M+H]+.To a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (415 mg, 0.78 mmol) in N,N-dimethylformamide (5 mL) at room temperature was added N-carbamidoacetamide (158 mg, 1.56 mmol), and the mixture was stirred at room temperature for 0.5 hour. Then, triethylamine (394 mg, 3.90 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. The mixed reaction solution was purified by high performance liquid chromatography (chromatographic strip conditions: Waters 2767/Qda, Sunfire C18, 19×250×10um; mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 26% B-36%; retention time: 7.5-9.0 min of 16 min) to obtain compound N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (95 mg, 0.16 mmol, yield: 20.5%), LCMS m/z: 597 [M+H] + .

将上述所得N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺(95mg)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；柱：

Figure PCTCN2024113428-ftappb-I100186
250*30mm 10μm；流动相A：超临界CO2；流动相B：异丙醇，A：B＝60：40；检测波长：214nm；流速：120mL/min；柱温：RT；柱压：100bar，进样量：8mL；循环时间：6.5min)纯化得到两个异构体：MDR-001-304-1和MDR-001-304-2：The N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (95 mg) obtained above was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column:
Figure PCTCN2024113428-ftappb-I100186
250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol, A:B=60:40; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar, injection volume: 8mL; cycle time: 6.5min) was purified to obtain two isomers: MDR-001-304-1 and MDR-001-304-2:

MDR-001-304-1：1.444min；(33.92mg，0.06mmol，收率：35.7％)，LCMS m/z：597[M+H]+.MDR-001-304-1: 1.444 min; (33.92 mg, 0.06 mmol, yield: 35.7%), LCMS m/z: 597 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.01(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.58(d，J＝8.4Hz，2H)，7.45-7.40(m，3H)，6.98-6.93(m，2H)，5.42-5.38(m，1H)，4.45(t，J＝11.6Hz，1H)，3.97-3.93(m，1H)，2.07(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.53 (s, 1H), 8.01 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.4Hz, 2H), 7.45-7.40 (m, 3H), 6.98-6.93(m, 2H), 5.42-5.38(m, 1H), 4.45(t, J=11.6Hz, 1H), 3.97-3.93(m, 1H), 2.07(s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.312. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.312.

MDR-001-304-2：2.297min；(35.97mg，0.06mmol，收率：37.86％)，LCMS m/z：597[M+H]+.MDR-001-304-2: 2.297 min; (35.97 mg, 0.06 mmol, yield: 37.86%), LCMS m/z: 597 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.01(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.58(d，J＝8.8Hz，2H)，7.45-7.40(m，3H)，6.98-6.93(m，2H)，5.42-5.38(m，1H)，4.45(t，J＝11.6Hz，1H)，3.97-3.93(m，1H)，2.07(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.53 (s, 1H), 8.01 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.8Hz, 2H), 7.45-7.40 (m, 3H), 6.98-6.93(m, 2H), 5.42-5.38(m, 1H), 4.45(t, J=11.6Hz, 1H), 3.97-3.93(m, 1H), 2.07(s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.312. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.312.

实施例4、N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺及其异构体(MDR-001-302-1和2)的合成：Example 4. Synthesis of N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (MDR-001-302-1 and 2):

1)、化合物1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮的合成：

Figure PCTCN2024113428-ftappb-I100187
1) Synthesis of compound 1-(4-chlorophenyl)-2-(thiophene-2-yl)ethan-1-one:
Figure PCTCN2024113428-ftappb-I100187

在0℃下，向溶有4-氯苯甲酸甲酯(5.00g，29.24mmol)和2-(噻吩-2-基)乙酸(4.15g，29.24mmol)的N，N二甲基甲酰胺(100mL)溶液中，加入双三甲基硅基胺基锂(1M的四氢呋喃溶液，91mL，90.64mmol)，室温搅拌1小时。将混合反应液用饱和氯化铵水溶液(20mL)淬灭，并用乙酸乙酯(200mL)萃取。合并的有机相用饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝20/1)纯化得到1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(6.31g，26.62mmol，收率：91.18％)，1.962min.LCMS m/z：237[M+H]+.At 0°C, lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 91 mL, 90.64 mmol) was added to a solution of methyl 4-chlorobenzoate (5.00 g, 29.24 mmol) and 2-(thiophene-2-yl)acetic acid (4.15 g, 29.24 mmol) in N,N-dimethylformamide (100 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (6.31 g, 26.62 mmol, yield: 91.18%), 1.962 min. LCMS m/z: 237 [M+H] + .

2)、化合物4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸乙酯化合物的合成：

Figure PCTCN2024113428-ftappb-I100188
2) Synthesis of the compound 4-(4-chlorophenyl)-4-oxo-3-(thiophene-2-yl)butyric acid ethyl ester:
Figure PCTCN2024113428-ftappb-I100188

在0℃下，向溶有1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(5.00g，21.10mmol)的二甲亚砜(100mL)溶液中，加入氢化钠(60％，w/w矿物油分散体，928mg，23.21mmol)，0℃搅拌拌1小时，然后在0℃下加入溴乙酸乙酯(3.88g，23.21mmol)，室温搅拌1小时。将混合反应液用饱和氯化铵水溶液(10mL)淬灭，并用乙酸乙酯(200mL)萃取。合并有机相用饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝20/1)纯化得到化合物4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸乙酯(5.20g，16.10mmol，收率：76.35％)，LCMS m/z：323[M+H]+.At 0°C, sodium hydride (60%, w/w mineral oil dispersion, 928 mg, 23.21 mmol) was added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (5.00 g, 21.10 mmol) in dimethyl sulfoxide (100 mL), stirred at 0°C for 1 hour, then ethyl bromoacetate (3.88 g, 23.21 mmol) was added at 0°C, and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to give compound 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoic acid ethyl ester (5.20 g, 16.10 mmol, yield: 76.35%), LCMS m/z: 323 [M+H] + .

3)、化合物4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸的合成：

Figure PCTCN2024113428-ftappb-I100189
3) Synthesis of compound 4-(4-chlorophenyl)-4-oxo-3-(thiophene-2-yl)butyric acid:
Figure PCTCN2024113428-ftappb-I100189

在室温下，向溶有4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸乙酯(5.00g，15.48mmol)的四氢呋喃(100mL)，水(50mL)和乙醇(50mL)溶液中，加入氢氧化锂(1.86g，77.40mmol)，室温搅拌1小时。将混合反应液用盐酸(1M)调节pH至4-5，并用乙酸乙酯(200mL)稀释。合并的有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到化合物4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸(4.51g，15.29mmol，收率：98.90％)，LCMS m/z：295[M+H]+.At room temperature, lithium hydroxide (1.86 g, 77.40 mmol) was added to a solution of ethyl 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoate (5.00 g, 15.48 mmol) in tetrahydrofuran (100 mL), water (50 mL) and ethanol (50 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was adjusted to pH 4-5 with hydrochloric acid (1 M) and diluted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoic acid (4.51 g, 15.29 mmol, yield: 98.90%), LCMS m/z: 295 [M+H] + .

4)、化合物6-(4-氯苯基)-5-(噻吩-2-基)-4，5-二氢哒嗪-3(2H)-酮的合成：

Figure PCTCN2024113428-ftappb-I100190
4) Synthesis of compound 6-(4-chlorophenyl)-5-(thiophene-2-yl)-4,5-dihydropyridazine-3(2H)-one:
Figure PCTCN2024113428-ftappb-I100190

在室温下，向溶有4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸(4.00g，13.56mmol)的乙醇(50mL)溶液中，加入水合肼(651mg，20.34mmol)，加热80℃搅拌2小时。将混合反应液过滤，滤饼用冰乙醇(10mL)洗涤，干燥，得到化合物6-(4-氯苯基)-5-(噻吩-2-基)-4，5-二氢哒嗪-3(2H)-酮(2.66g，9.14mmol，收率：67.51％)，LCMS m/z：291[M+H]+.At room temperature, hydrazine hydrate (651 mg, 20.34 mmol) was added to a solution of 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoic acid (4.00 g, 13.56 mmol) in ethanol (50 mL), and the mixture was heated to 80°C and stirred for 2 hours. The mixed reaction liquid was filtered, and the filter cake was washed with ice ethanol (10 mL) and dried to obtain compound 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazine-3(2H)-one (2.66 g, 9.14 mmol, yield: 67.51%), LCMS m/z: 291 [M+H] + .

5)、化合物3-(4-氯苯基)-4-(噻吩-2-基)-1，4，5，6-四氢哒嗪的合成：

Figure PCTCN2024113428-ftappb-I100191
5) Synthesis of compound 3-(4-chlorophenyl)-4-(thiophene-2-yl)-1,4,5,6-tetrahydropyridazine:
Figure PCTCN2024113428-ftappb-I100191

在0℃下，向溶有6-(4-氯苯基)-5-(噻吩-2-基)-4，5-二氢哒嗪-3(2H)-酮(2.00g，6.88mmol)的四氢呋喃(40mL)溶液中，加入硼烷(1M的四氢呋喃溶液，13.76mL，13.76mmol)，室温搅拌混合物2小时。在0℃下，将混合反应液用甲醇(40mL)淬灭，室温搅拌0.5小时，将混合反应液减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝2/1)纯化得到化合物3-(4-氯苯基)-4-(噻吩-2-基)-1，4，5，6-四氢哒嗪(1.05g，3.79mmol，收率：55.26％)，LCMS m/z：277[M+H]+.At 0°C, borane (1M tetrahydrofuran solution, 13.76 mL, 13.76 mmol) was added to a solution of 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazine-3(2H)-one (2.00 g, 6.88 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours. At 0°C, the mixed reaction solution was quenched with methanol (40 mL), stirred at room temperature for 0.5 hours, and the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give compound 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine (1.05 g, 3.79 mmol, yield: 55.26%), LCMS m/z: 277 [M+H] + .

6)、化合物3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺的合成：

Figure PCTCN2024113428-ftappb-I100192
6) Synthesis of compound 3-(4-chlorophenyl)-4-(thiophene-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide:
Figure PCTCN2024113428-ftappb-I100192

在室温条件下，向溶有(4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(1.18g，4.17mmol)的甲苯溶液(20mL)中，加入3-(4-氯苯基)-4-(噻吩-2-基)-1，4，5，6-四氢哒嗪(1.05g，3.79mmol)，加热110℃搅拌2小时。将混合反应液并通过硅胶柱色谱(石油醚/乙酸乙酯＝3/1)纯化得到化合物3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(2.08g，3.94mmol，收率：92.5％)。Rt：2.066min.LCMS：m/z：528[M+H]+.At room temperature, 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine (1.05 g, 3.79 mmol) was added to a toluene solution (20 mL) containing methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.18 g, 4.17 mmol), and the mixture was heated to 110°C and stirred for 2 hours. The mixed reaction solution was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (2.08 g, 3.94 mmol, yield: 92.5%). Rt: 2.066 min. LCMS: m/z: 528 [M+H] + .

7)、1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成

Figure PCTCN2024113428-ftappb-I100193
7) Synthesis of 1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium
Figure PCTCN2024113428-ftappb-I100193

在室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(500mg，0.95mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(174mg，1.14mmol)和4-二甲氨基吡啶(580mg，4.75mmol)，加热50℃搅拌3小时。将混合反应液减压浓缩化合物1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(598mg，粗品)，LCMS m/z：632[M+H]+ Phosphorus oxychloride (174 mg, 1.14 mmol) and 4-dimethylaminopyridine (580 mg, 4.75 mmol) were added to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (500 mg, 0.95 mmol) in dichloromethane (20 mL) at room temperature, and the mixture was heated at 50°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure to obtain compound 1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (598 mg, crude product), LCMS m/z: 632 [M+H] +

8)、N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺及其异构体(MDR-001-302-1和2)的合成：

Figure PCTCN2024113428-ftappb-I100194
8) Synthesis of N-(N′-((3-(4-chlorophenyl)-4-(thiophene-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (MDR-001-302-1 and 2):
Figure PCTCN2024113428-ftappb-I100194

在室温条件下，向溶有1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(598mg，0.94mmol)的N，N二甲基甲酰胺(10mL)溶液中，加入N-氨基甲脒基乙酰胺(949mg，9.40mmol)和N，N-二异丙基乙胺(1.21g，9.40mmol)，室温搅拌2小时。将混合反应液倒入水(10mL)中，并用乙酸乙酯(30mL)萃取。合并有机相用饱和食盐水(5mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过快速反相柱色谱(色谱柱：球形C18，20-40um，80g；流动相A：水(0.1％FA)；流动相B：乙腈；流速：65mL/min；梯度：12min内得到5％B-80％B；检测器：254nm)纯化。当流动相B达到73％时，收集含有产物的积分减压浓缩得到化合物N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺(200mg，0.33mmol，收率：34.66％)，LCMS m/z：611[M+H]+。At room temperature, N-aminocarboxamidinoacetamide (949 mg, 9.40 mmol) and N,N-diisopropylethylamine (1.21 g, 9.40 mmol) were added to a solution of 1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (598 mg, 0.94 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (5 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic column: spherical C18, 20-40um, 80g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 65mL/min; gradient: 5%B-80%B in 12min; detector: 254nm). When mobile phase B reached 73%, the integral containing the product was collected and concentrated under reduced pressure to obtain compound N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (200mg, 0.33mmol, yield: 34.66%), LCMS m/z: 611[M+H] + .

将上述所得N-(N′-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺(80mg，0.13mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100195
色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：乙腈(+0.1％7.0M氨甲醇)，A：B＝65：45；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：8.0mL；循环时间：7.2min)纯化得到两个异构体：MDR-001-302-1和MDR-001-302-2。 The N-(N′-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (80 mg, 0.13 mmol) obtained above was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100195
Chromatographic column size: 250*25mm 10μm; mobile phase A; supercritical CO2 ; mobile phase B: acetonitrile (+0.1% 7.0M ammonia methanol), A:B=65:45; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 7.2min) was purified to obtain two isomers: MDR-001-302-1 and MDR-001-302-2.

MDR-001-302-1：峰1：2.177min；(21.04mg，0.03mmol，收率：26.30％)，LCMS m/z：611[M+H]+.MDR-001-302-1: Peak 1: 2.177 min; (21.04 mg, 0.03 mmol, yield: 26.30%), LCMS m/z: 611 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.04-8.02(m，2H)，7.86-7.84(m，2H)，7.61-7.59(m，2H)，7.40-7.39(m，1H)，7.34-7.32(m，2H)，6.92-6.90(m，1H)，6.77-6.76(m，1H)，4.68(s，1H)，4.36(d，J＝12.4Hz，1H)，3.27-3.20(m，1H)，2.25-2.17(m，1H)，2.10(s，3H)，2.05-2.02(m，1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.66(s, 1H), 8.04-8.02(m, 2H), 7.86-7.84(m, 2H), 7.61-7.59(m, 2H), 7.40-7.39(m, 1H), 7.34-7.32(m, 2H), 6.92-6.90(m, 1H) ), 6.77-6.76 (m, 1H), 4.68 (s, 1H), 4.36 (d, J=12.4Hz, 1H), 3.27-3.20 (m, 1H), 2.25-2.17 (m, 1H), 2.10 (s, 3H), 2.05-2.02 (m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.293 19 F NMR (377MHz, DMSO-d 6 ) δ-61.293

MDR-001-302-2：峰2：3.328min；(18.76mg，0.03mmol，收率：23.45％)，LCMS m/z：611[M+H]+.MDR-001-302-2: Peak 2: 3.328 min; (18.76 mg, 0.03 mmol, yield: 23.45%), LCMS m/z: 611 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.04-8.02(m，2H)，7.86-7.84(m，2H)，7.61-7.59(m，2H)，7.40-7.32(m，1H)，7.34-7.32(m，2H)，6.92-6.90(m，1H)，6.77-6.76(m，1H)，4.68(s，1H)，4.36(d，J＝12.8Hz，1H)，3.27-3.20(m，1H)，2.25-2.19(m，1H)，2.10(s，3H)，2.05-2.02(m，1H). 1 H NMR (400MHz, DMSO-d6) δ10.66 (s, 1H), 8.04-8.02 (m, 2H), 7.86-7.84 (m, 2H), 7.61-7.59 (m, 2H), 7.40-7.32 (m, 1H), 7.34-7.32 (m, 2H), 6.92- 6.90 (m, 1H), 6.77-6.76 (m, 1H), 4.68 (s, 1H), 4.36 (d, J=12.8Hz, 1H), 3.27-3.20(m, 1H), 2.25-2.19(m, 1H), 2.10(s, 3H), 2.05-2.02(m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.297.

实施例5、N-((E)-N′-(Z)-(3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(MDR-001-301-1和MDR-001-301-2)的合成：Example 5, Synthesis of N-((E)-N′-(Z)-(3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoformimidoyl)acetamide (MDR-001-301-1 and MDR-001-301-2):

1)、2-(2，6-二溴苯基)乙烷-1-醇的的合成

Figure PCTCN2024113428-ftappb-I100196
1) Synthesis of 2-(2,6-dibromophenyl)ethane-1-ol
Figure PCTCN2024113428-ftappb-I100196

在室温下，向溶有2-(2，6-二溴苯基)乙酸(5.0g，17.0mmol)的四氢呋喃(20.0mL)溶液中，加入硼烷四氢呋喃(68mL，68.0mmol，1M)，加热80℃搅拌16小时。LCMS显示反应完成。将混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并的有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯＝3/1)纯化得到2-(2，6-二溴苯基)乙烷-1-醇(4.1g，14.63mmol，收率：86％)，At room temperature, to a solution of 2-(2,6-dibromophenyl)acetic acid (5.0 g, 17.0 mmol) in tetrahydrofuran (20.0 mL), add borane tetrahydrofuran (68 mL, 68.0 mmol, 1 M), heat to 80 ° C and stir for 16 hours. LCMS shows that the reaction is complete. The mixed reaction solution is diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (petroleum ether/ethyl acetate=3/1) to give 2-(2,6-dibromophenyl)ethane-1-ol (4.1 g, 14.63 mmol, yield: 86%),

1H NMR(400MHz，DMSO-d6)δ7.63(d，J＝8.0Hz，2H)，7.09(t，J＝8.0Hz，1H)，4.93(t，J＝5.4Hz，1H)，3.56-3.43(m，2H)，3.17-3.01(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.63 (d, J=8.0Hz, 2H), 7.09 (t, J=8.0Hz, 1H), 4.93 (t, J=5.4Hz, 1H), 3.56-3.43 (m, 2H), 3.17-3.01 (m, 2H).

2)、1，3-二溴-2-(2-溴乙基)苯的合成

Figure PCTCN2024113428-ftappb-I100197
2) Synthesis of 1,3-dibromo-2-(2-bromoethyl)benzene
Figure PCTCN2024113428-ftappb-I100197

在0℃下，向溶有2-(2，6-二溴苯基)乙烷-1-醇(4.1g，14.6mmol)和NBS(2.8g，16.1mmol)的二氯甲烷(40.0mL)溶液中，加入PPh3(4.2g，16.1mmol)，室温搅拌16小时。TLC(石油醚/乙酸乙酯＝50/1，Rf＝0.5)显示原料消失。将混合反应液加水(150mL)稀释，并用二氯甲烷(80mL×3)萃取。合并的有机相无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝50/1)纯化得到1，3-二溴-2-(2-溴乙基)苯(3.0g，8.75mmol，收率：60.0％)。At 0°C, PPh3 (4.2 g, 16.1 mmol) was added to a solution of 2-(2,6-dibromophenyl)ethane-1-ol (4.1 g, 14.6 mmol) and NBS (2.8 g, 16.1 mmol) in dichloromethane (40.0 mL), and the mixture was stirred at room temperature for 16 hours. TLC (petroleum ether/ethyl acetate = 50/1, R f = 0.5) showed that the starting material disappeared. The mixed reaction solution was diluted with water (150 mL) and extracted with dichloromethane (80 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to give 1,3-dibromo-2-(2-bromoethyl)benzene (3.0 g, 8.75 mmol, yield: 60.0%).

1H NMR(400MHz，DMSO-d6)δ7.68(d，J＝8.0Hz，2H)，7.17(t，J＝8.0Hz，1H)，3.67-3.56(m，2H)，3.51-3.42(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.68 (d, J=8.0Hz, 2H), 7.17 (t, J=8.0Hz, 1H), 3.67-3.56 (m, 2H), 3.51-3.42 (m, 2H).

3)、2-溴双环[4.2.0]辛烷-1(6)，2，4-三烯的合成

Figure PCTCN2024113428-ftappb-I100198
3) Synthesis of 2-bromobicyclo[4.2.0]octane-1(6),2,4-triene
Figure PCTCN2024113428-ftappb-I100198

在-78℃下，向溶有1，3-二溴-2-(2-溴乙基)苯(4.2g，1235mmol)的T四氢呋喃(30mL)溶液中，加入n-BuLi(1.6M，7.7mL，12.35mmol)，-78℃下，搅拌2小时，所得混合反应液用饱和饱和氯化铵水溶液(10mL)稀释，并用乙酸乙酯(20mL×3)萃取。合并有机相用饱和是盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到2-溴二环[4.2.0]辛-1(6)，2，4-三烯(2.1g，粗产物)，直接下一步，没有进一步纯化。 At -78°C, n-BuLi (1.6M, 7.7mL, 12.35mmol) was added to a solution of 1,3-dibromo-2-(2-bromoethyl)benzene (4.2g, 1235mmol) in tetrahydrofuran (30mL), and stirred at -78°C for 2 hours. The resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (10mL) and extracted with ethyl acetate (20mL×3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-bromobicyclo[4.2.0]octan-1(6),2,4-triene (2.1g, crude product), which was directly used in the next step without further purification.

4)、二环[4.2.0]辛-1(6)，2，4-三烯-2-基氨基甲酸叔-丁基酯的合成

Figure PCTCN2024113428-ftappb-I100199
4) Synthesis of tert-butyl bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate
Figure PCTCN2024113428-ftappb-I100199

在氮气保护下，向溶有2-溴二环[4.2.0]辛-1(6)，2，4-三烯(1.9g，10.44mmol)的1，4-二氧六环(100mL)溶液中，加入氨基甲酸叔丁酯(12.2g，104.4mmol)，碳酸铯(6.8g，20.88mmol)，Brettphs G3 Pd(945ng，1.044mmol)，密封，加热100℃搅拌16小时。反应完成后，将混合反应液减压浓缩并通过硅胶(石油库/乙酸乙酯＝20/1)纯化得到粗产物。粗产物再通过反相快速柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15min；检测波长：254nm)。在70％B下，收集含有产物的级分，减压浓缩得到二环[4.2.0]辛-1(6)，2，4-三烯-2-基氨基甲酸叔丁基酯(1.3g，5.94mmol，收率：57.02％)，LCMS m/z：164[M-56+H]+ Under nitrogen protection, tert-butyl carbamate (12.2 g, 104.4 mmol), cesium carbonate (6.8 g, 20.88 mmol), Brettphs G3 Pd (945 ng, 1.044 mmol) were added to a solution of 1,4-dioxane (100 mL) containing 2-bromobicyclo[4.2.0]octane-1(6),2,4-triene (1.9 g, 10.44 mmol) and sealed, heated at 100° C. and stirred for 16 hours. After the reaction was completed, the mixed reaction solution was concentrated under reduced pressure and purified by silica gel (petroleum depot/ethyl acetate=20/1) to obtain a crude product. The crude product was then purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 min; detection wavelength: 254 nm). At 70% B, fractions containing the product were collected and concentrated under reduced pressure to give tert-butyl bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate (1.3 g, 5.94 mmol, yield: 57.02%), LCMS m/z: 164 [M-56+H] +

5)、(5-溴双环[4.2.0]辛-1(6)，2，4-三烯-2-基)氨基甲酸叔丁酯的合成

Figure PCTCN2024113428-ftappb-I100200
5) Synthesis of tert-butyl (5-bromobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamate
Figure PCTCN2024113428-ftappb-I100200

在室温下，向溶有二环[4.2.0]辛-1(6)，2，4-三烯-2-基氨基甲酸叔丁基酯(1.33g，6.07mmol)的乙腈(20mL)溶液中，加入N-溴代丁二酰亚胺(1.08g，6.07mmol)，室温搅拌20小时。LCMS显示反应完成。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯＝10/1)纯化得到(5-溴双环[4.2.0]辛-1(6)，2，4-三烯-2-基)氨基甲酸叔丁酯(1.7g，5.70mmol，收率：94.44％)，LCMS m/z：298[M+H]+ At room temperature, N-bromosuccinimide (1.08 g, 6.07 mmol) was added to a solution of tert-butyl bicyclo[4.2.0]oct-1(6),2,4-triene-2-ylcarbamate (1.33 g, 6.07 mmol) in acetonitrile (20 mL), and stirred at room temperature for 20 hours. LCMS showed that the reaction was complete. The resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1) to give tert-butyl (5-bromobicyclo[4.2.0]octan-1(6),2,4-trien-2-yl)carbamate (1.7 g, 5.70 mmol, yield: 94.44%), LCMS m/z: 298 [M+H] +

6)、5-((叔丁氧羰基)氨基)双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯的合成

Figure PCTCN2024113428-ftappb-I100201
6) Synthesis of ethyl 5-((tert-butyloxycarbonyl)amino)bicyclo[4.2.0]oct-1(6),2,4-triene-2-carboxylate
Figure PCTCN2024113428-ftappb-I100201

在室温下，向溶有(5-溴双环[4.2.0]辛-1(6)，2，4-三烯-2-基)氨基甲酸叔丁酯(1.7g，5.70mmol)的乙醇(20mL)溶液中，加入乙酸钾(1.68g，17.11mmol)，Pd(dppf)Cl2(462mg，0.57mmol)，一氧化氛围下，加热80℃搅拌20小时。LCMS显示反应完成。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯＝10/1)纯化得到5-((叔丁氧羰基)氨基)双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯(1.3g，4.47mmol，收率：78.31％)，LCMS m/z：236[M-56+H]+ At room temperature, potassium acetate (1.68 g, 17.11 mmol) and Pd(dppf)Cl 2 (462 mg, 0.57 mmol) were added to a solution of tert-butyl (5-bromobicyclo[4.2.0]octan-1(6),2,4-trien-2-yl)carbamate (1.7 g, 5.70 mmol) in ethanol (20 mL). The mixture was heated at 80°C and stirred for 20 hours under an oxidizing atmosphere. LCMS showed that the reaction was complete. The resulting mixed reaction liquid was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1) to give ethyl 5-((tert-butoxycarbonyl)amino)bicyclo[4.2.0]oct-1(6),2,4-triene-2-carboxylate (1.3 g, 4.47 mmol, yield: 78.31%), LCMS m/z: 236 [M-56+H] +

7)、5-氨基双环[4.2.0]八-1(6)，2，4-三烯-2-羧酸乙酯的合成

Figure PCTCN2024113428-ftappb-I100202
7) Synthesis of ethyl 5-aminobicyclo[4.2.0]octa-1(6),2,4-triene-2-carboxylate
Figure PCTCN2024113428-ftappb-I100202

在室温下，向溶有5-((叔丁氧羰基)氨基)双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯(1.3g，4.46mmol)的二氯甲烷(10mL)溶液中，加入2，2，2-三氟乙酸(3mL)，室温搅拌3小时。LCMS显示反应完成。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到5-氨基双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯(850mg，4.46mmol，收率：99.64％)，LCMS m/z：192[M+H]+ At room temperature, 2,2,2-trifluoroacetic acid (3 mL) was added to a solution of 5-((tert-butyloxycarbonyl)amino)bicyclo[4.2.0]octane-1(6),2,4-triene-2-carboxylic acid ethyl ester (1.3 g, 4.46 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete. The resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-aminobicyclo[4.2.0]octane-1(6),2,4-triene-2-carboxylic acid ethyl ester (850 mg, 4.46 mmol, yield: 99.64%), LCMS m/z: 192 [M+H] +

8)、5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯的合成

Figure PCTCN2024113428-ftappb-I100203
8) Synthesis of ethyl 5-chlorobicyclo[4.2.0]octane-1(6),2,4-triene-2-carboxylate
Figure PCTCN2024113428-ftappb-I100203

在室温下，向溶有5-氨基双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯(800mg，4.19mmol)的乙腈(20mL)溶液中，加入亚硝酸叔丁酯(4.3g，41.89mmol)，氯化亚铜(4.1g，41.89mmol)，室温搅拌16小时。TLC(石油醚：乙酸乙酯＝10：1，Rf＝0.52nm)显示反应完成。将混合反应液倒入水(200mL)中，并用乙酸乙酯(100mL×3)萃取。合并的有机相用饱和碳酸氢钠(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝10/1)纯化的得到5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯(430mg，2.04mmol，收率：48.69％)，LCMS m/z：211[M+H]+ At room temperature, tert-butyl nitrite (4.3 g, 41.89 mmol) and cuprous chloride (4.1 g, 41.89 mmol) were added to a solution of 5-aminobicyclo[4.2.0]octan-1(6),2,4-triene-2-carboxylic acid ethyl ester (800 mg, 4.19 mmol) in acetonitrile (20 mL), and the mixture was stirred at room temperature for 16 hours. TLC (petroleum ether:ethyl acetate = 10:1, R f = 0.52 nm) showed that the reaction was complete. The mixed reaction solution was poured into water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 5-chlorobicyclo[4.2.0]octan-1(6),2,4-triene-2-carboxylic acid ethyl ester (430 mg, 2.04 mmol, yield: 48.69%), LCMS m/z: 211 [M+H] +

9)、1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-2-苯基乙烷-1-酮的合成

Figure PCTCN2024113428-ftappb-I100204
9) Synthesis of 1-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-2-phenylethane-1-one
Figure PCTCN2024113428-ftappb-I100204

在室温下，向溶有5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-羧酸乙酯(430mg，2.04mmol)的N，N-二甲基甲酰胺(10mL)溶液，中加入2-苯基乙酸(277mg，2.04mmol)，LiHMDS(1.0M 6.1mL，6.12mmol)，0℃至室温搅拌3小时。TLC显示反应完成。将混合反应液倒入水(200mL)中，并用乙酸乙酯(100mL×3)萃取。合并的有机相用饱和碳酸氢钠(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝10/1)纯化得到1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-2-苯基乙烷-1-酮(400mg，1.56mmol，收率：76.33％)，LCMS m/z：257[M+H]+ At room temperature, 2-phenylacetic acid (277 mg, 2.04 mmol) and LiHMDS (1.0 M 6.1 mL, 6.12 mmol) were added to a solution of 5-chlorobicyclo[4.2.0]octan-1(6),2,4-triene-2-carboxylic acid ethyl ester (430 mg, 2.04 mmol) in N,N-dimethylformamide (10 mL), and stirred at 0°C to room temperature for 3 hours. TLC showed that the reaction was complete. The mixed reaction solution was poured into water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 1-(5-chlorobicyclo[4.2.0]octan-1(6),2,4-trien-2-yl)-2-phenylethan-1-one (400 mg, 1.56 mmol, yield: 76.33%), LCMS m/z: 257 [M+H] +

10)、1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-3-羟基-2-苯基丙-1-酮的合成

Figure PCTCN2024113428-ftappb-I100205
10) Synthesis of 1-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-3-hydroxy-2-phenylpropan-1-one
Figure PCTCN2024113428-ftappb-I100205

向溶有1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-2-苯基乙烷-1-酮(500mg，1.9mmol)的四氢呋喃(20mL)溶液中，加入碳酸钾(790mg，5.7mmol)，多聚甲醛(1170mg，38.9mmol)，加热40℃搅拌5小时。将混合反应液过滤、减压浓缩得到1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-3-羟基-2-苯基丙-1-酮(500mg，粗品)，LCMS m/z：287[M+H]+。Potassium carbonate (790 mg, 5.7 mmol) and paraformaldehyde (1170 mg, 38.9 mmol) were added to a solution of 1-(5-chlorobicyclo[4.2.0]octan-1(6),2,4-trien-2-yl)-2-phenylethane-1-one (500 mg, 1.9 mmol) in tetrahydrofuran (20 mL), and the mixture was heated at 40°C and stirred for 5 hours. The mixed reaction liquid was filtered and concentrated under reduced pressure to obtain 1-(5-chlorobicyclo[4.2.0]octan-1(6),2,4-trien-2-yl)-3-hydroxy-2-phenylpropan-1-one (500 mg, crude product), LCMS m/z: 287 [M+H] + .

11)、1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-2-苯基丙-2-烯-1-酮的合成

Figure PCTCN2024113428-ftappb-I100206
11) Synthesis of 1-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-phenylprop-2-en-1-one
Figure PCTCN2024113428-ftappb-I100206

向溶有1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-3-羟基-2-苯基丙-1-酮(500mg，1.85mmol)的甲苯(10mL)溶液中，加入对甲苯磺酸(706mg，3.72mmol)，加热80℃搅拌3小时。LCMS显示反应完成。将所得混合反应液用饱和氯化铵(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯＝10/1)纯化得到1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-2-苯基丙-2-烯-1-酮(350mg，1.30mmol，收率：74.78％)，LCMS m/z：269[M+H]+ To a toluene (10 mL) solution of 1-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-3-hydroxy-2-phenylpropan-1-one (500 mg, 1.85 mmol) was added p-toluenesulfonic acid (706 mg, 3.72 mmol), and the mixture was heated at 80°C and stirred for 3 hours. LCMS showed that the reaction was complete. The resulting mixed reaction solution was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1) to give 1-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-phenylprop-2-en-1-one (350 mg, 1.30 mmol, yield: 74.78%), LCMS m/z: 269 [M+H] +

12)、3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑的合成

Figure PCTCN2024113428-ftappb-I100207
12) Synthesis of 3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole
Figure PCTCN2024113428-ftappb-I100207

在室温下，向溶有1-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-2-苯基丙-2-烯-1-酮(350mg，1.3mmol)的乙醇(5mL)溶液中，加入一水合肼(83mg，2.6mmol)，加热80℃搅拌3小时。LCMS显示反应完成。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝5/1)纯化得到3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑(310mg，1.09mmol，收率：84.24％)，LCMS m/z：283[M+H]+.At room temperature, add hydrazine monohydrate (83 mg, 2.6 mmol) to a solution of 1-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-2-phenylprop-2-ene-1-one (350 mg, 1.3 mmol) in ethanol (5 mL), heat to 80°C and stir for 3 hours. LCMS shows that the reaction is complete. The resulting mixed reaction solution is diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases are washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give 3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole (310 mg, 1.09 mmol, yield: 84.24%), LCMS m/z: 283 [M+H] + .

13)、3-(5-氯双环[4.2.0]八-1(6)，2，4-三烯-2-基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成

Figure PCTCN2024113428-ftappb-I100208
13) Synthesis of 3-(5-chlorobicyclo[4.2.0]octa-1(6),2,4-triene-2-yl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
Figure PCTCN2024113428-ftappb-I100208

在室温下，向溶有3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑(300mg，1.06mmol)的甲苯(5mL)溶液中，加入(4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(301mg，1.06mmol)，加热110℃搅拌3小时。LCMS显示反应完成。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯＝5/1)纯化得到3-(5-氯双环[4.2.0]八-1(6)，2，4-三烯-2-基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(100mg，0.19mmol，收率：17.60％)，LCMS m/z：534[M+H]+ At room temperature, to a solution of 3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-triene-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole (300 mg, 1.06 mmol) in toluene (5 mL), add methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (301 mg, 1.06 mmol), and heat to 110°C with stirring for 3 hours. LCMS showed that the reaction was complete. The resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1) to give 3-(5-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (100 mg, 0.19 mmol, yield: 17.60%), LCMS m/z: 534 [M+H] +

14)、(Z)-1-((3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲氨基)吡啶-1-鎓的合成

Figure PCTCN2024113428-ftappb-I100209
14) Synthesis of (Z)-1-((3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium
Figure PCTCN2024113428-ftappb-I100209

在室温下，向溶有3-(5-氯双环[4.2.0]八-1(6)，2，4-三烯-2-基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(100mg，0.18mmol)的二氯甲烷(5mL)溶液中，加热4-二甲氨基吡啶(114mg，0.9mmol)，三氯氧磷(55mg，0.36mmol)，加热50℃搅拌2小时。反应完成后，将混合反应液减压浓缩，无需进一步纯化。LCMS m/z：638[M]+ At room temperature, 4-dimethylaminopyridine (114 mg, 0.9 mmol) and phosphorus oxychloride (55 mg, 0.36 mmol) were added to a solution of 3-(5-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (100 mg, 0.18 mmol) in dichloromethane (5 mL), and the mixture was heated at 50°C and stirred for 2 hours. After the reaction was completed, the mixed reaction solution was concentrated under reduced pressure without further purification. LCMS m/z: 638[M] +

15)、N-((E)-N′-(Z)-(3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺的合成

Figure PCTCN2024113428-ftappb-I100210
15) Synthesis of N-((E)-N′-(Z)-(3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethyliminoyl)acetamide
Figure PCTCN2024113428-ftappb-I100210

向溶有(Z)-1-((3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲氨基)吡啶-1-鎓(100mg，0.15mmol)的N，N- 二甲基甲酰胺(3mL)溶液中，加入N-氨基甲亚胺酰基乙酰胺(76mg，0.75mmol)，三乙胺(75mg，0.75mmol)，室温搅拌2小时。将混合反应液减压浓缩并通过反相快速色柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15min；检测波长：254nm)。在80％B下，收集含有产物的级分，减压浓缩得到N-((E)-N′-(Z)-(3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(38mg，0.062mmol，收率：39.3％)，LCMS m/z：617[M+H]+ To a solution of (Z)-1-((3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (100 mg, 0.15 mmol) was added N,N- N-aminomethylimide acetamide (76 mg, 0.75 mmol) and triethylamine (75 mg, 0.75 mmol) were added to the dimethylformamide (3 mL) solution and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and passed through reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 min; detection wavelength: 254 nm). At 80% B, fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide (38 mg, 0.062 mmol, yield: 39.3%), LCMS m/z: 617 [M+H] +

16)、MDR-001-301-1和MDR-001-301-2的制备

Figure PCTCN2024113428-ftappb-I100211
16) Preparation of MDR-001-301-1 and MDR-001-301-2
Figure PCTCN2024113428-ftappb-I100211

将化合物N-((E)-N′-(Z)-(3-(5-氯双环[4.2.0]辛-1(6)，2，4-三烯-2-基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(38mg，0.062mmol)通过超临界流体色谱(色普条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100212
柱尺寸：250*25mm 10μm；流动相A；超临界CO2流动相B：IPA(+0.1％7.0mol/l氨/甲醇)，A：B＝75：25；波长：214nm；流量：120mL/min柱温：RT；柱压：100bar，进样量：5.0mL；循环时间：4.49min)制备得到两种异构体：MDR-001-301-1和MDR-001-301-2：Compound N-((E)-N′-(Z)-(3-(5-chlorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminocarbamoyl)acetamide (38 mg, 0.062 mmol) was purified by supercritical fluid chromatography (chromatography conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100212
Column size: 250*25mm 10μm; mobile phase A; supercritical CO 2 mobile phase B: IPA (+0.1% 7.0mol/l ammonia/methanol), A:B=75:25; wavelength: 214nm; flow rate: 120mL/min column temperature: RT; column pressure: 100bar, injection volume: 5.0mL; cycle time: 4.49min) to prepare two isomers: MDR-001-301-1 and MDR-001-301-2:

MDR-001-301-1：峰1：chiralHPLC：1.467min，(11.13mg，0.018mmol，收率：29.28％)，LCMS：m/z：617.3[M+H]+。MDR-001-301-1: Peak 1: chiralHPLC: 1.467 min, (11.13 mg, 0.018 mmol, yield: 29.28%), LCMS: m/z: 617.3 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.56(s，1H)，8.01(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.36-7.30(m，2H)，7.28-7.21(m，3H)，7.13(s，2H)，5.02-4.87(m，1H)，4.44(t，J＝11.6Hz，1H)，3.86-3.77(m，1H)，3.13-3.04(m，3H)，2.96-2.81(m，1H)，2.08(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.56 (s, 1H), 8.01 (d, J=8.0Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.36-7.30 (m, 2H), 7.28-7.21 (m, 3H), 7.13 (s, 2H), 5.02-4.87 (m, 1H), 4.44 (t, J=11.6Hz, 1H), 3.86-3.77 (m, 1H), 3.13-3.04 (m, 3H), 2.96-2.81 (m, 1H), 2.08 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ61.297.

MDR-001-301-2：峰2：chiral HPLC：2.143min；(15.43mg，0.025mmol，收率：40.60％)，LCMS m/z：617[M+H]+。MDR-001-301-2: Peak 2: chiral HPLC: 2.143 min; (15.43 mg, 0.025 mmol, yield: 40.60%), LCMS m/z: 617 [M+H]+.

1H NMR(400MHz，DMSO-d6)δ10.56(s，1H)，8.01(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.36-7.30(m，2H)，7.28-7.21(m，3H)，7.13(s，2H)，5.02-4.87(m，1H)，4.44(t，J＝11.6Hz，1H)，3.86-3.77(m，1H)，3.13-3.04(m，3H)，2.96-2.81(m，1H)，2.08(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.56 (s, 1H), 8.01 (d, J=8.0Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.36-7.30 (m, 2H), 7.28-7.21 (m, 3H), 7.13 (s, 2H), 5.02-4.87 (m, 1H), 4.44 (t, J=11.6Hz, 1H), 3.86-3.77 (m, 1H), 3.13-3.04 (m, 3H), 2.96-2.81 (m, 1H), 2.08 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.297.

实施例6、N-((E)-N′-((Z)-((S)3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体和N-((E)-N′- ((Z)-((R)3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体(MDR-001-302-1和MDR-001-302-2)的合成：Example 6, N-((E)-N′-((Z)-((S)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer and N-((E)-N′- Synthesis of ((Z)-((R)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomers (MDR-001-302-1 and MDR-001-302-2):

1)、1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮的合成报告

Figure PCTCN2024113428-ftappb-I100213
1) Synthesis report of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one
Figure PCTCN2024113428-ftappb-I100213

在0℃下，向溶有4-氯苯甲酸甲酯(5.00g，29.24mmol)和2-(噻吩-2-基)乙酸(4.15g，29.24mmol)的N，N二甲基甲酰胺(100mL)溶液中，加入双三甲基硅基胺基锂(1M的四氢呋喃溶液，91mL，90.64mmol)，室温搅拌1小时。将混合反应液用饱和氯化铵水溶液(20mL)淬灭，并用乙酸乙酯(200mL)萃取。合并的有机相用饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝20/1)纯化得到1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(6.31g，26.62mmol，收率：91.18％)，1.962min.LCMS m/z：237[M+H]+.At 0°C, lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 91 mL, 90.64 mmol) was added to a solution of methyl 4-chlorobenzoate (5.00 g, 29.24 mmol) and 2-(thiophene-2-yl)acetic acid (4.15 g, 29.24 mmol) in N,N-dimethylformamide (100 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (6.31 g, 26.62 mmol, yield: 91.18%), 1.962 min. LCMS m/z: 237 [M+H] + .

2)、4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸乙酯化合物的合成

Figure PCTCN2024113428-ftappb-I100214
2) Synthesis of ethyl 4-(4-chlorophenyl)-4-oxo-3-(thiophene-2-yl)butanoate
Figure PCTCN2024113428-ftappb-I100214

在0℃下，向溶有1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(5.00g，21.10mmol)的二甲亚砜(100mL)溶液中，加入氢化钠(60％，w/w矿物油分散体，928mg，23.21mmol)，0℃搅拌拌1小时，然后在0℃下加入溴乙酸乙酯(3.88g，23.21mmol)，室温搅拌1小时。将混合反应液用饱和氯化铵水溶液(10mL)淬灭，并用乙酸乙酯(200mL)萃取。合并有机相用饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝20/1)纯化得到化合物4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸乙酯(5.20g，16.10mmol，收率：76.35％)，LCMS m/z：323[M+H]+.At 0°C, sodium hydride (60%, w/w mineral oil dispersion, 928 mg, 23.21 mmol) was added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (5.00 g, 21.10 mmol) in dimethyl sulfoxide (100 mL), stirred at 0°C for 1 hour, then ethyl bromoacetate (3.88 g, 23.21 mmol) was added at 0°C, and stirred at room temperature for 1 hour. The mixed reaction liquid was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1) to give compound 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoic acid ethyl ester (5.20 g, 16.10 mmol, yield: 76.35%), LCMS m/z: 323 [M+H] + .

3)、4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸的合成

Figure PCTCN2024113428-ftappb-I100215
3) Synthesis of 4-(4-chlorophenyl)-4-oxo-3-(thiophene-2-yl)butyric acid
Figure PCTCN2024113428-ftappb-I100215

在室温下，向溶有4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸乙酯(5.00g，15.48mmol)的四氢呋喃(100mL)，水(50mL)和乙醇(50mL)溶液中，加入氢氧化锂(1.86g，77.40mmol)，室温搅拌1小时。将混合反应液用盐酸(1M)调节pH至4-5，并用乙酸乙酯(200mL)稀释。合并的有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到化合物4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸(4.51g，15.29mmol，收率：98.90％)，LCMS m/z：295[M+H]+.At room temperature, lithium hydroxide (1.86 g, 77.40 mmol) was added to a solution of ethyl 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoate (5.00 g, 15.48 mmol) in tetrahydrofuran (100 mL), water (50 mL) and ethanol (50 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was adjusted to pH 4-5 with hydrochloric acid (1 M) and diluted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butanoic acid (4.51 g, 15.29 mmol, yield: 98.90%), LCMS m/z: 295 [M+H] + .

4)、6-(4-氯苯基)-5-(噻吩-2-基)-4，5-二氢哒嗪-3(2H)-酮的合成

Figure PCTCN2024113428-ftappb-I100216
4) Synthesis of 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazine-3(2H)-one
Figure PCTCN2024113428-ftappb-I100216

在室温下，向溶有4-(4-氯苯基)-4-氧代-3-(噻吩-2-基)丁酸(4.00g，13.56mmol)的乙醇(50mL)溶液中，加入水合肼(651mg，20.34mmol)，加热80℃搅拌2小时。将混合反应液过滤，滤饼用冰乙醇(10mL)洗涤，干燥，得到化合物6-(4-氯苯基)-5-(噻吩-2-基)-4，5-二氢哒嗪-3(2H)-酮(2.66g，9.14 mmol，收率：67.51％)，LCMS m/z：291[M+H]+.At room temperature, hydrazine hydrate (651 mg, 20.34 mmol) was added to a solution of 4-(4-chlorophenyl)-4-oxo-3-(thiophen-2-yl)butyric acid (4.00 g, 13.56 mmol) in ethanol (50 mL), and the mixture was heated at 80°C and stirred for 2 hours. The mixed reaction liquid was filtered, and the filter cake was washed with ice ethanol (10 mL) and dried to obtain compound 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazin-3(2H)-one (2.66 g, 9.14 mmol, yield: 67.51%), LCMS m/z: 291 [M+H] + .

5)、3-(4-氯苯基)-4-(噻吩-2-基)-1，4，5，6-四氢哒嗪的合成

Figure PCTCN2024113428-ftappb-I100217
5) Synthesis of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine
Figure PCTCN2024113428-ftappb-I100217

在0℃下，向溶有6-(4-氯苯基)-5-(噻吩-2-基)-4，5-二氢哒嗪-3(2H)-酮(2.00g，6.88mmol)的四氢呋喃(40mL)溶液中，加入硼烷(1M的四氢呋喃溶液，13.76mL，13.76mmol)，室温搅拌混合物2小时。在0℃下，将混合反应液用甲醇(40mL)淬灭，室温搅拌0.5小时，将混合反应液减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝2/1)纯化得到化合物3-(4-氯苯基)-4-(噻吩-2-基)-1，4，5，6-四氢哒嗪(1.05g，3.79mmol，收率：55.26％)，LCMS m/z：277[M+H]+.At 0°C, borane (1M tetrahydrofuran solution, 13.76 mL, 13.76 mmol) was added to a solution of 6-(4-chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydropyridazine-3(2H)-one (2.00 g, 6.88 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours. At 0°C, the mixed reaction solution was quenched with methanol (40 mL), stirred at room temperature for 0.5 hours, and the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give compound 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine (1.05 g, 3.79 mmol, yield: 55.26%), LCMS m/z: 277 [M+H] + .

6)、3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺的合成

Figure PCTCN2024113428-ftappb-I100218
6) Synthesis of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide
Figure PCTCN2024113428-ftappb-I100218

在室温条件下，向溶有(4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(1.18g，4.17mmol)的甲苯溶液(20mL)中，加入3-(4-氯苯基)-4-(噻吩-2-基)-1，4，5，6-四氢哒嗪(1.05g，3.79mmol)，加热110℃搅拌2小时。将混合反应液并通过硅胶柱色谱(石油醚/乙酸乙酯＝3/1)纯化得到化合物3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(2.08g，3.94mmol，收率：92.5％)。Rt：2.066min.LCMS：m/z：528[M+H]+.At room temperature, 3-(4-chlorophenyl)-4-(thiophen-2-yl)-1,4,5,6-tetrahydropyridazine (1.05 g, 3.79 mmol) was added to a toluene solution (20 mL) containing methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.18 g, 4.17 mmol), and the mixture was heated to 110°C and stirred for 2 hours. The mixed reaction solution was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (2.08 g, 3.94 mmol, yield: 92.5%). Rt: 2.066 min. LCMS: m/z: 528 [M+H] + .

7)、(Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成

Figure PCTCN2024113428-ftappb-I100219
7) Synthesis of (Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium
Figure PCTCN2024113428-ftappb-I100219

在室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(500mg，0.95mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(174mg，1.14mmol)和4-二甲氨基吡啶(580mg，4.75mmol)，加热50℃搅拌3小时。将混合反应液减压浓缩化合物(Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(598mg，粗品)，LCMS m/z：632[M+H]+.To a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (500 mg, 0.95 mmol) in dichloromethane (20 mL) was added phosphorus oxychloride (174 mg, 1.14 mmol) and 4-dimethylaminopyridine (580 mg, 4.75 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 3 hours. The mixed reaction solution was concentrated under reduced pressure to obtain compound (Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (598 mg, crude product), LCMS m/z: 632 [M+H] + .

8)、N-((E)-N′-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺的合成

Figure PCTCN2024113428-ftappb-I100220
8) Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide
Figure PCTCN2024113428-ftappb-I100220

在室温条件下，向溶有Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(598mg，0.94mmol)的N，N二甲基甲酰胺(10mL)溶液中，加入N-氨基甲脒基乙酰胺(949mg，9.40mmol)和N，N-二异丙基乙胺(1.21g，9.40mmol)，室温搅拌2小时。将混合反应液倒入水(10mL)中，并用乙酸乙酯(30mL)萃取。合并有机相用饱和食盐水(5mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过快速反相柱色谱(色谱柱：球形C18，20-40um，80g；流动相A：水(0.1％FA)；流动相B：乙腈；流速：65mL/min；梯度：12min内得到5％B-80％B；检测器：254nm)纯化。当流动相B达到73％时，收集含有产物的积分减压浓缩得到化合物N-((E)-N′-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺(200mg，0.33mmol，收率：34.66％)，LCMS m/z：611[M+H]+ At room temperature, N-aminocarboxamidinoacetamide (949 mg, 9.40 mmol) and N,N-diisopropylethylamine (1.21 g, 9.40 mmol) were added to a solution of Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (598 mg, 0.94 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (5 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic column: spherical C18, 20-40um, 80g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 65mL/min; gradient: 5%B-80%B in 12min; detector: 254nm). When mobile phase B reached 73%, the integral containing the product was collected and concentrated under reduced pressure to give compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (200mg, 0.33mmol, yield: 34.66%), LCMS m/z: 611[M+H] +

9)、N-((E)-N′-((Z)-((S)3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体和N-((E)-N′-((Z)-((R)3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体的分离：

Figure PCTCN2024113428-ftappb-I100221
9), separation of N-((E)-N′-((Z)-((S)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomers and N-((E)-N′-((Z)-((R)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomers:
Figure PCTCN2024113428-ftappb-I100221

将化合物N-((E)-N′-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺(80mg，0.13mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100222
色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：乙腈(+0.1％7.0M氨甲醇)，A：B＝65：45；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：8.0mL；循环时间：7.2min)纯化得到两个异构体：MDR-001-302-1和MDR-001-302-2。Compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (80 mg, 0.13 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100222
Chromatographic column size: 250*25mm 10μm; mobile phase A; supercritical CO2 ; mobile phase B: acetonitrile (+0.1% 7.0M ammonia methanol), A:B=65:45; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 7.2min) was purified to obtain two isomers: MDR-001-302-1 and MDR-001-302-2.

MDR-001-302-1：峰1：2.177min；N-((E)-N′-((Z)-((S)3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体(21.04mg，0.03mmol，收率：26.30％)，LCMS m/z：611[M+H]+.MDR-001-302-1: Peak 1: 2.177 min; N-((E)-N′-((Z)-((S)3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (21.04 mg, 0.03 mmol, yield: 26.30%), LCMS m/z: 611 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.04-8.02(m，2H)，7.86-7.84(m，2H)，7.61-7.59(m，2H)，7.40-7.39(m，1H)，7.34-7.32(m，2H)，6.92-6.90(m，1H)，6.77-6.76(m，1H)，4.68(s，1H)，4.36(d，J＝12.4Hz， 1H)，3.27-3.20(m，1H)，2.25-2.17(m，1H)，2.10(s，3H)，2.05-2.02(m，1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.66(s, 1H), 8.04-8.02(m, 2H), 7.86-7.84(m, 2H), 7.61-7.59(m, 2H), 7.40-7.39(m, 1H ), 7.34-7.32(m, 2H), 6.92-6.90(m, 1H), 6.77-6.76(m, 1H), 4.68(s, 1H), 4.36(d, J=12.4Hz, 1H), 3.27-3.20(m, 1H), 2.25-2.17(m, 1H), 2.10(s, 3H), 2.05-2.02(m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.293. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.293.

MDR-001-302-2：峰2：3.328min；N-((E)-N′-((Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映体(18.76mg，0.03mmol，收率：23.45％)，LCMS m/z：611[M+H]+ MDR-001-302-2: Peak 2: 3.328 min; N-((E)-N′-((Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (18.76 mg, 0.03 mmol, yield: 23.45%), LCMS m/z: 611 [M+H] +

1H NMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.04-8.02(m，2H)，7.86-7.84(m，2H)，7.61-7.59(m，2H)，7.40-7.32(m，1H)，7.34-7.32(m，2H)，6.92-6.90(m，1H)，6.77-6.76(m，1H)，4.68(s，1H)，4.36(d，J＝12.8Hz，1H)，3.27-3.20(m，1H)，2.25-2.19(m，1H)，2.10(s，3H)，2.05-2.02(m，1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.66(s, 1H), 8.04-8.02(m, 2H), 7.86-7.84(m, 2H), 7.61-7.59(m, 2H), 7.40-7.32(m, 1H), 7.34-7.32(m, 2H), 6.92-6.90(m, 1H ), 6.77-6.76 (m, 1H), 4.68 (s, 1H), 4.36 (d, J=12.8Hz, 1H), 3.27-3.20 (m, 1H), 2.25-2.19 (m, 1H), 2.10 (s, 3H), 2.05-2.02 (m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.297.

实施例7、N-((E)-N′-((Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或R-对映异构体(MDR-001-304-1和MDR-001-304-2)的合成：Example 7, Synthesis of N-((E)-N′-((Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or R-enantiomer (MDR-001-304-1 and MDR-001-304-2):

1)、1-(4-氯苯基)-2-(噻吩-2-基)丙-2-烯-1-酮的合成

Figure PCTCN2024113428-ftappb-I100223
1) Synthesis of 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one
Figure PCTCN2024113428-ftappb-I100223

室温条件下，向溶有1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(2.07g，8.73mmol)的干燥的四氢呋喃(40mL)溶液中，加入多聚甲醛(2.62g，87.30mmol)和碳酸钾(3.61g，26.19mmol)，加热40℃搅拌2小时。将混合反应液过滤、滤液用四氢呋喃(20mL)洗涤。收集滤液减压浓缩1-(4-氯苯基)-2-(噻吩-2-基)丙-2-烯-1-酮(2.17g，粗品)，用于下一步，无需进一步纯化，LCMS m/z：249[M+H]+ At room temperature, paraformaldehyde (2.62 g, 87.30 mmol) and potassium carbonate (3.61 g, 26.19 mmol) were added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (2.07 g, 8.73 mmol) in dry tetrahydrofuran (40 mL), and the mixture was heated at 40°C and stirred for 2 hours. The mixed reaction solution was filtered and the filtrate was washed with tetrahydrofuran (20 mL). The filtrate was collected and concentrated under reduced pressure to obtain 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one (2.17 g, crude product), which was used in the next step without further purification. LCMS m/z: 249 [M+H] +

2)、3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑的合成

Figure PCTCN2024113428-ftappb-I100224
2) Synthesis of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole
Figure PCTCN2024113428-ftappb-I100224

室温下，，向溶有1-(4-氯苯基)-2-(噻吩-2-基)丙-2-烯-1-酮(2.17g，8.71mmol)的四氢呋喃(5mL)溶液中，加入N2H4.H2O(2.23g，69.68mmol)，加热80℃搅拌4小时。将混合反应液减压浓缩。残余物通过硅胶(二氯甲烷/乙酸乙酯＝25/1)纯化得到3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(830mg，3.16mmol，收率：36.2％)，LCMS m/z：263[M+H]+.At room temperature, N 2 H 4 .H 2 O (2.23 g, 69.68 mmol) was added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)prop-2-en-1-one (2.17 g, 8.71 mmol) in tetrahydrofuran (5 mL), and the mixture was heated at 80°C and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel (dichloromethane/ethyl acetate = 25/1) to give 3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (830 mg, 3.16 mmol, yield: 36.2%), LCMS m/z: 263 [M+H] + .

3)、3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成

Figure PCTCN2024113428-ftappb-I100225
3) Synthesis of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
Figure PCTCN2024113428-ftappb-I100225

室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(830mg，3.16mmol)的甲苯(10mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸酯(894mg，3.16mmol)，加热110℃搅拌3小时。将混合反应液减压浓缩。残余物用异丙醇(50mL)打浆，过滤。收集固体真空干燥得到3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(1.15g，2.24mmol，收率：70.9％)，LCMS m/z：514[M+H]+ At room temperature, to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (830 mg, 3.16 mmol) in toluene (10 mL), ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (894 mg, 3.16 mmol) was added, and the mixture was heated to 110° C. and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was slurried with isopropanol (50 mL) and filtered. The collected solid was dried in vacuo to give 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.15 g, 2.24 mmol, yield: 70.9%), LCMS m/z: 514 [M+H] +

4)、(E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯的合成

Figure PCTCN2024113428-ftappb-I100226
4) Synthesis of (E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride
Figure PCTCN2024113428-ftappb-I100226

在室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(400mg，0.78mmol)的氯苯(8mL)溶液中，五氯化磷(649mg，3.12mmol)，加热140℃搅拌2小时。将混合反应液减压浓缩得到(E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(1.15g，粗品)，直接用于下一步，无需进一步纯化。LCMS m/z：532[M+H]+ Phosphorus pentachloride (649 mg, 3.12 mmol) was added to a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (400 mg, 0.78 mmol) in chlorobenzene (8 mL) at room temperature, and the mixture was heated to 140°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain (E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (1.15 g, crude product), which was used directly in the next step without further purification. LCMS m/z: 532 [M+H] +

5)、N-((E)-N′-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺的合成

Figure PCTCN2024113428-ftappb-I100227
5) Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide
Figure PCTCN2024113428-ftappb-I100227

在室温下，向(E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(415mg，0.78mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入N-氨基甲酰亚胺乙酰胺(158mg，1.56mmol)，室温搅拌0.5小时，然后加入三乙胺(394mg，3.90mmol)，室温搅拌0.5小时。将混合反应液通过高效液相色谱(色谱条条件：Waters 2767/Qda，Sunfire C18，19×250×10um；流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：26％B-36％；保留时间：7.5-9.0min of 16 min)纯化得到化合物N-((E)-N′-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺(95mg，0.16mmol，收率：20.5％)，LCMS m/z：597[M+H]+.To a solution of (E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (415 mg, 0.78 mmol) in N,N-dimethylformamide (5 mL) at room temperature was added N-carbamidoacetamide (158 mg, 1.56 mmol), the mixture was stirred at room temperature for 0.5 hour, and then triethylamine (394 mg, 3.90 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. The mixed reaction solution was purified by high performance liquid chromatography (chromatographic strip conditions: Waters 2767/Qda, Sunfire C18, 19×250×10um; mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 26% B-36%; retention time: 7.5-9.0 min of 16 min) to obtain compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (95 mg, 0.16 mmol, yield: 20.5%), LCMS m/z: 597 [M+H] + .

6)、N-((E)-N′-((Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或R-对映异构体的制备

Figure PCTCN2024113428-ftappb-I100228
6) Preparation of N-((E)-N′-((Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or R-enantiomer
Figure PCTCN2024113428-ftappb-I100228

将N-((E)-N′-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基(((4-(三氟甲基)苯基)磺酰基)亚氨)甲基)氨基甲酰亚胺基)乙酰胺(95mg，0.15mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；柱：

Figure PCTCN2024113428-ftappb-I100229
250*30mm 10μm；流动相A：超临界CO2；流动相B：异丙醇，A：B＝60：40；检测波长：214nm；流速：120mL/min；柱温：RT；柱压：100bar，进样量：8mL；循环时间：6.5min)纯化得到两个异构体：MDR-001-304-1和MDR-001-304-2：N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoimido)acetamide (95 mg, 0.15 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column:
Figure PCTCN2024113428-ftappb-I100229
250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol, A:B=60:40; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar, injection volume: 8mL; cycle time: 6.5min) was purified to obtain two isomers: MDR-001-304-1 and MDR-001-304-2:

MDR-001-304-1 Chiral HPLC：1.444min；N-((E)-N′-((Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体(33.92mg，0.06mmol，收率：35.7％)，LCMS m/z：597[M+H]+.MDR-001-304-1 Chiral HPLC: 1.444 min; N-((E)-N′-((Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (33.92 mg, 0.06 mmol, yield: 35.7%), LCMS m/z: 597 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.01(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.58(d，J＝8.4Hz，2H)，7.45-7.40(m，3H)，6.98-6.93(m，2H)，5.42-5.38(m，1H)，4.45(t，J＝11.6Hz，1H)，3.97-3.93(m，1H)，2.07(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.53 (s, 1H), 8.01 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.4Hz, 2H), 7.45-7.40 (m, 3H), 6.98-6.93(m, 2H), 5.42-5.38(m, 1H), 4.45(t, J=11.6Hz, 1H), 3.97-3.93(m, 1H), 2.07(s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.312. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.312.

MDR-001-304-2：Chiral HPLC：2.297min.N-((E)-N′-((Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰基)乙酰胺或对映异构体(35.97mg，0.06mmol，收率：37.86％)，LCMS m/z：597[M+H]+.MDR-001-304-2: Chiral HPLC: 2.297 min. N-((E)-N′-((Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (35.97 mg, 0.06 mmol, yield: 37.86%), LCMS m/z: 597 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.01(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.58(d，J＝8.8Hz，2H)，7.45-7.40(m，3H)，6.98-6.93(m，2H)，5.42-5.38(m，1H)，4.45(t，J＝11.6Hz，1H)，3.97-3.93(m，1H)，2.07(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.53 (s, 1H), 8.01 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.8Hz, 2H), 7.45-7.40 (m, 3H), 6.98-6.93(m, 2H), 5.42-5.38(m, 1H), 4.45(t, J=11.6Hz, 1H), 3.97-3.93(m, 1H), 2.07(s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.312. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.312.

实施例8、(S，Z)-3-(4-氯苯基)-N-(4，8-二氧-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或其对映体(MRANK-111-012A-1和MRANK-111-012A-2)的合成：Example 8. Synthesis of (S,Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or its enantiomers (MRANK-111-012A-1 and MRANK-111-012A-2):

1)、1-((N-(叔丁氧羰基)氨基甲酰)氨基甲酰基)环丙烷-1-羧酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100230
1) Synthesis of methyl 1-((N-(tert-butyloxycarbonyl)carbamoyl)carbamoyl)cyclopropane-1-carboxylate
Figure PCTCN2024113428-ftappb-I100230

在-20℃下，向溶有1-(甲氧羰基)环丙烷-1-羧酸(500mg，3.47mmol)，氨基甲酰氨基甲酸叔丁酯(608mg，3.82mmol)和HATU(1.98g，5.20mmol)的DMF(20mL)溶液中，加入DIEA(448mg，3.47mmol)，-20℃继续搅拌3小时。将混合物用EtOAc(100mL)稀释，并用饱和食盐水(100mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱层析纯化(条件如下：柱：球形C18，20-40um，120g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：30min内5％B-50％B；检测器：214nm)纯化，在40％B下，收集含有产物的级分，减压浓缩和冻干得到1-((N-(叔丁氧羰基)氨基甲酰)氨基甲酰基)环丙烷-1-羧酸甲酯(500mg，1.86mmol，50.3％)，LCMS m/z：286.2[M+H]+ To a solution of 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (500 mg, 3.47 mmol), tert-butyl carbamoylcarbamate (608 mg, 3.82 mmol) and HATU (1.98 g, 5.20 mmol) in DMF (20 mL) was added DIEA (448 mg, 3.47 mmol) at -20°C, and stirring was continued for 3 hours at -20°C. The mixture was diluted with EtOAc (100 mL), washed with saturated brine (100 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40um, 120g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5% B-50% B in 30min; detector: 214nm), at 40% B, the fractions containing the product were collected, concentrated under reduced pressure and lyophilized to give 1-((N-(tert-butyloxycarbonyl)carbamoyl)carbamoyl)cyclopropane-1-carboxylic acid methyl ester (500mg, 1.86mmol, 50.3%), LCMS m/z: 286.2[M+H] +

2)、1-(氨基甲脒基氨基甲酰基)环丙烷-1-羧酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100231
2) Synthesis of 1-(aminocarbamidylaminoformyl)cyclopropane-1-carboxylic acid methyl ester
Figure PCTCN2024113428-ftappb-I100231

向1-((N-(叔丁氧羰基)氨基甲酰)氨基甲酰基)环丙烷-1-羧酸甲酯(500mg，1.86mmol)的DCM(5mL)溶液中，加入TFA(1mL)，室温搅拌1小时。将混合反应物减压浓缩得到To a solution of 1-((N-(tert-butyloxycarbonyl)carbamoyl)carbamoyl)cyclopropane-1-carboxylic acid methyl ester (500 mg, 1.86 mmol) in DCM (5 mL) was added TFA (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain

1-(氨基甲脒基氨基甲酰基)环丙烷-1-羧酸甲酯(300mg，粗品)，LCMS m/z：186.1[M+H]+.1-(Carbamidylcarbamoyl)cyclopropane-1-carboxylic acid methyl ester (300 mg, crude product), LCMS m/z: 186.1 [M+H] + .

3)、(Z)-3-(4-氯苯基)-N-(4，8-二氧代-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺的合成

Figure PCTCN2024113428-ftappb-I100232
3) Synthesis of (Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide
Figure PCTCN2024113428-ftappb-I100232

在-20℃下，向溶有(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(100mg，0.19mmol)，1-((N-(叔丁氧羰基)氨基甲酰)氨基甲酰基)环丙烷-1-羧酸甲酯(71mg，0.38mmol)的THF(5mL)溶液中，加入LiHMDS(0.58mL，0.58mmol)，-20℃，搅拌10分钟。将混合反应液通过反相快速柱色谱纯化(条件如下：柱：球形C18，20-40um，40g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：30分钟内5％B-50％B；检测器：214nm)。在60％B下，收集含有产物的级分，减压浓缩并冻干得到(Z)-3-(4-氯苯基)-N-(4，8-二氧代-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺(30mg，0.047mmol，收率：24.6％)，LCMS m/z：643.1[M+H]+.To a solution of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (100 mg, 0.19 mmol) and methyl 1-((N-(tert-butoxycarbonyl)carbamoyl)carbamoyl)cyclopropane-1-carboxylate (71 mg, 0.38 mmol) in THF (5 mL) was added LiHMDS (0.58 mL, 0.58 mmol) at -20°C and stirred at -20°C for 10 minutes. The mixed reaction solution was purified by reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40um, 40g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%B-50%B in 30 minutes; detector: 214nm). At 60%B, the fractions containing the product were collected, concentrated under reduced pressure and lyophilized to give (Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (30mg, 0.047mmol, yield: 24.6%), LCMS m/z: 643.1[M+H] + .

4)、(S，Z)-3-(4-氯苯基)-N-(4，8-二氧-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体和(R，Z)-3-(4-氯苯基)-N-(4，8-二氧-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体的合成

Figure PCTCN2024113428-ftappb-I100233
4), (S, Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer and (R, Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer synthesis
Figure PCTCN2024113428-ftappb-I100233

将化合物(Z)-3-(4-氯苯基)-N-(4，8-二氧代-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺(30mg，0.047mmol)通过超临界流体色谱纯化(条件：系统：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100234
柱尺寸：250*30mm 10μm；流动相A：超临界CO2；流动相B：甲醇(+0.1％7.0mol/l氨在甲醇中)，A：B＝85：15：检测波长：214nm；流量：140mL/min；柱温：RT；背压：100bar)纯化得到两个构型单一的异构体：MRANK-111-012A-1和MRANK-111-012A-2：Compound (Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (30 mg, 0.047 mmol) was purified by supercritical fluid chromatography (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100234
Column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: methanol (+0.1% 7.0mol/l ammonia in methanol), A:B=85:15: detection wavelength: 214nm; flow rate: 140mL/min; column temperature: RT; back pressure: 100bar) was purified to obtain two isomers with single configuration: MRANK-111-012A-1 and MRANK-111-012A-2:

MRANK-111-012A-1：峰1：Chiral HPLC：2.561min；(S，Z)-3-(4-氯苯基)-N-(4，8-二氧-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(9.21mg，0.014mmol，收率：30.7％)，LCMS m/z：643.1[M+H]+.MRANK-111-012A-1: Peak 1: Chiral HPLC: 2.561 min; (S, Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (9.21 mg, 0.014 mmol, yield: 30.7%), LCMS m/z: 643.1 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ11.76(s，2H)，8.02(d，J＝8.0Hz，2H)，7.85(d，J＝8.0Hz，2H)，7.54(d，J＝8.4Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.35-7.23(m，5H)，5.14-5.10(m，1H)，4.53(t，J＝12.0Hz，1H)，3.87-3.83(m，1H)，1.74(s，4H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.76 (s, 2H), 8.02 (d, J=8.0Hz, 2H), 7.85 (d, J=8.0Hz, 2H), 7.54 (d, J=8.4Hz, 2H), 7.40 (d, J=8.4H z, 2H), 7.35-7.23 (m, 5H), 5.14-5.10 (m, 1H), 4.53 (t, J=12.0Hz, 1H), 3.87-3.83 (m, 1H), 1.74 (s, 4H).

19F NMR(377MHz，DMSO-d6)：δ-61.36719F NMR (377MHz, DMSO-d 6 ): δ-61.367

MRANK-111-012A-2：峰2：Chiral HPLC：3.747min；(R，Z)-3-(4-氯苯基)-N-(4，8-二氧-5，7-二氮杂螺[2.5]辛-5-烯-6-基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(4.67mg，0.0072mmol，收率：15.3％)，LCMS m/z：643.1[M+H]+.MRANK-111-012A-2: Peak 2: Chiral HPLC: 3.747 min; (R, Z)-3-(4-chlorophenyl)-N-(4,8-dioxo-5,7-diazaspiro[2.5]oct-5-en-6-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (4.67 mg, 0.0072 mmol, yield: 15.3%), LCMS m/z: 643.1 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ11.76(s，2H)，8.02(d，J＝8.0Hz，2H)，7.85(d，J＝8.4Hz，2H)，7.54(d，J＝8.8Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.35-7.23(m，5H)，5.14-5.10(m，1H)，4.53(t，J＝12.0Hz，1H)，3.87-3.83(m，1H)，1.74(s，4H).1H NMR (400MHz, DMSO-d 6 ): δ11.76 (s, 2H), 8.02 (d, J=8.0Hz, 2H), 7.85 (d, J=8.4Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.40 (d, J=8.4H z, 2H), 7.35-7.23 (m, 5H), 5.14-5.10 (m, 1H), 4.53 (t, J=12.0Hz, 1H), 3.87-3.83 (m, 1H), 1.74 (s, 4H).

19F NMR(377MHz，DMSO-d6)：δ-61.36719F NMR (377MHz, DMSO-d 6 ): δ-61.367

实施例9、N-((E)-N′-((Z)-(3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(MDR-001-305A-1和MDR-001-305A-2)的合成：Example 9, Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide (MDR-001-305A-1 and MDR-001-305A-2):

1)、(E)-((1-(4-氯苯基)-2-苯基乙烯基)氧基)三甲基硅烷的合成

Figure PCTCN2024113428-ftappb-I100235
1) Synthesis of (E)-((1-(4-chlorophenyl)-2-phenylvinyl)oxy)trimethylsilane
Figure PCTCN2024113428-ftappb-I100235

在-78℃下，向溶有1-(4-氯苯基)-2-苯基乙烷-1-酮(1.0g，4.34mmol)的四氢呋喃(10mL)溶液中， 加入LDA(4.3mL，8.69mmol，2.0M)，-78℃搅拌1小时，然后加入TMSCl(938mg，8.69mmol)，-78℃搅拌3小时。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到(E)-((1-(4-氯苯基)-2-苯基乙烯基)氧基)三甲基硅烷(1.3g，粗品)，直接用于下一步，没有进行进一步纯化。At -78°C, add 1-(4-chlorophenyl)-2-phenylethan-1-one (1.0 g, 4.34 mmol) in tetrahydrofuran (10 mL). LDA (4.3 mL, 8.69 mmol, 2.0 M) was added, stirred at -78 ° C for 1 hour, then TMSCl (938 mg, 8.69 mmol) was added, and stirred at -78 ° C for 3 hours. The resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (E)-((1-(4-chlorophenyl)-2-phenylvinyl)oxy)trimethylsilane (1.3 g, crude product), which was used directly in the next step without further purification.

2)、1-(4-氯苯基)-3-甲氧基-3-甲基-2-苯基丁-1-酮的合成

Figure PCTCN2024113428-ftappb-I100236
2) Synthesis of 1-(4-chlorophenyl)-3-methoxy-3-methyl-2-phenylbutan-1-one
Figure PCTCN2024113428-ftappb-I100236

在78℃下，向溶有(E)-((1-(4-氯苯基)-2-苯基乙烯基)氧基)三甲基硅烷(600mg，1.98mmol)的二氯甲烷(10mL)溶液中，加入2，2-二甲氧基丙烷(411mg，3.96mmol)TiCl4(2.97mL，2.97mmol，1.0M)，-78℃搅拌3小时。将所得混合物用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15min；检测器：254nm)纯化。当流动相达到90％B时，收集含有所需产物的级分，并在减压下浓缩，得到白色固体产物1-(4-氯苯基)-3-甲氧基-3-甲基-2-苯基丁-1-酮(130mg，0.42mmol，收率：21.66％)，LCMS m/z：303[M+H]+。At 78°C, 2,2-dimethoxypropane (411 mg, 3.96 mmol) and TiCl 4 (2.97 mL, 2.97 mmol, 1.0 M) were added to a solution of (E)-((1-(4-chlorophenyl)-2-phenylvinyl)oxy)trimethylsilane (600 mg, 1.98 mmol) in dichloromethane (10 mL), and the mixture was stirred at -78°C for 3 hours. The resulting mixture was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 min; detector: 254 nm). When the mobile phase reached 90% B, the fractions containing the desired product were collected and concentrated under reduced pressure to give a white solid product 1-(4-chlorophenyl)-3-methoxy-3-methyl-2-phenylbutan-1-one (130 mg, 0.42 mmol, yield: 21.66%), LCMS m/z: 303 [M+H] + .

3)、1-(4-氯苯基)-3-甲基-2-苯基丁-2-烯-1-酮的合成

Figure PCTCN2024113428-ftappb-I100237
3) Synthesis of 1-(4-chlorophenyl)-3-methyl-2-phenylbut-2-ene-1-one
Figure PCTCN2024113428-ftappb-I100237

向溶有1-(4-氯苯基)-3-甲氧基-3-甲基-2-苯基丁-1-酮(200mg，0.66mmol)的甲醇(5mL)溶液中，加入氢氧化钠(128mg，3.3mmol)，加热50℃搅拌16小时。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到1-(4-氯苯基)-3-甲基-2-苯基丁-2-烯-1-酮(200mg，粗品)，直接用于下一步骤，不进行进一步纯化。LCMS m/z/：271[M+H]+ Sodium hydroxide (128 mg, 3.3 mmol) was added to a methanol (5 mL) solution containing 1-(4-chlorophenyl)-3-methoxy-3-methyl-2-phenylbutan-1-one (200 mg, 0.66 mmol), and the mixture was heated at 50°C and stirred for 16 hours. The resulting mixed reaction solution was diluted with a saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-chlorophenyl)-3-methyl-2-phenylbut-2-ene-1-one (200 mg, crude product), which was used directly in the next step without further purification. LCMS m/z/: 271[M+H] +

4)、3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑的合成

Figure PCTCN2024113428-ftappb-I100238
4) Synthesis of 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazole
Figure PCTCN2024113428-ftappb-I100238

向1-(4-氯苯基)-3-甲基-2-苯基丁-2-烯-1-酮(200mg，0.73mmol)的乙醇(5mL)溶液中，加入NH2NH2.H2O(35mg，0.80mmol)，加热80℃搅拌2小时。将所得混合反应液用饱和氯化铵水溶液(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩纯化得到3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑(200mg，粗品)，直接用于下一步骤，不进行进一步纯化。LCMS m/z：285[M+H]+。NH 2 NH 2 .H 2 O (35 mg, 0.80 mmol) was added to a solution of 1-(4-chlorophenyl)-3-methyl-2-phenylbut-2-en-1-one (200 mg, 0.73 mmol) in ethanol (5 mL), and the mixture was heated at 80°C and stirred for 2 hours. The resulting mixed reaction solution was diluted with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazole (200 mg, crude product), which was used directly in the next step without further purification. LCMS m/z: 285 [M+H] + .

5)、3-(4-氯苯基)-5，5-二甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成
5) Synthesis of 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑(200mg，0.70mmol)的甲苯(5mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(198mg，0.70mmol)，加热110℃搅拌4小时。将混合反应液减压浓缩并通过硅胶柱色谱法(石油醚/乙酸乙酯＝3/1)纯化得到3-(4-氯苯基)-5，5-二甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(270mg，0.50mmol，收率：71.81％)，LCMS m/z：536[M+H]+.At room temperature, methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (198 mg, 0.70 mmol) was added to a toluene (5 mL) solution of 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazole (200 mg, 0.70 mmol), and the mixture was heated to 110° C. and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (270 mg, 0.50 mmol, yield: 71.81%), LCMS m/z: 536[M+H] + .

6)、(Z)-1-((3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
6) Synthesis of (Z)-1-((3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)iminomethyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氯苯基)-5，5-二甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(270mg，0.50mmol)的二氯甲烷(10mL)溶液中，加入4-二甲基氨基吡啶(307mg，2.50mmol)，三氯氧磷(153mg，0.10mmol)，加热50℃搅拌3小时。将混合反应液减压浓缩(Z)-1-((3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基甲基)-4-(二甲基氨基)吡啶-1-鎓(300mg，粗品)，直接用于下一步骤，没有进一步纯化，LCMS m/z：641[M+H]+ To a solution of 3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (270 mg, 0.50 mmol) in dichloromethane (10 mL) was added 4-dimethylaminopyridine (307 mg, 2.50 mmol) and phosphorus oxychloride (153 mg, 0.10 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 3 hours. The mixed reaction solution was concentrated under reduced pressure. (Z)-1-((3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)iminomethyl)-4-(dimethylamino)pyridin-1-ium (300 mg, crude product) was used directly in the next step without further purification. LCMS m/z: 641 [M+H] +

7)、N-((E)-N′-((Z)-(3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺的合成
7) Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethyliminoyl)acetamide

在室温下，向溶有(Z)-1-((3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基甲基)-4-(二甲基氨基)吡啶-1-鎓(300mg，0.46mmol)的N，N-二甲基甲酰胺(3mL)溶液中，加入N-氨基甲亚胺酰基乙酰胺(94mg，0.93mmol)和三乙胺(139mg，1.38mmol)，室温搅拌2小时。将混合反应液减压浓缩并通过反相柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)纯化，在70％B下，收集含有的级分，减压下浓缩得到N-((E)-N′-((Z)-(3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(140mg，0.22mmol，收率：48.44％)，LCMS m/z：619[M+H]+ To a solution of (Z)-1-((3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)iminomethyl)-4-(dimethylamino)pyridin-1-ium (300 mg, 0.46 mmol) in N,N-dimethylformamide (3 mL) at room temperature were added N-aminomethylimidoyl acetamide (94 mg, 0.93 mmol) and triethylamine (139 mg, 1.38 mmol), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm). At 70%B, the fractions containing were collected and concentrated under reduced pressure to give N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide (140mg, 0.22mmol, yield: 48.44%), LCMS m/z: 619[M+H] +

8)、MDR-001-305A-1和MDR-001-305A-2的拆分：
8) Separation of MDR-001-305A-1 and MDR-001-305A-2:

化合物N-((E)-N′-((Z)-(3-(4-氯苯基)-5，5-二甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(140mg，0.22mmol)通过SFC纯化(色谱条件：体系：Waters SFC 150；柱名：柱尺寸：250*30mm 100μm；流动相A：超临界CO2流动相B：IPA(+0.1％7.0mol/L氨/甲醇)，A：B＝65：35；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar；进样量：8.0mL；循环时间：4.5分钟)得到两种异构体：MDR-001-305A-1和MDR-001-305A-2：Compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (140 mg, 0.22 mmol) was purified by SFC (chromatographic conditions: system: Waters SFC 150; column name: Column size: 250*30mm 100μm; mobile phase A: supercritical CO2 mobile phase B: IPA (+0.1% 7.0mol/L ammonia/methanol), A:B=65:35; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar; injection volume: 8.0mL; cycle time: 4.5 minutes) to obtain two isomers: MDR-001-305A-1 and MDR-001-305A-2:

MDR-001-305A-1：峰1：Chiral HPLC：0.565min：0.565min；化合物MDR-001-305A-1(64.11mg，0.10mmol，收率：45.79％)，LCMS m/z：619[M+H]+。MDR-001-305A-1: Peak 1: Chiral HPLC: 0.565 min: 0.565 min; Compound MDR-001-305A-1 (64.11 mg, 0.10 mmol, yield: 45.79%), LCMS m/z: 619 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.62(s，1H)，8.03-7.94(m，2H)，7.88-7.80(m，2H)，7.49-7.23(m，8H)，4.65(s，1H)，2.11(s，3H)，1.57(s，3H)，1.21(s，3H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.62 (s, 1H), 8.03-7.94 (m, 2H), 7.88-7.80 (m, 2H), 7.49-7.23 (m, 8H), 4.65 (s, 1H), 2.11 (s, 3H), 1.57 (s, 3H), 1.21 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.278. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.278.

MDR-001-305A-2：峰2：chiral HPLC：0.986min；化合物MDR-001-305A-2(73.26mg，0.11mmol，收率：收率：52.32％)，LCMS：m/z：619.3[m+H]+。MDR-001-305A-2: Peak 2: chiral HPLC: 0.986 min; compound MDR-001-305A-2 (73.26 mg, 0.11 mmol, yield: 52.32%), LCMS: m/z: 619.3 [m+H] + .

1H NMR(400MHz，DMSO-d6)δ10.62(s，1H)，8.03-7.94(m，2H)，7.88-7.80(m，2H)，7.49-7.23(m，8H)，4.65(s，1H)，2.11(s，3H)，1.57(s，3H)，1.29(s，3H)。 1 H NMR (400MHz, DMSO-d 6 )δ10.62 (s, 1H), 8.03-7.94 (m, 2H), 7.88-7.80 (m, 2H), 7.49-7.23 (m, 8H), 4.65 (s, 1H), 2.11 (s, 3H), 1.57 (s, 3H), 1.29 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.278. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.278.

实施例10、N-((E)-N′-(Z)-(4-(4-氯苯基)-3-苯基-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺(化合物401)的合成：Example 10. Synthesis of N-((E)-N′-(Z)-(4-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide (Compound 401):

1)、2-(4-氯苯基)-1-苯基乙烷-1-酮的合成
1) Synthesis of 2-(4-chlorophenyl)-1-phenylethane-1-one

在0℃下，向溶有苯甲酸甲酯(5.00g，36.76mmol)的N，N-二甲基甲酰胺(50mL)溶液中，加入2-(4-氯苯基)乙酸(6.29g，36.76mmol)，LiHMDS(1M的四氢呋喃溶液，114mL，113.96mmol)，室温搅拌1小时。将混合反应液用饱和氯化铵(100mL)淬灭，并用乙酸乙酯(150mL×2)萃取。合并有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到2-(4-氯苯基)-1-苯基乙烷-1-酮(7.85g，33.98mmol，收率：92.4％)，LCMS m/z：231[M+H]+。At 0°C, 2-(4-chlorophenyl)acetic acid (6.29 g, 36.76 mmol) and LiHMDS (1 M tetrahydrofuran solution, 114 mL, 113.96 mmol) were added to a solution of methyl benzoate (5.00 g, 36.76 mmol) in N,N-dimethylformamide (50 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (150 mL×2). The combined organic phases were washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(4-chlorophenyl)-1-phenylethane-1-one (7.85 g, 33.98 mmol, yield: 92.4%), LCMS m/z: 231[M+H] + .

2)、2-(4-氯苯基)-1-苯基丙基-2-烯-1-酮的合成
2) Synthesis of 2-(4-chlorophenyl)-1-phenylpropyl-2-ene-1-one

室温下，向溶有2-(4-氯苯基)-1-苯基乙烷-1-酮(3.00g，12.99mmol)的四氢呋喃(60mL)溶液中，加入多聚甲醛(3.90g，129.90mmol)，碳酸钾(5.38g，38.97mmol)，加热40℃搅拌16小时。将所得混合物过滤并减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝50/1)纯化得到2-(4-氯苯基)-1-苯基丙-2-烯-1-酮(1.50g，6.17mmol，收率：47.4％)。At room temperature, paraformaldehyde (3.90 g, 129.90 mmol) and potassium carbonate (5.38 g, 38.97 mmol) were added to a solution of 2-(4-chlorophenyl)-1-phenylethane-1-one (3.00 g, 12.99 mmol) in tetrahydrofuran (60 mL), and the mixture was heated at 40°C and stirred for 16 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1) to give 2-(4-chlorophenyl)-1-phenylprop-2-ene-1-one (1.50 g, 6.17 mmol, yield: 47.4%).

1H NMR(400MHz，DMSO-d6)δ7.84(d，J＝2，2H)，7.69-7.65(m，1H)，7.53(d，J＝5.6，2H)，7.46(s，4H)，6.27(s，1H)，5.67(s，1H). 1 H NMR (400MHz, DMSO-d6) δ7.84 (d, J=2, 2H), 7.69-7.65 (m, 1H), 7.53 (d, J=5.6, 2H), 7.46 (s, 4H), 6.27 (s, 1H), 5.67 (s, 1H).

3)、4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑的合成
3) Synthesis of 4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole

在室温下向溶有2-(4-氯苯基)-1-苯基丙-2-烯-1-酮(1.30g，5.35mmol)的乙醇(15mL)溶液中，加入水合肼(2.14g，42.80mmol)，加热80℃搅拌4小时。将所得混合反应液减压浓缩，得到4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑(1.04g，粗品)，LCMS m/z：298[M+41+H]+。To a solution of 2-(4-chlorophenyl)-1-phenylprop-2-en-1-one (1.30 g, 5.35 mmol) in ethanol (15 mL) was added hydrazine hydrate (2.14 g, 42.80 mmol) at room temperature, and the mixture was heated at 80°C and stirred for 4 hours. The resulting mixed reaction liquid was concentrated under reduced pressure to obtain 4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (1.04 g, crude product), LCMS m/z: 298 [M+41+H] + .

4)、4-(4-氯苯基)-3-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成
4) Synthesis of 4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑(840mg，3.27mmol)的甲苯(8mL)溶液中，加入(4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(925mg，3.27mmol)，加热110℃搅拌2小时。将混合反应液加水(10mL)淬灭，并用乙酸乙酯(10mL×2)萃取。合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝4/1)纯化得到4-(4-氯苯基)-3-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(868mg，1.71mmol，收率：52％)，LCMS m/z：508[M+H]+。At room temperature, add methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (925 mg, 3.27 mmol) to a solution of 4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (840 mg, 3.27 mmol) in toluene (8 mL), heat to 110°C and stir for 2 hours. The mixed reaction solution is quenched with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic phase is washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to give 4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (868 mg, 1.71 mmol, yield: 52%), LCMS m/z: 508 [M+H] + .

5)、(E)-4-(4-氯苯基)-3-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯的合成
5) Synthesis of (E)-4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride

在室温条件下，向溶有4-(4-氯苯基)-3-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(368mg，0.72mmol)的氯苯(10mL)溶液中，加入五氯化磷(285mg，1.37mmol)，氮气保护加热140℃搅拌2小时。将混合物反应液减压浓缩得到化合物(E)-4-(4-氯苯基)-3-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(381mg，粗品)，LCMS m/z：526[M+H]+。Phosphorus pentachloride (285 mg, 1.37 mmol) was added to a solution of 4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (368 mg, 0.72 mmol) in chlorobenzene (10 mL) at room temperature, and the mixture was heated at 140°C and stirred for 2 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain compound (E)-4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (381 mg, crude product), LCMS m/z: 526 [M+H] + .

6)、N-((E)-N′-(Z)-(4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺的合成
6) Synthesis of N-((E)-N′-(Z)-(4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide

在室温下，向溶有(E)-4-(4-氯苯基)-3-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(381mg，0.72mmol)的N，N-二甲基甲酰胺(4mL)溶液中，加入N-氨基甲酰亚胺乙酰胺(364mg，3.60mmol)，室温搅拌1小时。将混合反应液通过反相快速色谱法(色谱条件：柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20分钟内5％B-80％B；检测器：214nm)纯化，当流动相B含量达到74％收集含有产物的级分，减压得到化合物N-((E)-N′-(Z)-(4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(123mg，0.21mmol，收率：28.7％)，LCMS m/z：591[M+H]+。To a solution of (E)-4-(4-chlorophenyl)-3-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (381 mg, 0.72 mmol) in N,N-dimethylformamide (4 mL) was added N-carbamidoacetamide (364 mg, 3.60 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixed reaction liquid was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-80%B in 20 minutes; detector: 214nm). When the content of mobile phase B reached 74%, the fractions containing the product were collected and reduced pressure to give compound N-((E)-N′-(Z)-(4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (123mg, 0.21mmol, yield: 28.7%), LCMS m/z: 591[M+H] + .

7)、N-((E)-N′-(Z)-(4-(4-氯苯基)-3-苯基-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺的合成
7) Synthesis of N-((E)-N′-(Z)-(4-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide

在室温条件下，向溶有N-((E)-N’-((Z)-(4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(25mg，0.04mmol)的四氢呋喃(2mL)溶液中，加入硝酸铈铵(219mg，0.40mmol)，室温搅拌2小时。将混合反应液减压浓缩并通过反相快速柱色谱法(色谱条件：柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20分钟内5％B-80％B；检测器：214nm)纯化，当流动相B含量达到74％时，收集含有所需产物的级分，减压浓缩得到N-((E)-N′-(Z)-(4-(4-氯苯基)-3-苯基-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺(11.47mg，0.02mmol，收率：46.0％)LCMS m/z：589[M+H]+。To a solution of N-((E)-N'-((Z)-(4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (25 mg, 0.04 mmol) in tetrahydrofuran (2 mL) was added cerium ammonium nitrate (219 mg, 0.40 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixed reaction liquid was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-80% B in 20 minutes; detector: 214 nm). When the content of mobile phase B reached 74%, the fractions containing the desired product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(4-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide (11.47 mg, 0.02 mmol, yield: 46.0%) LCMS m/z: 589 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ11.19(s，1H)，8.91(s，2H)，8.43(s，1H)，8.10(d，J＝8.0，2H)，7.89(d，J＝8.4，2H)，7.43-7.28(m，9H)，2.08(s，3H). 1 H NMR (400MHz, DMSO-d6) δ 11.19 (s, 1H), 8.91 (s, 2H), 8.43 (s, 1H), 8.10 (d, J=8.0, 2H), 7.89 (d, J=8.4, 2H), 7.43-7.28 (m, 9H), 2.08 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.35，-73.72 19 F NMR (377MHz, DMSO-d6) δ-61.35, -73.72

实施例11、N-((E)-N′-(Z)-((S)4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或R-对映体(MDR-001-401A-1和MDR-001-401A-2)的分离制备：
Example 11, Separation and Preparation of N-((E)-N′-(Z)-((S)4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or R-enantiomer (MDR-001-401A-1 and MDR-001-401A-2):

将实施例10步骤6所得的N-((E)-N′-(Z)-(4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(98mg，0.166mmol)通过超临界流体制备色谱(条件：体系：Waters SFC 80；柱名：柱尺寸：250*25mm 10μm流动相A超临界CO2流动相B：IPA，A：B＝55：45波长：214nm流量：120mL/min柱温：室温，柱压：100bar，注射：4.0mL；循环时间：5.5分钟)纯化得到两种异构体：MDR-001-401A-1和MDR-001-401A-2：N-((E)-N′-(Z)-(4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (98 mg, 0.166 mmol) obtained in step 6 of Example 10 was purified by supercritical fluid preparative chromatography (conditions: system: Waters SFC 80; column name: Column size: 250*25mm 10μm mobile phase A supercritical CO 2 mobile phase B: IPA, A:B=55:45 wavelength: 214nm flow rate: 120mL/min column temperature: room temperature, column pressure: 100bar, injection: 4.0mL; cycle time: 5.5 minutes) purification to obtain two isomers: MDR-001-401A-1 and MDR-001-401A-2:

MDR-001-401A-1：峰1：chiral-HPLC：2.855min；N-((E)-N′-(Z)-((R)4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(26.56mg，0.045mmol，收率：27.1％)，LCMS：m/z：591[M+H]+。MDR-001-401A-1: Peak 1: chiral-HPLC: 2.855 min; N-((E)-N′-(Z)-((R)4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (26.56 mg, 0.045 mmol, yield: 27.1%), LCMS: m/z: 591 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.54(s，1H)，8.02(d，J＝8.4，2H)，7.83(d，J＝8.4，2H)，7.51(d，J＝5.2，2H)，7.39-7.30(m，7H)，5.10-5.06(m，1H)，4.48(t，J＝11.6，1H)，3.88-3.84(m，1H)，2.08(s，3H). 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.02 (d, J = 8.4, 2H), 7.83 (d, J = 8.4, 2H), 7.51 (d, J = 5.2, 2 H), 7.39-7.30 (m, 7H), 5.10-5.06 (m, 1H), 4.48 (t, J=11.6, 1H), 3.88-3.84 (m, 1H), 2.08 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.30 19 F NMR (377MHz, DMSO-d6) δ-61.30

MDR-001-401A-2：峰2：chiral-HPLC：3.244min；N-((E)-N′-(Z)-((S)4-(4-氯苯基)-3-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(25.81mg，0.044mmol，收率：26.3％)，LCMS m/z：591[M+H]+。MDR-001-401A-2: Peak 2: chiral-HPLC: 3.244 min; N-((E)-N′-(Z)-((S)4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoimido)acetamide or enantiomer (25.81 mg, 0.044 mmol, yield: 26.3%), LCMS m/z: 591 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.54(s，1H)，8.02(d，J＝8.0，2H)，7.83(d，J＝8.4，2H)，7.51(d，J＝5.2，2H)，7.38-7.29(m，7H)，5.10-5.06(m，1H)，4.49(t，J＝12，1H)，3.88-3.84(m，1H)，2.08(s，3H). 1 H NMR (400MHz, DMSO-d6) δ10.54 (s, 1H), 8.02 (d, J = 8.0, 2H), 7.83 (d, J = 8.4, 2H), 7.51 (d, J = 5.2, 2H), 7.38-7.29 (m, 7H), 5.10-5.06 (m, 1H), 4.49 (t, J=12, 1H), 3.88-3.84 (m, 1H), 2.08 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.30 19 F NMR (377MHz, DMSO-d6) δ-61.30

实施例12、N-((E)-N′-((Z)-(3-(4-氯苯基)-4-苯基-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-402)的合成：
Example 12, Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-phenyl-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-402):

向溶有N-((E)-N’-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基氨基甲酰)乙酰胺(100mg，0.17mmol)的四氢呋喃(3mL)溶液中，加入硝酸铈铵(278mg，0.51mmol)，室温搅拌4小时。将混合反应液减压浓缩并通过反相柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)纯化，当流动相B含量达到75％时，收集含有所需产物的级分，减压浓缩得到N-((E)-N′-((Z)-(3-(4-氯苯基)-4-苯基-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(73.41mg，0.12mmol，收率：73.66％)，LCMS m/z：589[M+H]+。 To a solution of N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methylcarbamoyl)acetamide (100 mg, 0.17 mmol) in tetrahydrofuran (3 mL) was added cerium ammonium nitrate (278 mg, 0.51 mmol), and the mixture was stirred at room temperature for 4 hours. The mixed reaction liquid was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm). When the content of mobile phase B reached 75%, the fractions containing the desired product were collected and concentrated under reduced pressure to give N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-phenyl-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (73.41mg, 0.12mmol, yield: 73.66%), LCMS m/z: 589[M+H] + .

1H NMR(400MHz，DMSO-d6)δ11.19(s，1H)，8.91(s，2H)，8.37(s，1H)，8.11(d，J＝8.0Hz，2H)，7.88(d，J＝8.4Hz，2H)，7.43-7.28(m，9H)，2.08(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.19 (s, 1H), 8.91 (s, 2H), 8.37 (s, 1H), 8.11 (d, J = 8.0Hz, 2H), 7.88 (d, J = 8.4Hz, 2H), 7.43-7.28 (m, 9H), 2.08 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.355. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.355.

实施例13、(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-胺(MDR-001-405)和(E)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺(MDR-001-405de)的合成：Example 13, Synthesis of (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-amine (MDR-001-405) and (E)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine (MDR-001-405de):

1)、4-(4-氯苯基)-4-氧代-3-苯基丁酸乙酯的合成
1) Synthesis of ethyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate

在5℃下，向溶有1-(4-氯苯基)-2-苯基乙烷-1-酮(5.00g，21.65mmol)的二甲基亚砜(100mL)溶液中，加入氢化钠(60％w/w矿物油分散体，951mg，23.78mmol)，然后在5℃下，搅拌1小时，并加入溴乙酸乙酯(3.97g，23.78mmol)，室温搅拌2小时。将混合反应液用饱和氯化铵水溶液(20mL)淬灭，并用乙酸乙酯(200mL)萃取。合并的有机相用饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝20/1)纯化得到4-(4-氯苯基)-4-氧代-3-苯基丁酸乙酯(4.03g，12.71mmol，收率：58.74％)，LCMS m/z：317[M+H]+.At 5°C, sodium hydride (60% w/w mineral oil dispersion, 951 mg, 23.78 mmol) was added to a solution of 1-(4-chlorophenyl)-2-phenylethane-1-one (5.00 g, 21.65 mmol) in dimethyl sulfoxide (100 mL), and then stirred at 5°C for 1 hour, and ethyl bromoacetate (3.97 g, 23.78 mmol) was added and stirred at room temperature for 2 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give ethyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate (4.03 g, 12.71 mmol, yield: 58.74%), LCMS m/z: 317 [M+H] + .

2)、4-(4-氯苯基)-4-氧代-3-苯基丁酸的合成
2) Synthesis of 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid

在室温下，向溶有4-(4-氯苯基)-4-氧代-3-苯基丁酸乙酯(3.53g，11.14mmol)的四氢呋喃(100mL)，水(50mL)和乙醇(50mL)溶液中，加入氢氧化钠(25％的水溶液，5.36mL，33.42mmol)，室温搅拌16小时。混合反应液用盐酸(1N)调节pH至4-5，并用乙酸乙酯(200mL)萃取。合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到化合物4-(4-氯苯基)-4-氧代-3-苯基丁酸(3.28g，11.35mmol，产率：102.18％)，LCMS m/z：289.1[M+H]+.At room temperature, sodium hydroxide (25% aqueous solution, 5.36 mL, 33.42 mmol) was added to a solution of ethyl 4-(4-chlorophenyl)-4-oxo-3-phenylbutyrate (3.53 g, 11.14 mmol) in tetrahydrofuran (100 mL), water (50 mL) and ethanol (50 mL), and stirred at room temperature for 16 hours. The mixed reaction solution was adjusted to pH 4-5 with hydrochloric acid (1N) and extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid (3.28 g, 11.35 mmol, yield: 102.18%), LCMS m/z: 289.1 [M+H] + .

3)、6-(4-氯苯基)-5-苯基-4，5-二氢哒嗪-3(2H)-酮的合成
3) Synthesis of 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one

在室温下，向溶有4-(4-氯苯基)-4-氧代-3-苯基丁酸(3.28g，11.35mmol)的乙醇(50mL)溶液中，加入水合肼(545mg，17.03mmol)，加热80℃搅拌2小时。将混合反应液减压浓缩。残余物用乙醇(10mL)打浆，过滤，滤饼用冰乙醇(5mL)洗涤，干燥得到6-(4-氯苯基)-5-苯基-4，5-二氢哒嗪-3(2H)-酮(2.30g，8.07mmol，收率：71.20％)，LCMS m/z：285[M+H]+.At room temperature, hydrazine hydrate (545 mg, 17.03 mmol) was added to a solution of 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid (3.28 g, 11.35 mmol) in ethanol (50 mL), and the mixture was heated at 80°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was slurried with ethanol (10 mL), filtered, and the filter cake was washed with ice ethanol (5 mL) and dried to give 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one (2.30 g, 8.07 mmol, yield: 71.20%), LCMS m/z: 285 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ11.22(s，1H)，7.75-7.72(m，2H)，7.46-7.43(m，2H)，7.35-7.31(m，2H)，7.27-7.23(m，1H)，7.19-7.17(m，2H)，4.68(d，J＝7.6Hz，1H)，3.12-3.06(m，1H)，2.47(s，1H). 1 H NMR (400MHz, DMSO-d6) δ11.22 (s, 1H), 7.75-7.72 (m, 2H), 7.46-7.43 (m, 2H), 7.35-7.31 (m, 2H) , 7.27-7.23 (m, 1H), 7.19-7.17 (m, 2H), 4.68 (d, J=7.6Hz, 1H), 3.12-3.06 (m, 1H), 2.47 (s, 1H).

4)、3-(4-氯苯基)-4-苯基-1，4，5，6-四氢哒嗪的合成
4) Synthesis of 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine

在0℃和氮气保护下，向溶有四氢铝锂(920mg，24.21mmol)的四氢呋喃(30mL)溶液中，加入6-(4-氯苯基)-5-苯基-4，5-二氢哒嗪-3(2H)-酮(2.30g，8.07mmol)的四氢呋喃(20mL)溶液，加热80℃搅拌0.5小时。在0℃下，将混合反应液用2N氢氧化钠(20mL)淬灭，并用乙酸乙酯(100mL)萃取。合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到3-(4-氯苯基)-4-苯基-1，4，5，6-四氢哒嗪(2.45g，粗品)，LCMS m/z：271[M+H]+.At 0°C and under nitrogen protection, a solution of 6-(4-chlorophenyl)-5-phenyl-4,5-dihydropyridazine-3(2H)-one (2.30 g, 8.07 mmol) in tetrahydrofuran (20 mL) was added to a solution of lithium aluminum tetrahydride (920 mg, 24.21 mmol) in tetrahydrofuran (30 mL), and the mixture was heated to 80°C and stirred for 0.5 hours. At 0°C, the mixed reaction solution was quenched with 2N sodium hydroxide (20 mL) and extracted with ethyl acetate (100 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine (2.45 g, crude product), LCMS m/z: 271 [M+H] + .

5)、3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-羧酰胺的合成
5) Synthesis of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide

在室温下，向3-(4-氯苯基)-4-苯基-1，4，5，6-四氢哒嗪(1.5g，5.54mmol)的甲苯(20mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(1.57g，5.55mmol)，加热110℃搅拌2小时。将混合反应减压浓缩，并用异丙醇(20mL)打浆，过滤，滤饼用冷异丙醇和己烷(1：1)的混合溶剂洗涤。将收集的固体在真空下干燥，得到化合物3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(2.3g，4.41mmol，收率：79.86％)，LCMS m/z：522[M+H]+ At room temperature, to a toluene (20 mL) solution of 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine (1.5 g, 5.54 mmol), ((4-(trifluoromethyl)phenyl)sulfonyl)carbamic acid methyl ester (1.57 g, 5.55 mmol) was added and heated to 110° C. with stirring for 2 hours. The mixed reaction was concentrated under reduced pressure, slurried with isopropanol (20 mL), filtered, and the filter cake was washed with a mixed solvent of cold isopropanol and hexane (1:1). The collected solid was dried under vacuum to give compound 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (2.3 g, 4.41 mmol, yield: 79.86%), LCMS m/z: 522 [M+H] +

1H NMR(400MHz，DMSO-d6)δ11.42(s，1H)，8.25(d，J＝8.0Hz，2H)，8.05(d，J＝8.0Hz，2H)，7.89(d，J＝8.6Hz，2H)，7.42(d，J＝8.8Hz，2H)，7.30(t，J＝7.6Hz，2H)，7.24-7.18(m，1H)，7.13(d，J＝7.2Hz，2H)，4.46(s，1H)，4.04-3.85(m，1H)，2.96-2.82(m，1H)，2.15-2.04(m，1H)，2.00-1.89(m，1H). 1 H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 8.25 (d, J = 8.0Hz, 2H), 8.05 (d, J = 8.0Hz, 2H), 7.89 (d, J = 8.6Hz, 2H), 7.42 (d, J = 8.8Hz, 2H), 7.30 (t, J = 7 .6Hz, 2H), 7.24-7.18 (m, 1H), 7.13 (d, J=7.2Hz, 2H), 4.46 (s, 1H), 4.04 -3.85(m, 1H), 2.96-2.82(m, 1H), 2.15-2.04(m, 1H), 2.00-1.89(m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.636。19F NMR (377MHz, DMSO-d6): δ-61.636.

6)、(Z)-1-((3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
6) Synthesis of (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(900mg，1.7mmol)的二氯甲烷(20mL)溶液中，加入三氯氧(5.2g，34.0mmol，20.0eq)，4-二甲氨基吡啶(1052mg，8.6mmol)，然后加热50℃搅拌20小时。将混合反应液减压浓缩，并通过反相柱色谱纯化(条件如下：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)。在80％B下收集含有所需产物的级分，并减压浓缩得到(Z)-1-((3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(1.0g，1.59mmol，收率：92.51％)。LCMS m/z：626[M]+。At room temperature, trichloroethane (5.2 g, 34.0 mmol, 20.0 eq) and 4-dimethylaminopyridine (1052 mg, 8.6 mmol) were added to a solution of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (900 mg, 1.7 mmol) in dichloromethane (20 mL), and then heated at 50° C. with stirring for 20 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (conditions are as follows: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 minutes; detector: 254 nm). Fractions containing the desired product were collected at 80% B and concentrated under reduced pressure to give (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (1.0 g, 1.59 mmol, yield: 92.51%). LCMS m/z: 626 [M] + .

7)、(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-胺(MDR-001-405)和 (E)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺(MDR-001-405de)的合成
7), (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-amine (MDR-001-405) and Synthesis of (E)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-amine (MDR-001-405de)

室温条件下，向溶有(Z)-1-((3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(360mg，0.57mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入(R)-2-乙酰氧基-4-胍-N，N，N-三甲基-4-氧代丁-1-胺鎓(349mg，1.43mmol)和三乙胺(173mg，1.71mmol)，室温搅拌2小时。将混合反应液减压浓缩，并用反相快速柱色谱(条件如下：柱：球形C18，20-40um，80g；流动相A：0.1％TFA；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15min；检测器：254nm)。在60％B下收集含有所需产物的级分，并在减压下浓缩，得到粗品。粗品通过制备级高效液相色谱(系统：Waters 2767/Qda；柱：sunfire C18，19*250*10um，80g；流动相A：0.1％TFA/H2O；流动相B：乙腈；流速：20mL/min；梯度：34-34％B；保留时间6.8-10.0min，16min)。在60％B下收集含有所需产物的级分，并在减压下浓缩得得到(2R)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(7.2mg 0.01mmol，收率：1.77％)。LCMS m/z：706[M+H]+，和(E)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-5，6-二氢哒嗪-1(4H)-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺(28.76mg，0.42mmol，收率：7.27％)，LCMS m/z：688[M]+。To a solution of (Z)-1-((3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (360 mg, 0.57 mmol) in N,N-dimethylformamide (5 mL) at room temperature were added (R)-2-acetoxy-4-guanidine-N,N,N-trimethyl-4-oxobutan-1-amine (349 mg, 1.43 mmol) and triethylamine (173 mg, 1.71 mmol), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and subjected to reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40um, 80g; mobile phase A: 0.1% TFA; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15min; detector: 254nm). The fractions containing the desired product were collected at 60%B and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (system: Waters 2767/Qda; column: sunfire C18, 19*250*10um, 80g; mobile phase A: 0.1%TFA/ H2O ; mobile phase B: acetonitrile; flow rate: 20mL/min; gradient: 34-34%B; retention time 6.8-10.0min, 16min). The fractions containing the desired product were collected at 60% B and concentrated under reduced pressure to give (2R)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methylguanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (7.2 mg 0.01 mmol, yield: 1.77%). LCMS m/z: 706 [M+H] + , and (E)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazin-1(4H)-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-amine (28.76 mg, 0.42 mmol, yield: 7.27%), LCMS m/z: 688 [M] + .

MDR-001-405MDR-001-405

1H NMR(400MHz，DMSO-d6)δ11.61-10.23(m，1H)，8.61-8.27(m，1H)，8.05(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.55(d，J＝8.8Hz，2H)，7.46-6.58(m，7H)，4.60-4.45(m，1H)，4.38(s，1H)，4.33-4.14(m，1H)，3.55-3.39(m，4H)，3.16(s，9H)，2.74-2.56(m，2H)，2.32-2.17(m，1H)，2.04-1.91(m，1H). 1 H NMR (400MHz, DMSO-d6) δ 11.61-10.23 (m, 1H), 8.61-8.27 (m, 1H), 8.05 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.55 (d, J = 8.8Hz, 2H), 7.46-6.58 (m , 7H), 4.60-4.45(m, 1H), 4.38(s, 1H), 4.33-4.14(m, 1H), 3.55-3.39(m, 4 H), 3.16 (s, 9H), 2.74-2.56 (m, 2H), 2.32-2.17 (m, 1H), 2.04-1.91 (m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.26719F NMR (377MHz, DMSO-d6): δ-61.267

MDR-001-405deMDR-001-405de

1H NMR(400MHz，DMSO-d6)δ11.59-10.78(m，1H)，8.50-8.25(m，1H)，8.05(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.54(d，J＝8.8Hz，2H)，7.33-7.16(m，7H)，7.04-6.91(m，1H)，6.59(d，J＝15.2Hz，1H)，4.40(s，1H)，4.35-4.18(m，3H)，3.22-3.05(m，11H)，2.31-2.17(m，1H)，2.06-1.94(m，1H). 1 H NMR (400MHz, DMSO-d6) δ 11.59-10.78 (m, 1H), 8.50-8.25 (m, 1H), 8.05 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.8Hz, 2H), 7.33-7.1 6(m, 7H), 7.04-6.91(m, 1H), 6.59(d, J=15.2Hz, 1H), 4.40(s, 1H), 4.35- 4.18(m, 3H), 3.22-3.05(m, 11H), 2.31-2.17(m, 1H), 2.06-1.94(m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.282。19F NMR (377MHz, DMSO-d6): δ-61.282.

实施例14、(S)-4-(((1-(4-氯苯基)-5-苯基-3-((4-(三氟甲基)苯基)磺酰胺基)-1H-吡唑-4-基)甲基)氨基)-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-铵(MDR-001-406)的合成：Example 14. Synthesis of (S)-4-(((1-(4-chlorophenyl)-5-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1H-pyrazol-4-yl)methyl)amino)-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-ammonium (MDR-001-406):

1)、1-(4-氯苯基)-5-苯基-1H-吡唑-3-胺的合成
1) Synthesis of 1-(4-chlorophenyl)-5-phenyl-1H-pyrazole-3-amine

将化合物1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)氨基甲酸叔丁酯(2.5g，6.76mmol)溶于二氯甲烷(50mL)和2，2，2-三氟乙酸(10mL)，25℃搅拌3小时。将混合反应液减压浓缩，并用饱和碳酸氢钠(50mL)调节pH到中性，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法纯化(石油醚/乙酸乙酯＝100％～0％，254nm)纯化得到1-(4-氯苯基)-5-苯基-1H-吡唑-3-胺(1.7g，6.30mmol，93.2％产率)，LCMS m/z：270[M+H]+。The compound tert-butyl 1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)carbamate (2.5 g, 6.76 mmol) was dissolved in dichloromethane (50 mL) and 2,2,2-trifluoroacetic acid (10 mL) and stirred at 25°C for 3 hours. The mixed reaction solution was concentrated under reduced pressure, and the pH was adjusted to neutral with saturated sodium bicarbonate (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100% to 0%, 254 nm) to obtain 1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-amine (1.7 g, 6.30 mmol, 93.2% yield), LCMS m/z: 270 [M+H] + .

2)、N-(1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺的合成
2) Synthesis of N-(1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide

向溶有1-(4-氯苯基)-5-苯基-1H-吡唑-3-胺(1.7g，6.30mmol)的吡啶(20mL)溶液中，加入4-(三氟甲基)苯磺酰氯(2.31g，9.45mmol)，25℃搅拌3小时。LCMS显示反应完成，将反应混合反应液减压浓缩，并用饱和NaHCO3(50mL)淬灭，再用EA(50mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100：0至1：1，254nm)纯化得到N-(1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(1.6g，3.35mmol，收率：53.1％)，LCMS m/z：478[M+H]+。4-(Trifluoromethyl)benzenesulfonyl chloride (2.31 g, 9.45 mmol) was added to a solution of 1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-amine (1.7 g, 6.30 mmol) in pyridine (20 mL), and the mixture was stirred at 25°C for 3 hours. LCMS showed that the reaction was complete, and the reaction mixture was concentrated under reduced pressure, quenched with saturated NaHCO 3 (50 mL), and extracted with EA (50 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0 to 1:1, 254 nm) to give N-(1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (1.6 g, 3.35 mmol, yield: 53.1%), LCMS m/z: 478 [M+H] + .

3)、N-(4-溴-1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺的合成
3) Synthesis of N-(4-bromo-1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide

向溶有N-(1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(1.6g，3.35mmol)的乙腈(20mL)溶液中，加入N-溴代丁二酰亚胺(1.19g，6.70mmol)，室温搅拌3.0小时。LCMS显示反应完成。将混合反应液加入水(50mL)中，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100：0to 1：1，254nm)纯化得到N-(4-溴-1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(1.4g，2.5mmol，收率：75.1％)，LCMS m/z：558[M+H]+。To a solution of N-(1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (1.6 g, 3.35 mmol) in acetonitrile (20 mL) was added N-bromosuccinimide (1.19 g, 6.70 mmol) and stirred at room temperature for 3.0 hours. LCMS showed that the reaction was complete. The mixed reaction solution was added to water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0 to 1:1, 254 nm) to give N-(4-bromo-1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (1.4 g, 2.5 mmol, yield: 75.1%), LCMS m/z: 558 [M+H] + .

4)、N-(1-(4-氯苯基)-5-苯基-4-乙烯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺的制备
4) Preparation of N-(1-(4-chlorophenyl)-5-phenyl-4-vinyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide

在室温条件下，向溶有N-(4-溴-1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(1.4g，2.5mmol)的1，4-二氧六环(30mL)和水(6mL)溶液中，加入三氟(乙烯基)硼酸钾(670mg，5.0mmol)，Pd(ppf)Cl2(914mg，1.25mmol)，K2CO3(1.04g，7.5mmol)，加热80℃搅拌16小时。将混合反应液加入水中(20mL)，并用乙酸乙酯(20mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100：0to 2：1，254nm)纯化得到N-(1-(4-氯苯基)-5-苯基-4-乙烯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(900mg， 1.78mmol，收率：71.1％)，LCMS m/z：504[M+H]+.To a solution of N-(4-bromo-1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (1.4 g, 2.5 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was added potassium trifluoro(vinyl)borate (670 mg, 5.0 mmol), Pd(ppf)Cl 2 (914 mg, 1.25 mmol), and K 2 CO 3 (1.04 g, 7.5 mmol) at room temperature, and the mixture was heated at 80°C with stirring for 16 hours. The mixed reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0 to 2:1, 254 nm) to give N-(1-(4-chlorophenyl)-5-phenyl-4-vinyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (900 mg, 1.78 mmol, yield: 71.1%), LCMS m/z: 504 [M+H] + .

5)、N-(1-(4-氯苯基)-4-甲酰基-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺的合成
5) Synthesis of N-(1-(4-chlorophenyl)-4-formyl-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide

向溶有N-(1-(4-氯苯基)-4-甲酰基-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(900mg，1.78mmol)的四氢呋喃(20mL)和水(4mL)溶液中，加入K2OsO4(328mg，0.89mmol)，25℃搅拌1小时。然后向上述反应物中，加入NaIO4(1.52g，7.12mmol，25℃搅拌1小时。将混合反应液加入水(20mL)，并用乙酸乙酯(20mL×3)萃取。合并有机相用饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100：0to 2：1，Rf＝0.4，254nm)纯化得到N-(1-(4-氯苯基)-4-甲酰基-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(400mg，0.79mmol，收率：44.3％)，LCMS m/z：506[M+H]+。To a solution of N-(1-(4-chlorophenyl)-4-formyl-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (900 mg, 1.78 mmol) in tetrahydrofuran (20 mL) and water (4 mL) was added K 2 OsO 4 (328 mg, 0.89 mmol) and stirred at 25°C for 1 hour. Then, NaIO 4 (1.52 g, 7.12 mmol) was added to the above reactants, and the mixture was stirred at 25°C for 1 hour. The mixed reaction solution was added with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0 to 2:1, Rf=0.4, 254 nm) to give N-(1-(4-chlorophenyl)-4-formyl-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (400 mg, 0.79 mmol, yield: 44.3%), LCMS m/z: 506[M+H] + .

6)、N-(4-(氨基甲基)-1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺的合成
6) Synthesis of N-(4-(aminomethyl)-1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide

向溶有N-(1-(4-氯苯基)-4-甲酰基-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(100mg，0.20mmol)的甲醇(2.0mL)溶液中，加入乙酸铵(77mg，1.0mmol)，25℃搅拌1小时.然后上述反应液中，加入NaBH3CN(15mg，0.24mmol)。将混合反应液加入水(10mL)，并用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100：0to 5：1，254nm)得到N-(4-(氨基甲基)-1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺(30mg，0.059mmol，收率：28.3％)，LCMS m/z：507[M+H]+。To a solution of N-(1-(4-chlorophenyl)-4-formyl-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (100 mg, 0.20 mmol) in methanol (2.0 mL) was added ammonium acetate (77 mg, 1.0 mmol) and stirred at 25°C for 1 hour. Then NaBH 3 CN (15 mg, 0.24 mmol) was added to the above reaction solution. The mixed reaction solution was added with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:0 to 5:1, 254 nm) to give N-(4-(aminomethyl)-1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide (30 mg, 0.059 mmol, yield: 28.3%), LCMS m/z: 507 [M+H] + .

7)、(S)-2-乙酰氧基-4-(((1-(4-氯苯基)-5-苯基-3-((4-(三氟甲基)苯基)磺酰胺基)-1H-吡唑-4-基)甲基)氨基)-N，N，N-三甲基-4-氧代丁烷-1-铵的合成
7) Synthesis of (S)-2-acetoxy-4-(((1-(4-chlorophenyl)-5-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1H-pyrazol-4-yl)methyl)amino)-N,N,N-trimethyl-4-oxobutane-1-ammonium

向溶有N-(4-(氨基甲基)-1-(4-氯苯基)-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺N-(4-(aminomethyl)-1-(4-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide was dissolved in

(30mg，0.059mmol)的二氯甲烷(2.0mL)溶液中，加入(S)-2-乙酰氧基-4-氯-N，N，N-三甲 基-4-氧代丁-1-铵(40mg，0.177mmol)，25℃搅拌1小时。将混合反应液加入水(10mL)，并用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100：0to2：1，254nm)纯化得到(S)-2-乙酰氧基-4-(((1-(4-氯苯基)-5-苯基-3-((4-(三氟甲基)苯基)磺酰胺基)-1H-吡唑-4-基)甲基)氨基)-N，N，N-三甲基-4-氧代丁烷-1-铵(30mg，0.043mmol，收率：73.1％)，LCMS m/z：692[M]+。To a solution of (30 mg, 0.059 mmol) in dichloromethane (2.0 mL) was added (S)-2-acetoxy-4-chloro-N,N,N-trimethylol N,N,N-trimethyl-4-oxobutane-1-ammonium (40 mg, 0.177 mmol) was added and stirred at 25 °C for 1 hour. The mixed reaction solution was added to water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 0 to 2: 1, 254 nm) to give (S)-2-acetoxy-4-(((1-(4-chlorophenyl)-5-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1H-pyrazol-4-yl)methyl)amino)-N,N,N-trimethyl-4-oxobutane-1-ammonium (30 mg, 0.043 mmol, yield: 73.1%), LCMS m/z: 692 [M] + .

8)、(S)-4-(((1-(4-氯苯基)-5-苯基-3-((4-(三氟甲基)苯基)磺酰胺基)-1H-吡唑-4-基)甲基)氨基)-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-铵的合成
8) Synthesis of (S)-4-(((1-(4-chlorophenyl)-5-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1H-pyrazol-4-yl)methyl)amino)-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-ammonium

向溶有(S)-2-乙酰氧基-4-(((1-(4-氯苯基)-5-苯基-3-((4-(三氟甲基)苯基)磺酰胺基)-1H-吡唑-4-基)甲基)氨基)-N，N，N-三甲基-4-氧代丁烷-1-铵(30mg，0.043mmol)的甲醇(2.0mL)溶液中，加入碳酸钾(12mg，0.086mmol)，25℃搅拌2小时。将混合物反应液减压浓缩，并通过制备级高效液相色谱(Waters 3767/QDA，柱：SunFire C18 19*250mm，10um；流动相A：10mmol/L％TFA/H2O，流动相B：ACN，流速：20mL/min；梯度：34％～44％；保留时间：6.0-7.0分钟，17分钟)纯化得到(S)-4-(((1-(4-氯苯基)-5-苯基-3-((4-(三氟甲基)苯基)磺酰胺基)-1H-吡唑-4-基)甲基)氨基)-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-铵(2.03mg，0.003mmol，收率7.2％)，LCMS m/z：650[M]+。To a solution of (S)-2-acetoxy-4-(((1-(4-chlorophenyl)-5-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1H-pyrazol-4-yl)methyl)amino)-N,N,N-trimethyl-4-oxobutane-1-aminium (30 mg, 0.043 mmol) in methanol (2.0 mL) was added potassium carbonate (12 mg, 0.086 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Waters 3767/QDA, column: SunFire C18 19*250 mm, 10 um; mobile phase A: 10 mmol/L% TFA/H2O, mobile phase B: ACN, flow rate: 20 mL/min; gradient: 34% to 44%; retention time: 6.0-7.0 min, 17 min) to give (S)-4-(((1-(4-chlorophenyl)-5-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonamido)-1H-pyrazol-4-yl)methyl)amino)-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-ammonium (2.03 mg, 0.003 mmol, yield 7.2%), LCMS m/z: 650 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.69(s，1H)，8.32(s，1H)，8.15(d，J＝8.0Hz，2H)，7.99(d，J＝7.6Hz，2H)，7.42(dd，J＝5.1，2.0Hz，3H)，7.37(d，J＝8.8Hz，2H)，7.24(dd，J＝6.8，3.0Hz，2H)，6.98(d，J＝8.8Hz，2H)，5.65(s，1H)，4.44(s，1H)，3.97(ddd，J＝44.4，14.6，4.8Hz，2H)，3.34(d，J＝2.8Hz，2H).3.14(s，9H)，2.27(ddd，J＝20.7，14.8，6.8Hz，2H) 1 H NMR (400MHz, DMSO-d6) δ10.69 (s, 1H), 8.32 (s, 1H), 8.15 (d, J=8.0Hz, 2H), 7.99 (d, J =7.6Hz, 2H), 7.42 (dd, J=5.1, 2.0Hz, 3H), 7.37 (d, J=8.8Hz, 2H), 7.24 (dd, J=6.8, 3. 0Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 5.65 (s, 1H), 4.44 (s, 1H), 3.97 (ddd, J=44.4, 14.6, 4.8Hz, 2H), 3.34 (d, J=2.8Hz, 2H). 3.14 (s, 9H), 2.27 (ddd, J=20.7, 14.8, 6.8Hz, 2H)

实施例15、N，N′-((氮烷二基二(亚甲基))二(1-(4-氯苯基)-5-苯基-1H-吡唑-4，3-二基))二(4-(三氟甲基)苯磺酰胺)(MDR-001-406A)的合成：
Example 15. Synthesis of N,N′-((azanediylbis(methylene))bis(1-(4-chlorophenyl)-5-phenyl-1H-pyrazole-4,3-diyl))bis(4-(trifluoromethyl)benzenesulfonamide) (MDR-001-406A):

向溶有(N-(1-(4-氯苯基)-4-甲酰基-5-苯基-1H-吡唑-3-基)-4-(三氟甲基)苯磺酰胺)(100mg，0.20mmol)的甲醇(2.0mL)溶液中，加入乙酸铵(77mg，1.0mmol)，25℃搅拌1小时。然后向上述反应物中加入氰基硼氢化钠(15mg，0.24mmol)，25℃搅拌16小时。将混合反应液减压浓缩，并通过制备级搞笑液相色谱(Waters 3767/QDA，柱：SunFire C18 19*250mm，10um；流动相A：10mmol/L％TFA/H2O，流动相B：乙腈，流速：15mL/min；梯度：44％～56％；保留时间：6.0-7.0分钟，17分钟)纯化得到N，N′-((氮烷二基二(亚甲基))二(1-(4-氯苯基)-5-苯基-1H-吡唑-4，3-二基))二(4-(三氟甲基)苯磺酰胺)(2.11mg，0.003mmol，收率：1.1％)，LCMS m/z：998[M+H]+。To a solution of (N-(1-(4-chlorophenyl)-4-formyl-5-phenyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzenesulfonamide) (100 mg, 0.20 mmol) in methanol (2.0 mL) was added ammonium acetate (77 mg, 1.0 mmol) and stirred at 25°C for 1 hour. Then sodium cyanoborohydride (15 mg, 0.24 mmol) was added to the above reaction and stirred at 25°C for 16 hours. The mixed reaction liquid was concentrated under reduced pressure and purified by preparative HPLC (Waters 3767/QDA, column: SunFire C18 19*250 mm, 10 um; mobile phase A: 10 mmol/L% TFA/H 2 O, mobile phase B: acetonitrile, flow rate: 15 mL/min; gradient: 44% to 56%; retention time: 6.0-7.0 min, 17 min) to give N,N′-((azanediylbis(methylene))bis(1-(4-chlorophenyl)-5-phenyl-1H-pyrazole-4,3-diyl))bis(4-(trifluoromethyl)benzenesulfonamide) (2.11 mg, 0.003 mmol, yield: 1.1%), LCMS m/z: 998 [M+H] + .

1H NMR(400MHz，MeOD-d4)δ8.09(d，J＝8.4Hz，4H)，7.87(d，J＝8.4Hz，4H)，7.41(d，J＝7.6Hz，5H)，7.36-7.24(m，4H)，7.19(d，J＝7.2Hz，5H)，6.97(d，J＝8.4Hz，4H)，4.07(s，4H). 1 H NMR (400MHz, MeOD-d4) δ8.09 (d, J=8.4Hz, 4H), 7.87 (d, J=8.4Hz, 4H), 7.41 (d, J=7.6H z, 5H), 7.36-7.24 (m, 4H), 7.19 (d, J=7.2Hz, 5H), 6.97 (d, J=8.4Hz, 4H), 4.07 (s, 4H).

实施例16、N-((E)-N′-(Z)-(-3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其对映体(MDR-001-305B-1A和MDR-001-305B-1B、MDR-001-305B-2A和MDR-001-305B-2B)的合成：Example 16, Synthesis of N-((E)-N′-(Z)-(-3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its enantiomers (MDR-001-305B-1A and MDR-001-305B-1B, MDR-001-305B-2A and MDR-001-305B-2B):

1)、(E)-((1-(4-氯苯基)-2-苯基乙烯基)氧基)三甲基硅烷的合成
1) Synthesis of (E)-((1-(4-chlorophenyl)-2-phenylvinyl)oxy)trimethylsilane

在-78℃和氮气保护下，向溶有1-(4-氯苯基)-2-苯基乙-1-酮(1.0g，4.33mmol)的四氢呋喃(20mL)溶液中，加入二异丙基氨基锂(4.33mL，8.66mmol)，在-78℃下，搅拌0.5小时，然后加入三甲基氯硅烷(944mg，8.66mmol)，室温搅拌混合物1小时。将混合反应液用饱和氯化铵水溶液(10mL)淬灭，并用乙酸乙酯(50mL)萃取。合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到(E)-((1-(4-氯苯基)-2-苯基乙烯基)氧基)三甲基硅烷(1.4g，4.62mmol，粗品)。Under nitrogen protection at -78°C, lithium diisopropylamide (4.33 mL, 8.66 mmol) was added to a solution of 1-(4-chlorophenyl)-2-phenylethan-1-one (1.0 g, 4.33 mmol) in tetrahydrofuran (20 mL), stirred at -78°C for 0.5 hours, then trimethylsilyl chloride (944 mg, 8.66 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (E)-((1-(4-chlorophenyl)-2-phenylvinyl)oxy)trimethylsilane (1.4 g, 4.62 mmol, crude product).

2)、1-(4-氯苯基)-3-羟基-2-苯基-1-戊酮的合成
2) Synthesis of 1-(4-chlorophenyl)-3-hydroxy-2-phenyl-1-pentanone

在-78℃和氮气保护下，向溶有(E)-((1-(4-氯苯基)-2-苯基乙烯基)氧基)三甲基硅烷(1.4g，4.62mmol)的二氯甲烷(20mL)溶液中，加入丙醛(536mg，9.24mmol)和四氯化钛(1M的四氢呋喃溶液，6.93mL，6.93mmol)，室温搅拌1小时。混合反应液用冰水(10mL)淬灭，并用二氯甲烷(50mL)萃取。合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到1-(4-氯苯基)-3-羟基-2-苯基戊-1-酮(1.5g，粗品)。LCMS：m/z：289.2[M+H]+.At -78 ° C and nitrogen protection, propionaldehyde (536 mg, 9.24 mmol) and titanium tetrachloride (1M tetrahydrofuran solution, 6.93 mL, 6.93 mmol) were added to a solution of (E)-((1-(4-chlorophenyl)-2-phenylvinyl)oxy)trimethylsilane (1.4 g, 4.62 mmol) in dichloromethane (20 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with ice water (10 mL) and extracted with dichloromethane (50 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(4-chlorophenyl)-3-hydroxy-2-phenylpentan-1-one (1.5 g, crude product). LCMS: m/z: 289.2 [M+H] + .

3)、(Z)-1-(4-氯苯基)-2-苯基-2-戊烯-1-酮的合成
3) Synthesis of (Z)-1-(4-chlorophenyl)-2-phenyl-2-penten-1-one

在室温下，向溶有1-(4-氯苯基)-3-羟基-2-苯基戊-1-酮(1.5g，5.19mmol)的甲苯(40mL)溶液中，加入对甲苯磺酸(986mg，5.19mmol)，然后将混合物在100℃下搅拌1小时。混合反应液用乙酸乙酯(80mL)稀释，并用饱和食盐水(20mL)洗涤，收集有机相无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(PE/EA＝6/1)纯化得到(Z)-1-(4-氯苯基)-2-苯基戊-2-烯-1-酮(800mg，2.95mmol，收率：57.14％)，LCMS m/z：271[M+H]+.At room temperature, p-toluenesulfonic acid (986 mg, 5.19 mmol) was added to a solution of 1-(4-chlorophenyl)-3-hydroxy-2-phenylpentan-1-one (1.5 g, 5.19 mmol) in toluene (40 mL), and the mixture was stirred at 100°C for 1 hour. The mixed reaction solution was diluted with ethyl acetate (80 mL) and washed with saturated brine (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=6/1) to give (Z)-1-(4-chlorophenyl)-2-phenylpentan-2-ene-1-one (800 mg, 2.95 mmol, yield: 57.14%), LCMS m/z: 271 [M+H] + .

4)、3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑的合成
4) Synthesis of 3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazole

在室温下，向溶有(Z)-1-(4-氯苯基)-2-苯基戊-2-烯-1-酮(800mg，2.95mmol)的乙醇(20mL)溶液中，加入水合肼(295mg，5.90mmol)，然后在80℃下搅拌2小时。将混合反应液用乙酸乙酯(50mL)稀释，饱和食盐水(10mL)洗涤。收集有机相无水硫酸钠干燥，过滤、减压浓缩得到3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑(900mg，3.15mmol，收率：107.01％)。LCMS m/z：285[M+H]+.At room temperature, hydrazine hydrate (295 mg, 5.90 mmol) was added to a solution of (Z)-1-(4-chlorophenyl)-2-phenylpent-2-en-1-one (800 mg, 2.95 mmol) in ethanol (20 mL), and then stirred at 80°C for 2 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated brine (10 mL). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazole (900 mg, 3.15 mmol, yield: 107.01%). LCMS m/z: 285[M+H] + .

5)、3-(4-氯苯基)-5-乙基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺及其异构体
5), 3-(4-chlorophenyl)-5-ethyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide and its isomers

在室温下，向溶有3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑(900mg，3.16mmol)的甲苯(30mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(894mg，3.16mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱(PE/EA＝3/1)纯化浓缩得到粗化合物。粗化合物通过反相色谱柱纯化，条件如下(色谱柱：球形C18，20-40um，330g；流动相A：水(10mmol/L NH4HCO3)；流动相B：乙腈；流速：100mL/min；梯度：5％B-60％B在12分钟内；检测器：254nm)纯化，在55％B下，含有所需产物的馏分减压浓缩得到两个异构体：305B-7-1和305B-7-2：At room temperature, methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (894 mg, 3.16 mmol) was added to a solution of 3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazole (900 mg, 3.16 mmol) in toluene (30 mL), and the mixture was heated at 110° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified and concentrated by silica gel column chromatography (PE/EA=3/1) to obtain a crude compound. The crude compound was purified by reverse phase chromatography under the following conditions (chromatographic column: spherical C18, 20-40um, 330g; mobile phase A: water (10mmol/L NH4HCO3 ); mobile phase B: acetonitrile; flow rate: 100mL/min; gradient: 5%B-60%B in 12 minutes; detector: 254nm). At 55%B, the fractions containing the desired product were concentrated under reduced pressure to give two isomers: 305B-7-1 and 305B-7-2:

305B-7-1：(340mg，0.63mmol，收率：20.11％)，tR＝13.495min，LCMS m/z：536[M+H]+.305B-7-1: (340 mg, 0.63 mmol, yield: 20.11%), t R =13.495 min, LCMS m/z: 536 [M+H] + .

305B-7-2：(145mg，0.27mmol，收率：8.57％)，tR＝13.639min；LCMS m/z：536[M+H]+.305B-7-2: (145 mg, 0.27 mmol, yield: 8.57%), t R =13.639 min; LCMS m/z: 536 [M+H] + .

6)、1-((Z)-(3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓及其异构体的合成
6) Synthesis of 1-((Z)-(3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium and its isomers

在室温下，向溶有上述3-(4-氯苯基)-5-乙基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺及其异构体(305B-7-1)(430mg，0.80mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(612mg，4.00mmol)和4-二甲氨基吡啶(488mg，4.00mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩的得到1-((Z)-(3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓及其异构体(514mg，0.80mmol，收率：100％)，LCMS m/z：640[M]+.At room temperature, phosphorus oxychloride (612 mg, 4.00 mmol) and 4-dimethylaminopyridine (488 mg, 4.00 mmol) were added to a solution of the above-mentioned 3-(4-chlorophenyl)-5-ethyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide and its isomer (305B-7-1) (430 mg, 0.80 mmol) in dichloromethane (20 mL), and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction liquid was concentrated under reduced pressure to obtain 1-((Z)-(3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium and its isomers (514 mg, 0.80 mmol, yield: 100%), LCMS m/z: 640 [M] + .

7)、N-((E)-N′-(Z)-(-3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体的合成
7) Synthesis of N-((E)-N′-(Z)-(-3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers

在室温下，向溶有1-((Z)-(3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓及其异构体(514mg，0.80mmol)的N，N二甲基甲酰胺(20mL)溶液中，加入N-氨基甲酰氨基乙酰胺(808mg，8.00mmol)和三乙胺(808mg，8.00mmol)，室温搅拌16小时。将混合反应液用乙酸乙酯(50mL)稀释。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过反相色谱柱(色谱条件：色谱柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：5％B-80％B，12min；检测器：254nm)纯化。在75％B下，将含有所需产物的馏分收集减压浓缩得到N-((E)-N′-(Z)-(3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(340mg，0.54mmol，收率：68.54％)。LCMS：m/z：619[M+H]+.At room temperature, N-carbamoylaminoacetamide (808 mg, 8.00 mmol) and triethylamine (808 mg, 8.00 mmol) were added to a solution of 1-((Z)-(3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium and its isomers (514 mg, 0.80 mmol) in N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (chromatographic conditions: chromatographic column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-80%B, 12min; detector: 254nm). At 75%B, the fractions containing the desired product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (340mg, 0.54mmol, yield: 68.54%). LCMS: m/z: 619[M+H] + .

8)、N-((E)-N′-(Z)-(3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其对映体的合成
8) Synthesis of N-((E)-N′-(Z)-(3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimido)acetamide and its enantiomers

将化合物N-((E)-N′-(Z)-(3-(4-氯苯基)-5-乙基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(90mg，0.16mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝60：40；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：4.0mL；循环时间：4.0min)纯化得到两个异构体：MDR-001-305B-1A和MDR-001-305B-1B：The compound N-((E)-N′-(Z)-(3-(4-chlorophenyl)-5-ethyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (90 mg, 0.16 mmol) were purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Column size: 250*25mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=60:40; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 4.0mL; cycle time: 4.0min) was purified to obtain two isomers: MDR-001-305B-1A and MDR-001-305B-1B:

MDR-001-305B-1A：Peak 1Chiral HPLC：2.494min；(35.00mg，0.06mmol，收率：38.89％)，LCMS m/z：619[M+H]+.MDR-001-305B-1A: Peak 1Chiral HPLC: 2.494 min; (35.00 mg, 0.06 mmol, yield: 38.89%), LCMS m/z: 619 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，7.98-7.96(m，2H)，7.85-7.83(m，2H)，7.58-7.56(m，2H)，7.42-7.40(m，2H)，7.32-7.24(m，5H)，4.77(s，1H)，4.25-4.23(m，1H)，2.09(s，3H)，2.04-1.98(m，1H)，1.85-1.76(m，1H)，0.89-0.85(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.63(s, 1H), 7.98-7.96(m, 2H), 7.85-7.83(m, 2H), 7.58-7.56(m, 2H), 7.42-7.40(m, 2H), 7.32-7.24(m, 5H), 4.77(s, 1H), 4.25-4.23(m, 1H), 2.09(s, 3H), 2.04-1.98(m, 1H), 1.85-1.76(m, 1H), 0.89-0.85(m, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.297.

MDR-001-305B-1B：Peak 2Chiral HPLC：3.849min；(35.05mg，0.06mmol，收率：38.94％yield)，LCMS m/z：619[M+H]+.MDR-001-305B-1B: Peak 2Chiral HPLC: 3.849 min; (35.05 mg, 0.06 mmol, yield: 38.94% yield), LCMS m/z: 619 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.62(s，1H)，7.98-7.96(m，2H)，7.85-7.83(m，2H)，7.59-7.56(m，2H)，7.42-7.40(m，2H)，7.32-7.24(m，5H)，4.77(s，1H)，4.25-4.23(m，1H)，2.09(s，3H)，2.04-1.98(m，1H)，1.85-1.76(m，1H)，0.89-0.85(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.62(s, 1H), 7.98-7.96(m, 2H), 7.85-7.83(m, 2H), 7.59-7.56(m, 2H), 7.42-7.40(m, 2H), 7.32-7.24(m, 5H), 4.77(s, 1H), 4.25-4.23(m, 1H), 2.09(s, 3H), 2.04-1.98(m, 1H), 1.85-1.76(m, 1H), 0.89-0.85(m, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.297.

8)、与上述类似的方法，从3-(4-氯苯基)-5-乙基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺异构体(305B-7-2)出发，可以得到另外2个异构体：8) Using a similar method as above, starting from 3-(4-chlorophenyl)-5-ethyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide isomer (305B-7-2), another two isomers can be obtained:

MDR-001-305B-2A：Peak 1Chiral HPLC：1.415min；(40.90mg，0.07mmol，收率：45％)，LCMS m/z：619[M+H]+.MDR-001-305B-2A: Peak 1Chiral HPLC: 1.415 min; (40.90 mg, 0.07 mmol, yield: 45%), LCMS m/z: 619 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.01-7.99(m，2H)，7.85-7.83(m，2H)，7.42-7.34(m，4H)，7.31-7.23(m，3H)，7.18(s，2H)，5.23(d，J＝10.8Hz，1H)，4.57-4.51(m，1H)，2.24-2.17(m，1H)，2.07(s，3H)，1.37-1.26(m，1H)，0.46(t，J＝7.2Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.53 (s, 1H), 8.01-7.99 (m, 2H), 7.85-7.83 (m, 2H), 7.42-7.34 (m, 4H), 7.31-7.23 (m, 3H), 7.18 (s, 2H), 5.23 (d, J=10.8Hz, 1H), 4.57-4.51 (m, 1H), 2.24-2.17 (m, 1H), 2.07 (s, 3H), 1.37-1.26 (m, 1H), 0.46 (t, J=7.2Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.293. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.293.

MDR-001-305B-2B：Peak 2Chiral HPLC：2.017min；(46.16mg，0.07mmol，收率：46.16％)，LCMS：m/z：619.4[M+H]+.MDR-001-305B-2B: Peak 2Chiral HPLC: 2.017 min; (46.16 mg, 0.07 mmol, yield: 46.16%), LCMS: m/z: 619.4 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.01-7.99(m，2H)，7.85-7.83(m，2H)，7.42-7.34(m，4H)，7.31-7.18(m，3H)，7.18(s，2H)，5.23(d，J＝10.8Hz，1H)，4.57-4.51(m，1H)，2.24-2.18(m，1H)，2.07(s，3H)，1.35-1.25(m，1H)，0.46(t，J＝7.2Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.53 (s, 1H), 8.01-7.99 (m, 2H), 7.85-7.83 (m, 2H), 7.42-7.34 (m, 4H), 7.31-7.18 (m, 3H), 7.18 (s, 2H), 5.23 (d, J=10.8Hz, 1H), 4.57-4.51 (m, 1H), 2.24-2.18 (m, 1H), 2.07 (s, 3H), 1.35-1.25 (m, 1H), 0.46 (t, J=7.2Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.293. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.293.

实施例17、(2R)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基-(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(MDR-001-408)和(E)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵(MDR-001-408de)的合成：Example 17, Synthesis of (2R)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl-(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (MDR-001-408) and (E)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazine-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene-1-ammonium (MDR-001-408de):

1)、(R)-2-乙酰氧基-4-(3-(叔丁氧基羰基)胍)-N，N，N-三甲基-4-氧代丁-1-胺的合成
1) Synthesis of (R)-2-acetoxy-4-(3-(tert-butoxycarbonyl)guanidine)-N,N,N-trimethyl-4-oxobutan-1-amine

在室温下，向溶有(R)-2-乙酰氧基-3-羧基-N，N，N-三甲基丙烷-1-铵氯化物(2000mg，8.34mmol)的二氯甲烷(40mL)溶液中，加入草酰氯(1060mg，8.34mmol)和N，N-二甲基甲酰胺(0.1mL)，然后加热40℃搅拌2小时。将上述混合物加入到溶有Boc-胍(1.46g，9.17mmol)和三乙胺(844mg，8.34mmol)的四氢呋喃(50mL)和H2O(1.0mL)溶液中，室温搅拌1小时。将混合反应液减压浓缩并通过反相柱色谱(条件如下(柱：球形C18，20-40um，330g；流动相A：水；流动相B：乙腈；流速：40mL/min；梯度：0％B 10min；检测器：214nm)纯化，在0％B下，收集含有所需产物的级分，减压浓缩得到(R)-2-乙酰氧基-4-(3-(叔丁氧基羰基)胍)-N，N，N-三甲基-4-氧代丁-1-胺(845mg，2.45mmol，收率：29.3％)，LCMS m/z：345[M]+.To a solution of (R)-2-acetoxy-3-carboxy-N,N,N-trimethylpropane-1-ammonium chloride (2000 mg, 8.34 mmol) in dichloromethane (40 mL) were added oxalyl chloride (1060 mg, 8.34 mmol) and N,N-dimethylformamide (0.1 mL) at room temperature, followed by heating at 40°C and stirring for 2 hours. The above mixture was added to a solution of Boc-guanidine (1.46 g, 9.17 mmol) and triethylamine (844 mg, 8.34 mmol) in tetrahydrofuran (50 mL) and H 2 O (1.0 mL), followed by stirring at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (conditions as follows (column: spherical C18, 20-40um, 330g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 0%B 10min; detector: 214nm), at 0%B, the fractions containing the desired product were collected and concentrated under reduced pressure to give (R)-2-acetoxy-4-(3-(tert-butoxycarbonyl)guanidine)-N,N,N-trimethyl-4-oxobutan-1-amine (845mg, 2.45mmol, yield: 29.3%), LCMS m/z: 345[M] + .

2)、(R)-2-乙酰氧基-4-胍-N，N，N-三甲基-4-氧代丁-1-铵的合成
2) Synthesis of (R)-2-acetoxy-4-guanidine-N,N,N-trimethyl-4-oxobutyl-1-ammonium

在室温下，向溶有(R)-2-乙酰氧基-4-(3-(叔丁氧基羰基)胍)-N，N，N-三甲基-4-氧代丁-1-胺(845mg，2.45mmol)的甲醇(5mL)溶液中，加入盐酸甲醇(20mL，4M)和2，2，2-三氟乙酸(5mL)，室温搅拌16小时。将混合反应液减压浓缩得到(R)-2-乙酰氧基-4-胍-N，N，N-三甲基-4-氧代丁-1-铵(600mg，粗品).LCMS m/z：245[M]+ At room temperature, methanol hydrochloride (20 mL, 4 M) and 2,2,2-trifluoroacetic acid (5 mL) were added to a solution of (R)-2-acetoxy-4-(3-(tert-butoxycarbonyl)guanidine)-N,N,N-trimethyl-4-oxobutan-1-amine (845 mg, 2.45 mmol) in methanol (5 mL), and stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure to obtain (R)-2-acetoxy-4-guanidine-N,N,N-trimethyl-4-oxobutan-1-amine (600 mg, crude product). LCMS m/z: 245 [M] +

3)、(Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
3) Synthesis of (Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-5，6-二氢哒嗪-1(4H)-甲酰胺(650mg，1.23mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(943mg，6.15mmol)，4-二甲氨基吡啶(600mg，4.92mmol)，加热50℃搅拌16小时。将混合反应液减压浓缩，并通过反相快速柱色谱纯化(条件如下：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)纯化，在85％B下，收集含有所需产物的级分，减压浓缩得到(Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(600mg0.95mmol，收率：77.2％)，LCMS m/z：632[M]+.To a solution of 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxamide (650 mg, 1.23 mmol) in dichloromethane (20 mL) was added phosphorus oxychloride (943 mg, 6.15 mmol) and 4-dimethylaminopyridine (600 mg, 4.92 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 16 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm). At 85%B, the fractions containing the desired product were collected and concentrated under reduced pressure to give (Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (600mg0.95mmol, yield: 77.2%), LCMS m/z: 632[M] + .

4)、(2R)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基-(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵和(E)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵的合成
4) Synthesis of (2R)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl-(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium and (E)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobutan-2-en-1-ammonium

室温条件下，向溶有(Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(600mg0.95mmol)的N，N-二甲基甲酰胺(15mL)溶液中，加入(R)-2-乙酰氧基-4-胍-N，N，N-三甲基-4-氧代丁-1-胺(582mg，2.38mmol)和三乙胺(288mg，2.85mmol)，然后室温搅拌2小时。将混合反应液减压浓缩并用反相快速柱色谱纯化(条件如下：柱：球形C18，20-40um，80g；流动相A：0.1％TFA；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15min；检测器：254nm)。在62％B下收集含有所需产物的级分，并在减压下浓缩，得到产物粗品，粗品再次通过制备级高效液相色谱(系统：Waters 2767/Qda；柱：Sunfire C18，19*250*10um，80g；流动相A：0.1％TFA/H2O；流动相B：乙腈；流速：20mL/min；梯度：34-34％B；保留时间4.9-9.0分钟，16分钟)。在58％B下收集含有所需产物的级分，并减压浓缩得到(2R)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基-(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(MDR-001-408)(21.61mg，0.03mmol，收率：3.2％)，LCMS m/z：712[M]+和(E)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-5，6-二氢哒嗪-1(4H)-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵(MDR-001-408de)(11.64mg，0.017mmol，收率：1.8％收率)，LCMS m/z：694[M]+.To a solution of (Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (600 mg 0.95 mmol) in N,N-dimethylformamide (15 mL) at room temperature were added (R)-2-acetoxy-4-guanidine-N,N,N-trimethyl-4-oxobutan-1-amine (582 mg, 2.38 mmol) and triethylamine (288 mg, 2.85 mmol), followed by stirring at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40um, 80g; mobile phase A: 0.1% TFA; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15min; detector: 254nm). The fractions containing the desired product were collected at 62%B and concentrated under reduced pressure to obtain a crude product, which was again purified by preparative high performance liquid chromatography (system: Waters 2767/Qda; column: Sunfire C18, 19*250*10um, 80g; mobile phase A: 0.1%TFA/H2O; mobile phase B: acetonitrile; flow rate: 20mL/min; gradient: 34-34%B; retention time 4.9-9.0 minutes, 16 minutes). Fractions containing the desired product were collected at 58% B and concentrated under reduced pressure to give (2R)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl-(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (MDR-001-408) (21.61 mg, 0.03 mmol, yield: 3.2%), LCMS m/z: 712 [M] + and (E)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-5,6-dihydropyridazin-1(4H)-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium (MDR-001-408de) (11.64 mg, 0.017 mmol, yield: 1.8% yield), LCMS m/z: 694 [M] + .

MDR-001-408MDR-001-408

1H NMR(400MHz，DMSO-d6)：δ8.47(s，1H)，8.05(d，J＝8.4Hz，2H)，7.84(d，J＝7.6Hz，2H)，7.61(d，J＝8.4Hz，2H)，7.39(dd，J1＝5.2Hz，J2＝1.2Hz，1H)，7.32(d，J＝8.8Hz，2H)，6.92-6.90(m，1H)6.78-6.75(m，1H)，4.67-4.65(m，1H)，4.52-4.47(m，1H)，4.37-4.34(m，1H)，3.47-3.34(m，3H)，3.27-3.15(m，10H)，2.64-2.54(m，1H)，2.22-2.19(m，1H)，2.04-2.01(m，1H). 1 H NMR (400MHz, DMSO-d6): δ8.47 (s, 1H), 8.05 (d, J=8.4Hz, 2H), 7.84 (d, J=7.6Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.39 (dd, J1=5.2Hz, J2=1.2Hz, 1H), 7.32 (d, J=8.8Hz, 2H), 6.92-6.90 (m , 1H) 6.78-6.75 (m, 1H), 4.67-4.65 (m, 1H), 4.52-4.47 (m, 1H), 4.37-4.34 (m, 1H), 3.47-3 .34(m, 3H), 3.27-3.15(m, 10H), 2.64-2.54(m, 1H), 2.22-2.19(m, 1H), 2.04-2.01(m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.275，19F NMR (377MHz, DMSO-d6): δ-61.275,

MDR-001-408deMDR-001-408de

1H NMR(400MHz，DMSO-d6)：δ8.45(s，1H)，8.04(d，J＝8.0Hz，2H)，7.83(d，J＝7.6Hz，2H)，7.60(d，J＝7.6Hz，2H)，7.40(d，J＝5.2Hz，1H)，7.27(d，J＝8.8Hz，2H)，6.96-6.91(m，2H)，6.76(d，J＝3.0Hz，1H)，6.56(d，J＝10.8Hz，1H)，4.68(s，1H)，4.38(d，J＝12.8Hz，1H)，4.19(d，J＝7.2Hz，2H)，3.27-3.24(m，1H)，3.10(s，10H)，2.22-2.16(m，1H)，2.06-2.02(m，1H). 1 H NMR (400MHz, DMSO-d6): δ8.45 (s, 1H), 8.04 (d, J=8.0Hz, 2H), 7.83 (d, J=7.6Hz, 2H), 7.6 0 (d, J=7.6Hz, 2H), 7.40 (d, J=5.2Hz, 1H), 7.27 (d, J=8.8Hz, 2H), 6.96-6.91 (m, 2H), 6.7 6 (d, J=3.0Hz, 1H), 6.56 (d, J=10.8Hz, 1H), 4.68 (s, 1H), 4.38 (d, J=12.8Hz, 1H), 4.19 (d , J=7.2Hz, 2H), 3.27-3.24(m, 1H), 3.10(s, 10H), 2.22-2.16(m, 1H), 2.06-2.02(m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.27519F NMR (377MHz, DMSO-d6): δ-61.275

实施例18、N-(E)-N′-((E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺)乙酰胺及其异构体(MDR-001-412-1和MDR-001-412-2)的合成：Example 18, Synthesis of N-(E)-N′-((E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide)acetamide and its isomers (MDR-001-412-1 and MDR-001-412-2):

1)、3-(4-氯苯基)-4-硝基-2-苯基丁酸甲酯的合成
1) Synthesis of methyl 3-(4-chlorophenyl)-4-nitro-2-phenylbutyrate

在-70℃和氮气下，向溶有苯乙酸甲酯(5.0g，33.33mmol)的四氢呋喃(100mL)溶液中，加入二异丙基氨基锂(50mL，1M的THF溶液，50mmol)，-70℃搅拌0.5小时，加入溶有(E)-1-氯-4-(2-硝基乙烯基)苯(6.13g，33.33mmol)的四氢呋喃(10mL)溶液，-70℃搅拌2小时。将混合反应液用饱和氯化铵水溶液(50mL)淬灭，并用乙酸乙酯(300mL)稀释。合并的有机相用饱和食盐水(150mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚：乙酸乙酯＝6：1)纯化得到两个异构体：412-3-P1和412-3-P2：At -70°C and nitrogen, lithium diisopropylamide (50 mL, 1M THF solution, 50 mmol) was added to a solution of methyl phenylacetate (5.0 g, 33.33 mmol) in tetrahydrofuran (100 mL), stirred at -70°C for 0.5 hours, and a solution of (E)-1-chloro-4-(2-nitrovinyl)benzene (6.13 g, 33.33 mmol) in tetrahydrofuran (10 mL) was added, and stirred at -70°C for 2 hours. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL) and diluted with ethyl acetate (300 mL). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain two isomers: 412-3-P1 and 412-3-P2:

412-3-P1：(2.40g，7.19mmol，收率：21.62％)，1H NMR(400MHz，DMSO-d6)δ7.52-7.36(m，9H)，4.83-4.77(m，1H)，4.31-4.26(m，1H)，4.24-4.21(m，1H)，4.09-4.05(m，1H)，3.33(s，3H).412-3-P1: (2.40 g, 7.19 mmol, yield: 21.62%), 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.52-7.36 (m, 9H), 4.83-4.77 (m, 1H), 4.31-4.26 (m, 1H), 4.24-4.21 (m, 1H), 4.09-4.05 (m, 1H), 3.33 (s, 3H).

412-3-P2：(3.60g，10.78mmol，收率：32.43％)，1H NMR(400MHz，DMSO-d6)δ7.26-7.10(m，9H)， 5.00-4.98(m，2H)，4.21-4.17(m，2H)，3.64(s，3H).412-3-P2: (3.60 g, 10.78 mmol, yield: 32.43%), 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.26-7.10 (m, 9H), 5.00-4.98(m, 2H), 4.21-4.17(m, 2H), 3.64(s, 3H).

2)、4-氨基-3-(4-氯苯基)-2-苯基丁酸甲酯的合成
2) Synthesis of methyl 4-amino-3-(4-chlorophenyl)-2-phenylbutyrate

在室温条件下，向溶有3-(4-氯苯基)-4-硝基-2-苯基丁酸甲酯(2.40g，7.19mmol)的乙醇(80mL)和水(20mL)溶液中，加入铁粉(2.01g，35.95mmol)和氯化铵(1.94g，35.95mmol)，加热70℃搅拌0.5小时。将混合反应液过滤，滤液用乙酸乙酯(200mL)稀释。合并的有机相用饱和食盐水(150mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到化合物4-氨基-3-(4-氯苯基)-2-苯基丁酸甲酯(1.90g，粗品)，LCMS m/z：304[M+H]+.At room temperature, iron powder (2.01 g, 35.95 mmol) and ammonium chloride (1.94 g, 35.95 mmol) were added to a solution of 3-(4-chlorophenyl)-4-nitro-2-phenylbutyric acid methyl ester (2.40 g, 7.19 mmol) in ethanol (80 mL) and water (20 mL), and the mixture was heated at 70°C and stirred for 0.5 hours. The mixed reaction liquid was filtered and the filtrate was diluted with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound 4-amino-3-(4-chlorophenyl)-2-phenylbutyric acid methyl ester (1.90 g, crude product), LCMS m/z: 304 [M+H] + .

3)、4-(4-氯苯基)-3-苯基吡咯烷-2-酮的合成
3) Synthesis of 4-(4-chlorophenyl)-3-phenylpyrrolidin-2-one

室温条件下，向溶有4-氨基-3-(4-氯苯基)-2-苯基丁酸甲酯(1.90g，6.25mmol)的甲醇(30mL)溶液中，加入甲醇钠(1.01g，18.75mmol)，将混合物在70℃搅拌1小时。将混合反应液加乙酸乙酯(200mL)稀释，并用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤。减压浓缩。残余物通过硅胶柱色谱(石油醚：乙酸乙酯＝1：5)纯化得到化合物4-(4-氯苯基)-3-苯基吡咯烷-2-酮(1.35g，4.96mmol，收率：79.88％)，LCMS m/z：272[M+H]+.At room temperature, sodium methoxide (1.01 g, 18.75 mmol) was added to a solution of methyl 4-amino-3-(4-chlorophenyl)-2-phenylbutyrate (1.90 g, 6.25 mmol) in methanol (30 mL), and the mixture was stirred at 70 ° C for 1 hour. The mixed reaction solution was diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain compound 4-(4-chlorophenyl)-3-phenylpyrrolidin-2-one (1.35 g, 4.96 mmol, yield: 79.88%), LCMS m/z: 272 [M+H] + .

4)、3-(4-氯苯基)-4-苯基吡咯烷的制备
4) Preparation of 3-(4-chlorophenyl)-4-phenylpyrrolidine

在室温下，向溶有4-(4-氯苯基)-3-苯基吡咯烷-2-酮(1.50g，5.51mmol)的四氢呋喃(15mL)溶液中，加入硼烷四氢呋喃(27.55mL，27.55mmol，1.05M)，加热60℃搅拌16小时。向混合反应液中，加入盐酸调节pH至3，室温搅拌2小时。将混合反应液减压浓缩并通过反相柱色谱柱(色谱条件：色谱柱：球形C18，20-20-50mmol/L；球形C18，20-40um，330g；流动相A：0.1％FA/水；流动相B：乙腈；流速：100mL/min；梯度：0.1％FA/水：100mL/min；梯度：5％B-95％B，30分钟；检测器：214nm)纯化得到3-(4-氯苯基)-4-苯基吡咯烷(1.00g，3.88mmol，收率：70.4％)，LCMS m/z：299[M+H+41]+ Borane tetrahydrofuran (27.55 mL, 27.55 mmol, 1.05 M) was added to a solution of 4-(4-chlorophenyl)-3-phenylpyrrolidin-2-one (1.50 g, 5.51 mmol) in tetrahydrofuran (15 mL) at room temperature, and the mixture was heated at 60°C and stirred for 16 hours. Hydrochloric acid was added to the mixed reaction solution to adjust the pH to 3, and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-20-50mmol/L; spherical C18, 20-40um, 330g; mobile phase A: 0.1% FA/water; mobile phase B: acetonitrile; flow rate: 100mL/min; gradient: 0.1% FA/water: 100mL/min; gradient: 5%B-95%B, 30 minutes; detector: 214nm) to obtain 3-(4-chlorophenyl)-4-phenylpyrrolidine (1.00g, 3.88mmol, yield: 70.4%), LCMS m/z: 299[M+H+41] +

5)、3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰胺的合成
5) Synthesis of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboxamide

在室温下，向溶有3-(4-氯苯基)-4-苯基吡咯烷(200mg，0.78mmol)的甲苯(3mL)溶液中加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(221mg，0.78mmol)，加热110℃搅拌3小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱柱(二氯甲烷/乙酸乙酯＝3/1)纯化得到3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰胺(160mg，0.31mmol，收率：39.7％)，LCMS m/z：509[M+H]+.At room temperature, methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (221 mg, 0.78 mmol) was added to a solution of 3-(4-chlorophenyl)-4-phenylpyrrolidine (200 mg, 0.78 mmol) in toluene (3 mL), and the mixture was heated at 110°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate = 3/1) to give 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboxamide (160 mg, 0.31 mmol, yield: 39.7%), LCMS m/z: 509 [M+H] + .

6)、(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰亚胺酰氯的合成
6) Synthesis of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboximidoyl chloride

室温条件下，向溶有3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰胺(5mL)溶液中，加入PCl5(374mg，1.80mmol)，加热80℃搅拌2小时。将混合反应液减压浓缩得到(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰亚胺酰氯无需进一步纯化即可用于下一步。LCMS m/z：527[M+H]+ At room temperature, PCl 5 (374 mg, 1.80 mmol) was added to a solution of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboxamide (5 mL), and the mixture was heated at 80°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboximidoyl chloride, which was used in the next step without further purification. LCMS m/z: 527 [M+H] +

7)、N-(E)-N′-((E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺)乙酰胺的合成
7) Synthesis of N-(E)-N′-((E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide)acetamide

在室温下，向溶有(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰亚胺酰氯(350mg，0.66mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入N-氨基甲酰乙酰胺(133mg，1.32mmol)，室温搅拌0.5小时，然后加入三乙胺(333mg，3.30mmol，5.0eq.)，室温搅拌16小时。将混合反应液通过制备级高效液相色谱(色谱条件：系统：Waters 2767/Qda，Sunfire C18，19×250×10um；流动相A：0.1％FA/水；B：ACN；流速：20mL/min；梯度：64％B-64％；保留时间：8.0-10.0min of 16min)纯化得到N-(E)-N′-((E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺)乙酰胺(80mg，0.14mmol，收率：20.3％)，LCMS m/z：592[M+H]+ To a solution of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboximidoyl chloride (350 mg, 0.66 mmol) in N,N-dimethylformamide (5 mL) at room temperature was added N-aminoacetamide (133 mg, 1.32 mmol), and the mixture was stirred at room temperature for 0.5 hour. Then, triethylamine (333 mg, 3.30 mmol, 5.0 eq.) was added, and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was purified by preparative HPLC (chromatographic conditions: system: Waters 2767/Qda, Sunfire C18, 19×250×10 um; mobile phase A: 0.1% FA/water; B: ACN; flow rate: 20 mL/min; gradient: 64% B-64%; retention time: 8.0-10.0 min of 16 min) to obtain N-(E)-N′-((E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide)acetamide (80 mg, 0.14 mmol, yield: 20.3%), LCMS m/z: 592 [M+H] +

8)、N-((E)-N′-(E)-((3R，4R)-3-(4-氯苯基)-4-苯基吡咯烷-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺)乙酰胺及其异构体的合成
8) Synthesis of N-((E)-N′-(E)-((3R, 4R)-3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide)acetamide and its isomers

化合物N-(E)-N′-((E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺)乙酰胺(80mg，0.14mmol)通过制备级超临界流体色谱(色谱条件：系统；Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A：超临界CO2；流动相B：IPA，A：B＝60：40；波长：214nm；流速：120mL/min；柱温：100℃；进样量：8mL；循环时间：8.0min)纯化得到两种异构体：MDR-001-412-1和MDR-001-412-2：Compound N-(E)-N′-((E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamide)acetamide (80 mg, 0.14 mmol) was purified by preparative supercritical fluid chromatography (chromatographic conditions: system; Waters SFC 150; column name: Column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: IPA, A:B=60:40; wavelength: 214nm; flow rate: 120mL/min; column temperature: 100℃; injection volume: 8mL; cycle time: 8.0min) was purified to obtain two isomers: MDR-001-412-1 and MDR-001-412-2:

MDR-001-412-1：Chiral HPLC：2.500min；(25.11mg，0.042mmol，收率：31.4％)，LCMS m/z：592[M+H]+.MDR-001-412-1: Chiral HPLC: 2.500 min; (25.11 mg, 0.042 mmol, yield: 31.4%), LCMS m/z: 592 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.30(s，1H)，7.98(d，J＝8.0Hz，2H)，7.82(d，J＝8.4Hz，2H)，，7.34-7.17(m，9H)，4.09-4.04(m，1H)，3.75-3.60(m，3H)，3.50(t，J＝10.8Hz，11.2Hz，1H)，3.32-3.25(m，1H)，2.00(d，J＝1.6Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.30(s, 1H), 7.98(d, J=8.0Hz, 2H), 7.82(d, J=8.4Hz, 2H),, 7.34-7.17(m, 9H), 4.09-4.04(m, 1H), 3.75-3.60 (m, 3H), 3.50 (t, J=10.8Hz, 11.2Hz, 1H), 3.32-3.25 (m, 1H), 2.00 (d, J=1.6Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.283. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.283.

MDR-001-412-2：ChiralHPLC：3.773min.(23.90mg，0.040mmol，收率：29.8％)，LCMS m/z：592[M+H]+.MDR-001-412-2: ChiralHPLC: 3.773 min. (23.90 mg, 0.040 mmol, yield: 29.8%), LCMS m/z: 592 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.30(s，1H)，7.98(d，J＝8.4Hz，2H)，7.82(d，J＝8.4Hz，2H)，7.31-7.17(m，9H)，4.09-4.04(m，1H)，3.75-3.59(m，3H)，3.53-3.50(m，1H)，3.32-3.15(m，1H)，2.000(d，J＝1.6Hz，1H). 1 H NMR (400MHz, DMSO-d 6 )δ10.30 (s, 1H), 7.98 (d, J=8.4Hz, 2H), 7.82 (d, J=8.4Hz, 2H), 7.31-7.17 (m, 9H), 4.09-4.0 4(m, 1H), 3.75-3.59(m, 3H), 3.53-3.50(m, 1H), 3.32-3.15(m, 1H), 2.000(d, J=1.6Hz, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.283. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.283.

实施例19、(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵盐(MDR-001-413)的合成：
Example 19, Synthesis of (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium salt (MDR-001-413):

在室温下，向溶有(E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯(180mg，0.34mmol)的N，N-二甲基甲酰胺(3mL)溶液中，加入(R)-2-乙酰氧基-4-胍-N，N，N-三甲基-4-氧代丁-1-铵(833mg，3.40mmol)，室温搅拌0.5小时，随后加入三乙胺(515mg，5.10mmol)，室温搅拌0.5小时。将混合反应液通过制备级高效液相色谱(系统：Waters 2767/Qda；柱：Sunfire C18，19×250×10um；流动相A：0.1％TFA/水；B：ACN；流速：20mL/min；梯度：32％B- 32％；保留时间：9.8-11.2min的18min)纯化得到(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵盐(10.55mg，0.02mmol，收率：4.5％)，LCMS：m/z：698[M]+。To a solution of (E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (180 mg, 0.34 mmol) in N,N-dimethylformamide (3 mL) was added (R)-2-acetoxy-4-guanidine-N,N,N-trimethyl-4-oxobutan-1-aminium (833 mg, 3.40 mmol) at room temperature, and the mixture was stirred at room temperature for 0.5 hour, followed by the addition of triethylamine (515 mg, 5.10 mmol) and the mixture was stirred at room temperature for 0.5 hour. The mixed reaction solution was purified by preparative high performance liquid chromatography (system: Waters 2767/Qda; column: Sunfire C18, 19×250×10 um; mobile phase A: 0.1% TFA/water; B: ACN; flow rate: 20 mL/min; gradient: 32% B- 32%; retention time: 9.8-11.2 min for 18 min) was purified to give (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium salt (10.55 mg, 0.02 mmol, yield: 4.5%), LCMS: m/z: 698 [M] + .

1H NMR(400MHz，DMSO-d6)δ8.02(d，J＝8.4Hz，2H)，7.83(d，J＝8.0Hz，2H)，7.60-7.57(m，2H)，7.44-7.40(m，3H)，6.98-6.93(m，2H)，5.39(d，J＝16.4Hz，1H)，4.50-4.40(m，2H)，3.97-3.92(m，1H)，3.43-3.33(m，4H)，3.15(s，9H)，2.60-2.56(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.02 (d, J=8.4Hz, 2H), 7.83 (d, J=8.0Hz, 2H), 7.60-7.57 (m, 2H), 7.44-7.40 (m, 3H), 6.98-6.93 (m, 2H), 5.3 9(d, J=16.4Hz, 1H), 4.50-4.40(m, 2H), 3.97-3.92(m, 1H), 3.43-3.33(m, 4H), 3.15(s, 9H), 2.60-2.56(m, 2H).

19F NMR(377MHz，DMSO-d6)δ-61.258， 19 F NMR (377MHz, DMSO-d 6 ) δ-61.258,

实施例20、(2R)-4-((E)-2-((Z)-(4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(MDR-001-414)和化合物(E)-4-((E)-2-((Z)-(4-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-N，N，N-三甲基-4-氧代丁烯-2-烯-1-铵(MDR-001-414de)的合成：Example 20, (2R)-4-((E)-2-((Z)-(4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (MDR-001-414) and Synthesis of compound (E)-4-((E)-2-((Z)-(4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-N,N,N-trimethyl-4-oxobutene-2-en-1-ammonium (MDR-001-414de):

1)、2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)乙酸乙酯的合成
1) Synthesis of ethyl 2-(bicyclo[4.2.0]octan-1(6),2,4-trien-3-yl)acetate

室温下，向溶有3-溴双环[4.2.0]辛-1(6)，2，4-三烯(3.00g，16.39mmol)的甲苯(50mL)溶液中，加入3-氧代丁酸甲酯(5.70g，49.17mmol)，K3PO4(13.89g，65.56mmol)，Pd(OAc)2(372mg，1.64mmol)和t-BuXphos(1.39g，3.28mmol)，氮气保护，加热120℃搅拌16小时。将混合反应液过滤，滤饼用乙酸乙酯洗涤。收集滤液加水(200mL)稀释，并用乙酸乙酯(100mL×3)萃取。合并的有机相用饱和碳酸氢钠(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱层析(石油醚/乙酸乙酯＝50/1)纯化得到化合物2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)乙酸乙酯(2.80g，15.91mmol，收率：89.8％)，At room temperature, 3-oxobutyric acid methyl ester (5.70 g, 49.17 mmol), K 3 PO 4 (13.89 g, 65.56 mmol), Pd(OAc) 2 (372 mg, 1.64 mmol) and t-BuXphos (1.39 g, 3.28 mmol) were added to a toluene (50 mL) solution containing 3 -bromobicyclo[4.2.0]octa- 1( 6), 2,4 -triene (3.00 g, 16.39 mmol) and the mixture was heated at 120°C and stirred for 16 hours under nitrogen protection. The mixed reaction liquid was filtered and the filter cake was washed with ethyl acetate. The collected filtrate was diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1) to give ethyl 2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)acetate (2.80 g, 15.91 mmol, yield: 89.8%).

1H NMR(400MHz，CD3Cl)δ7.12(d，J＝7.6Hz，1H)，7.06-7.01(m，2H)，3.75(s，3H)，3.69(s，2H)，3.19-3.16(m，4H). 1 H NMR (400MHz, CD 3 Cl) δ 7.12 (d, J=7.6Hz, 1H), 7.06-7.01 (m, 2H), 3.75 (s, 3H), 3.69 (s, 2H), 3.19-3.16 (m, 4H).

2)、2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)乙酸的合成
2) Synthesis of 2-(bicyclo[4.2.0]oct-1(6),2,4-triene-3-yl)acetic acid

室温下，向溶有2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)乙酸乙酯(2.80g，15.91mmol)的四氢呋喃(30mL)和水(30mL)中，加入氢氧化锂(764mg，31.82mmol)，室温搅拌16小时。将混合反应液加水(200mL)淬灭，并用乙酸乙酯(50mL×3)萃取。水相用盐酸(1M)调节pH至3，再用乙酸乙酯(50mL×3)萃取。合并有机相无水硫酸钠干燥，过滤并，减压浓缩得到2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)乙酸(2.00g，12.35mmol，收率：83.8％)，At room temperature, lithium hydroxide (764 mg, 31.82 mmol) was added to tetrahydrofuran (30 mL) and water (30 mL) containing ethyl 2-(bicyclo[4.2.0]octan-1(6),2,4-triene-3-yl)acetate (2.80 g, 15.91 mmol), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was quenched by adding water (200 mL) and extracted with ethyl acetate (50 mL×3). The aqueous phase was adjusted to pH 3 with hydrochloric acid (1 M), and then extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(bicyclo[4.2.0]octan-1(6),2,4-triene-3-yl)acetic acid (2.00 g, 12.35 mmol, yield: 83.8%).

1H NMR(400MHz，CD3Cl)δ7.09(d，J＝7.6Hz，1H)，7.02-6.99(m，2H)，3.61(s，2H)，3.15(s，4H). 1 H NMR (400MHz, CD 3 Cl) δ 7.09 (d, J=7.6Hz, 1H), 7.02-6.99 (m, 2H), 3.61 (s, 2H), 3.15 (s, 4H).

3)、2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)乙-1-酮的合成
3) Synthesis of 2-(bicyclo[4.2.0]oct-1(6),2,4-triene-3-yl)-1-(4-chlorophenyl)ethan-1-one

室温下，向溶有2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)乙酸(1.80g，11.11mmol)的四氢呋喃(50mL)溶液中，加入4-氯苯甲酸甲酯(1.90g，11.11mmol)和LiHMDS(33.33mL，1M的四氢呋喃溶液，33.33mmol)，氮气保护下，室温搅拌1小时。将混合反应液加水(200mL)淬灭，并用乙酸乙酯(100mL×3)萃取。合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝50/1)纯化得到2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)乙-1-酮(2.50g，9.73mmol，收率：87.6％)。At room temperature, methyl 4-chlorobenzoate (1.90 g, 11.11 mmol) and LiHMDS (33.33 mL, 1 M tetrahydrofuran solution, 33.33 mmol) were added to a solution of 2-(bicyclo[4.2.0]octan-1(6),2,4-triene-3-yl)acetic acid (1.80 g, 11.11 mmol) in tetrahydrofuran (50 mL), and stirred at room temperature for 1 hour under nitrogen protection. The mixed reaction solution was quenched by adding water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1) to give 2-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)ethan-1-one (2.50 g, 9.73 mmol, yield: 87.6%).

1H NMR(400MHz，CD3Cl)δ8.05-8.03(m，2H)，7.61-7.59(m，2H)，7.07-6.97(m，3H)，4.32(s，2H)，3.09(s，4H). 1 H NMR (400MHz, CD 3 Cl) δ 8.05-8.03 (m, 2H), 7.61-7.59 (m, 2H), 7.07-6.97 (m, 3H), 4.32 (s, 2H), 3.09 (s, 4H).

4)、2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)-3-羟基丙-1-酮的合成
4) Synthesis of 2-(bicyclo[4.2.0]oct-1(6),2,4-triene-3-yl)-1-(4-chlorophenyl)-3-hydroxypropan-1-one

在室温下，向溶有2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)乙-1-酮(700mg，2.72mmol)的四氢呋喃(10mL)溶液中，加入多聚甲醛(816mg，27.20mmol)和碳酸钾(1.13g，8.16mmol)加热40℃搅拌2小时。将混合反应液过滤，滤液用四氢呋喃(2mL)洗涤，收集滤液减压浓缩得到2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)-3-羟基丙-1-酮(700mg，粗品)，该化合物无需进一步纯化即可用于下一步。LCMS m/z：287[M+H]+ At room temperature, paraformaldehyde (816 mg, 27.20 mmol) and potassium carbonate (1.13 g, 8.16 mmol) were added to a solution of 2-(bicyclo[4.2.0]octan-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)ethan-1-one (700 mg, 2.72 mmol) in tetrahydrofuran (10 mL), and the mixture was heated at 40°C and stirred for 2 hours. The mixed reaction solution was filtered, and the filtrate was washed with tetrahydrofuran (2 mL). The filtrate was collected and concentrated under reduced pressure to give 2-(bicyclo[4.2.0]octan-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)-3-hydroxypropan-1-one (700 mg, crude product), which was used in the next step without further purification. LCMS m/z: 287 [M+H] +

5)、2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)丙-2-烯-1-酮的合成
5) Synthesis of 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)prop-2-en-1-one

在室温下，向溶有2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)-3-羟基丙-1-酮(400mg，1.39mmol)的甲苯(8mL)溶液，加入对甲苯磺酸(397mg，2.09mmol)，加热80℃搅拌1小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝10/1)纯化得到2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)丙-2-烯-1-酮(266mg，0.99mmol，收率：71.2％)，LCMS m/z：269[M+H]+.At room temperature, p-toluenesulfonic acid (397 mg, 2.09 mmol) was added to a toluene (8 mL) solution of 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)-3-hydroxypropan-1-one (400 mg, 1.39 mmol), and the mixture was heated to 80°C and stirred for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)prop-2-en-1-one (266 mg, 0.99 mmol, yield: 71.2%), LCMS m/z: 269[M+H] + .

6)、4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑的合成
6) Synthesis of 4-(bicyclo[4.2.0]oct-1(6),2,4-triene-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole

室温下，向溶有2-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-1-(4-氯苯基)丙-2-烯-1-酮(266mg，0.99mmol)的四氢呋喃(5mL)溶液中，加入NH2NH2.H2O(396mg，7.92mmol)，加热80℃搅拌4小时。将混合反应液减压浓缩，并用硅胶柱色谱法(二氯甲烷/乙酸乙酯＝15/1)纯化得到4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑(205mg，0.72mmol，收率：73％)，LCMS m/z：283[M+H]+ At room temperature, NH2NH2.H2O (396 mg, 7.92 mmol) was added to a solution of 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-1-(4-chlorophenyl)prop- 2- en - 1 -one (266 mg, 0.99 mmol) in tetrahydrofuran (5 mL), and the mixture was heated at 80°C and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/ethyl acetate=15/1) to give 4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (205 mg, 0.72 mmol, yield: 73%), LCMS m/z: 283 [M+H] +

7)、4-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成
7) Synthesis of 4-(bicyclo[4.2.0]oct-1(6),2,4-triene-3-yl)-3-(4-chlorophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑(216mg，0.76mmol)的甲苯(5mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸乙酯(216mg，0.76mmol)，加热120℃搅拌3小时。将混合反应液减压浓，并在硅胶(二氯甲烷/乙酸乙酯＝10/1)纯化得到4-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(210mg，0.39mmol，收率：51.6％)，LCMS m/z：534[M+H]+ To a solution of 4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (216 mg, 0.76 mmol) in toluene (5 mL) was added ethyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (216 mg, 0.76 mmol) at room temperature, and the mixture was heated at 120°C with stirring for 3 hours. The mixed reaction solution was concentrated under reduced pressure and purified on silica gel (dichloromethane/ethyl acetate=10/1) to give 4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (210 mg, 0.39 mmol, yield: 51.6%), LCMS m/z: 534 [M+H] +

8)、(E)-4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-N-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-碳杂亚胺甲酰基氯的合成
8) Synthesis of (E)-4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbazyl imide carboxylic acid chloride

室温下，向溶有4-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(170mg，0.32mmol)的氯苯(1mL)溶液中，加入五氯化磷(133mg，0.64mmol)，加热80℃搅拌20小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝15/1)纯化得到(E)-4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-N-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-碳杂亚胺甲酰基氯(80mg，0.14mmol，收率：45.5％)，LCMS m/z：552[M+H]+ Phosphorus pentachloride (133 mg, 0.64 mmol) was added to a solution of 4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (170 mg, 0.32 mmol) in chlorobenzene (1 mL) at room temperature, and the mixture was heated at 80°C with stirring for 20 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to give (E)-4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbazyl imide carboxylic acid chloride (80 mg, 0.14 mmol, yield: 45.5%), LCMS m/z: 552 [M+H] +

9)、(2R)-4-((E)-2-((Z)-(4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(MDR-001-414)和化合物(E)-4-((E)-2-((Z)-(4-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-N，N，N-三甲基-4-氧代丁烯-2-烯-1-铵(MDR-001-414de)的合成
9), (2R)-4-((E)-2-((Z)-(4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (MDR-001-414) and Synthesis of the compound (E)-4-((E)-2-((Z)-(4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-N,N,N-trimethyl-4-oxobutene-2-en-1-ammonium (MDR-001-414de)

在室温下，向溶有(E)-4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-N-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-碳杂亚胺甲酰基氯(80mg，0.14mmol)的N，N-二甲基甲酰胺(1mL)溶液中，加入(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵盐(67mg，0.28mmol)，室温搅拌0.5小时，然后加入三乙胺(28mg，0.28mmol)，室温搅拌16小时。将混合反应液减压浓缩并通过高效液相色谱(系统：Waters 2767/Qda；柱：Column：Sunfire C18，19×250×10um；：流动相A：0.1％TFA/水；流动相B：ACN；流速：20mL/min；梯度：64％B-64％；保留时间：8.0-10.0min(16min))纯化得到两个化合物：MDR-001-414和MDR-001-414de： To a solution of (E)-4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboimidate chloride (80 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) at room temperature was added (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium salt (67 mg, 0.28 mmol), and the mixture was stirred at room temperature for 0.5 hour. Then, triethylamine (28 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (system: Waters 2767/Qda; column: Sunfire C18, 19×250×10 um; mobile phase A: 0.1% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 64% B-64%; retention time: 8.0-10.0 min (16 min)) to obtain two compounds: MDR-001-414 and MDR-001-414de:

MDR-001-414：化合物(2R)-4-((E)-2-((Z)-(4-(二环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(11.89mg，0.02mmol，收率：11.4％)，LCMS m/z：718[M+H]+ MDR-001-414: Compound (2R)-4-((E)-2-((Z)-(4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (11.89 mg, 0.02 mmol, yield: 11.4%), LCMS m/z: 718 [M+H] +

11H NMR(400MHz，DMSO-d6)δ10.66(s，1H)，8.02(d，J＝8.0Hz，2H)，7.84(d，J＝8.8Hz，2H)，7.53(d，J＝8.4Hz，2H)，7.39(d，J＝8.4Hz，2H)，7.09(t，J＝7.6Hz，6.8Hz，1H)，7.02-6.96(m，2H)，5.77(t，J＝4.8Hz，6.0Hz，1H)，5.00-4.96(m，1H)，4.53-4.46(m，2H)，3.86-3.82(m，1H)，3.51-3.44(m，2H)，3.15(s，9H)，3.06(s，4H)，2.67-2.59(m，4H). 11 H NMR (400MHz, DMSO-d 6 ) δ10.66 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.8Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 7.09 (t, J=7.6Hz, 6.8Hz, 1H), 7.02-6.96 (m, 2H ), 5.77 (t, J=4.8Hz, 6.0Hz, 1H), 5.00-4.96 (m, 1H), 4.53-4.46 (m, 2H), 3.86- 3.82 (m, 1H), 3.51-3.44 (m, 2H), 3.15 (s, 9H), 3.06 (s, 4H), 2.67-2.59 (m, 4H).

19F NMR(377MHz，DMSO-d6)δ-61.268， 19 F NMR (377MHz, DMSO-d 6 ) δ-61.268,

MDR-001-414de(E)-4-((E)-2-((Z)-(4-(双环[4.2.0]辛-1(6)，2，4-三烯-3-基)-3-(4-氯苯基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍基)-N，N，N-三甲基-4-氧代丁烯-2-烯-1-铵(6.06mg，0.01mmol，收率：5.9％)LCMS m/z：718[M+H]+.MDR-001-414de(E)-4-((E)-2-((Z)-(4-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)-3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidino)-N,N,N-trimethyl-4-oxobutene-2-en-1-ammonium (6.06 mg, 0.01 mmol, yield: 5.9%) LCMS m/z: 718 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.48(s，1H)，8.02(d，J＝8.4Hz，2H)，7.80(d，J＝8.8Hz，2H)，7.51(d，J＝8.8Hz，2H)，7.38(d，J＝8.8Hz，2H)，7.09(d，J＝8.8Hz，1H)，7.02-6.98(m，2H)，6.90-6.84(m，1H)，6.54-6.49(m，1H)，4.98-4.91(m，1H)，4.47-4.39(m，1H)，4.16(d，J＝4.8Hz，2H)，3.86-3.82(m，2H)，3.15(s，1H)，3.08-3.06(s，13H). 1 H NMR (400 MHz, DMSO-d 6 ) δ8.48 (s, 1H), 8.02 (d, J = 8.4Hz, 2H), 7.80 (d, J = 8.8Hz, 2H), 7.51 (d, J = 8. 8Hz, 2H), 7.38 (d, J=8.8Hz, 2H), 7.09 (d, J=8.8Hz, 1H), 7.02-6.98 (m, 2H), 6 .90-6.84(m, 1H), 6.54-6.49(m, 1H), 4.98-4.91(m, 1H), 4.47-4.39(m, 1H), 4.16 (d, J=4.8Hz, 2H), 3.86-3.82 (m, 2H), 3.15 (s, 1H), 3.08-3.06 (s, 13H).

19F NMR(377MHz，DMSO-d6)δ-61.23. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.23.

实施例21、2-氨基-N-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)乙烷-1-磺酰胺(MDR-001-500)的合成：Example 21, Synthesis of 2-amino-N-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)ethane-1-sulfonamide (MDR-001-500):

1)、(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基甲酸叔丁酯的合成
1) Synthesis of tert-butyl (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)carbamate

在室温条件下，向溶有5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羧酸(3.00g，7.85mmol)的叔丁醇(60mL)溶液中，加入叠氮磷酸二苯酯(2.16g，7.85mmol)，三乙胺(1.59g，15.70mmol)，氮气保护加热85℃搅拌16小时。将混合反应液加水(20mL)淬灭，并用乙酸乙酯(60mL×2)萃取。合并的有机相用饱和食盐水(60mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝5/1)纯化得到化合物(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基甲酸叔丁酯(1.22g，2.69mmol，收率：34.2％)，LCMS m/z：452[M+H]+。At room temperature, diphenylphosphoryl azide (2.16 g, 7.85 mmol) and triethylamine (1.59 g, 15.70 mmol) were added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (3.00 g, 7.85 mmol) in tert-butyl alcohol (60 mL). The mixture was heated at 85 °C and stirred for 16 hours under nitrogen protection. The mixed reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic phase was washed with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give tert-butyl (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)carbamate (1.22 g, 2.69 mmol, yield: 34.2%), LCMS m/z: 452 [M+H] + .

2)、5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-胺的合成
2) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amine

在室温条件下，向溶有(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基甲酸叔丁酯(1.22g，2.69mmol)的二氯甲烷(5mL)溶液中，加入2，2，2-三氟乙酸(5mL)，室温搅拌2小时。将混合反应液二氯甲烷(100mL)稀释，并用饱和的碳酸钠溶液调节pH到7-8。有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱析法(石油醚/乙酸乙酯＝2/1)纯化得到化合物5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-胺(604mg，1.71mmol，收率：63.5％)，LCMS m/z：352[M+H]+。At room temperature, 2,2,2-trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)carbamate (1.22 g, 2.69 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with dichloromethane (100 mL), and the pH was adjusted to 7-8 with a saturated sodium carbonate solution. The organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-amine (604 mg, 1.71 mmol, yield: 63.5%), LCMS m/z: 352[M+H] + .

3)、N-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-(1，3-二氧代异吲哚啉-2-基)乙烷-1-磺酰胺的合成
3) Synthesis of N-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-(1,3-dioxoisoindolin-2-yl)ethane-1-sulfonamide

在室温条件下，向溶有5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-胺(200mg，0.57mmol)的吡啶(20mL)溶液中，加2-(1，3-二氧代异吲哚啉-2-基)乙烷-1-磺酰氯(236mg，0.86mmol)，氮气保护加热70℃搅拌2小时。将混合反应液加水(30mL)淬灭，并用乙酸乙酯(40mL×2)萃取。合并的有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(石油醚/乙酸乙酯＝2/1)纯化得到化合物N-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-(1，3-二氧代异吲哚啉-2-基)乙烷-1-磺酰胺(120mg，0.20mmol，收率：35.9％)，LCMS m/z：589[M+H]+。At room temperature, add 2-(1,3-dioxoisoindolin-2-yl)ethane-1-sulfonyl chloride (236 mg, 0.86 mmol) to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-amine (200 mg, 0.57 mmol) in pyridine (20 mL), and heat at 70 ° C with nitrogen protection and stir for 2 hours. The mixed reaction liquid is quenched with water (30 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phase is washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give compound N-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-(1,3-dioxoisoindolin-2-yl)ethane-1-sulfonamide (120 mg, 0.20 mmol, yield: 35.9%), LCMS m/z: 589 [M+H] + .

4)、2-氨基-N-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)乙烷-1-磺酰胺的合成
4) Synthesis of 2-amino-N-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)ethane-1-sulfonamide

在室温下，向溶有N-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-(1，3-二氧代异吲哚啉-2-基)乙烷-1-磺酰胺(120mg，0.20mmol)的四氢呋喃(10mL)溶液中，加入水合肼(128mg，4.00mmol)，加热60℃搅拌1小时。将混合反应液过滤并减压浓缩。残余物通过反相快速色谱法(色谱条件：色谱柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20min内得到5％B-50％B；检测器：214nm)纯化得到化合物2-氨基-N-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)乙烷-1-磺酰胺(54.99mg，0.12mmol，收率：58.7％)，LCMS m/z：459[M+H]+。To a solution of N-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-(1,3-dioxoisoindolin-2-yl)ethane-1-sulfonamide (120 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was added hydrazine hydrate (128 mg, 4.00 mmol) at room temperature, and the mixture was heated at 60° C. with stirring for 1 hour. The mixed reaction liquid was filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (chromatographic conditions: chromatographic column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5% B-50% B in 20min; detector: 214nm) to give compound 2-amino-N-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)ethane-1-sulfonamide (54.99mg, 0.12mmol, yield: 58.7%), LCMS m/z: 459[M+H] + .

1H NMR(400MHz，DMSO-d6)δ7.72(d，J＝1.6Hz，1H)，7.54-7.49(m，2H)，7.43(d，J＝8.4Hz，2H)，7.17(d，J＝8.8Hz，2H)，3.31(t，J＝6.8Hz，2H)，3.05(t，J＝6.8Hz，2H)，1.97(s，3H). 1 H NMR (400MHz, DMSO-d6) δ7.72 (d, J=1.6Hz, 1H), 7.54-7.49 (m, 2H), 7.43 (d, J=8.4Hz, 2 H), 7.17 (d, J=8.8Hz, 2H), 3.31 (t, J=6.8Hz, 2H), 3.05 (t, J=6.8Hz, 2H), 1.97 (s, 3H).

实施例22、(R)-4-((5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(MDR-001-501)的合成：Example 22, Synthesis of (R)-4-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)amino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (MDR-001-501):

1)、(R)-2-乙酰氧基-4-((5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基)-N，N，N-三甲基-4-氧代丁-1-铵的合成
1) Synthesis of (R)-2-acetoxy-4-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)amino)-N,N,N-trimethyl-4-oxobutyl-1-ammonium

在室温条件下，向溶有(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-胺(200mg，0.57mmol)的四氢呋喃(4mL)溶液中，加入(R)-2-乙酰氧基-4-氯-N，N，N-三甲基-4-氧代丁烷-1-铵(2.80mL)，室温混搅拌2小时。将混合反应液过滤并减压浓缩。残余物通过反相快快速柱色谱法(色谱条件：色谱柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20min内得到5％B-50％B；检测器：214nm)纯化，讲流动相B含量达到5％时，收集含有产物的级分，减压浓缩得到化合物(R)-2-乙酰氧基-4-((5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基)-N，N，N-三甲基-4-氧代丁-1-铵(163mg，0.30mmol，收率：53.3％)，LCMS：m/z：537[M]+。At room temperature, (R)-2-acetoxy-4-chloro-N,N,N-trimethyl-4-oxobutane-1-ammonium (2.80 mL) was added to a solution of (4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: chromatographic column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-50%B in 20min; detector: 214nm). When the content of mobile phase B reached 5%, the fractions containing the product were collected and concentrated under reduced pressure to give compound (R)-2-acetoxy-4-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)amino)-N,N,N-trimethyl-4-oxobutan-1-ammonium (163mg, 0.30mmol, yield: 53.3%), LCMS: m/z: 537[M] + .

2)、(R)-4-((5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵的合成
2) Synthesis of (R)-4-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)amino)-2-hydroxy-N,N,N-trimethyl-4-oxobutyl-1-ammonium

在室温条件下，向溶有(R)-2-乙酰氧基-4-((5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基)-N，N，N-三甲基-4-氧代丁-1-铵(153mg，0.28mmol)的甲醇(5mL)和水(2.5mL)溶液中，加入氢氧化锂(13mg，0.56mmol)，室温搅拌1小时。将所得混合反应液过滤并减压浓缩。残余物通过制备级高效液相色谱纯化(色谱条件：系统：Waters 2767/QDA，色谱柱：Sunfire C18 19*250*10μm；流动相A：0.1％FA/H2O，B：乙腈；流速：20ml/min；梯度：30-30％；保留时间：18分钟8.0-12.0min)纯化得到化合物(R)-4-((5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-基)氨基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(36.47mg，0.11mmol，收率：25.8％)，LCMS m/z：461[M+H]+。To a solution of (R)-2-acetoxy-4-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)amino)-N,N,N-trimethyl-4-oxobutan-1-aminium (153 mg, 0.28 mmol) in methanol (5 mL) and water (2.5 mL) was added lithium hydroxide (13 mg, 0.56 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The resulting mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic conditions: system: Waters 2767/QDA, column: Sunfire C18 19*250*10 μm; mobile phase A: 0.1% FA/ H2O , B: acetonitrile; flow rate: 20 ml/min; gradient: 30-30%; retention time: 18 minutes 8.0-12.0 min) to give compound (R)-4-((5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)amino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (36.47 mg, 0.11 mmol, yield: 25.8%), LCMS m/z: 461 [M+H]+.

1H NMR(400MHz，DMSO-d6)δ10.46(s，1H)，7.75(s，1H)，7.57-7.52(m，2H)，7.45(d，J＝4.8Hz，2H)，7.19(d，J＝4.8Hz，2H)，6.63-6.45(m，1H)，4.54(d，J＝6.8Hz，1H)，3.43(t，J＝10.0Hz，2H)，3.16(s，9H)，2.60-2.54(m，2H)，1.9(s，3H). 1 H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 7.75 (s, 1H), 7.57-7.52 (m, 2H), 7.45 (d, J = 4.8Hz, 2H), 7.19 (d, J = 4.8Hz, 2 H), 6.63-6.45 (m, 1H), 4.54 (d, J=6.8Hz, 1H), 3.43 (t, J=10.0Hz, 2H), 3.16 (s, 9H), 2.60-2.54 (m, 2H), 1.9 (s, 3H).

实施例23、(R)-4-(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(MDR-001-502)的合成：Example 23, Synthesis of (R)-4-(2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazino)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (MDR-001-502):

1)、2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼-1-羧酸叔丁酯的合成
1) Synthesis of tert-butyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxylate

室温条件下，向溶有5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羧酸(1.50g，3.95mmol)，肼基甲酸叔丁酯(1.56g，11.85mmol)，HATU(2.25g，5.93mmol)的DMF(20mL)溶液中，加入DIEA(1.53g，11.85mmol)，室温搅拌2小时。将混合反应液反应液倒入水(200mL)中，并用乙酸乙酯(150mL×2)萃取，合并有机相用饱和食盐水(200×5mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝2/1)得到(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼-1-羧酸叔丁酯(1.27g，2.56mmol，收率：64.8％)，LCMS m/z：439[M-56]+.At room temperature, DIEA (1.53 g, 11.85 mmol) was added to a DMF (20 mL) solution containing 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1.50 g, 3.95 mmol), tert-butyl carbazate (1.56 g, 11.85 mmol), and HATU (2.25 g, 5.93 mmol), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was poured into water (200 mL), extracted with ethyl acetate (150 mL × 2), and the combined organic phases were washed with saturated brine (200 × 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to give tert-butyl (2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxylate (1.27 g, 2.56 mmol, yield: 64.8%), LCMS m/z: 439 [M-56] + .

2)、5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-碳酰肼的合成
2) Synthesis of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazide

室温下，向溶有2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼-1-羧酸叔丁酯(600mg，1.21mmol)的二氯甲烷(12mL)溶液中，加入2，2，2-三氟乙酸(6mL)溶液，室温搅拌1小时。将混合反应液减压浓缩。残余物通过反相快速柱色谱(色谱柱：球形C18，20-40um，330g；流动相A：水(0.05％TFA)；流动相B：乙腈；流速：60mL/min；梯度：5-95％B 30min；检测：214nm)纯化得到5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-碳酰肼(470mg，1.19mmol，收率：98％)。LCMSm/z：397[M+H+2]+. At room temperature, 2,2,2-trifluoroacetic acid (6 mL) solution was added to a solution of tert-butyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine-1-carboxylate (600 mg, 1.21 mmol) in dichloromethane (12 mL), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 um, 330 g; mobile phase A: water (0.05% TFA); mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5-95% B 30 min; detection: 214 nm) to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazide (470 mg, 1.19 mmol, yield: 98%). LCMS m/z: 397 [M+H+2] + .

3)、(R)-2-乙酰氧基-4-(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼基)-N，N，N-三甲基-4-氧代丁-1-铵的合成
3) Synthesis of (R)-2-acetoxy-4-(2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine)-N,N,N-trimethyl-4-oxobutyl-1-ammonium

室温条件下，向溶有5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-碳酰肼(470mg，1.19mmol)的四氢呋喃(5mL)溶液中，加入三乙胺(120mg，1.19mmol)和(R)-2-乙酰氧基-4-氯-N，N，N-三甲基-4-氧代丁烷-1-铵(279mg，1.25mmol)，室温搅拌1小时。将混合反应液通过反相快速柱色谱法(色谱柱：球形C18，20-40um，40g；流动相A：水(0.05％TFA)；流动相B：乙腈；流速：50mL/min；梯度：5-95％B 30min；检测：214nm)纯化。当梯度为5％B时收集含有产物的级分，减压浓缩得到(R)-2-乙酰氧基-4-(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼基)-N，N，N-三甲基-4-氧代丁-1-铵(466mg，0.80mmol，收率：67.2％)，LCMS m/z：582[M+2]+ At room temperature, triethylamine (120 mg, 1.19 mmol) and (R)-2-acetoxy-4-chloro-N,N,N-trimethyl-4-oxobutane-1-ammonium (279 mg, 1.25 mmol) were added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazide (470 mg, 1.19 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 um, 40 g; mobile phase A: water (0.05% TFA); mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5-95% B 30 min; detection: 214 nm). When the gradient was 5% B, the fractions containing the product were collected and concentrated under reduced pressure to give (R)-2-acetoxy-4-(2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazino)-N,N,N-trimethyl-4-oxobutan-1-ammonium (466 mg, 0.80 mmol, yield: 67.2%), LCMS m/z: 582 [M+2] +

4)、(R)-4-(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵的合成
4) Synthesis of (R)-4-(2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine)-2-hydroxy-N,N,N-trimethyl-4-oxobutyl-1-ammonium

室温下向溶有502-6((R)-2-乙酰氧基-4-(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼基)-N，N，N-三甲基-4-氧代丁-1-铵(466mg，0.80mmol)的四氢呋喃(6mL)和水(3mL)溶液中，加入氢氧化锂(41mg，1.72mmol)，室温搅拌30分钟。将混合反应液减压浓缩并通过反相快速柱色谱法(色谱柱：球形C18，20-40um，80g；流动相A：水(0.05％TFA)；流动相B：乙腈；流速：40mL/min；梯度：5-50％B 10min；检测：214nm)纯化，当梯度为5％B时，收集含有产物的级分，减压浓缩得到化合物(R)-4-(2-(5-(4-氯苯基)-1-(2，4-二氯苯基)-4-甲基-1H-吡唑-3-羰基)肼基)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(245mg，0.45mmol，收率：56.5％)，LCMS m/z：540[M+2]+.To a solution of 502-6((R)-2-acetoxy-4-(2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine)-N,N,N-trimethyl-4-oxobutan-1-ammonium (466 mg, 0.80 mmol) in tetrahydrofuran (6 mL) and water (3 mL) was added lithium hydroxide (41 mg, 1.72 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40 um, 80 g; mobile phase A: water (0.05% TFA); mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5-50% B 10min; detection: 214nm) purification, when the gradient is 5%B, the fractions containing the product are collected and concentrated under reduced pressure to obtain compound (R)-4-(2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)hydrazine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (245mg, 0.45mmol, yield: 56.5%), LCMS m/z: 540[M+2] + .

1H NMR(400MHz，DMSO-d6)δ10.06(s，1H)，8.51(s，1H)，7.80-7.75(m，2H)，7.61-7.59(m，1H)，7.49-7.46(m，2H)，7.26-7.23(m，2H)，4.51-4.46(m，1H)，3.50-3.45(m，2H)，3.14(s，9H)，2.51-2.45(m，1H)，2.43-2.32(m，1H)，2.24(s，3H). 1 H NMR (400MHz, DMSO-d6) δ10.06 (s, 1H), 8.51 (s, 1H), 7.80-7.75 (m, 2H), 7.61-7.59 (m, 1H), 7.49-7.46 (m, 2H), 7.26- 7.23(m, 2H), 4.51-4.46(m, 1H), 3.50-3.45(m, 2H), 3.14(s, 9H), 2.51-2.45(m, 1H), 2.43-2.32(m, 1H), 2.24(s, 3H).

实施例24、(5Z，8Z，11Z，14Z，17Z)-N-((E)-N′-((Z)-((R)3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)二十碳-5，8，11，14，17-五烯酰胺及其对映体(MDR-001-601S和MDR-001-601R)的合成：Example 24. Synthesis of (5Z, 8Z, 11Z, 14Z, 17Z)-N-((E)-N′-((Z)-((R)3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoformimidoyl)eicosyl-5,8,11,14,17-pentaenamide and its enantiomers (MDR-001-601S and MDR-001-601R):

1)、(5Z，8Z，11Z，14Z，17Z)-二十碳-5，8，11，14，17-五烯酰氯的合成：
1) Synthesis of (5Z, 8Z, 11Z, 14Z, 17Z)-20-carbon-5, 8, 11, 14, 17-pentaenoyl chloride:

在0℃下，向溶有(5Z，8Z，11Z，14Z，17Z)-二十碳-5，8，11，14，17-五烯酸(1.00g，3.31mmol)的二氯甲烷(10mL)溶剂中，加入草酰氯(841mg，6.62mmol)和N，N-二甲基甲酰胺(2滴)，0℃搅拌2小时。薄层色谱显示(石油醚：乙酸乙酯＝1：1，Rf＝0.6)有新产物。将混合物反应液减压浓缩得到化合物(5Z，8Z，11Z，14Z，17Z)-二十碳-5，8，11，14，17-五烯酰氯(1.20g，粗品)。At 0°C, oxalyl chloride (841 mg, 6.62 mmol) and N,N-dimethylformamide (2 drops) were added to a dichloromethane (10 mL) solvent containing (5Z, 8Z, 11Z, 14Z, 17Z)-eicosane-5, 8, 11, 14, 17-pentaenoic acid (1.00 g, 3.31 mmol), and stirred at 0°C for 2 hours. Thin layer chromatography showed (petroleum ether: ethyl acetate = 1: 1, Rf = 0.6) a new product. The reaction mixture was concentrated under reduced pressure to obtain compound (5Z, 8Z, 11Z, 14Z, 17Z)-eicosane-5, 8, 11, 14, 17-pentaenoic acid chloride (1.20 g, crude product).

1H NMR(400MHz，DMSO-d6)δ5.34-5.27(m，10H)，2.22-2.18(m，8H)，2.22-2.18(m，2H)，2.07-2.02(m，4H)，1.56-1.53(m，2H)，0.94-0.90(m，3H). 1 H NMR (400MHz, DMSO-d6) δ5.34-5.27(m, 10H), 2.22-2.18(m, 8H), 2.22-2.18(m, 2H), 2.07-2.02(m, 4H), 1.56-1.53(m, 2H), 0.94-0.90(m, 3H).

2)、(5Z，8Z，11Z，14Z，17Z)-N-氨基甲亚胺酰基二十碳-5，8，11，14，17-五烯酰胺甲酸叔丁酯的合成：
2) Synthesis of (5Z, 8Z, 11Z, 14Z, 17Z)-N-aminomethyliminoyl 20-carbon-5, 8, 11, 14, 17-pentaenoamide formate tert-butyl ester:

在0℃下，向溶有(5Z，8Z，11Z，14Z，17Z)-二十碳-5，8，11，14，17-五烯酰氯(300mg，0.93mmol)和氨基甲亚胺酰基氨基甲酸叔丁酯(223mg，1.40mmol)的二氯甲烷(3mL)溶液中，加入三乙胺(376mg，3.72mmol)，0℃搅拌16小时。LCMS显示出37％的产物。将混合物用饱和绿环铵水溶液(50mL)淬灭，并用二氯甲烷(30mL×2)萃取。合并的有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相柱色谱(色谱条件：柱：球形C18，20-40um，120g；流动相A：水(0.1％NH3.H2O)；流动相B：乙腈；流速：100mL/min；梯度：0％B-100％B走20分钟；检测器：254nm)纯化得到(5Z，8Z，11Z，14Z，17Z)-N-氨基甲亚胺酰基二十碳-5，8，11，14，17-五烯酰胺甲酸叔丁酯(150mg，0.34mmol，收率：36.1％)，LCMS m/z：444[M+H]+ At 0°C, triethylamine (376 mg, 3.72 mmol) was added to a solution of (5Z, 8Z, 11Z, 14Z, 17Z)-20-carbon-5, 8, 11, 14, 17-pentaenoyl chloride (300 mg, 0.93 mmol) and aminomethylimidoylcarbamic acid tert-butyl ester (223 mg, 1.40 mmol) in dichloromethane (3 mL), and stirred at 0°C for 16 hours. LCMS showed 37% of the product. The mixture was quenched with saturated aqueous green ammonium solution (50 mL) and extracted with dichloromethane (30 mL × 2). The combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 120 g; mobile phase A: water (0.1% NH3.H2O ); mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 0% B-100% B for 20 minutes; detector: 254 nm) to give (5Z, 8Z, 11Z, 14Z, 17Z)-N-aminomethyliminoyl eicosapenta-5, 8, 11, 14, 17-pentaenamide formic acid tert-butyl ester (150 mg, 0.34 mmol, yield: 36.1%), LCMS m/z: 444 [M+H] +

3)、(5Z，8Z，11Z，14Z，17Z)-N-氨基甲亚胺酰基二十碳-5，8，11，14，17-五烯酰胺的合成：
3) Synthesis of (5Z, 8Z, 11Z, 14Z, 17Z)-N-aminomethyliminoyl 20-carbon-5, 8, 11, 14, 17-pentaenoic acid amide:

在室温下，向溶有(5Z，8Z，11Z，14Z，17Z)-N-氨基甲亚胺酰基二十碳-5，8，11，14，17-五烯酰胺甲酸叔丁酯(150mg，0.34mmol)的二氯甲烷(10mL)溶液中，加入2，2，2-三氟乙酸(3mL)，室温搅拌2小时。将混合反应液用二氯甲烷(20mL)稀释并减压浓缩得到(5Z，8Z，11Z，14Z，17Z)-N-氨基甲亚胺酰基二十碳-5，8，11，14，17-五烯酰胺(250mg，粗品)，LCMS m/z：344[M+H]+。At room temperature, 2,2,2-trifluoroacetic acid (3 mL) was added to a solution of (5Z,8Z,11Z,14Z,17Z)-N-aminoformimidoyl eicosa-5,8,11,14,17-pentaenamide formic acid tert-butyl ester (150 mg, 0.34 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with dichloromethane (20 mL) and concentrated under reduced pressure to obtain (5Z,8Z,11Z,14Z,17Z)-N-aminoformimidoyl eicosa-5,8,11,14,17-pentaenamide (250 mg, crude product), LCMS m/z: 344 [M+H] + .

4)、((5Z，8Z，11Z，14Z，17Z)-N-((E)-N′-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)二十碳-5，8，11，14，17-五烯酰胺的合成
4) Synthesis of ((5Z, 8Z, 11Z, 14Z, 17Z)-N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethyliminoyl)eicosyl-5,8,11,14,17-pentaenamide

在室温下，向溶有(5Z，8Z，11Z，14Z，17Z)-N-氨基甲亚胺酰基二十碳-5，8，11，14，17-五烯酰胺(261mg，0.76mmol)，(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-碳杂亚胺酰氯(200mg，0.38mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入三乙胺(307mg，3.04mmol)，室温搅拌1小时。LCMS显示8％的产物。将混合反应液加水(50mL)淬灭，并用乙酸乙酯(30mL×2)萃取。合并的有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相柱色谱(色谱条件：柱：球形C18，20-40um，120g；流动相A：水(0.1％NH3.H2O)；流动相B：乙腈；流速：60mL/min；梯度：30％B-100％B，20分钟；检测器：254nm)。在100％B下，收集含有所需产物的组分，减压浓缩得到((5Z，8Z，11Z，14Z，17Z)-N-((E)-N′-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)二十碳-5，8，11，14，17-五烯酰胺(50mg，0.06mmol，收率：15.7％)，LCMS m/z：833[M+H]+。At room temperature, triethylamine (307 mg, 3.04 mmol) was added to a solution of (5Z, 8Z, 11Z, 14Z, 17Z)-N-aminomethyliminoyl eicosa-5, 8, 11, 14, 17-pentaenamide (261 mg, 0.76 mmol), (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbazyl chloride (200 mg, 0.38 mmol) in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 1 hour. LCMS showed 8% of the product. The mixed reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 120 g; mobile phase A: water (0.1% NH3.H2O ); mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 30% B-100% B, 20 minutes; detector: 254 nm). At 100% B, the fractions containing the desired product were collected and concentrated under reduced pressure to give ((5Z,8Z,11Z,14Z,17Z)-N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)eicosyl-5,8,11,14,17-pentaenamide (50 mg, 0.06 mmol, yield: 15.7%), LCMS m/z: 833 [M+H] + .

5)、(5Z，8Z，11Z，14Z，17Z)-N-((E)-N′-((Z)-((S)3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)二十碳-5，8，11，14，17-五烯酰胺及其对映体的分离：
5), (5Z, 8Z, 11Z, 14Z, 17Z)-N-((E)-N′-((Z)-((S)3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)eicosyl-5,8,11,14,17-pentaenamide and separation of its enantiomers:

将((5Z，8Z，11Z，14Z，17Z)-N-((E)-N′-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)二十碳-5，8，11，14，17-五烯酰(90mg，0.10mmol)通过超临界流体色谱(色谱条件：Waters SFC 150，柱：REGIS(S，S)WHELK-O1，1250*25mm 10um；A：超临界CO2，流动相B：ACN；A：B＝75：25；波长：214nm；流速：120mL/min；柱温：RT；柱压：100bar；注射液：2.0mL；循环时间：8.0分钟；样品溶液的制备：将样品溶解在约30mLACN中)得到两个异构体：(5Z，8Z，11Z，14Z，17Z)-N-((E)-N′-((Z)-((R)3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)二十碳-5，8，11，14，17-五烯酰胺及其对映体(MDR-001-601S和MDR-001-601R)：((5Z,8Z,11Z,14Z,17Z)-N-((E)-N′-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)eicosyl-5,8,11,14,17-pentaenoyl (90 mg, 0.10 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: Waters SFC 150, column: REGIS (S,S) WHELK-O1, 1250*25 mm 10 um; A: supercritical CO 2 , mobile phase B: ACN; A: B = 75:25; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar; injection: 2.0mL; circulation time: 8.0min; sample solution preparation: dissolve the sample in about 30mL ACN) to obtain two isomers: (5Z, 8Z, 11Z, 14Z, 17Z)-N-((E)-N′-((Z)-((R)3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethyliminoyl)eicosyl-5,8,11,14,17-pentaenamide and its enantiomers (MDR-001-601S and MDR-001-601R):

MDR-001-601S：峰1：3.109min；(10.45mg，0.01mmol，收率：11.6％)，LCMS m/z：833[M+H]+.MDR-001-601S: Peak 1: 3.109 min; (10.45 mg, 0.01 mmol, yield: 11.6%), LCMS m/z: 833 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.52(s，1H)，8.00(d，J＝8.0Hz，2H)，7.81(d，J＝8.4Hz，2H)，7.50(d，J＝8.8Hz，2H)，7.36-7.24(m，7H)，5.38-5.25(m，10H)，5.05-5.00(m，1H)，4.51-4.46(m，1H)，3.89-3.85(m，1H)，2.82-2.75(m，8H)，2.39-2.36(m，2H)，2.08-1.99(m，5H)，1.62-1.55(m，2H)，0.91(t，J＝7.2Hz，3H). 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 8.00 (d, J=8.0Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.36-7.24 (m, 7H), 5.38-5.25 (m, 10H), 5.05 -5.00(m,1H),4.51-4.46(m,1H),3.89-3.85(m,1H),2.82-2.75(m,8H),2.3 9-2.36 (m, 2H), 2.08-1.99 (m, 5H), 1.62-1.55 (m, 2H), 0.91 (t, J=7.2Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.34. 19 F NMR (377MHz, DMSO-d6) δ-61.34.

MDR-001-601R：峰2：3.984min；(6.16mg，0.01mmol，收率：6.8％)，LCMSm/z：833[M+H]+.MDR-001-601R: Peak 2: 3.984 min; (6.16 mg, 0.01 mmol, yield: 6.8%), LCMS m/z: 833 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.52(s，1H)，8.01(d，J＝8.4Hz，2H)，7.81(d，J＝8.8Hz，2H)，7.50(d，J＝8.4Hz，2H)，7.36-7.22(m，7H)，5.39-5.24(m，10H)，5.05-5.00(m，1H)，4.51-4.46(m，1H)，3.89-3.85(m，1H)，2.85-2.78(m，8H)，2.45-2.33(m，2H)，2.08-1.99(m，4H)，1.62-1.55(m，3H)，0.91(t，J＝7.6Hz，3H). 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 7.36-7.22 (m, 7H), 5.39-5.24 (m, 10H), 5.05 -5.00(m,1H),4.51-4.46(m,1H),3.89-3.85(m,1H),2.85-2.78(m,8H),2.4 5-2.33 (m, 2H), 2.08-1.99 (m, 4H), 1.62-1.55 (m, 3H), 0.91 (t, J=7.6Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.34. 19 F NMR (377MHz, DMSO-d6) δ-61.34.

实施例25、(Z)-2-(3-(4-氯苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氨基)乙烷-1-磺酸(MDR-001-603A)的合成：
Example 25, Synthesis of (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoylamino)ethane-1-sulfonic acid (MDR-001-603A):

在室温下，向溶有(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-碳杂亚胺酰氯(60mg，0.11mmol)的N，N-二甲基甲酰胺(4mL)溶液中，加入2-胍基乙烷-1-磺酸(37mg，0.22mmol)，三乙胺(22mg，0.22mmol)，室温搅拌1小时。将所得混合物过滤并减压浓缩。残余物通过制备级高效液相色谱(系统：Waters 2767/QDA，色谱柱：Sunfire C18，19*250mm，10um；流动相A：0.05％TFA/H2O，流动相B：乙腈；流速：20mL/min；梯度：75-95％保留时间：8.0分钟(17分钟))纯化得到(Z)-2-(3-(4-氯苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氨基)乙烷-1-磺酸At room temperature, 2-guanidinoethane-1-sulfonic acid (37 mg, 0.22 mmol) and triethylamine (22 mg, 0.22 mmol) were added to a solution of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboimidoyl chloride (60 mg, 0.11 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (system: Waters 2767/QDA, column: Sunfire C18, 19*250 mm, 10 um; mobile phase A: 0.05% TFA/H 2 O, mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: 75-95% retention time: 8.0 min (17 min)) to give (Z)-2-(3-(4-chlorophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoylamino)ethane-1-sulfonic acid.

(8.65mg，0.01mmol，收率：12.3％)，LCMS m/z：615[M+H]+。(8.65 mg, 0.01 mmol, yield: 12.3%), LCMS m/z: 615 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.7(s，1H)，(d，J＝8.4，2H)，8.02(d，J＝8.4，2H)，7.82(d，J＝8.4，2H)，7.69(d，J＝8.8，2H)，7.44(d，J＝8.8，2H)，7.33(t，J＝7.2，2H)，7.27-7.20(m，3H)，5.07(t，J＝6.8，1H)，4.48(t，J＝11.2，1H)，3.96-3.92(m，1H)，3.67-3.63(m，2H)，2.72-2.68(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.7 (s, 1H), (d, J = 8.4, 2H), 8.02 (d, J = 8.4, 2H), 7.82 (d, J = 8.4, 2H), 7.69 (d, J = 8.8, 2H), 7.44 (d, J = 8.8, 2H), 7.33 (t, J = 7. 2, 2H), 7.27-7.20 (m, 3H), 5.07 (t, J=6.8, 1H), 4.48 (t, J=11.2, 1H), 3.96-3.92 (m, 1H), 3.67-3.63 (m, 2H), 2.72-2.68 (m, 2H).

19F NMR(377MHz，DMSO-d6)δ-61.32 19 F NMR (377MHz, DMSO-d 6 ) δ-61.32

实施例26、N-((E)-N′-((Z)-((S)-3-(4-氯苯基)-4-(1，1-二羟基噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺及其对映体(MDR-001-701-1和MDR-001-701-2)的合成：
Example 26, Synthesis of N-((E)-N′-((Z)-((S)-3-(4-chlorophenyl)-4-(1,1-dihydroxythiophene-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide and its enantiomers (MDR-001-701-1 and MDR-001-701-2):

在室温下，向溶有N-((E)-N′-((Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺或对映体(100mg，0.17mmol)的二氯甲烷溶液(5mL)中，加入3-氯过氧苯甲酸(74mg，0.43mmol)和三氟化硼·乙醚(11mg，0.08mmol)，加热40℃搅拌2小时。将混合反应液减压浓缩。残余物通过制备级高效液相色谱(色谱条件：系统：Waters 2767/QDA柱：Sunfire C18，19*250mm*10um，流速：20mL/min；流动相A：0.05％TFA/H2O；流动相B：乙腈；梯度：53-58％B；保留时间：9-10min，16分钟，检测器：214nm)。收集含有产物的级分，冻干得到N-((E)-N′-((Z)-((S)-3-(4-氯苯基)-4-(1，1-二羟基噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(26mg，0.04mmol，收率：24.6％)，LCMS m/z：629[M+H]+.To a solution of N-((E)-N′-((Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (100 mg, 0.17 mmol) in dichloromethane (5 mL) were added 3-chloroperoxybenzoic acid (74 mg, 0.43 mmol) and boron trifluoride·ethyl ether (11 mg, 0.08 mmol) at room temperature, and the mixture was heated at 40° C. with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic conditions: system: Waters 2767/QDA column: Sunfire C18, 19*250 mm*10 um, flow rate: 20 mL/min; mobile phase A: 0.05% TFA/ H2O ; mobile phase B: acetonitrile; gradient: 53-58% B; retention time: 9-10 min, 16 minutes, detector: 214 nm). The fractions containing the product were collected and lyophilized to give N-((E)-N′-((Z)-((S)-3-(4-chlorophenyl)-4-(1,1-dihydroxythiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (26 mg, 0.04 mmol, yield: 24.6%), LCMS m/z: 629 [M+H] + .

MDR-001-701-1：峰1手性HPLC保留时间：1.124min；(26mg，0.04mmol，产率24.6％)，LCMS m/z：629[M+H]+ MDR-001-701-1: Peak 1 chiral HPLC retention time: 1.124 min; (26 mg, 0.04 mmol, yield 24.6%), LCMS m/z: 629 [M+H] +

1H NMR(400MHz，DMSO-d6)δ10.54(s，1H)，8.01(d，J＝8.4Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.53(s，4H)，7.27(d，J＝7.2Hz，1H)，7.03(dd，J＝6.4，4.4Hz，1H)，6.43(d，J＝4.4Hz，1H)，5.01(dd，J＝11.6，4.4Hz，1H)，4.28(t，J＝11.8Hz，1H)，4.14(dd，J＝12.0，4.8Hz，1H)，2.07(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.54 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.53 (s, 4H), 7.27 (d, J = 7.2Hz, 1H), 7.03 (dd, J = 6.4, 4.4Hz, 1 H), 6.43 (d, J=4.4Hz, 1H), 5.01 (dd, J=11.6, 4.4Hz, 1H), 4.28 (t, J=11.8Hz, 1H), 4.14 (dd, J=12.0, 4.8Hz, 1H), 2.07 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.324. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.324.

MDR-001-701-2：峰1手性HPLC保留时间：1.200min；(26mg，0.04mmol，产率23.5％)，LCMS：m/z＝629.3[M+H]+ MDR-001-701-2: Peak 1 chiral HPLC retention time: 1.200 min; (26 mg, 0.04 mmol, yield 23.5%), LCMS: m/z=629.3 [M+H] +

1H NMR(400MHz，DMSO-d6)δ10.54(s，1H)，8.01(d，J＝8.4Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.53(s，4H)，7.27(d，J＝6.8Hz，1H)，7.03(dd，J＝7.2，4.8Hz，1H)，6.43(d，J＝4.0Hz，1H)，5.00(dd，J＝11.6，4.4Hz，1H)，4.28(t，J＝11.6Hz，1H)，4.14(dd，J＝12.0，4.8Hz，1H)，2.07(s，3H). 1 H NMR (400MHz, DMSO-d6) δ 10.54 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.53 (s, 4H), 7.27 (d, J = 6.8Hz, 1H), 7.03 (dd, J = 7. 2, 4.8Hz, 1H), 6.43 (d, J=4.0Hz, 1H), 5.00 (dd, J=11.6, 4.4Hz, 1H), 4.28 (t, J=11.6Hz, 1H), 4.14 (dd, J=12.0, 4.8Hz, 1H), 2.07 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.326. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.326.

实施例27、N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MDR-001-702-1、MDR-001-702-2、MDR-001-702-3和MDR-001-702-4)的合成：Example 27, Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimido)acetamide and its isomers (MDR-001-702-1, MDR-001-702-2, MDR-001-702-3 and MDR-001-702-4):

1)、1-(4-氯苯基)-3-羟基-2-(噻吩-2-基)丁-1-酮的合成
1) Synthesis of 1-(4-chlorophenyl)-3-hydroxy-2-(thiophen-2-yl)butan-1-one

在室温下，向溶有1-(4-氯苯基)-2-(噻吩-2-基)乙-1-酮(2.00g，8.44mmol)的四氢呋喃(50mL)溶液中，的溶液中，加入乙醛(3.71g，84.40mmol)和碳酸钾(3.49g，25.32mmol)，室温搅拌16小时。将混合反应液过滤，滤饼用四氢呋喃(25mL)洗涤，收集滤液减压浓缩得到1-(4-氯苯基)-3-羟基-2-(噻吩-2-基)丁-1-酮(2.37g，粗品)，直接用于下一步，无需进一步纯化，LCMS m/z：281[M+H]+.At room temperature, acetaldehyde (3.71 g, 84.40 mmol) and potassium carbonate (3.49 g, 25.32 mmol) were added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethan-1-one (2.00 g, 8.44 mmol) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was filtered, the filter cake was washed with tetrahydrofuran (25 mL), and the filtrate was collected and concentrated under reduced pressure to obtain 1-(4-chlorophenyl)-3-hydroxy-2-(thiophen-2-yl)butan-1-one (2.37 g, crude product), which was used directly in the next step without further purification. LCMS m/z: 281 [M+H] + .

2)、(Z)-1-(4-氯苯基)-2-(噻吩-2-基)丁-2-烯-1-酮的合成
2) Synthesis of (Z)-1-(4-chlorophenyl)-2-(thiophen-2-yl)but-2-en-1-one

在室温下，向溶有1-(4-氯苯基)-3-羟基-2-(噻吩-2-基)-1-丁酮(2.37g，8.43mmol)的甲苯(40mL)溶液中，加入对甲苯磺酸(2.40g，12.65mmol)，加热80℃搅拌1小时。将混合反应液减压浓缩，残余物通过硅胶柱色谱(石油醚/乙酸乙酯＝10/1)纯化的得到化合物(Z)-1-(4-氯苯基)-2-(噻吩-2-基)丁-2-烯-1-酮(1.00g，3.80mmol，收率：45.1％)，LCMS m/z：263[M+H]+。At room temperature, p-toluenesulfonic acid (2.40 g, 12.65 mmol) was added to a toluene (40 mL) solution of 1-(4-chlorophenyl)-3-hydroxy-2-(thiophen-2-yl)-1-butanone (2.37 g, 8.43 mmol), and the mixture was heated to 80°C and stirred for 1 hour. The mixed reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound (Z)-1-(4-chlorophenyl)-2-(thiophen-2-yl)but-2-en-1-one (1.00 g, 3.80 mmol, yield: 45.1%), LCMS m/z: 263 [M+H] + .

3)、3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑的合成
3) Synthesis of 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole

在室温条件下，向溶有溶有(Z)-1-(4-氯苯基)-2-(噻吩-2-基)丁-2-烯-1-酮(1.00g，3.80mmol)的乙醇(20mL)溶液中，加入NH2NH2.H2O(973mg，30.40mmol)，加热80℃搅拌4小时。将混合反应液减压浓缩，并通过硅胶柱色谱(石油醚/乙酸乙酯＝5/1)纯化得到化合物3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(590mg，2.13mmol，收率：56.1％)，LCMS m/z：277[M+H]+ At room temperature, NH2NH2.H2O (973 mg, 30.40 mmol) was added to a solution of (Z)-1-(4-chlorophenyl)-2-(thiophen-2-yl)but-2-en-1-one (1.00 g, 3.80 mmol) in ethanol ( 20 mL ), and the mixture was heated to 80°C and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (590 mg, 2.13 mmol, yield: 56.1%), LCMS m/z: 277 [M+H] +

4)、3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成
4) Synthesis of 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(590mg，2.13mmol)的甲苯(8mL)溶液中，加入(4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(603mg，2.13mmol)，加热110℃搅拌4小时。将混合反应液减压浓缩，并通过硅胶柱色谱(二氯甲烷/甲醇＝30/1)纯化得到3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(360mg，0.68mmol，收率：31.9％)，LCMS m/z：528[M+H]+。To a solution of 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (590 mg, 2.13 mmol) in toluene (8 mL) was added methyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (603 mg, 2.13 mmol) at room temperature, and the mixture was heated at 110° C. and stirred for 4 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane/methanol=30/1) to give 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (360 mg, 0.68 mmol, yield: 31.9%), LCMS m/z: 528 [M+H] + .

5)、(Z)-1-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
5) Synthesis of (Z)-1-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(170mg，0.32mmol)的二氯甲烷(3mL)溶液中，加入4-二甲氨基吡啶(195mg，1.60mmol)和三氯氧磷(245mg，1.60mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到(Z)-1-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(203mg，粗品)，直接用于下一步，无需进一步纯化，LCMS m/z：633[M+H]+。To a solution of 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (170 mg, 0.32 mmol) in dichloromethane (3 mL) was added 4-dimethylaminopyridine (195 mg, 1.60 mmol) and phosphorus oxychloride (245 mg, 1.60 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction liquid was concentrated under reduced pressure to give (Z)-1-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (203 mg, crude product), which was used directly in the next step without further purification. LCMS m/z: 633 [M+H] + .

6)、N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺的合成
6) Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide

在室温条件下，向溶有(Z)-1-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(203mg，0.32mmol)的N，N-二甲基甲酰胺(10mL)溶液中，加入N-氨基甲亚胺酰基乙酰胺(129mg，1.28mmol)和三乙胺(259mg，2.56mmol)，室温搅拌1小时。将混合反应液减压浓缩，并通反相快速柱色谱纯化(色谱条件：色谱柱：球形C18，20-40um，330g；流动相A：水(含0.1％FA)；流动相B：乙腈；流速：80mL/min；梯度：5％-95％B 30min；检测器：214nm)纯化，。在70％B下，收集产物的级分，减压浓缩得到N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(100mg，0.16mmol，收率：51％)，LCMS m/z：611[M+H]+。To a solution of (Z)-1-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (203 mg, 0.32 mmol) in N,N-dimethylformamide (10 mL) at room temperature were added N-aminomethyliminoylacetamide (129 mg, 1.28 mmol) and triethylamine (259 mg, 2.56 mmol), and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (chromatographic conditions: chromatographic column: spherical C18, 20-40um, 330g; mobile phase A: water (containing 0.1% FA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%-95% B 30min; detector: 214nm). At 70% B, the product fractions were collected and concentrated under reduced pressure to give N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (100mg, 0.16mmol, yield: 51%), LCMS m/z: 611[M+H] + .

7)N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺各异构体(MDR-001-702-1，MDR-001-702-2和MDR-001-702-3/4)的分离制备：
7) Separation and preparation of each isomer of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimido)acetamide (MDR-001-702-1, MDR-001-702-2 and MDR-001-702-3/4):

化合物N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(100mg，0.16mmol)通过超临界流体色谱(系统：Waters SFC 150 Waters SFC 150；色谱柱名称：色谱柱尺寸：250*40mm 10μm；流动相A：超临界CO2；流动相B：IPA(+0.1％7.0mol/1氨水在MeOH中)，A：B＝70：30；波长：214nm；流量：120mL/min；色谱柱温度：室温；背压：100bar；进样：5.0mL；循环时间：13.79min)纯化得到3个异构体：MDR-001-702-1，MDR-001-702-2and MDR-001-702-3/4：Compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoylimido)acetamide (100 mg, 0.16 mmol) was purified by supercritical fluid chromatography (system: Waters SFC 150 Waters SFC 150; column name: Column size: 250*40mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (+0.1% 7.0mol/1 ammonia in MeOH), A:B=70:30; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; back pressure: 100bar; injection: 5.0mL; cycle time: 13.79min) was purified to obtain 3 isomers: MDR-001-702-1, MDR-001-702-2and MDR-001-702-3/4:

MDR-001-702-1：峰1：chiral HPLC：4.212min；(12.92mg，0.02mmol，收率：12.9％)，LCMS m/z：611[M+H]+.MDR-001-702-1: Peak 1: chiral HPLC: 4.212 min; (12.92 mg, 0.02 mmol, yield: 12.9%), LCMS m/z: 611 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.61(s，1H)，7.99(d，J＝6.8Hz，2H)，7.84(d，J＝8.0Hz，2H)，7.60(d，J＝7.6Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.40(d，J＝4.8Hz，1H)，6.95-6.91(m，2H)，5.01(s，1H)，4.42-4.40(m，1H)，2.08(s，3H)，1.44(d，J＝4.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.61 (s, 1H), 7.99 (d, J = 6.8Hz, 2H), 7.84 (d, J = 8.0Hz, 2H), 7.60 (d, J = 7.6Hz, 2H), 7.45 (d, J = 8.0Hz, 2H), 7 .40 (d, J=4.8Hz, 1H), 6.95-6.91 (m, 2H), 5.01 (s, 1H), 4.42-4.40 (m, 1H), 2.08 (s, 3H), 1.44 (d, J=4.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.297. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.297.

MDR-001-702-1：峰2：chiral HPLC：6.261min；(1.56mg，0.002mmol，收率：1.56％)，LCMS m/z：611[M+H]+.MDR-001-702-1: Peak 2: chiral HPLC: 6.261 min; (1.56 mg, 0.002 mmol, yield: 1.56%), LCMS m/z: 611 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.48(s，1H)，7.99(d，J＝8.4Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.46-7.44(m，3H)，7.41-7.39(m，2H)，6.98-6.96(m，1H)，6.84(d，J＝2.8Hz，1H)，5.51(d，J＝10.8Hz，1H)，4.76-4.72(m，1H)，2.06(s，3H)，1.12(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.48 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.46-7.44 (m, 3H), 7.41-7.39 (m, 2H), 6.98-6.9 6 (m, 1H), 6.84 (d, J = 2.8Hz, 1H), 5.51 (d, J = 10.8Hz, 1H), 4.76-4.72 (m, 1H), 2.06 (s, 3H), 1.12 (d, J = 6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.304. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.304.

MDR-001-702-3/4：峰3：chiral HPLC：4.437-5.758min；(45mg，0.07mmol，收率：45％)，LCMS m/z：611[M+H]+.MDR-001-702-3/4: Peak 3: chiral HPLC: 4.437-5.758 min; (45 mg, 0.07 mmol, yield: 45%), LCMS m/z: 611 [M+H] + .

化合物MDR-001-702-3和MDR-001-702-4的进一步分离制备：Further separation and preparation of compounds MDR-001-702-3 and MDR-001-702-4:

将化合物MDR-001-702-3/4(45mg，0.07mmol)通过制备级超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/1氨甲醇)，A：B＝85：15；波长：214nm；流速：120mL/min；色谱柱温度：室温；进样压力：100bar；进样量：1.0mL；循环时间：12.92min)纯化得到两种异构体：MDR-001-702-3和MDR-001-702-4：Compound MDR-001-702-3/4 (45 mg, 0.07 mmol) was purified by preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Column size: 250*25mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (+0.1% 7.0mol/1 ammonia methanol), A:B=85:15; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; injection pressure: 100bar; injection volume: 1.0mL; cycle time: 12.92min) was purified to obtain two isomers: MDR-001-702-3 and MDR-001-702-4:

MDR-001-702-3：峰1：chiral HPLC：4.447min；(15.87mg，0.03mmol，收率：35.2％)，LCMS m/z：611[M+H]+.MDR-001-702-3: Peak 1: chiral HPLC: 4.447 min; (15.87 mg, 0.03 mmol, yield: 35.2%), LCMS m/z: 611 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.62(s，1H)，7.99(d，J＝7.2Hz，2H)，7.84(d，J＝7.6Hz，2H)，7.61(d，J＝7.6Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.40(d，J＝4.8Hz，1H)，6.95-6.91(m，2H)，5.01(s，1H)，4.42-4.40(m，1H)，2.06(s，3H)，1.45(d，J＝5.6Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.62 (s, 1H), 7.99 (d, J = 7.2Hz, 2H), 7.84 (d, J = 7.6Hz, 2H), 7.61 (d, J = 7.6Hz, 2H), 7.45 (d, J = 8.0Hz, 2H), 7 .40 (d, J=4.8Hz, 1H), 6.95-6.91 (m, 2H), 5.01 (s, 1H), 4.42-4.40 (m, 1H), 2.06 (s, 3H), 1.45 (d, J=5.6Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.301. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.301.

MDR-001-702-4：峰2：chiral HPLC：5.645min；(2.91mg，0.005mmol，收率：6.5％)，LCMS m/z： 611[M+H]+.MDR-001-702-4: Peak 2: chiral HPLC: 5.645 min; (2.91 mg, 0.005 mmol, yield: 6.5%), LCMS m/z: 611[M+H] + .

1H NMR(400MHz，DMSO-d6)10.48(s，1H)，7.99(d，J＝8.4Hz，2H)，7.84(d，J＝8.0Hz，2H)，7.46-7.44(m，3H)，7.41-7.39(m，2H)，6.98-6.96(m，1H)，6.84(d，J＝2.8Hz，1H)，5.51(d，J＝10.8Hz，1H)，4.76-4.72(m，1H)，2.06(s，3H)，1.12(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )10.48 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.84 (d, J=8.0Hz, 2H), 7.46-7.44 (m, 3H), 7.41-7.39 (m, 2H), 6.98-6.96 (m, 1H), 6.84 (d, J = 2.8Hz, 1H), 5.51 (d, J = 10.8Hz, 1H), 4.76-4.72 (m, 1H), 2.06 (s, 3H), 1.12 (d, J = 6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.305. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.305.

实施例28、(Z)-3-(4-氯苯基)-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺及其异构体(MDR-001-806-1和MDR-001-806-2)的合成：Example 28, Synthesis of (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide and its isomers (MDR-001-806-1 and MDR-001-806-2):

1)、(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯的合成
1) Synthesis of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride

室温下，向溶有3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(1.2g，2.37mmol)的氯苯(50mL)溶液中，加入PCl5(980mg，4.74mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩得到(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(1200mg，2.28mmol，收率：96％)，直接用于下一步，没有进一步纯化。LCMS m/z：526[M+H]+。At room temperature, PCl5 (980 mg, 4.74 mmol) was added to a solution of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.2 g, 2.37 mmol) in chlorobenzene (50 mL), and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure to give (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (1200 mg, 2.28 mmol, yield: 96%), which was used directly in the next step without further purification. LCMS m/z: 526 [M+H] + .

2)、(Z)-3-(4-氯苯基)-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺的合成
2) Synthesis of (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide

在室温下，向溶有(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(1200mg，2.28mmol)的DMF(20mL)溶液中，加入2-氨基乙烷-1-磺酰胺(566mg，4.56mmol)和三乙胺(465mg，4.56mmol)，室温搅拌2小时。将混合反应液用乙酸乙酯(100mL)稀释，并用食盐水(50mL×3)洗涤。收集有机相相用无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(条件：柱：球形C18，20-40um，330g；流动相A：水(0.1％FA)；流动相B：乙腈；流速：80mL/min；梯度：在40分钟内5％B-75％B；检测器：254nm))纯化，在60％B下，收集含有产物的级分，减压浓缩得到(Z)-3-(4-氯苯基)-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺(800mg，1.30mmol，收率：57.1％)，LCMS m/z：614[M+H]+.At room temperature, 2-aminoethane-1-sulfonamide (566 mg, 4.56 mmol) and triethylamine (465 mg, 4.56 mmol) were added to a solution of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (1200 mg, 2.28 mmol) in DMF (20 mL), and stirred at room temperature for 2 hours. The mixed reaction solution was diluted with ethyl acetate (100 mL) and washed with brine (50 mL×3). The collected organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions: column: spherical C18, 20-40 um, 330 g; mobile phase A: water (0.1% FA); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-75% B in 40 minutes; detector: 254 nm)). At 60% B, the fractions containing the product were collected and concentrated under reduced pressure to give (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (800 mg, 1.30 mmol, yield: 57.1%), LCMS m/z: 614 [M+H] + .

3)、(Z)-3-(4-氯苯基)-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺异构体(MDR-001-806-1和MDR-001-806-2)的制备：
3) Preparation of (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MDR-001-806-1 and MDR-001-806-2):

化合物(Z)-3-(4-氯苯基)-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺(800mg，1.30mmol)通过超临界流体色谱(色谱条件：体系：Waters SFC 150；柱名：柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/1氨在MEOH中)，A：B＝65：35波长：214nm流量：120mL/min柱温：RT背压：100bar，进样量：5.0mL；循环时间：12.0min)制备分离得到两种异构体：MDR-001-806-1和MDR-001-806-2：Compound (Z)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (800 mg, 1.30 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Column size: 250*30mm 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0mol/1 ammonia in MEOH), A:B=65:35 wavelength: 214nm flow rate: 120mL/min column temperature: RT back pressure: 100bar, injection volume: 5.0mL; cycle time: 12.0min) preparation and separation to obtain two isomers: MDR-001-806-1 and MDR-001-806-2:

MDR-001-806-1：峰1，chiral HPLC：2.663min；(305.91mg，0.498mmol，38.3％yield)，LCMS m/z：614[M+H]+.MDR-001-806-1: Peak 1, chiral HPLC: 2.663min; (305.91mg, 0.498mmol, 38.3% yield), LCMS m/z: 614[M+H] + .

1H NMR(400MHz，DMSO-d6)：δ8.25(t，J＝5.6Hz，1H)，8.03(d，J＝8.0Hz，2H)，7.85(d，J＝8.4Hz，2H)，7.72(d，J＝8.8Hz，2H)，7.46-7.44(m，2H)，7.35-7.32(m，2H)，7.28-7.22(m，3H)，7.04(s，2H)，5.10(dd，J1＝10.8Hz，J2＝4.0Hz，1H)，4.55(t，J＝11.2Hz，1H)，4.06(dd，J1＝11.2Hz，J2＝4.4Hz，1H)，3.73(dd，J1＝12.8Hz，J2＝6.8Hz，2H)，3.30-3.26(m，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.25 (t, J=5.6Hz, 1H), 8.03 (d, J=8.0Hz, 2H), 7.85 (d, J=8.4Hz, 2H), 7.72 (d , J=8.8Hz, 2H), 7.46-7.44(m, 2H), 7.35-7.32(m, 2H), 7.28-7.22(m, 3H), 7.04(s , 2H), 5.10 (dd, J1=10.8Hz, J2=4.0Hz, 1H), 4.55 (t, J=11.2Hz, 1H), 4.06 (dd, J1= 11.2Hz, J2＝4.4Hz, 1H), 3.73(dd, J1＝12.8Hz, J2＝6.8Hz, 2H), 3.30-3.26(m, 2H).

19F NMR(377MHz，DMSO-d6)：δ-61.330. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.330.

MDR-001-806-2：峰2，chiral HPLC：3.621min，(329.18mg，0.536mmol，41.2％yield)，LCMS m/z：614[M+H]+.MDR-001-806-2: Peak 2, chiral HPLC: 3.621min, (329.18mg, 0.536mmol, 41.2% yield), LCMS m/z: 614[M+H] + .

1H NMR(400MHz，DMSO-d6)：δ8.25(t，J＝5.6Hz，1H)，8.03(d，J＝8.0Hz，2H)，7.85(d，J＝8.4Hz，2H)，7.71(d，J＝8.4Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.35-7.32(m，2H)，7.28-7.22(m，3H)，7.04(s，2H)，5.10(dd，J1＝11.2Hz，J2＝4.4Hz，1H)，4.55(t，J＝11.2Hz，1H)，4.06(dd，J1＝11.2Hz，J2＝4.4Hz，1H)，3.73(dd，J1＝12.8Hz，J2＝6.8Hz，2H)，3.30-3.26(m，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.25 (t, J=5.6Hz, 1H), 8.03 (d, J=8.0Hz, 2H), 7.85 (d, J=8.4Hz, 2H), 7.71 (d, J＝8.4Hz, 2H), 7.45(d, J＝8.8Hz, 2H), 7.35-7.32(m, 2H), 7.28-7.22(m, 3H), 7.04( s, 2H), 5.10 (dd, J1=11.2Hz, J2=4.4Hz, 1H), 4.55 (t, J=11.2Hz, 1H), 4.06 (dd, J1 =11.2Hz, J2=4.4Hz, 1H), 3.73 (dd, J1=12.8Hz, J2=6.8Hz, 2H), 3.30-3.26 (m, 2H).

19F NMR(377MHz，DMSO-d6)：δ-61.330. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.330.

实施例29、N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺及其异构体(MRANK-111-001-1、MRANK-111-001-2、MRANK-111-001-3和MRANK-111-001-4)的合成：Example 29. Synthesis of N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide and its isomers (MRANK-111-001-1, MRANK-111-001-2, MRANK-111-001-3 and MRANK-111-001-4):

1)、(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
1) Synthesis of (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

向3-(4-氰基苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(5.00 g，9.76mmol)的二氯甲烷(100mL)溶液中，加入DMAP(3.57g，29.28mmol)和POCl3(2.24g，1.36mL，14.64mmol)，加热60℃搅拌2小时。将混合反应液减压浓缩得到(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(8.6g，粗品)，LCMS m/z：617[M]+.To 3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (5.00 g, 9.76mmol) in dichloromethane (100mL), DMAP (3.57g, 29.28mmol) and POCl3 (2.24g, 1.36mL, 14.64mmol) were added, and the mixture was heated at 60°C and stirred for 2 hours. The mixed reaction liquid was concentrated under reduced pressure to obtain (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (8.6g, crude product), LCMS m/z: 617[M] + .

2)、N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺的合成
2) Synthesis of N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethyliminoyl)acetamide

向(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(8.6g，9.76mmol)的DMF溶液中，加入N-氨基甲酰乙酰胺(4.93g，48.8mmol)和三乙胺(6.90g，9.6mL，68.32mmol)，室温搅拌16小时。混合反应液用乙酸乙酯(250mL)稀释，并用饱和食盐水(200mL×3)洗涤，无水硫酸钠干燥，过滤减压浓缩。残余物用反相快速柱色谱(条件如下：柱：球形C18，20-40μm，330g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：5％-70％B40分钟，检测器：214nm)纯化，在70％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(1.9g，3.19mmol，收率：22.8％)，LCMS m/z：596[M+H]+。To a DMF solution of (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (8.6 g, 9.76 mmol) was added N-carbamoylacetamide (4.93 g, 48.8 mmol) and triethylamine (6.90 g, 9.6 mL, 68.32 mmol), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was diluted with ethyl acetate (250 mL), washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40 μm, 330 g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5%-70% B 40 minutes, detector: 214 nm), and the fractions containing the product were collected at 70% B and concentrated under reduced pressure to give N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide (1.9 g, 3.19 mmol, yield: 22.8%), LCMS m/z: 596 [M+H] + .

3)、N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺异构体(化合物001-4-1和001-4-2)的制备
3) Preparation of N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide isomers (compounds 001-4-1 and 001-4-2)

将N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺(1.9g，3.19mmol)的乙酸乙酯(40mL)溶液打浆4小时。将浆液过滤得到主要包含001-4-1的滤饼(1.47g)和主要包含001-4-2的母液。滤饼(1.47g)用ACN/EA(40mL/10mL)继续打浆过夜，得到白色固体产物001-4-1(500mg，0.84mmol，收率：26.3％)。LCMS：RT＝11.178min，m/z：596.2[M+H]+。合并的打浆母液通过硅胶柱(DCM/EA＝3/1)纯化得到001-4-2(400mg，0.67mmol，收率：21％)，LCMS m/z：596[M+H]+ A solution of N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethyliminoyl)acetamide (1.9 g, 3.19 mmol) in ethyl acetate (40 mL) was slurried for 4 hours. The slurry was filtered to obtain a filter cake (1.47 g) mainly containing 001-4-1 and a mother liquor mainly containing 001-4-2. The filter cake (1.47 g) was further slurried with ACN/EA (40 mL/10 mL) overnight to obtain a white solid product 001-4-1 (500 mg, 0.84 mmol, yield: 26.3%). LCMS: RT=11.178 min, m/z: 596.2 [M+H] + . The combined slurry mother liquor was purified by silica gel column (DCM/EA=3/1) to give 001-4-2 (400 mg, 0.67 mmol, yield: 21%), LCMS m/z: 596 [M+H] +

4)、N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺异构体(MRANK-111-001-1和MRANK-111-001-2)的制备
4) Preparation of N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide isomers (MRANK-111-001-1 and MRANK-111-001-2)

将化合物001-4-1(500mg，0.84mmol)通过SFC制备分离(条件：系统：Waters SFC 150；色谱柱：尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/L氨甲醇)，A：B＝70：30；检测波长：214nm；流速：120mL/min；柱温：RT；背压：100bar，进样量：3.0mL；循环时间：8.0min)得到两个化合物：MRANK-111-001-1和MRANK-111-001-2：Compound 001-4-1 (500 mg, 0.84 mmol) was separated by SFC preparation (conditions: system: Waters SFC 150; column: Size: 250*30mm 10μm; mobile phase A; supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/L ammonia methanol), A:B=70:30; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar, injection volume: 3.0mL; cycle time: 8.0min) to obtain two compounds: MRANK-111-001-1 and MRANK-111-001-2:

MRANK-111-001-1：峰1：ChiralHPLC：1.941min；(184.36mg，0.31mmol，收率：36.9％)，LCMS m/z：596[M+H]+.MRANK-111-001-1: Peak 1: ChiralHPLC: 1.941 min; (184.36 mg, 0.31 mmol, yield: 36.9%), LCMS m/z: 596 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ10.64(s，1H)，8.00(d，J＝7.6Hz，2H)，7.85(d，J＝8.0Hz，2H)，7.80(d，J＝8.4Hz，2H)，7.68(d，J＝8.8Hz，2H)，7.33-7.23(m，5H)，4.67(s，1H)，4.37-4.34(m，1H)，2.10(s，3H)，1.48(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.64 (s, 1H), 8.00 (d, J=7.6Hz, 2H), 7.85 (d, J=8.0Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.68 (d, J=8 .8Hz, 2H), 7.33-7.23(m, 5H), 4.67(s, 1H), 4.37-4.34(m, 1H), 2.10(s, 3H), 1.48(d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.31 19 F NMR (377MHz, DMSO-d 6 ): δ-61.31

MRANK-111-001-2：峰2：ChiralHPLC：2.717min；(171.88mg，0.29mmol，收率：34.5％)，LCMS m/z：596[M+H]+.MRANK-111-001-2: Peak 2: ChiralHPLC: 2.717 min; (171.88 mg, 0.29 mmol, yield: 34.5%), LCMS m/z: 596 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ10.64(s，1H)，8.00(d，J＝7.2Hz，2H)，7.85(d，J＝7.6Hz，2H)，7.80(d，J＝8.4Hz，2H)，7.68(d，J＝8.8Hz，2H)，7.33-7.23(m，5H)，4.67(s，1H)，4.37-4.34(m，1H)，2.10(s，3H)，1.48(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.64 (s, 1H), 8.00 (d, J=7.2Hz, 2H), 7.85 (d, J=7.6Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.68 (d, J=8 .8Hz, 2H), 7.33-7.23(m, 5H), 4.67(s, 1H), 4.37-4.34(m, 1H), 2.10(s, 3H), 1.48(d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.31. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.31.

5)、N-((E)-N′-(Z)-(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲亚胺酰基)乙酰胺异构体(MRANK-111-001-3和MRANK-111-001-4)的制备
5) Preparation of N-((E)-N′-(Z)-(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminomethylimidoyl)acetamide isomers (MRANK-111-001-3 and MRANK-111-001-4)

化合物001-4-2(400mg，0.67mmol)通过SFC制备分离(条件：系统：Waters SFC 150；色谱柱：尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/L氨甲醇)，A：B＝65：35；检测波长：214nm；流速：120mL/min；柱温：RT；背压：100bar，进样量：3.0mL；循环时间：8.0min)得到两个化合物：MRANK-111-001-3和MRANK-111-001-4：Compound 001-4-2 (400 mg, 0.67 mmol) was separated by SFC preparation (conditions: system: Waters SFC 150; column: Size: 250*30mm 10μm; mobile phase A; supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/L ammonia methanol), A:B=65:35; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar, injection volume: 3.0mL; cycle time: 8.0min) to obtain two compounds: MRANK-111-001-3 and MRANK-111-001-4:

MRANK-111-001-3：峰1，Chiral HPLC：1.766min；(172.62mg，0.29mmol，收率：43.3％)，LCMS m/z：596[M+H]+.MRANK-111-001-3: Peak 1, Chiral HPLC: 1.766 min; (172.62 mg, 0.29 mmol, yield: 43.3%), LCMS m/z: 596 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ10.53(s，1H)，8.00(d，J＝8.4Hz，2H)，7.84(d，J＝8.0Hz，2H)，7.76(d，J＝8.4Hz，2H)，7.54(d，J＝8.4Hz，2H)，7.32-7.23(m，3H)，7.10(s，2H)，5.21(d，J＝11.2Hz，1H)，4.84-4.80(m，1H)，2.08(s，3H)，1.00(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.53 (s, 1H), 8.00 (d, J = 8.4Hz, 2H), 7.84 (d, J = 8.0Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.4Hz, 2H), 7 .32-7.23 (m, 3H), 7.10 (s, 2H), 5.21 (d, J = 11.2Hz, 1H), 4.84-4.80 (m, 1H), 2.08 (s, 3H), 1.00 (d, J = 6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.31. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.31.

MRANK-111-001-4：Peak 2Chiral HPLC：2.802min；(161.11mg，0.27mmol，收率：40.3％)，LCMS m/z：596[M+H]+.MRANK-111-001-4: Peak 2Chiral HPLC: 2.802 min; (161.11 mg, 0.27 mmol, yield: 40.3%), LCMS m/z: 596 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ10.53(s，1H)，8.00(d，J＝8.4Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.76(d，J＝8.4Hz，2H)，7.54(d，J＝8.4Hz，2H)，7.32-7.23(m，3H)，7.10(s，2H)，5.21(d，J＝11.2Hz，1H)，4.85-4.80(m，1H)，2.08(s，3H)，1.00(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.53 (s, 1H), 8.00 (d, J = 8.4Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.4Hz, 2H), 7 .32-7.23 (m, 3H), 7.10 (s, 2H), 5.21 (d, J = 11.2Hz, 1H), 4.85-4.80 (m, 1H), 2.08 (s, 3H), 1.00 (d, J = 6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.31. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.31.

实施例30、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺及其异构体(MRANK-111-01-1、MRANK-111- 01-2、MRANK-111-01-3和MRANK-111-01-4)的合成：Example 30, (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide and isomers thereof (MRANK-111-01-1, MRANK-111- Synthesis of MRANK-01-2, MRANK-111-01-3 and MRANK-111-01-4):

1)、(E)-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯的合成
1) Synthesis of (E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(3.00g，5.75mmol)的氯苯(30mL)溶液中，加入五氯化磷(2.39g，11.50mmol)，氮气氛围下，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱法(PE/EA＝1/1)纯化得到(E)-3-(4-氯苯基)-5-甲基4-苯基-N-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(2.15g，3.98mmol，收率：69.3％)，LCMS m/z：540[M+H]+。Phosphorus pentachloride (2.39 g, 11.50 mmol) was added to a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (3.00 g, 5.75 mmol) in chlorobenzene (30 mL) at room temperature, and the mixture was heated at 100° C. and stirred for 2 hours under a nitrogen atmosphere. The mixed reaction liquid was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=1/1) to give (E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (2.15 g, 3.98 mmol, yield: 69.3%), LCMS m/z: 540 [M+H] + .

2)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺的合成
2) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide

在0℃下，向溶有(E)-3-(4-氯苯基)-5-甲基4-苯基-N-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(300mg，0.56mmol)的DMF(5mL)溶液中，加入N-氨基甲酰甲磺酰胺(230mg，1.68mmol)，t-BuOK(314mg，2.80mmol，1M的THF溶液)，室温搅拌2小时。将混合反应液通过反相快速柱色谱法(条件如下：柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20min内5％B-80％B；检测器：214nm)在62％B下，收集含有产物的级分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺(146mg，0.23mmol，收率：42％)，LCMS m/z：641[M+H]+。To a solution of (E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (300 mg, 0.56 mmol) in DMF (5 mL) at 0°C were added N-carbamoylmethanesulfonamide (230 mg, 1.68 mmol) and t-BuOK (314 mg, 2.80 mmol, 1 M solution in THF), and the mixture was stirred at room temperature for 2 hours. The mixed reaction liquid was subjected to reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40 um, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-80% B in 20 min; detector: 214 nm) at 62% B, and the fractions containing the product were collected and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (146 mg, 0.23 mmol, yield: 42%), LCMS m/z: 641 [M+H] + .

3)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(111-01-4-1和111-01-4-2)的制备：
3) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (111-01-4-1 and 111-01-4-2):

化合物(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三 氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺(146g，0.23mmol)通过SFC纯化(条件：系统：岛津LC-20AP；柱名：柱尺寸：250*25mm 10m；流动相A正己烷；流动相B：IPA(+0.3％7.0mol/1氨在MeOH中)，A：B＝60：40；波长：254nm；流量：50mL/min；柱温：RT；注射液：4mL；循环时间：20min)纯化得到两个异构体：111-01-4-1和111-01-4-2：Compound (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(triphenyl)phenyl)- The 2-(4-(2-fluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (146 g, 0.23 mmol) was purified by SFC (conditions: system: Shimadzu LC-20AP; column name: Column size: 250*25mm 10m; mobile phase A: n-hexane; mobile phase B: IPA (+0.3% 7.0 mol/1 ammonia in MeOH), A: B = 60:40; wavelength: 254nm; flow rate: 50mL/min; column temperature: RT; injection: 4mL; cycle time: 20min) to obtain two isomers: 111-01-4-1 and 111-01-4-2:

111-01-4-1：RT：1.424min；(100mg，0.16mmol，收率：68.4％)，LCMS m/z：641[M+H]+。111-01-4-1: RT: 1.424 min; (100 mg, 0.16 mmol, yield: 68.4%), LCMS m/z: 641 [M+H] + .

111-01-4-2：。RT：1.423min；(45mg，0.07mmol，收率：30.8％)，LCMS m/z：641[M+H]+。111-01-4-2: RT: 1.423 min; (45 mg, 0.07 mmol, yield: 30.8%), LCMS m/z: 641 [M+H] + .

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-01-1和MRANK-111-01-2)的合成：
4) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-01-1 and MRANK-111-01-2):

将混合反应液111-01-4-1(100mg，0.16mmol)通过SFC纯化(条件：体系：Waters SFC 80；柱名：柱尺寸：250*30mm 10μm；流动相A超临界CO2；流动相B：IPA(+0.1％DEA)，A：B＝60：40；波长：254nm；流量：60mL/min；柱温：RT；背压：100bar，进样量：4.5mL；循环时间：4.8min)纯化得到两个异构体：MRANK-111-01-1和MRANK-111-1-2：The mixed reaction solution 111-01-4-1 (100 mg, 0.16 mmol) was purified by SFC (conditions: system: Waters SFC 80; column name: Column size: 250*30mm 10μm; mobile phase A supercritical CO 2 ; mobile phase B: IPA (+0.1% DEA), A:B=60:40; wavelength: 254nm; flow rate: 60mL/min; column temperature: RT; back pressure: 100bar, injection volume: 4.5mL; cycle time: 4.8min) was purified to obtain two isomers: MRANK-111-01-1 and MRANK-111-1-2:

MRANK-111-01-1：峰1，chiral-HPLC：1.618min；(5.74mg，0.009mmol，收率：5.7％)，LCMSm/z：641[M+H]+。MRANK-111-01-1: Peak 1, chiral-HPLC: 1.618 min; (5.74 mg, 0.009 mmol, yield: 5.7%), LCMS m/z: 641 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ8.03(d，J＝8.4Hz，2H)，7.88(d，J＝8.4Hz，2H)，7.71(s，2H)，7.45(d，J＝8.4Hz，2H)，7.30-7.22(m，5H)，4.70(s，1H)，4.28(d，J＝7.2Hz，1H)，2.67(s，3H)，1.38(d，J＝4.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.03 (d, J=8.4Hz, 2H), 7.88 (d, J=8.4Hz, 2H), 7.71 (s, 2H), 7.45 (d, J=8.4Hz, 2H), 7. 30-7.22 (m, 5H), 4.70 (s, 1H), 4.28 (d, J = 7.2Hz, 1H), 2.67 (s, 3H), 1.38 (d, J = 4.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.48. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.48.

MRANK-111-01-2：峰2，chiral-HPLC：2.543min；(4.18mg，0.0065mmol，收率：4.1％)，LCMS m/z：641[M+H]+MRANK-111-01-2: Peak 2, chiral-HPLC: 2.543 min; (4.18 mg, 0.0065 mmol, yield: 4.1%), LCMS m/z: 641 [M+H]+

1H NMR(400MHz，DMSO-d6)：δ8.03(d，J＝8.0Hz，2H)，7.88(d，J＝8.4Hz，2H)，7.70(s，2H)，7.44(d，J＝8.0Hz，2H)，7.30-7.23(m，5H)，4.69(s，1H)，4.28(d，J＝6.4Hz，1H)，2.57(s，3H)，1.38(d，J＝5.2Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.03 (d, J=8.0Hz, 2H), 7.88 (d, J=8.4Hz, 2H), 7.70 (s, 2H), 7.44 (d, J=8.0Hz, 2H), 7. 30-7.23 (m, 5H), 4.69 (s, 1H), 4.28 (d, J = 6.4Hz, 1H), 2.57 (s, 3H), 1.38 (d, J = 5.2Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.49. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.49.

5)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-5-甲基-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-01-3和MRANK-111-01-4)的制备
5) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-01-3 and MRANK-111-01-4)

将混合物111-01-4-2(45mg，0.07mmol)通过SFC纯化(条件：体系：Waters SFC 150；柱名：CHIRAL ART Collulose SC柱尺寸：250*30mm 10m；流动相A超临界CO2；流动相B：IPA(+0.1％7.0mol/1氨在甲醇中)，A：B＝60：40；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar，进样量：8.0mL；循环时间：4.35，in)纯化得到两个异构体：MRANK-111-01-3和MRANK-111-101-4：The mixture 111-01-4-2 (45 mg, 0.07 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: CHIRAL ART Collulose SC; column size: 250*30 mm 10 m; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (+0.1% 7.0 mol/1 ammonia in methanol), A:B=60:40; wavelength: 214 nm; flow rate: 120 mL/min; column temperature: RT; back pressure: 100 bar, injection volume: 8.0 mL; cycle time: 4.35, in) to obtain two isomers: MRANK-111-01-3 and MRANK-111-101-4:

MRANK-111-01-3：峰1；chiral-HPLC：1.933min；(0.89mg，0.0014mmol，收率：1.9％)，LCMS m/z：641[M+H]+。MRANK-111-01-3: peak 1; chiral-HPLC: 1.933 min; (0.89 mg, 0.0014 mmol, yield: 1.9%), LCMS m/z: 641 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ9.43(s，1H)，8.01(d，J＝8.4Hz，2H)，7.93(t，J＝8.4Hz，2H)，7.57(s，2H)，7.41(d，J＝8.4Hz，2H)，7.30-7.23(m，5H)，5.20(d，J＝10.4Hz，1H)，4.85-4.79(m，1H)，2.67(s，3H)，0.79(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ9.43 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.93 (t, J = 8.4Hz, 2H), 7.57 (s, 2H), 7.41 (d, J = 8.4Hz, 2H), 7.30-7.23(m, 5H), 5.20(d, J=10.4Hz, 1H), 4.85-4.79(m, 1H), 2.67(s, 3H), 0.79(s, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.49. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.49.

MRANK-111-01-4：峰2，chiral-HPLC：3.013min；(1.37mg，0.002mmol，收率：3.0％)，LCMS m/z：641[M+H]+。MRANK-111-01-4: Peak 2, chiral-HPLC: 3.013 min; (1.37 mg, 0.002 mmol, yield: 3.0%), LCMS m/z: 641 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ9.42(s，1H)，8.01(d，J＝8.4Hz，2H)，7.93(d，J＝7.6Hz，2H)，7.57(d，J＝6.4Hz，2H)，7.41(d，J＝8.4Hz，2H)，7.27-7.13(m，5H)，5.20(d，J＝10.4Hz，1H)，4.85-4.78(m，1H)，2.66(s，3H)，0.79(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ9.42 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.93 (d, J = 7.6Hz, 2H), 7.57 (d, J = 6.4Hz, 2H), 7.41 (d, J = 8. 4Hz, 2H), 7.27-7.13 (m, 5H), 5.20 (d, J=10.4Hz, 1H), 4.85-4.78 (m, 1H), 2.66 (s, 3H), 0.79 (s, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.49. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.49.

实施例31、(Z)-3-(4-氰基苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酸酰亚胺及其异构体(MRANK-111-002-1、MRANK-111-002-2、MRANK-111-1002-3和MRANK111-002-4)的合成：Example 31, Synthesis of (Z)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid imide and its isomers (MRANK-111-002-1, MRANK-111-002-2, MRANK-111-1002-3 and MRANK111-002-4):

1)、1-(4-溴苯基)-3-羟基-2-苯基丁-1-酮的合成
1) Synthesis of 1-(4-bromophenyl)-3-hydroxy-2-phenylbutan-1-one

向溶有1-(4-溴苯基)-2-苯基乙烷-1-酮(20g，72.7mmol)的THF(300mL)溶液中，加入K2CO3(30g，218.1mmol)和乙醛(16g，263.3mmol)，室温搅拌16小时。将混合反应液过滤，收集滤液减压浓缩得到1-(4-溴苯基)-3-羟基-2-苯基丁-1-酮(25g)，直接用于下一步，不进一步纯化。LCMS m/z：342[M+H+Na]+.K 2 CO 3 (30 g, 218.1 mmol) and acetaldehyde (16 g, 263.3 mmol) were added to a THF (300 mL) solution containing 1-(4-bromophenyl)-2-phenylethane-1-one (20 g, 72.7 mmol) and stirred at room temperature for 16 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 1-(4-bromophenyl)-3-hydroxy-2-phenylbutan-1-one (25 g), which was used directly in the next step without further purification. LCMS m/z: 342 [M+H+Na] + .

2)、1-(4-溴苯基)-2-苯基丁-2-烯-1-酮的制备
2) Preparation of 1-(4-bromophenyl)-2-phenylbut-2-ene-1-one

向化合物1-(4-溴苯基)-3-羟基-2-苯基丁-1-酮(25g，78.36mmol)的甲苯(300mL)溶液中，加入TSOH.H2O(14.8g，78.36mmol)，加热90℃下拌3小时。将混合反应液减压浓缩。残余物通过硅胶色谱法(PE/EA＝10/1)纯化得到1-(4-溴苯基)-2-苯基丁-2-烯-1-酮002-3(21.3g，7.07mmol，收率：90.6％)。LCMS M/Z＝301.0[M+H]+.To a toluene (300 mL) solution of the compound 1-(4-bromophenyl)-3-hydroxy-2-phenylbutan-1-one (25 g, 78.36 mmol), TSOH.H2O (14.8 g, 78.36 mmol) was added, and the mixture was heated at 90°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=10/1) to give 1-(4-bromophenyl)-2-phenylbut-2-ene-1-one 002-3 (21.3 g, 7.07 mmol, yield: 90.6%). LCMS M/Z=301.0[M+H] + .

3)、3-(4-溴苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑的合成
3) Synthesis of 3-(4-bromophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole

向溶有1-(4-溴苯基)-2-苯基丁-2-烯-1-酮(21.3g，71.0mmol)的EtOH(200mL)溶液中，加入NH2NH2.H2O(3.76g，71.0mmol)，加热80℃搅拌1小时。将所得混合反应液用饱和NH4Cl(200mL)稀释，并用乙酸乙酯(100mL×3)萃取。合并有机相用饱和食盐水(200mL)洗涤，无水Na2SO4干燥，过滤、减压浓缩得到3-(4-溴苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(22g，粗品)，直接用于下一步反应，无需进一步纯化。LCMS m/z：317[M+2+H]+.NH 2 NH 2 .H 2 O (3.76 g, 71.0 mmol) was added to a solution of 1-(4-bromophenyl)-2-phenylbut-2-en-1-one (21.3 g, 71.0 mmol) in EtOH (200 mL), and the mixture was heated at 80°C and stirred for 1 hour. The resulting mixed reaction solution was diluted with saturated NH 4 Cl (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 3-(4-bromophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (22 g, crude product), which was used directly in the next step without further purification. LCMS m/z: 317 [M+2+H] + .

4)、4-(5-甲基-4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈的合成
4) Synthesis of 4-(5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile

向溶有3-(4-溴苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(22g，69.8mmol)的DMF(200mL)溶液中，加入Zn(CN)2(8.98g，76.8mmol)和Pd(PPh3)4(4.0g，3.49mmol)，氮气保护下，加热100℃搅拌16小时。将混合反应液用饱和NH4Cl(200mL)稀释，并用EA(100mL×3)萃取。合的并有机相，用饱和食盐水(200mL)洗涤，无水Na2SO4干燥，过滤、减压浓缩。残余物通过硅胶色谱法柱层析(PE/EA＝3/1)纯化的得到4-(5-甲基-4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈(16.0g，61.3mmol，收率：87.9％)，LCMS m/z：303[M+H+ACN]+.Zn(CN) 2 (8.98 g, 76.8 mmol) and Pd(PPh 3 ) 4 (4.0 g, 3.49 mmol) were added to a DMF (200 mL) solution of 3-(4-bromophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (22 g, 69.8 mmol), and the mixture was heated at 100°C and stirred for 16 hours under nitrogen protection. The mixed reaction liquid was diluted with saturated NH 4 Cl (200 mL) and extracted with EA (100 mL×3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give 4-(5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (16.0 g, 61.3 mmol, yield: 87.9%), LCMS m/z: 303 [M+H+ACN] + .

5)、3-(4-氰基苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成
5) Synthesis of 3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有-(5-甲基-4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈(3.4g，13.0mmol)的甲苯(50mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(3.6g，13.0mmol)，加热110℃搅拌16小时。将混合反应液减压浓缩。残余物通过硅胶色谱法(PE/EA＝1/1)纯化得到3-(4-氰基苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(4.2g，8.2mmol，收率：63.06％)，LCMSm/z：513[M+H]+.At room temperature, to a solution of -(5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (3.4 g, 13.0 mmol) in toluene (50 mL) was added methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (3.6 g, 13.0 mmol), and the mixture was heated to 110°C and stirred for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=1/1) to give 3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (4.2 g, 8.2 mmol, yield: 63.06%), LCMS m/z: 513 [M+H] + .

6)(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
6. Synthesis of (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氰基苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(3.4g，6.6mmol)的二氯甲烷(100mL)溶液中，加入DMAP(2.4g，19.9mmol)和POCl3(2.0g，13.2mmol)，加热50℃搅拌3小时。将混合反应液减压浓缩并通过反相相快速柱色谱纯化(条件如下：柱：球形C18，20-40um，330g；流动相A：H2O；流动相B：乙腈；流速：80mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)。在70％B下，收集含有所需产物的级分，减压浓缩得到(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(2.8g，4.5mmol，收率：68.29％)，LCMS m/z：617[M]+.At room temperature, DMAP (2.4 g, 19.9 mmol) and POCl3 (2.0 g, 13.2 mmol) were added to a solution of 3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (3.4 g, 6.6 mmol) in dichloromethane (100 mL), and the mixture was heated at 50°C with stirring for 3 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40 um, 330 g; mobile phase A: H2O; mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5% B-100% B, 15 minutes; detector: 254 nm). At 70% B, fractions containing the desired product were collected and concentrated under reduced pressure to give (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (2.8 g, 4.5 mmol, yield: 68.29%), LCMS m/z: 617 [M] + .

7)、(Z)-3-(4-氰基苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酸酰亚胺的合成
7) Synthesis of (Z)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid imide

在室温下，向溶有(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(1.8g，2.9mmol)的DMF(20mL)溶 液中，加入2-氨基乙烷-1-磺酰胺(932mg，5.8mmol)和三乙胺(586mg，5.8mmol)，室温搅拌2小时。将混合反应液用反相快速柱色谱纯化(条件如下：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15min；检测器：254nm)纯化。在60％B下，收集含有产物的级分，减压浓缩得到(Z)-3-(4-氰基苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酸酰亚胺(1.0g，1.62mmol，收率：55.55％)，LCMS m/z：619[M+H]+ At room temperature, (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (1.8 g, 2.9 mmol) was dissolved in DMF (20 mL). 2-Aminoethane-1-sulfonamide (932 mg, 5.8 mmol) and triethylamine (586 mg, 5.8 mmol) were added to the solution and stirred at room temperature for 2 hours. The mixed reaction solution was purified by reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40 um, 80 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B-100% B, 15 min; detector: 254 nm). At 60% B, fractions containing the product were collected and concentrated under reduced pressure to give (Z)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid imide (1.0 g, 1.62 mmol, yield: 55.55%), LCMS m/z: 619 [M+H] +

8)(Z)-3-(4-氰基苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酸酰亚胺异构体(MRANK-111-002-1/2、MRANK-111-1002-3和MRANK111-002-4)的分离制备：
8) Separation and preparation of (Z)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid imide isomers (MRANK-111-002-1/2, MRANK-111-1002-3 and MRANK111-002-4):

化合物(Z)-3-(4-氰基苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酸酰亚胺(1.0g，1.62mmol)通过SFC制备分离(条件：体系：Waters SFC 150；柱名：柱尺寸：250*30mm 10μm；流动相A超临界CO2流动相B：IPA，A：B＝55：45波长：214nm流量：140mL/min柱温：RT背压：100巴，进样量：8.0毫升；循环时间：8.0min)得到三种异构体：MRANK-111-002-1/2和MRANK-111-2002-3和MRANK-11-002-4：Compound (Z)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid imide (1.0 g, 1.62 mmol) was separated by SFC preparation (conditions: system: Waters SFC 150; column name: Column size: 250*30mm 10μm; mobile phase A supercritical CO 2 mobile phase B: IPA, A:B=55:45 wavelength: 214nm flow rate: 140mL/min column temperature: RT back pressure: 100 bar, injection volume: 8.0 ml; cycle time: 8.0min) to obtain three isomers: MRANK-111-002-1/2 and MRANK-111-2002-3 and MRANK-11-002-4:

MRANK-111-002-3：峰2：chiral-HPLC：2.562min；(145.81mg，0.23mmol，收率：14.58％)，LCMS m/z：619[M+H]+.MRANK-111-002-3: Peak 2: chiral-HPLC: 2.562 min; (145.81 mg, 0.23 mmol, yield: 14.58%), LCMS m/z: 619 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.18(s，1H)，8.05(d，J＝8.4Hz，2H)，7.90(d，J＝8.4Hz，2H)，7.81(d，J＝8.4Hz，2H)，7.71(d，J＝8.4Hz，2H)，7.33-7.23(m，3H)，7.16-7.01(m，4H)，5.18(d，J＝10.8Hz，1H)，4.89-4.74(m，1H)，3.92-3.83(m，2H)，3.40-3.32(m，2H)，0.74(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.18 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8.4Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.71 (d, J = 8.4Hz, 2H), 7.33-7.23 (m, 3H) , 7.16-7.01 (m, 4H), 5.18 (d, J = 10.8Hz, 1H), 4.89-4.74 (m, 1H), 3.92-3.83 (m, 2H), 3.40-3.32 (m, 2H), 0.74 (d, J = 6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.363. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.363.

MRANK-111-002-4：峰3chiralHPLC：3.931min；(143.18mg，0.23mmol，14.31％产率)，LCMS：m/z：619.3[M+H]+.MRANK-111-002-4: Peak 3 chiral HPLC: 3.931 min; (143.18 mg, 0.23 mmol, 14.31% yield), LCMS: m/z: 619.3 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.18(s，1H)，8.05(d，J＝8.4Hz，2H)，7.90(d，J＝8.4Hz，2H)，7.81(d，J＝8.4Hz，2H)，7.71(d，J＝8.4Hz，2H)，7.33-7.23(m，3H)，7.16-7.01(m，4H)，5.18(d，J＝10.8Hz，1H)，4.89-4.74(m，1H)，3.92-3.83(m，2H)，3.40-3.32(m，2H)，0.74(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.18 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8.4Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.71 (d, J = 8.4Hz, 2H), 7.33-7.23 (m, 3H) , 7.16-7.01 (m, 4H), 5.18 (d, J = 10.8Hz, 1H), 4.89-4.74 (m, 1H), 3.92-3.83 (m, 2H), 3.40-3.32 (m, 2H), 0.74 (d, J = 6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.363. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.363.

化合物MRANK-111-002-1/2(600mg，0.96mmol)再次通过SFC制备分离(条件：体系：Waters SFC 150；柱名：柱尺寸：250*40mm 10m流动相A超临界CO2流动相B：IPA，A：B＝70：30波长：214nm流量：140mL/min柱温：RT背压：100巴，注射：7.5mL；循环时间：7.73min)得到两种异构体：MRANK-111-002-1和MRANK-111-002-2：Compound MRANK-111-002-1/2 (600 mg, 0.96 mmol) was separated again by SFC preparation (conditions: system: Waters SFC 150; column name: Column size: 250*40mm 10m mobile phase A supercritical CO 2 mobile phase B: IPA, A:B=70:30 wavelength: 214nm flow rate: 140mL/min column temperature: RT back pressure: 100 bar, injection: 7.5mL; cycle time: 7.73min) to obtain two isomers: MRANK-111-002-1 and MRANK-111-002-2:

MRANK-111-002-1：峰1chiral-HPLC：2.151min；(231.42mg，0.37mmol，收率：38.57％)，LCMS  m/z：619[M+H]+.MRANK-111-002-1: Peak 1 chiral-HPLC: 2.151 min; (231.42 mg, 0.37 mmol, yield: 38.57%), LCMS m/z：619[M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.42-8.33(m，1H)，8.00(d，J＝8.4Hz，2H)，7.91-7.79(m，6H)，7.35-7.20(m，5H)，7.06(s，2H)，4.73(s，1H)，4.56-4.48(m，1H)，3.90-3.77(m，2H)，3.39-3.32(m，2H)，1.30(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.42-8.33(m, 1H), 8.00(d, J=8.4Hz, 2H), 7.91-7.79(m, 6H), 7.35-7.20(m, 5H), 7.06(s, 2H) , 4.73 (s, 1H), 4.56-4.48 (m, 1H), 3.90-3.77 (m, 2H), 3.39-3.32 (m, 2H), 1.30 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.354. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.354.

MRANK-111-002-2：峰2手性HPLC：3.096min；(222.25mg，0.35mmol，收率：37.04％)，LCMS m/z：619[M+H]+.MRANK-111-002-2: Peak 2 chiral HPLC: 3.096 min; (222.25 mg, 0.35 mmol, yield: 37.04%), LCMS m/z: 619 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.42-8.33(m，1H)，8.00(d，J＝8.4Hz，2H)，7.91-7.79(m，6H)，7.35-7.20(m，5H)，7.06(s，2H)，4.73(s，1H)，4.56-4.48(m，1H)，3.90-3.77(m，2H)，3.39-3.32(m，2H)，1.30(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.42-8.33(m, 1H), 8.00(d, J=8.4Hz, 2H), 7.91-7.79(m, 6H), 7.35-7.20(m, 5H), 7.06(s, 2H) , 4.73 (s, 1H), 4.56-4.48 (m, 1H), 3.90-3.77 (m, 2H), 3.39-3.32 (m, 2H), 1.30 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.354. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.354.

实施例32、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺异构体(MRANK-111-02-1和MRANK-111-02-2)的合成：Example 32, Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-02-1 and MRANK-111-02-2):

1)、化合物02-3的合成
1) Synthesis of compound 02-3

在0℃下，向溶有叔丁氧羰基胍(5.00g，31.45mmol)的四氢呋喃(100mL)溶液中，加入甲基磺酰氯(3.62g，31.45mmol)和三乙胺(3.34g，33.02mmol)，室温搅拌1小时。将混合反应液过滤，收集滤液减压浓缩得到化合物02-3(7.94g，33.50mmol，收率：＞99％)，LCMS m/z：238[M+H]+ At 0°C, methylsulfonyl chloride (3.62 g, 31.45 mmol) and triethylamine (3.34 g, 33.02 mmol) were added to a solution of tert-butyloxycarbonylguanidine (5.00 g, 31.45 mmol) in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 1 hour. The mixed reaction liquid was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain compound 02-3 (7.94 g, 33.50 mmol, yield: >99%), LCMS m/z: 238 [M+H] +

2)、化合物N-氨基甲酰甲磺酰胺的合成
2) Synthesis of compound N-carbamoylmethanesulfonamide

在0℃下，向溶有化合物02-3(5.25g，22.15mmol，1.0eq。)的二氯甲烷(40mL)溶液中加入三氟乙酸(20.0mL)，室温搅拌6小时。将混合反应液减压浓缩得到粗产物。粗产物中加入异丙醇(30mL)室温打浆2小时。将混合反应液过滤，收集滤饼真空干燥得到N-氨基甲酰甲磺酰胺(2.57g，18.59mmol，收率：84％)，LCMS m/z：138[M+H]+ Trifluoroacetic acid (20.0 mL) was added to a solution of compound 02-3 (5.25 g, 22.15 mmol, 1.0 eq.) in dichloromethane (40 mL) at 0°C and stirred at room temperature for 6 hours. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product. Isopropanol (30 mL) was added to the crude product and slurried at room temperature for 2 hours. The mixed reaction solution was filtered, and the filter cake was collected and vacuum dried to obtain N-carbamoyl methanesulfonamide (2.57 g, 18.59 mmol, yield: 84%), LCMS m/z: 138 [M+H] +

3)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺的合成
3) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide

向溶有(E)-3-(4-氯苯基)-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯(350mg，0.66mmol)和02-4甲磺酰基胍(271mg，1.98mmol)的DMF(8mL)溶液中，加入叔丁醇钾(1.0mol/L的四氢呋喃溶液，3.3mL，3.3mmol)，室温搅拌4小时。将混合反应液通过反相柱(柱：球形C18，20-40μm，40g；流动相A：0.03％TFA水；流动相B：乙腈；流速：40mL/min；梯度：5％B 5min，5-70％B 20min；检测器：214nm)。在70％B下，收集含产物的馏分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H- 吡唑-1-甲酰亚胺(75mg，0.12mmol，收率：18.2％)LCMS m/z：627[M+H]+。Potassium tert-butoxide (1.0 mol/L tetrahydrofuran solution, 3.3 mL, 3.3 mmol) was added to a DMF (8 mL) solution of (E)-3-(4-chlorophenyl)-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbonyl chloride (350 mg, 0.66 mmol) and 02-4-methylsulfonylguanidine (271 mg, 1.98 mmol), and stirred at room temperature for 4 hours. The mixed reaction solution was passed through a reverse phase column (column: spherical C18, 20-40 μm, 40 g; mobile phase A: 0.03% TFA water; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B 5 min, 5-70% B 20 min; detector: 214 nm). At 70% B, fractions containing the product were collected and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H- Pyrazole-1-carboximide (75 mg, 0.12 mmol, yield: 18.2%) LCMS m/z: 627 [M+H] + .

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺异构体(MRANK-111-02-1和MRANK-111-02-2)的分离制备：
4) Separation and preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-02-1 and MRANK-111-02-2):

将化合物(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺(75mg，0.12mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：甲醇(+0.1％7.0mol/L氨甲醇)，A：B＝45：55；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：5.5mL；循环时间：11.0min)纯化得到：单体MRANK-111-02-1和单体MRANK-111-02-2：Compound (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (75 mg, 0.12 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: methanol (+0.1% 7.0mol/L ammonia methanol), A:B=45:55; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 5.5mL; cycle time: 11.0min) was purified to obtain: monomer MRANK-111-02-1 and monomer MRANK-111-02-2:

MRANK-111-02-1：Peak 1Chiral HPLC：1.060min；(28.46mg，0.045mmol，收率：37.9％)，LCMS m/z：672[M+H]+.MRANK-111-02-1: Peak 1Chiral HPLC: 1.060 min; (28.46 mg, 0.045 mmol, yield: 37.9%), LCMS m/z: 672 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.66(s，1H)，8.05(d，J＝8.4Hz，2H)，7.87(d，J＝8.4Hz，2H)，7.61(s，2H)，7.41(d，J＝8.4Hz，2H)，7.34-7.21(m，5H)，5.02(d，J＝8.0Hz，1H)，4.48(t，J＝10.8Hz，1H)，3.85(dd，J＝12.0Hz，4.0Hz，1H)，2.72(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.66 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.87 (d, J = 8.4Hz, 2H), 7.61 (s, 2H), 7.41 (d, J = 8.4Hz, 2H), 7.34-7 .21 (m, 5H), 5.02 (d, J=8.0Hz, 1H), 4.48 (t, J=10.8Hz, 1H), 3.85 (dd, J=12.0Hz, 4.0Hz, 1H), 2.72 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.39 19 F NMR (377MHz, DMSO-d 6 ) δ-61.39

MRANK-111-02-2：Peak 2Chiral HPLC：2.544min；(22.09mg，0.035mmol，收率：29.4％)，LCMS m/z：627[M+H]+.MRANK-111-02-2: Peak 2Chiral HPLC: 2.544 min; (22.09 mg, 0.035 mmol, yield: 29.4%), LCMS m/z: 627 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.61(s，1H)，8.05(d，J＝7.6Hz，2H)，7.87(d，J＝8.0Hz，2H)，7.62(s，2H)，7.41(d，J＝8.0Hz，2H)，7.34-7.23(m，5H)，5.02(d，J＝6.4Hz，1H)，4.49(t，J＝7.6Hz，1H)，3.85(dd，J＝12.0Hz，4.4Hz，1H)，2.70(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.61 (s, 1H), 8.05 (d, J = 7.6Hz, 2H), 7.87 (d, J = 8.0Hz, 2H), 7.62 (s, 2H), 7.41 (d, J = 8.0Hz, 2H), 7.34- 7.23 (m, 5H), 5.02 (d, J=6.4Hz, 1H), 4.49 (t, J=7.6Hz, 1H), 3.85 (dd, J=12.0Hz, 4.4Hz, 1H), 2.70 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.40 19 F NMR (377MHz, DMSO-d 6 ) δ-61.40

实施例33、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氰基苯基)-5-甲基-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺(MRANK-111-03--1、MRANK-111-03-2、MRANK-111-03-3和MRANK-111-03-4)的合成：Example 33, Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (MRANK-111-03-1, MRANK-111-03-2, MRANK-111-03-3 and MRANK-111-03-4):

1)、(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
1) Synthesis of (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氰基苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(2.00g，3.90mmol)的DCM(10mL)溶液中，加入DMAP(952mg，7.80mmol)和POCl3(1.19g，7.80mmmol)，氮气氛围加热50℃条件搅拌1小时。将混合反应液通过反相快速柱色谱法(条件如下：柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20分钟内5％B-50％B；检测器：214nm。)在46％B下，收集含有产物的级分，减压浓缩得到(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基甲基)-4-(二甲基氨基)吡啶-1-鎓(800mg，1.29mmol，收率：33.1％)，LCMS m/z：617[M]+。To a solution of 3-(4-cyanophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (2.00 g, 3.90 mmol) in DCM (10 mL) at room temperature, DMAP (952 mg, 7.80 mmol) and POCl3 (1.19 g, 7.80 mmol) were added, and the mixture was heated at 50°C under nitrogen atmosphere with stirring for 1 hour. The mixed reaction liquid was subjected to reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-50%B in 20 minutes; detector: 214nm.) At 46%B, the fractions containing the product were collected and concentrated under reduced pressure to give (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)iminomethyl)-4-(dimethylamino)pyridin-1-ium (800mg, 1.29mmol, yield: 33.1%), LCMS m/z: 617[M] + .

2)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氰基苯基)-5-甲基-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺的合成
2) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide

在0℃下，向溶有(Z)-1-((3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基甲基)-4-(二甲基氨基)吡啶-1-鎓(400mg，0.65mmol)的DMF(5mL)溶液中，加入N-氨基甲酰甲磺酰胺(267mg，1.95mmol)，t-BuOK(364mg，3.25mmol，1M的THF溶液)，室温搅拌3小时。将混合反应液通过反相快速柱色谱(条件如下：柱：球形C18，20-40um，40g；流动相A：水(0.1％TFA)；流动相B：乙腈；流速：50mL/min；梯度：20分钟内5％B-80％B；检测器：214nm。)在62％B下，收集含有产物的级分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氰基苯基)-5-甲基-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺(120mg，0.19mmol，收率：29％)，LCMS m/z：631[M+H]+。To a solution of (Z)-1-((3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)iminomethyl)-4-(dimethylamino)pyridin-1-ium (400 mg, 0.65 mmol) in DMF (5 mL) at 0°C were added N-carbamoylmethanesulfonamide (267 mg, 1.95 mmol) and t-BuOK (364 mg, 3.25 mmol, 1 M solution in THF), and the mixture was stirred at room temperature for 3 hours. The mixed reaction liquid was subjected to reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40 um, 40 g; mobile phase A: water (0.1% TFA); mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-80% B in 20 minutes; detector: 214 nm.) At 62% B, the fractions containing the product were collected and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (120 mg, 0.19 mmol, yield: 29%), LCMS m/z: 631 [M+H] + .

3)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氰基苯基)-5-甲基-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺(111-03-3-1、MRANK-111-03-3和MRANK-111-03-4)的制备：
3) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (111-03-3-1, MRANK-111-03-3 and MRANK-111-03-4):

将(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氰基苯基)-5-甲基-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺(150mg，0.24mmol)通过超临界流体色谱纯化(条件：体系：Waters SFC 150；柱名：柱尺寸：250*25mm 10m；流动相A超临界CO2，；流动相B：MeOH(在MeOH中+0.1％7.0mol/1氨)，A：B＝60：40；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar，注入：2.0mL；循环时间：4.0min)纯化得到混合物111-03-3-M(100mg，0.16mmol)和单体MRANK-111-03-3和单体MRANK111-03-4。(Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide (150 mg, 0.24 mmol) was purified by supercritical fluid chromatography (conditions: system: Waters SFC 150; column name: Column size: 250*25mm 10m; mobile phase A: supercritical CO2; mobile phase B: MeOH (+0.1% 7.0mol/1 ammonia in MeOH), A:B=60:40; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar, injection: 2.0mL; cycle time: 4.0min) was purified to obtain a mixture 111-03-3-M (100mg, 0.16mmol) and monomer MRANK-111-03-3 and monomer MRANK111-03-4.

MRANK-111-03-3：峰1，chiral-HPLC：2.659min；(2.95mg，0.005mmol，收率：1.9％)，LCMS m/z：632[M+H]+。MRANK-111-03-3: Peak 1, chiral-HPLC: 2.659 min; (2.95 mg, 0.005 mmol, yield: 1.9%), LCMS m/z: 632 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ9.49(s，1H)，8.02(d，J＝8.4Hz，2H)，7.93(d，J＝7.6Hz，2H)，7.81(d，J＝8.4Hz，2H)，7.71(d，J＝7.6Hz，2H)，4.27-7.17(m，5H)，5.25(d，J＝10.8Hz，1H)，4.89-4.81(m，1H)，2.66(s，3H)，0.80(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ9.49 (s, 1H), 8.02 (d, J = 8.4Hz, 2H), 7.93 (d, J = 7.6Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.71 (d, J = 7. 6Hz, 2H), 4.27-7.17(m, 5H), 5.25(d, J=10.8Hz, 1H), 4.89-4.81(m, 1H), 2.66(s, 3H), 0.80(s, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.51. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.51.

MRANK-111-03-4：峰4：chiral-HPLC：4.429min；(1.30mg，0.002mmol，收率：0.8％)，LCMS m/z：632[M+H]+。 MRANK-111-03-4: Peak 4: chiral-HPLC: 4.429 min; (1.30 mg, 0.002 mmol, yield: 0.8%), LCMS m/z: 632 [M+H]+.

1H NMR(400MHz，DMSO-d6)：δ8.02(d，J＝8.0Hz，2H)，7.90(d，J＝7.6Hz，2H)，7.78(d，J＝7.6Hz，2H)，7.27-7.18(m，5H)，5.18(s，1H)，4.81(s，1H)，2.70(d，J＝15.2Hz，3H)，0.86(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.02 (d, J=8.0Hz, 2H), 7.90 (d, J=7.6Hz, 2H), 7.78 (d, J=7.6Hz, 2H), 7.27 -7.18(m, 5H), 5.18(s, 1H), 4.81(s, 1H), 2.70(d, J=15.2Hz, 3H), 0.86(s, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.41. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.41.

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氰基苯基)-5-甲基-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-03-1和MRANK-111-03-2)的制备
4) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-5-methyl-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-03-1 and MRANK-111-03-2)

将混合物111-03-3-M(100mg，0.16mmol)通过超临界流体色谱(条件：体系：Waters SFC 150；柱名：柱尺寸：250*30mm 10m；流动相A超临界CO2，；流动相B：IPA(+0.2％DEA)，A：B＝65：35；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar，进样量：8.0mL；循环时间：7.48min)制备分离得到：单体MRANK-111-03-1和单体MRANK-111-103-2：The mixture 111-03-3-M (100 mg, 0.16 mmol) was purified by supercritical fluid chromatography (conditions: system: Waters SFC 150; column name: Column size: 250*30mm 10m; mobile phase A supercritical CO2; mobile phase B: IPA (+0.2% DEA), A: B = 65:35; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar, injection volume: 8.0mL; cycle time: 7.48min) preparation and separation to obtain: monomer MRANK-111-03-1 and monomer MRANK-111-103-2:

MRANK-111-03-1：峰2，chiral-HPLC：2.897min；(32.67mg，0.052mmol，收率：32.6％)，LCMS m/z：632[M+H]+。MRANK-111-03-1: Peak 2, chiral-HPLC: 2.897 min; (32.67 mg, 0.052 mmol, yield: 32.6%), LCMS m/z: 632 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ9.53(s，1H)，8.04(d，J＝8.4Hz，2H)，7.90(d，J＝8.4Hz，2H)，7.85(s，4H)，7.31-7.25(m，5H)，4.76(s，1H)，4.32(d，J＝4.4Hz，1H)，2.58(s，3H)，1.40(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ9.53 (s, 1H), 8.04 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8.4Hz, 2H), 7.85 (s, 4H), 7. 31-7.25 (m, 5H), 4.76 (s, 1H), 4.32 (d, J=4.4Hz, 1H), 2.58 (s, 3H), 1.40 (s, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.52. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.52.

MRANK-111-03-2：峰3chiral-HPLC：3.172min；(31.00mg，0.05mmol，收率：31.0％)LCMS m/z：632[M+H]+。MRANK-111-03-2: Peak 3 chiral-HPLC: 3.172 min; (31.00 mg, 0.05 mmol, yield: 31.0%) LCMS m/z: 632 [M+H] + .

1H NMR(400MHz，DMSO-d6)：δ9.53(s，1H)，8.05(d，J＝8.0Hz，2H)，7.90(d，J＝8.4Hz，2H)，7.84(s，4H)，7.31-7.24(m，5H)，4.76(s，1H)，4.32(d，J＝4.0Hz，1H)，2.58(s，3H)，1.40(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ9.53 (s, 1H), 8.05 (d, J = 8.0Hz, 2H), 7.90 (d, J = 8.4Hz, 2H), 7.84 (s, 4H), 7. 31-7.24 (m, 5H), 4.76 (s, 1H), 4.32 (d, J=4.0Hz, 1H), 2.58 (s, 3H), 1.40 (s, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.51. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.51.

实施例34、(Z)-N-((E)-氨基(甲磺酰胺基)亚甲基)-3-(4-氰基苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒(MRANK-111-04-1和MRANK-111-04-2)的合成：Example 34, Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (MRANK-111-04-1 and MRANK-111-04-2):

1)、3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成
1) Synthesis of 3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(2.00g，3.94mmol)和K4Fe(CN)6.3H2O(4.99g，11.82mmol)的DMA(50mL)溶液中，加入Xphos Pd G3(668mg，0.79mmol)和Na2CO3(1.23g，11.82mmol)，N2保护加热130℃搅拌5小时。将混合反应液倒入水(300mL)中，并用EA(100mL×3)萃取。合并的有机相，用无水Na2SO4干燥，过滤、减压滤液。残余物通过硅胶柱色谱纯化(DCM：EA＝5：1)纯化得到3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(600mg，1.20mmol，收率：30.5％)，LCMS m/z：499[M+H]+. At room temperature, Xphos Pd G 3 (668 mg, 0.79 mmol) and Na 2 CO 3 (1.23 g, 11.82 mmol) were added to a solution of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1 -carboxamide (2.00 g, 3.94 mmol) and K 4 Fe(CN) 6 .3H 2 O (4.99 g, 11.82 mmol) in DMA (50 mL), and the mixture was heated at 130° C. under N 2 protection and stirred for 5 hours. The mixed reaction solution was poured into water (300 mL) and extracted with EA (100 mL×3). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was decompressed. The residue was purified by silica gel column chromatography (DCM:EA=5:1) to give 3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (600 mg, 1.20 mmol, yield: 30.5%), LCMS m/z: 499 [M+H] + .

2)、(Z)-1-((3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
2) Synthesis of (Z)-1-((3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(500mg，1.00mmol)的DCM(10mL)溶液中，加入DMAP(610mg，5.00mmol)和POCl3(306mg，2.00mmol)。N2保护下，加热50℃搅拌5小时。将混合反应液减压浓缩。残余物通过反相柱色谱(条件如下，柱：球形C18，20-40um，220g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：5％B-95％B，30分钟；检测器：214nm)。在40％B下，收集含有产物的级分，减压浓缩得到(Z)-1-(3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(320mg，0.53mmol，收率：53.0％)，LCMS m/z：603[M+H]+.At room temperature, DMAP (610 mg, 5.00 mmol) and POCl3 (306 mg, 2.00 mmol) were added to a solution of 3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (500 mg, 1.00 mmol) in DCM (10 mL). Under N2 protection, the mixture was heated at 50°C and stirred for 5 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (conditions are as follows, column: spherical C18, 20-40 um, 220 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-95% B, 30 minutes; detector: 214 nm). At 40% B, fractions containing the product were collected and concentrated under reduced pressure to give (Z)-1-(3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (320 mg, 0.53 mmol, yield: 53.0%), LCMS m/z: 603 [M+H] + .

3)、(Z)-N-((E)-氨基(甲磺酰胺基)亚甲基)-3-(4-氰基苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒的合成
3) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide

在室温下，向溶有(Z)-1-(3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(200mg，0.33mmol)的DMF(4mL)溶液中，加入N-氨基甲酰亚胺甲磺酰胺(136mg，0.99mmol)，t-BuOK(185mg，1.65mmol，1M的THF)，0℃搅拌1小时。将混合反应液通过反相柱色谱纯化(条件如下，柱：球形C18，20-40um，40g；流动相A：水(0.1％TFA)；流动相B：乙腈；流速：50mL/min；梯度：10分钟内5％B-95％B；检测器：214nm)纯化，在54％B下，收集含有产物的级分，减压浓缩得到(Z)-N-((E)-氨基(甲磺酰胺基)亚甲基)-3-(4-氰基苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒(35mg，0.06mmol，收率：18.2％)，LCMS m/z：618[M+H]+.To a solution of (Z)-1-(3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (200 mg, 0.33 mmol) in DMF (4 mL) at room temperature were added N-carbamide methanesulfonamide (136 mg, 0.99 mmol) and t-BuOK (185 mg, 1.65 mmol, 1 M in THF), and the mixture was stirred at 0°C for 1 hour. The mixed reaction solution was purified by reverse phase column chromatography (conditions are as follows, column: spherical C18, 20-40um, 40g; mobile phase A: water (0.1% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-95%B in 10 minutes; detector: 214nm), and the fractions containing the product were collected at 54%B and concentrated under reduced pressure to obtain (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (35mg, 0.06mmol, yield: 18.2%), LCMS m/z: 618[M+H] + .

4)、(Z)-N-((E)-氨基(甲磺酰胺基)亚甲基)-3-(4-氰基苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒(MRANK-111-04-1和MRANK-111-04-2)的制备：
4), Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (MRANK-111-04-1 and MRANK-111-04-2):

将混合物(Z)-N-((E)-氨基(甲磺酰胺基)亚甲基)-3-(4-氰基苯基)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲脒(35mg，0.06mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A：超临界CO2；流动相B：甲醇(+0.1％7.0mol/1氨的甲醇溶液)，A：B＝50：50；波长：214nm；流速：140mL/min；柱温：室温；柱压：100bar，进样量：8.0mL；循环时间：5.0min)纯化得到单体MRANK-111-04-1和单体MRANK-111-04-2：The mixture (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-cyanophenyl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (35 mg, 0.06 mmol) was subjected to supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: methanol (+0.1% 7.0mol/1 ammonia in methanol solution), A:B=50:50; wavelength: 214nm; flow rate: 140mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 5.0min) was purified to obtain monomer MRANK-111-04-1 and monomer MRANK-111-04-2:

MRANK-111-04-1：Peak 1Chiral HPLC：2.771min；(9.00mg，0.01mmol，收率：25.7％)，LCMS m/z：618[M+H]+.MRANK-111-04-1: Peak 1Chiral HPLC: 2.771 min; (9.00 mg, 0.01 mmol, yield: 25.7%), LCMS m/z: 618 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.06(d，J＝7.6Hz，2H)，7.89(d，J＝5.2Hz，2H)，7.83-7.76(m，4H)，7.34-7.28(m，4H)，7.25-7.21(m，1H)，5.12-5.08(m，1H)，4.54(t，J＝12Hz，11.6Hz，1H)，3.90-3.86(m，1H)，2.68-2.66(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.06 (d, J=7.6Hz, 2H), 7.89 (d, J=5.2Hz, 2H), 7.83-7.76 (m, 4H), 7.34-7.28 (m, 4H), 7.25-7.2 1(m, 1H), 5.12-5.08(m, 1H), 4.54(t, J=12Hz, 11.6Hz, 1H), 3.90-3.86(m, 1H), 2.68-2.66(m, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.48. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.48.

MRANK-111-04-2：Peak 2 ChiralHPLC：3.744min；(8.84mg，0.01mmol，收率：25.2％)，LCMS：m/z：618.3[M+H]+.MRANK-111-04-2: Peak 2 ChiralHPLC: 3.744 min; (8.84 mg, 0.01 mmol, yield: 25.2%), LCMS: m/z: 618.3 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.06(d，J＝8.0Hz，2H)，7.88(d，J＝8.0Hz，2H)，7.83-7.81(m，4H)，7.34-7.26(m，4H)，7.25-7.22(m，1H)，5.11-5.09(m，1H)，4.54(t，J＝11.6Hz，1H)，3.90-3.86(m，1H)，2.69-2.67(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.06 (d, J=8.0Hz, 2H), 7.88 (d, J=8.0Hz, 2H), 7.83-7.81 (m, 4H), 7.34-7.26 (m, 4H), 7.25-7 .22 (m, 1H), 5.11-5.09 (m, 1H), 4.54 (t, J=11.6Hz, 1H), 3.90-3.86 (m, 1H), 2.69-2.67 (m, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.44. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.44.

实施例35、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-06-1和MRANK-111-06-2)的合成：Example 35. Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorobenzene)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-06-1 and MRANK-111-06-2):

1)、3-(4-氯苯基)-N-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
1) Synthesis of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑(2.00g，7.79mmol)的甲苯(20mL)溶液中，加入(4-氯苯基)磺酰基)氨基甲酸甲酯(1.94g，7.79mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩并通过异丙醇打浆，过滤得到3-(4-氯苯基)-N-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(3.70g，粗品)，LCMS m/z：474[M+H]+.At room temperature, methyl (4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (2.00 g, 7.79 mmol) was added to a toluene (20 mL) solution, and the mixture was heated to 110°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and slurried with isopropanol, and filtered to obtain 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (3.70 g, crude product), LCMS m/z: 474 [M+H] + .

2)、(E)-3-(4-氯苯基)-N-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯的合成
2) Synthesis of (E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride

在室温下，向溶有3-(4-氯苯基)-N-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(1.00g，2.11mmol)的氯苯(20mL)溶液中，加入五氯化磷(877mg，4.22mmol)，加热100℃搅拌3小时。将混合反应液减压浓缩，异丙醇打浆，过滤得到((E)-3-(4-氯苯基)-N-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(407mg，0.83mmol，收率：39.30％)，LCMS m/z：494[M]+.At room temperature, phosphorus pentachloride (877 mg, 4.22 mmol) was added to a solution of 3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.00 g, 2.11 mmol) in chlorobenzene (20 mL), and the mixture was heated at 100°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure, slurried with isopropanol, and filtered to obtain ((E)-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (407 mg, 0.83 mmol, yield: 39.30%), LCMS m/z: 494 [M] + .

3)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺的合成
3) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide

在0℃下，向溶有((E)-3-(4-氯苯基)-N-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(200mg，0.41mmol)和N-氨基甲酰甲磺酰胺(167mg，1.22mmol)的四氢呋喃(5mL)溶液中，加入叔丁醇钾(1.22mL，1.22mmol)，室温搅拌1小时。将混合反应液减压浓缩。残余物通过反相柱色谱(条件如下(柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：40mL/min；梯度：10分钟内5％B-95％B；检测器：214nm)纯化，在63.3％B下，收集含有产物的级分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺(100mg，0.17mmol，收率：41.46％)，LCMS m/z：593[M+H]+.To a solution of ((E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (200 mg, 0.41 mmol) and N-carbamoylmethanesulfonamide (167 mg, 1.22 mmol) in tetrahydrofuran (5 mL) at 0°C, potassium tert-butoxide (1.22 mL, 1.22 mmol) was added and stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (conditions as follows (column: spherical C18, 20-40 um, 80 g; Mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-95% B in 10 minutes; detector: 214 nm) was purified, and the fractions containing the product were collected at 63.3% B and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorobenzene)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide (100 mg, 0.17 mmol, yield: 41.46%), LCMS m/z: 593 [M+H] + .

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-06-1和MRANK-111-06-2)的制备：
4) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorobenzene)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-06-1 and MRANK-111-06-2):

将化合物Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺(100mg，0.17mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：甲醇(+0.1％7.0mol/l氨甲醇)，A：B＝55：45；波长：254nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：8.0mL；循环时间：11.1min)制备纯化得到单体MRANK-111-06-1和单体MRANK-111-06-2：Compound Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide (100 mg, 0.17 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: methanol (+0.1% 7.0mol/l ammonia methanol), A:B=55:45; wavelength: 254nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 11.1min) was prepared and purified to obtain monomer MRANK-111-06-1 and monomer MRANK-111-06-2:

MRANK-111-06-1：Peak 1 Chiral HPLC：1.687min；(8.47mg，0.014mmol，收率：8.2％)，LCMS m/z：593[M+H]+.MRANK-111-06-1: Peak 1 Chiral HPLC: 1.687 min; (8.47 mg, 0.014 mmol, yield: 8.2%), LCMS m/z: 593 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.56(s，1H)，7.84(d，J＝8.8Hz，2H)，7.65(d，J＝6.8Hz，2H)，7.57(d，J＝8.0Hz，2H)，7.42(d，J＝8.4Hz，2H)，7.34-7.21(m，5H)，5.03(d，J＝10.4Hz，1H)，4.48(t，J＝10.4Hz，1H)，3.83(dd，J＝12.0Hz，8.0Hz，1H)，2.70(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.56 (s, 1H), 7.84 (d, J = 8.8Hz, 2H), 7.65 (d, J = 6.8Hz, 2H), 7.57 (d, J = 8.0Hz, 2H), 7.42 (d, J = 8.4Hz, 2H), 7. 34-7.21 (m, 5H), 5.03 (d, J=10.4Hz, 1H), 4.48 (t, J=10.4Hz, 1H), 3.83 (dd, J=12.0Hz, 8.0Hz, 1H), 2.70 (s, 3H).

MRANK-111-06-2：Peak 2 Chiral HPLC：2.908min；(8.01mg，0.014mmol，收率8.0％)，LCMS m/z：593[M+H]+.MRANK-111-06-2: Peak 2 Chiral HPLC: 2.908 min; (8.01 mg, 0.014 mmol, yield 8.0%), LCMS m/z: 593 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.53(s，1H)，7.85(d，J＝8.4Hz，2H)，7.65(s，2H)，7.58(d，J＝8.0Hz，2H)，7.43(d，J＝8.0Hz，2H)，7.34-7.21(m，5H)，5.03(d，J＝8.0Hz，1H)，4.50(t，J＝11.6Hz，1H)，3.84(dd，J＝12.4Hz，4.4Hz，1H)，2.69(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.53 (s, 1H), 7.85 (d, J = 8.4Hz, 2H), 7.65 (s, 2H), 7.58 (d, J = 8.0Hz, 2H), 7.43 (d, J = 8.0Hz, 2H), 7.34-7 .21 (m, 5H), 5.03 (d, J=8.0Hz, 1H), 4.50 (t, J=11.6Hz, 1H), 3.84 (dd, J=12.4Hz, 4.4Hz, 1H), 2.69 (s, 3H).

实施例36、4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N’-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺及其异构体(MRANK-111-07-1/2、MRANK-111-07-3和MRANK-111-07-4)的合成：Example 36, 4), Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-N'-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide and its isomers (MRANK-111-07-1/2, MRANK-111-07-3 and MRANK-111-07-4):

1)、N-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
1) Synthesis of N-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有4-(5-甲基-4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈(500mg，1.91mmol)的甲苯(10mL)溶液中，加入(4-氯苯基)磺酰基)氨基甲酸甲酯(478mg，1.91mmol)，，加热110℃搅拌4小时。将混合反应液通过硅胶柱色谱法(PE/EA＝1/1)纯化的得到N-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(500mg，1.04mmol，收率：54.52％)，LCMSm/z：497[M+H]+.At room temperature, methyl (4-chlorophenyl)sulfonyl)carbamate (478 mg, 1.91 mmol) was added to a toluene (10 mL) solution of 4-(5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (500 mg, 1.91 mmol), and the mixture was heated to 110°C and stirred for 4 hours. The mixed reaction solution was purified by silica gel column chromatography (PE/EA=1/1) to obtain N-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (500 mg, 1.04 mmol, yield: 54.52%), LCMS m/z: 497 [M+H] + .

2)、(Z)-1-((((4-氯苯基)磺酰基)亚氨基)(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
2) Synthesis of (Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有N-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(500mg，1.04mmol)的二氯甲烷(15mL)溶液中，加入DMAP(382mg，3.13mmol)，POCl3(318mg，2.08mmol)，加热50℃搅拌3小时。将混合反应液通过反相柱色谱纯化(条件如下：柱：球形C18，20-40um，330g；流动相A：H2O；流动相B：乙腈；流速：80mL/min；梯度：5％B-100％B，15分钟；检测器：254nm)纯化，在70％B下，收集含有产物的级分，减压浓缩得到(Z)-1-((((4-氯苯基)磺酰基)亚氨基)(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)-4-(二甲基氨基)吡啶-1-鎓(560mg，0.95mmol，收率：91.95％)，LCMS m/z：583[M]+. To a solution of N-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (500 mg, 1.04 mmol) in dichloromethane (15 mL) were added DMAP (382 mg, 3.13 mmol) and POCl 3 (318 mg, 2.08 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 3 hours. The mixed reaction solution was purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40um, 330g; mobile phase A: H2O; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm), and the fractions containing the product were collected at 70%B and concentrated under reduced pressure to give (Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-4-(dimethylamino)pyridin-1-ium (560mg, 0.95mmol, yield: 91.95%), LCMS m/z: 583[M] + .

3)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N’-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺的合成

Figure PCTCN2024113428-ftappb-I100379
3) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-N'-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide
Figure PCTCN2024113428-ftappb-I100379

在室温下，向溶有Z)-1-((((4-氯苯基)磺酰基)亚氨基)(3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)-4-(二甲基氨基)吡啶-1-鎓(560mg，0.95mmol)的DMF(10mL)溶液中，加入N-氨基甲酰甲磺酰胺(650mg，4.75mmol)，t-BuOK(1.9mL，1.9mmol，1.0M的THF溶液)，室温搅拌2小时。将混合反应液用饱和NH4Cl(50mL)稀释，并用EA(50mL×3)萃取。合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通反相快速柱色谱纯化(条件如下(柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：60mL/min；梯度：5％B-100％B，15分钟；检测器：254nm纯化)。在60％B下，收集含有产物的馏分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N’-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺(300mg，0.50mmol，收率：52.35％)，LCMS m/z：598[M+H]+ To a solution of Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-4-(dimethylamino)pyridin-1-ium (560 mg, 0.95 mmol) in DMF (10 mL) was added N-carbamoylmethanesulfonamide (650 mg, 4.75 mmol) and t-BuOK (1.9 mL, 1.9 mmol, 1.0 M THF solution) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixed reaction liquid was diluted with saturated NH 4 Cl (50 mL) and extracted with EA (50 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions are as follows (column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B-100%B, 15 minutes; detector: 254nm purification). At 60%B, the fractions containing the product were collected and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-N'-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide (300mg, 0.50mmol, yield: 52.35%), LCMS m/z: 598[M+H] +

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N’-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-07-M和MRANK-111-107-4)的制备

Figure PCTCN2024113428-ftappb-I100380
4) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-N'-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-07-M and MRANK-111-107-4)
Figure PCTCN2024113428-ftappb-I100380

化合物(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N’-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺(100mg，0.16mmol)通过SFC纯化(条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100381
柱尺寸：250*30mm 10m流动相A超临界CO2流动相B：IPA，A：B＝60：40波长：214nm流量：140mL/min柱温：RT背压：100巴，进样量：8.0mL；循环时间：7.0min)制备得到混合物MRANK-111-07-M(80mg，0.13mmol)和单体MRANK-111-07-4：Compound (Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide (100 mg, 0.16 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100381
Column size: 250*30mm 10m mobile phase A supercritical CO2 mobile phase B: IPA, A:B=60:40 wavelength: 214nm flow rate: 140mL/min column temperature: RT back pressure: 100 bar, injection volume: 8.0mL; cycle time: 7.0min) to prepare a mixture MRANK-111-07-M (80mg, 0.13mmol) and a monomer MRANK-111-07-4:

MRANK-111-07-4：峰2：chiral-HPLC：3.639min；(11.36mg，0.018mmol，收率：11.36％)，LCMS m/z：598[M+H]+.MRANK-111-07-4: Peak 2: chiral-HPLC: 3.639 min; (11.36 mg, 0.018 mmol, yield: 11.36%), LCMS m/z: 598 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ7.80(d，J＝7.2Hz，4H)，7.70(d，J＝7.2Hz，2H)，7.61(d，J＝7.2Hz，2H)，7.30-7.13(m，5H)，5.22(d，J＝10.8Hz，1H)，4.81(d，J＝6.4Hz，1H)，2.73(s，3H)，0.82(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.80 (d, J=7.2Hz, 4H), 7.70 (d, J=7.2Hz, 2H), 7.61 (d, J=7.2Hz, 2H), 7.30-7.13 (m, 5H), 5.22 (d, J = 10.8Hz, 1H), 4.81 (d, J = 6.4Hz, 1H), 2.73 (s, 3H), 0.82 (s, 3H).

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N’-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺异构体(MRANK-111-07-1/2和MRANK-111-07-3)的制备
4) Preparation of (Z)-N-((E)-amino(methylsulfonamido)methylene)-N'-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide isomers (MRANK-111-07-1/2 and MRANK-111-07-3)

化合物MRANK-111-07-M(80mg，0.13mmol)通过SFC纯化(条件：体系：Waters SFC 150；柱名：AS柱尺寸：250*40mm 10μm：流动相A超临界CO2流动相B：MeOH，A：B＝70：30；波长：214nm；流量：140mL/min柱温：RT背压：100bar；进样量：7.5mL；循环时间：7.0min)分离制备得到混合物MRANK-111-07-1/2和单体MRANK-111-107-3：Compound MRANK-111-07-M (80 mg, 0.13 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: AS column size: 250*40mm 10μm: mobile phase A supercritical CO 2 mobile phase B: MeOH, A:B=70:30; wavelength: 214nm; flow rate: 140mL/min column temperature: RT back pressure: 100bar; injection volume: 7.5mL; cycle time: 7.0min) to separate and prepare the mixture MRANK-111-07-1/2 and the monomer MRANK-111-107-3:

MRANK-111-07-1/2：峰1：chiral-HPLC：5.184min和6.023min；(55mg，0.091mmol，收率：68.75％)，LCMS m/z：598[M+H]+.MRANK-111-07-1/2: Peak 1: chiral-HPLC: 5.184 min and 6.023 min; (55 mg, 0.091 mmol, yield: 68.75%), LCMS m/z: 598 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.14(s，1H)，7.83-7.66(m，6H)，7.49(d，J＝8.4Hz，2H)，7.38-7.22(m，5H)，6.83-6.57(m，2H)，4.45(s，1H)，4.28-4.19(m，1H)，2.54-2.51(m，3H)，1.40(d，J＝6.0Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.14 (s, 1H), 7.83-7.66 (m, 6H), 7.49 (d, J=8.4Hz, 2H), 7.38-7.22 (m, 5H), 6.83-6. 57 (m, 2H), 4.45 (s, 1H), 4.28-4.19 (m, 1H), 2.54-2.51 (m, 3H), 1.40 (d, J=6.0Hz, 3H).

MRANK-111-07-3：峰2：chiral HPLC：4.196分钟；(11.77mg，0.19mmol，14.71％收率)，LCMS：m/z：598.2[M+H]+.MRANK-111-07-3: Peak 2: chiral HPLC: 4.196 min; (11.77 mg, 0.19 mmol, 14.71% yield), LCMS: m/z: 598.2 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.07(s，1H)，7.82(d，J＝7.2Hz，2H)，7.75(d，J＝7.2Hz，2H)，7.63(d，J＝7.2Hz，2H)，7.54(d，J＝7.6Hz，2H)，7.37-7.18(m，5H)，7.15-6.96(m，2H)，5.05(d，J＝10.4Hz，1H)，4.78-4.67(m，1H)，2.68(s，3H)，0.94(d，J＝4.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.07 (s, 1H), 7.82 (d, J = 7.2Hz, 2H), 7.75 (d, J = 7.2Hz, 2H), 7.63 (d, J = 7.2Hz, 2H), 7.54 (d, J = 7.6Hz, 2H), 7.37 -7.18 (m, 5H), 7.15-6.96 (m, 2H), 5.05 (d, J=10.4Hz, 1H), 4.78-4.67 (m, 1H), 2.68 (s, 3H), 0.94 (d, J=4.8Hz, 3H).

实施例37、(Z)-3-(4-氯苯基)-N′-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-N-(2-胺磺酰基乙基)-4，5-二氢-1H-吡唑-1-羧酰胺异构体(MRANK-111-10-1和MRANK-111-10-2)的合成：Example 37. Synthesis of (Z)-3-(4-chlorophenyl)-N′-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide isomers (MRANK-111-10-1 and MRANK-111-10-2):

1)、4-(五氟-λ6-硫烷基)苯磺酰氯的制备
1) Preparation of 4-(pentafluoro-λ 6 -sulfanyl)benzenesulfonyl chloride

在室温下，向溶有4-(五氟-λ6-硫烷基)苯胺(1.00g，4.57mmol)的乙腈(7mL)溶液中，加入亚硝酸异戊酯(1.07g，9.14mmol)和Ru(bpy)3Cl2-6H2O(17mg，0.02285mmol)，室温将搅拌5min，然后在0℃下，缓慢加入水(411mg，22.85mmol)和氯化亚砜(2.72g，22.85mol)，反应液LED(450nm)照射室温搅拌16小时。将混合反应液用乙酸乙酯(30mL)稀释，饱和食盐水(10mL)洗涤有机相，用无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱层析色谱法(PE/EA＝4/1)纯化得到4-(五氟-λ6-硫烷基)苯磺酰氯(900mg，2.97mmol，收率：65.21％)。1H NMR(400MHz，CDCl3)：δ8.19-8.17(m，2H)，8.05-8.03(m，2H).At room temperature, isoamyl nitrite (1.07 g, 9.14 mmol) and Ru(bpy) 3 Cl 2 -6H 2 O (17 mg, 0.02285 mmol) were added to a solution of 4-(pentafluoro-λ 6 -sulfanyl)aniline (1.00 g, 4.57 mmol) in acetonitrile (7 mL), and the mixture was stirred at room temperature for 5 min. Then, water (411 mg, 22.85 mmol) and thionyl chloride (2.72 g, 22.85 mol) were slowly added at 0°C, and the reaction solution was irradiated with LED (450 nm) and stirred at room temperature for 16 hours. The mixed reaction solution was diluted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=4/1) to give 4-(pentafluoro-λ 6 -sulfanyl)benzenesulfonyl chloride (900 mg, 2.97 mmol, yield: 65.21%). 1 H NMR (400 MHz, CDCl 3 ): δ 8.19-8.17 (m, 2H), 8.05-8.03 (m, 2H).

2)、4-(五氟-λ6-硫烷基)苯磺酰胺的合成
2) Synthesis of 4-(pentafluoro-λ 6 -sulfanyl)benzenesulfonamide

将溶有4-(五氟-λ6-硫烷基)苯磺酰氯(180mg，0.59mmol)的氨甲醇(20mL)溶液室温搅拌1小时。将反应液减压浓缩得到4-(五氟-λ6-硫烷基)苯磺酰胺(170mg，粗品)。A solution of 4-(pentafluoro-λ 6 -sulfanyl)benzenesulfonyl chloride (180 mg, 0.59 mmol) in ammonia methanol (20 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 4-(pentafluoro-λ 6 -sulfanyl)benzenesulfonamide (170 mg, crude product).

1H NMR(400MHz，DMSO-d6)：δ8.17-8.15(m，2H)，8.04-8.02(m，2H)，7.20(s，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.17-8.15 (m, 2H), 8.04-8.02 (m, 2H), 7.20 (s, 2H).

3)、((4-(五氟-λ6-硫烷基)苯基)磺酰基)氨基甲酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100386
3) Synthesis of methyl ((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)carbamate
Figure PCTCN2024113428-ftappb-I100386

在0℃下，向溶有4-(五氟-λ6-硫烷基)苯磺酰胺(170mg，0.60mmol)的乙腈(10mL)溶液中，加入三乙胺(152mg，1.50mmol)和氯甲酸甲酯(86mg，0.90mmol)，室温搅拌2小时。将混合反应液减压浓缩并用乙酸乙酯(10mL)稀释，饱和碳酸氢钠水溶液(20mL)。水相加入浓盐酸得到油状物，然后用乙酸乙酯(20mL)萃取，饱和食盐水(10mL)洗涤有机相，无水硫酸钠干燥，过滤、减压浓缩得到((4-(五氟-λ6-硫烷基)苯基)磺酰基)氨基甲酸甲酯(140mg，0.41mmol，收率：68.62％)。Triethylamine (152 mg, 1.50 mmol) and methyl chloroformate (86 mg, 0.90 mmol) were added to a solution of 4-(pentafluoro-λ 6 -sulfanyl)benzenesulfonamide (170 mg, 0.60 mmol) in acetonitrile (10 mL) at 0°C and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (10 mL) and saturated sodium bicarbonate aqueous solution (20 mL). Concentrated hydrochloric acid was added to the aqueous phase to obtain an oily substance, which was then extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl ((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)carbamate (140 mg, 0.41 mmol, yield: 68.62%).

1H NMR(400MHz，DMSO-d6)：δ8.23-8.21(m，2H)，8.13-8.11(m，2H)，3.60(s，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ 8.23-8.21 (m, 2H), 8.13-8.11 (m, 2H), 3.60 (s, 3H).

4)、3-(4-氯苯基)-N-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成

Figure PCTCN2024113428-ftappb-I100387
4) Synthesis of 3-(4-chlorophenyl)-N-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
Figure PCTCN2024113428-ftappb-I100387

在室温下，向溶有((4-(五氟-λ6-硫烷基)苯基)磺酰基)氨基甲酸甲酯(140mg，0.41mmol)的甲苯(10mL)溶液中，加入3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑(95mg，0.37mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱层析色谱法(PE/EA＝3/1)纯化得到3-(4-氯苯基)-N-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(70mg，0.12mmol，收率：30.17％)。LCMS：m/z：56[M+H]+.At room temperature, 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (95 mg, 0.37 mmol) was added to a solution of methyl ((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)carbamate (140 mg, 0.41 mmol) in toluene (10 mL), and the mixture was heated at 110° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1) to give 3-(4-chlorophenyl)-N-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (70 mg, 0.12 mmol, yield: 30.17%). LCMS: m/z: 56 [M+H] + .

5)、(Z)-1-((3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-硫烷基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成

Figure PCTCN2024113428-ftappb-I100388
5) Synthesis of (Z)-1-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium
Figure PCTCN2024113428-ftappb-I100388

在室温下，向溶有3-(4-氯苯基)-N-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(70mg，0.12mmol)的二氯甲烷(5mL)溶液中，加入4-二甲氨基吡啶(73mg，0.60mmol)和三氯氧磷(55mg，0.36mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩。残余物通过反相快速柱色谱纯化(条件件：柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：40mL/min；梯度：5％B-60％B，12分钟；检测器：214nm)。在55％B下，收集含有所需产物的级分，减压浓缩，得到(Z)-1-((3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-硫烷基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(90mg，0.13mmol，收率：＞99％)，LCMS m/z：670[M]+.To a solution of 3-(4-chlorophenyl)-N-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (70 mg, 0.12 mmol) in dichloromethane (5 mL) was added 4-dimethylaminopyridine (73 mg, 0.60 mmol) and phosphorus oxychloride (55 mg, 0.36 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions: column: spherical C18, 20-40 um, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-60% B, 12 minutes; detector: 214 nm). At 55% B, fractions containing the desired product were collected and concentrated under reduced pressure to give (Z)-1-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (90 mg, 0.13 mmol, yield: >99%), LCMS m/z: 670 [M] + .

6)、(Z)-3-(4-氯苯基)-N′-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-N-(2-胺磺酰基乙基)-4，5-二氢-1H-吡唑-1-羧酰胺的合成

Figure PCTCN2024113428-ftappb-I100389
6) Synthesis of (Z)-3-(4-chlorophenyl)-N′-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-N-(2-aminosulfonylethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
Figure PCTCN2024113428-ftappb-I100389

在室温下，向溶有(Z)-1-((3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-硫烷基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(70mg，0.10mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入2-氨基乙磺酰氨基单盐酸盐(32mg，o.20mmol)和三乙胺(30mg，0.30mmol)，室温搅拌1小时。将混合反应液用乙酸乙酯(20mL)稀释，饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(条件件如下：柱：球形C18，20-40um，40g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：40mL/min；梯度：10分钟内5％B-70％B；检测器：214nm)纯化。在65％B下，收集含有产物的级分，减压浓缩得到(Z)-3-(4-氯苯基)-N′-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-N-(2-胺磺酰基乙基)-4，5-二氢-1H-吡唑-1-羧酰胺(40mg，0.06mmol，收率：57.06％)。LCMS m/z：672[M+H]+.To a solution of (Z)-1-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (70 mg, 0.10 mmol) in N,N-dimethylformamide (5 mL) was added 2-aminoethanesulfonylamino monohydrochloride (32 mg, 0.20 mmol) and triethylamine (30 mg, 0.30 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixed reaction liquid was diluted with ethyl acetate (20 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40um, 40g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 5%B-70%B in 10 minutes; detector: 214nm). At 65%B, the fractions containing the product were collected and concentrated under reduced pressure to give (Z)-3-(4-chlorophenyl)-N′-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (40mg, 0.06mmol, yield: 57.06%). LCMS m/z: 672[M+H] + .

7)、(Z)-3-(4-氯苯基)-N′-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-N-(2-胺磺酰基乙基)-4，5-二氢-1H-吡唑-1-羧酰胺异构体(MRANK-111-10-1和MRANK-111-10-2)的制备

Figure PCTCN2024113428-ftappb-I100390
7) Preparation of (Z)-3-(4-chlorophenyl)-N′-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide isomers (MRANK-111-10-1 and MRANK-111-10-2)
Figure PCTCN2024113428-ftappb-I100390

将(Z)-3-(4-氯苯基)-N′-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-N-(2-胺磺酰基乙基)-4，5-二氢-1H-吡唑-1-羧酸酰胺(40mg，0.06mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100391
色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝65：35；波长：214nm；流速：140mL/min；柱温：室温；柱压：100bar，进样量：5.5mL；循环时间：11.0min)纯化得到两个异构体：MRANK-111-10-1和MRANK-111-10-2：(Z)-3-(4-chlorophenyl)-N′-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-N-(2-aminosulfonylethyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (40 mg, 0.06 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100391
Chromatographic column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=65:35; wavelength: 214nm; flow rate: 140mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 5.5mL; cycle time: 11.0min) was purified to obtain two isomers: MRANK-111-10-1 and MRANK-111-10-2:

MRANK-111-10-1：峰1：Chiral HPLC：3.341min，(13.09mg，0.019mmol，收率：32.72％)，LCMS：m/z：672.1[M+H]+.MRANK-111-10-1: Peak 1: Chiral HPLC: 3.341 min, (13.09 mg, 0.019 mmol, yield: 32.72%), LCMS: m/z: 672.1 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.27-8.24(m，1H)，8.06-8.00(m，4H)，7.71-7.69(m，2H)，7.46-7.44(m，2H)，7.35-7.32(m，2H)，7.28-7.23(m，3H)，7.03(s，2H)，5.13-5.09(m，1H)，4.55(t，J＝11.2Hz，1H)，4.09-4.05(m，1H)，3.76-3.71(m，2H)，3.31-3.27(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.27-8.24(m, 1H), 8.06-8.00(m, 4H), 7.71-7.69(m, 2H), 7.46-7.44(m, 2H), 7.35-7.32(m, 2H), 7.28-7.23(m, 3H ), 7.03 (s, 2H), 5.13-5.09 (m, 1H), 4.55 (t, J=11.2Hz, 1H), 4.09-4.05 (m, 1H), 3.76-3.71 (m, 2H), 3.31-3.27 (m, 2H).

MRANK-111-10-2：峰2：Chiral HPLC：4.614min；(14.06mg，0.020mmol，收率：35.15％)，LCMS m/z：672[M+H]+.MRANK-111-10-2: Peak 2: Chiral HPLC: 4.614 min; (14.06 mg, 0.020 mmol, yield: 35.15%), LCMS m/z: 672 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.27-8.24(m，1H)，8.06-8.00(m，4H)，7.71-7.69(m，2H)，7.46-7.44(m，2H)，7.35-7.32(m，2H)，7.28-7.23(m，3H)，7.03(s，2H)，5.13-5.09(m，1H)，4.55(t，J＝11.2Hz，1H)，4.09-4.05(m，1H)，3.76-3.71(m，2H)，3.32-3.25(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.27-8.24(m, 1H), 8.06-8.00(m, 4H), 7.71-7.69(m, 2H), 7.46-7.44(m, 2H), 7.35-7.32(m, 2H), 7.28-7.23(m, 3H ), 7.03 (s, 2H), 5.13-5.09 (m, 1H), 4.55 (t, J=11.2Hz, 1H), 4.09-4.05 (m, 1H), 3.76-3.71 (m, 2H), 3.32-3.25 (m, 2H).

实施例38、(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵及其异构体(MDR-001-407-1和MDR-001-407-2)和(E)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵及其异构体(MDR-001-407de-1和MDR-001-407de-2)的合成：Example 38, (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium and isomers thereof (MDR-001-407-1 and MDR-001-407-2) and (E)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium and its isomers (MDR-001-407de-1 and MDR-001-407de-2):

1)、3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺的合成

Figure PCTCN2024113428-ftappb-I100392
1) Synthesis of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide
Figure PCTCN2024113428-ftappb-I100392

在室温下，向溶有((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(1.00g，3.53mmol)的甲苯(15mL)溶液中，加入3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑(953mg，3.71mmol)，氮气保护，加热110℃搅拌2小时。将混合反应液减压浓缩，并用异丙醇(20mL)打浆，过滤。滤饼用冷异丙醇和己烷(1：1)洗涤，减压浓缩得到3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(1.64g，3.64mmol，收氯：91.1％)，LCMS m/z：508[M+H]+.At room temperature, 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (953 mg, 3.71 mmol) was added to a solution of methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.00 g, 3.53 mmol) in toluene (15 mL), and the mixture was heated at 110°C and stirred for 2 hours under nitrogen protection. The mixed reaction solution was concentrated under reduced pressure, slurried with isopropanol (20 mL), and filtered. The filter cake was washed with cold isopropanol and hexane (1:1), and concentrated under reduced pressure to give 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.64 g, 3.64 mmol, chlorine yield: 91.1%), LCMS m/z: 508 [M+H] + .

2)、(Z)-3-(4-氯苯基)-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯的合成

Figure PCTCN2024113428-ftappb-I100393
2) Synthesis of (Z)-3-(4-chlorophenyl)-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride
Figure PCTCN2024113428-ftappb-I100393

在室温下，向溶有3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(1.64g，3.23mmol)的氯苯(25mL)溶液中，加入五氯化磷(1.28g，6.14mmol)，然后氮气保护，加热140℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱法(石油醚/乙酸乙酯＝1/1)纯化得到(Z)-3-(4-氯苯基)-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(1.00g，1.90mmol，收率：58.8％)，LCMS m/z：526[M+H]+.At room temperature, phosphorus pentachloride (1.28 g, 6.14 mmol) was added to a solution of 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.64 g, 3.23 mmol) in chlorobenzene (25 mL), and then the mixture was heated at 140°C and stirred for 2 hours under nitrogen protection. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain (Z)-3-(4-chlorophenyl)-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (1.00 g, 1.90 mmol, yield: 58.8%), LCMS m/z: 526[M+H] + .

3)、(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵和(E)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵的合成

Figure PCTCN2024113428-ftappb-I100394
3) Synthesis of (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium and (E)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobutan-2-en-1-ammonium
Figure PCTCN2024113428-ftappb-I100394

在室温下，向溶有(Z)-3-(4-氯苯基)-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(250mg，0.48mmol)的N，N-二甲基甲酰胺(5mL)溶液中，加入(R)-2-乙酰氧基-4-胍-N，N，N-三甲基-4-氧代丁烷-4-氧代丁-1-胺(118mg，0.48mol)和三乙胺(48mg，0.48mmol)，然后室温搅拌16小时。将所得混合物过滤并减压浓缩。残余物通过制备级高效液相色谱(系统：Waters 2767/Qda：柱：Sunfire C18 19*250*10μm；流动相A：0.1％FA/H2O，流动相B：ACN；流速：20ml/min；梯度：33-33％；保留时间：7.7-9.0分钟，16分钟，减压浓缩，得到白色固体化合物MDR-001-407(23.58mg，0.03mmol，收率：7.7％)，LCMS m/z：692[M]+和MDR-001-407de(7.09mg，0.01mmol，收率：2.2％)，LCMS m/z：674[M]+ At room temperature, to a solution of (Z)-3-(4-chlorophenyl)-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (250 mg, 0.48 mmol) in N,N-dimethylformamide (5 mL), (R)-2-acetoxy-4-guanidine-N,N,N-trimethyl-4-oxobutane-4-oxobutan-1-amine (118 mg, 0.48 mol) and triethylamine (48 mg, 0.48 mmol) were added, and then stirred at room temperature for 16 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (system: Waters 2767/Qda: column: Sunfire C18 19*250*10 μm; mobile phase A: 0.1% FA/H2O, mobile phase B: ACN; flow rate: 20 ml/min; gradient: 33-33%; retention time: 7.7-9.0 min, 16 min, and concentrated under reduced pressure to give white solid compounds MDR-001-407 (23.58 mg, 0.03 mmol, yield: 7.7%), LCMS m/z: 692 [M] + and MDR-001-407de (7.09 mg, 0.01 mmol, yield: 2.2%), LCMS m/z: 674 [M] +

MDR-001-407：(2R)-4-((E)-2-((Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(23.58mg，0.03mmol，收率：7.7％)，LCMS m/z：692[M]+ MDR-001-407: (2R)-4-((E)-2-((Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (23.58 mg, 0.03 mmol, yield: 7.7%), LCMS m/z: 692 [M] +

1H NMR(400MHz，DMSO-d6)：δ10.74(s，1H)，8.03(d，J＝8.4，2H)，7.83(d，J＝8.0，2H)，7.52(d，J＝7.6，2H)，7.39(d，J＝0.8，2H)，7.33-7.22(m，5H)，5.04-5.00(m，1H)，4.49(t，J＝11.6，2H)，3.89-3.84(m，1H)，3.45-3.35(m，2H)，3.24(s，9H)，2.56-2.59(m，2H) 1 H NMR (400MHz, DMSO-d6): δ10.74 (s, 1H), 8.03 (d, J=8.4, 2H), 7.83 (d, J=8.0, 2H), 7.52 (d, J=7.6, 2H), 7.39 (d, J=0.8, 2H), 7.3 3-7.22 (m, 5H), 5.04-5.00 (m, 1H), 4.49 (t, J=11.6, 2H), 3.89-3.84 (m, 1H), 3.45-3.35 (m, 2H), 3.24 (s, 9H), 2.56-2.59 (m, 2H)

19F NMR(377MHz，DMSO-d6)δ-61.27， 19 F NMR (377MHz, DMSO-d6) δ-61.27,

MDR-001-407de：(E)-4-((E)-2-(Z)-(3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵的合成(7.09mg，0.01mmol，收率：2.2％)，LCMS m/z：674[M]+ MDR-001-407de: Synthesis of (E)-4-((E)-2-(Z)-(3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium (7.09 mg, 0.01 mmol, yield: 2.2%), LCMS m/z: 674 [M] +

1H NMR(400MHz，DMSO-d6)：δ8.45(s，1H)，8.02(d，J＝8.4，2H)，7.81(d，J＝8.0，2H)，7.52(d，J＝8.8，2H)，7.38(d，J＝8.8，2H)，7.34-7.21(m，5H)，6.90-6.86(m，1H)，6.55(d，J＝13.6，1H)，5.03-4.99(m，1H)，4.51-4.44(m，1H)，4.17(d，J＝7.2，2H)，3.08(s，9H). 1 H NMR (400MHz, DMSO-d6): δ8.45 (s, 1H), 8.02 (d, J=8.4, 2H), 7.81 (d, J=8.0, 2H), 7.52 (d, J=8.8, 2H), 7.38 (d, J=8.8, 2H), 7.34- 7.21 (m, 5H), 6.90-6.86 (m, 1H), 6.55 (d, J=13.6, 1H), 5.03-4.99 (m, 1H), 4.51-4.44 (m, 1H), 4.17 (d, J=7.2, 2H), 3.08 (s, 9H).

19F NMR(377MHz，DMSO-d6)δ-61.27， 19 F NMR (377MHz, DMSO-d6) δ-61.27,

4)化合物(R)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或S-对映体的合成

Figure PCTCN2024113428-ftappb-I100395
4) Synthesis of the compound (R)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or the S-enantiomer
Figure PCTCN2024113428-ftappb-I100395

化合物3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰(11.20g，mmol)通过超临界流体色谱(条件：系统：Waters SFC 80；色谱柱名称：CHIRAL ART Collulose SC；色谱柱尺寸：250×40mm 10μm；流动相A；超临界CO2；流动相B：MEOH(+0.1％7.0mol/L氨在MEOH 中)，A：B＝45：55；波长：214nm；流速：140mL/min；色谱柱温度：RT；背压：100bar；进样量：8.0mL；循环时间：9.5min)纯化得到两种异构体：407-1A和407-1B：Compound 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylate (11.20 g, mmol) was purified by supercritical fluid chromatography (conditions: system: Waters SFC 80; column name: CHIRAL ART Collulose SC; column size: 250×40 mm 10 μm; mobile phase A: supercritical CO 2 ; mobile phase B: MEOH (+0.1% 7.0 mol/L ammonia in MEOH) (middle), A: B = 45:55; wavelength: 214nm; flow rate: 140mL/min; column temperature: RT; back pressure: 100bar; injection volume: 8.0mL; cycle time: 9.5min) to obtain two isomers: 407-1A and 407-1B:

407-1A：峰1：chiral-HPLC：1.719min；(R)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(5.7g，11.22mmol，收率：25.7％)，LCMS m/z：508[M+H]+。407-1A: Peak 1: chiral-HPLC: 1.719 min; (R)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (5.7 g, 11.22 mmol, yield: 25.7%), LCMS m/z: 508 [M+H] + .

407-1A：峰2：chiral-HPLC：3.974min；(S)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(5.5g，10.83mmol，收率：24.9％)，LCMS m/z：508[M+H]407-1A: Peak 2: chiral-HPLC: 3.974 min; (S)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (5.5 g, 10.83 mmol, yield: 24.9%), LCMS m/z: 508 [M+H]

5)、(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯或S-对映体的合成

Figure PCTCN2024113428-ftappb-I100396
5) Synthesis of (R, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or S-enantiomer
Figure PCTCN2024113428-ftappb-I100396

在室温下，向溶有(R)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(2.90g，5.70mmol)的氯苯(20mL)溶液中，加入PCl5(2.37g，11.42mmol)，加热100℃搅拌3小时。将混合反应液减压浓缩。残余物通过柱色谱(PE：DCM＝1：5)纯化得到化合物(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯或对映体(1.6g，3.0mmol，收率：53.4％)，LCMS m/z：526[M+H]+ At room temperature, PCl 5 (2.37 g, 11.42 mmol) was added to a solution of (R)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1- carboxamide or enantiomer (2.90 g, 5.70 mmol) in chlorobenzene (20 mL), and the mixture was heated at 100°C and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (PE:DCM=1:5) to give compound (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid chloride or enantiomer (1.6 g, 3.0 mmol, yield: 53.4%), LCMS m/z: 526 [M+H] +

6)、(R)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其S-对映体和(E)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其S-对映体的合成

Figure PCTCN2024113428-ftappb-I100397
6) Synthesis of (R)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or its S-enantiomer and (E)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobutan-2-en-1-aminium or its S-enantiomer
Figure PCTCN2024113428-ftappb-I100397

在室温下，向溶有(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(925mg，4.56mmol)的DMF(20mL)溶液中加入(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯或对映体(1200mg，2.28mmol)，25℃搅拌反应10分钟，然后加入TEA(692mg，2.40mmol)，25℃搅拌20小时。将混合反应液通过反相柱色谱(条件：色谱柱：球形C18，20-40um，330g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：3.0eq：80mL/min；梯度：5％-100％B 30分钟，检测器：214nm)纯化，在65％B浓度下，收集含有所需产物的馏分减压浓缩得到粗产物(800mg)。粗产物通过prep-HPLC(Waters 2767/Qda：色谱柱：Sunfire C18 19×250×250)：流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：39-39％；保留时间：8.5-13.0min of 18min)纯化得到两个异构体：MDR-001-407-1和MDR-001-407de-1：To a solution of (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (925 mg, 4.56 mmol) in DMF (20 mL) was added (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or enantiomer (1200 mg, 2.28 mmol) at room temperature, the reaction was stirred at 25°C for 10 minutes, and then TEA (692 mg, 2.40 mmol) was added and stirred at 25°C for 20 hours. The mixed reaction liquid was purified by reverse phase column chromatography (conditions: chromatographic column: spherical C18, 20-40um, 330g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 3.0eq: 80mL/min; gradient: 5%-100% B 30 minutes, detector: 214nm), and the fractions containing the desired product were collected and concentrated under reduced pressure at 65% B concentration to obtain a crude product (800mg). The crude product was purified by prep-HPLC (Waters 2767/Qda: chromatographic column: Sunfire C18 19×250×250): mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39-39%; retention time: 8.5-13.0 min of 18 min) to obtain two isomers: MDR-001-407-1 and MDR-001-407de-1:

MDR-001-407-1：(R)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或S-对映体(205.75mg，0.3mmol，收率：13.2％)RT：8.367min.LCMS m/z：692[M]+.MDR-001-407-1: (R)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or S-enantiomer (205.75 mg, 0.3 mmol, yield: 13.2%) RT: 8.367 min. LCMS m/z: 692 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.67(s，1H)，8.02(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.52(d，J＝8.4Hz，2H)，7.38(d，J＝8.8Hz，2H)，7.34-7.22(m，5H)，5.77(s，1H)，5.06-5.02(m，1H)，4.54-4.46(m，2H)，3.90-3.86(m，1H)，3.44-3.35(m，2H)，3.16(s，9H)，2.67-2.61(m，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.67 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.38 (d, J = 8.8Hz, 2H), 7.34-7.22 (m, 5 H), 5.77 (s, 1H), 5.06-5.02 (m, 1H), 4.54-4.46 (m, 2H), 3.90-3.86 (m, 1H), 3.44-3.35 (m, 2H), 3.16 (s, 9H), 2.67-2.61 (m, 2H).

19F NMR(377MHz，DMSO-d6)：δ-61.271，-74.158. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.271, -74.158.

MDR-001-407de-1：(E)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或S-对映体(86.41mg，0.128mmol，收率：5.6％)。RT：8.402min.LCMS：m/z：674.2[M]+.MDR-001-407de-1: (E)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or S-enantiomer (86.41 mg, 0.128 mmol, yield: 5.6%). RT: 8.402 min. LCMS: m/z: 674.2 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.97(s，1H)，8.02(d，J＝8.0Hz，2H)，7.82(d，J＝8.0Hz，2H)，7.52(d，J＝8.4Hz，2H)，7.39(d，J＝8.8Hz，2H)，7.34-7.23(m，5H)，6.99-6.96(m，1H)，6.57(d，J＝15.2Hz，1H)，5.08-5.04(m，1H)，4.54-4.48(m，1H)，4.21(d，J＝7.2Hz，2H)，3.91-3.87(m，1H)，3.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.97 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.82 (d, J = 8.0Hz, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.39 (d, J = 8.8Hz, 2H), 7.34-7.23 (m, 5H), 6.9 9-6.96 (m, 1H), 6.57 (d, J=15.2Hz, 1H), 5.08-5.04 (m, 1H), 4.54-4.48 (m, 1H), 4.21 (d, J=7.2Hz, 2H), 3.91-3.87 (m, 1H), 3.11 (s, 9H).

19F NMR(377MHz，DMSO-d6)：δ-61.311，-73.595. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.311, -73.595.

7)、(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯或对映体的合成

Figure PCTCN2024113428-ftappb-I100398
7) Synthesis of (S, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or enantiomer
Figure PCTCN2024113428-ftappb-I100398

在室温下，向溶有(S)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(1.00g，1.97mmol)的氯苯(10mL)溶液中，加入PCl5(819mg，3.94mmol)，加热100℃搅拌3小时。将混合反应液浓缩反应溶液。残余物IPA打浆并过滤。收集滤饼，得到化合物(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯或对映体(520mg，0.99mmol，收率：50.3％)，LCMS m/z：526[M+H]+ At room temperature, PCl 5 (819 mg, 3.94 mmol) was added to a solution of (S)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1- carboxamide or enantiomer (1.00 g, 1.97 mmol) in chlorobenzene (10 mL), and the mixture was heated at 100°C and stirred for 3 hours. The mixed reaction solution was concentrated. The residue was slurried with IPA and filtered. The filter cake was collected to obtain compound (S, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid chloride or enantiomer (520 mg, 0.99 mmol, yield: 50.3%), LCMS m/z: 526 [M+H] +

8)、(R)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体和(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体的合成

Figure PCTCN2024113428-ftappb-I100399
8), (R)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its enantiomer and (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobutan-2-en-1-ammonium or its enantiomer
Figure PCTCN2024113428-ftappb-I100399

在室温下，向溶有(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(325mg，1.60mmol，2.)的DMF(8mL)溶液中，加入(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰氯或对映体(420mg，0.80mmol)，反应液在25℃条件下搅拌反应10分钟，然后加入TEA(242mg，2.40mmol)。将混合物在25℃条件下搅拌20小时。混合物通过反相快速柱色谱(条件如下：色谱柱：球形C18，20-40um，330g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：5％-100％B 30分钟，检测器：214nm)。在65％B浓度下，收集含有所需产物的馏分，减压浓缩得到粗品(240mg)。粗产物经prep-HPLC(Waters 2767/Qda：色谱柱：Sunfire C18 19×250×250)：流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：39-39％；保留时间：8.4-12.4min of 18min)纯化得到两个异构体：MDR-001-407-2和MDR-001-407de-2：To a solution of (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (325 mg, 1.60 mmol, 2.) in DMF (8 mL) at room temperature, (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or enantiomer (420 mg, 0.80 mmol) was added, and the reaction solution was stirred at 25° C. for 10 minutes, and then TEA (242 mg, 2.40 mmol) was added. The mixture was stirred at 25° C. for 20 hours. The mixture was subjected to reverse phase flash column chromatography (conditions are as follows: chromatographic column: spherical C18, 20-40um, 330g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%-100% B 30 minutes, detector: 214nm). At 65% B concentration, the fractions containing the desired product were collected and concentrated under reduced pressure to obtain a crude product (240mg). The crude product was purified by prep-HPLC (Waters 2767/Qda: chromatographic column: Sunfire C18 19×250×250): mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39-39%; retention time: 8.4-12.4 min of 18 min) to obtain two isomers: MDR-001-407-2 and MDR-001-407de-2:

MDR-001-407-2：(R)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(19.82mg，0.03mmol，收率：3.6％)RT：8.745min.LCMS：m/z：692.2[M]+.MDR-001-407-2: (R)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer (19.82 mg, 0.03 mmol, yield: 3.6%) RT: 8.745 min. LCMS: m/z: 692.2 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.67(s，1H)，8.02(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.53(d，J＝8.4Hz，2H)，7.38(d，J＝8.4Hz，2H)，7.33-7.30(m，2H)，7.25-7.22(m，3H)，5.77(s，1H)，5.06-5.02(m，1H)，4.54-4.46(m，2H)，3.89-3.86(m，1H)，3.44-3.35(m，2H)，3.16(s，9H)，2.67-2.61(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.67 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.4Hz, 2H), 7.38 (d, J = 8.4Hz, 2H), 7.33-7.30 (m, 2H), 7.25-7 .22(m, 3H), 5.77(s, 1H), 5.06-5.02(m, 1H), 4.54-4.46(m, 2H), 3.89-3.86(m, 1H), 3.44-3.35(m, 2H), 3.16(s, 9H), 2.67-2.61(m, 2H).

19F NMR(377MHz，DMSO-d6)δ-61.269，-74.181. 19 F NMR (377MHz, DMSO-d 6 ) δ -61.269, -74.181.

MDR-001-407de-2：(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体(19.38mg，0.03mmol，收率：3.6％)。RT：8.795min.LCMS：m/z：674.4[M]+.MDR-001-407de-2: (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer (19.38 mg, 0.03 mmol, yield: 3.6%). RT: 8.795 min. LCMS: m/z: 674.4 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.96(s，1H)，8.02(d，J＝8.4Hz，2H)，7.82(d，J＝8.4Hz，2H)，7.52(d，J ＝8.4Hz，2H)，7.40(d，J＝8.8Hz，2H)，7.34-7.30(m，2H)，7.28-7.23(m，3H)，7.01-6.94(m，1H)，6.58(d，J＝15.2Hz，1H)，5.08-5.04(m，1H)，4.54-4.48(m，1H)，4.21(d，J＝7.2Hz，2H)，3.91-3.87(m，1H)，3.11(s，9H).1H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 8.02 (d, J = 8.4Hz, 2H), 7.82 (d, J = 8.4Hz, 2H), 7.52 (d, J =8.4Hz, 2H), 7.40 (d, J = 8.8Hz, 2H), 7.34-7.30 (m, 2H), 7.28-7.23 (m, 3H), 7.01-6.94 (m, 1H), 6.58 (d, J = 1 5.2Hz, 1H), 5.08-5.04 (m, 1H), 4.54-4.48 (m, 1H), 4.21 (d, J=7.2Hz, 2H), 3.91-3.87 (m, 1H), 3.11 (s, 9H).

19F NMR(377MHz，DMSO-d6)δ-61.313，-74.377.19F NMR (377MHz, DMSO-d6) δ-61.313, -74.377.

实施例39、(2R)-4-((E)-2-(E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵及其异构体(MDR-001-411)和(2R)-4-((E)-2-(E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵及其异构体(MDR-001-411de)的合成：

Figure PCTCN2024113428-ftappb-I100400
Example 39, Synthesis of (2R)-4-((E)-2-(E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium and its isomers (MDR-001-411) and (2R)-4-((E)-2-(E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium and its isomers (MDR-001-411de):
Figure PCTCN2024113428-ftappb-I100400

在室温下，向溶有(E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)吡咯烷-1-甲酰亚胺基酰氯(350mg，0.66mmol)的N，N二甲基甲酰胺(5mL)溶液中，加入(R)-乙酰氧基-4-胍基-N，N，N-三甲基-4-氧代丁-1-铵(485mg，1.98mmol)和三乙胺(200mg，1.98mmol)，然后加热50℃搅拌16小时。将混合反应液减压浓缩并通过制备高效液相色谱(条件如下：系统：Waters 2767/QDA，色谱柱：Ultimate XB-Phenyl，21.2*250mm，10μm；流动相A：0.05％TFA/H2O，流动相B：乙腈；流速：20mL/min；梯度：47％-48％；保留时间：16min的8.0-11.0min)纯化得到(2R)-4-((E)-2-(E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(3.27mg，0.005mmol，收率：0.71％)，LCMS m/z：693[M]+和(2R)-4-((E)-2-(E)-(3-(4-氯苯基)-4-苯基吡咯烷-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵及其异构体(MDR-001-411de)(10.06mg，0.015mmol，收率：2.25％)，LCMSm/z：675[M]+.To a solution of (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-1-carboximidoyl chloride (350 mg, 0.66 mmol) in N,N-dimethylformamide (5 mL) at room temperature were added (R)-acetoxy-4-guanidino-N,N,N-trimethyl-4-oxobutan-1-aminium (485 mg, 1.98 mmol) and triethylamine (200 mg, 1.98 mmol), and the mixture was heated at 50°C with stirring for 16 hours. The mixed reaction solution was concentrated under reduced pressure and purified by preparative HPLC (conditions as follows: system: Waters 2767/QDA, column: Ultimate XB-Phenyl, 21.2*250 mm, 10 μm; mobile phase A: 0.05% TFA/H 2 O, mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: 47%-48%; retention time: 8.0-11.0 min of 16 min) to give (2R)-4-((E)-2-(E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (3.27 mg, 0.005 mmol, yield: 0.71%), LCMS m/z: 693 [M] + and (2R)-4-((E)-2-(E)-(3-(4-chlorophenyl)-4-phenylpyrrolidin-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium and its isomers (MDR-001-411de) (10.06 mg, 0.015 mmol, yield: 2.25%), LCMS m/z: 675 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.41(s，1H)，7.99-7.97(m，2H)，7.83-7.81(m，2H)，7.34-7.18(m，9H)，5.66(d，J＝4.4Hz，1H)，4.46(s，1H)，4.09-4.04(m，1H)，3.76-3.72(m，1H)，3.67-3.63(m，1H)，3.55-3.50(m，2H)，3.35-3.33(m，2H)，3.12(s，9H)，3.56-3.52(m，2H). 1 H NMR (400MHz, DMSO-d6) δ10.41 (s, 1H), 7.99-7.97 (m, 2H), 7.83-7.81 (m, 2H), 7.34-7.18 (m, 9H), 5.66 (d, J=4.4Hz, 1H), 4.46 (s, 1H ), 4.09-4.04(m, 1H), 3.76-3.72(m, 1H), 3.67-3.63(m, 1H), 3.55-3.50(m, 2H), 3.35-3.33(m, 2H), 3.12(s, 9H), 3.56-3.52(m, 2H).

19F NMR(377MHz，DMSO-d6)δ-61.230，19F NMR(377MHz, DMSO-d6)δ-61.230,

1H NMR(400MHz，DMSO-d6)δ10.76(s，1H)，7.99-7.97(m，2H)，7.81-7.79(m，2H)，7.32-7.17(m，9H)，6.93-6.87(m，1H)，6.54-6.50(m，1H)，4.15(d，J＝8.0Hz，2H)，4.11-4.06(m，1H)，3.78-3.74(m，1H)，3.70-3.60(m，2H)，3.55-3.48(m，1H)，3.12-3.10(m，1H)，3.07(s，9H). 1 H NMR (400MHz, DMSO-d6) δ10.76 (s, 1H), 7.99-7.97 (m, 2H), 7.81-7.79 (m, 2H), 7.32-7.17 (m, 9H), 6.93-6.87 (m, 1H), 6.54-6.50 (m, 1H) , 4.15 (d, J=8.0Hz, 2H), 4.11-4.06 (m, 1H), 3.78-3.74 (m, 1H), 3.70-3.60 (m, 2H), 3.55-3.48 (m, 1H), 3.12-3.10 (m, 1H), 3.07 (s, 9H).

19F NMR(377MHz，DMSO-d6)δ-61.278 19 F NMR(377MHz, DMSO-d6)δ-61.278

实施例40、(R)-4-(((E)-2-(Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵及其对映体的三氟乙酸盐(MDR-001-413-1和MDR-001-413-2)和(E)-4-(((E)-2-(Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-氨基及其对映体的三氟乙酸盐(MDR-001-413de-1和MDR-001-413de-2)的合成：Example 40, (R)-4-(((E)-2-(Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium and its enantiomers trifluoroacetate salts (MDR-001-413-1 and MDR-001-413-2) and Synthesis of (E)-4-(((E)-2-(Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene-1-amino and its enantiomers trifluoroacetate salt (MDR-001-413de-1 and MDR-001-413de-2):

1)、(R)-3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或对映体和(S)-3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺及其对映体的制备

Figure PCTCN2024113428-ftappb-I100401
1), (R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer and (S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide and its enantiomer preparation
Figure PCTCN2024113428-ftappb-I100401

化合物3-(4-氯苯基)-4-(噻吩-2-基)-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(11g，21-40mmol)通过SFC(条件：体系：Waters SFC 150；柱名：CHIRAL ART Collulose SC；柱尺寸：250×40mm 10μm；流动相A；超临界CO2；流动相B：MeOH(MeOH中加入0.1％，7.0mol/L氨)，A：B＝45：55；波长：214nm；流量：140mL/min；柱温：RT；背压：100bar，进样量：8.0mL；循环时间：9.5min)得到两个异构体：化合物413-1A和化合物413-1B：Compound 3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (11 g, 21-40 mmol) was subjected to SFC (conditions: system: Waters SFC 150; column name: CHIRAL ART Collulose SC; column size: 250×40 mm 10 μm; mobile phase A: supercritical CO 2 ; mobile phase B: MeOH (0.1%, 7.0 mol/L ammonia was added to MeOH), A:B=45:55; wavelength: 214 nm; flow rate: 140 mL/min; column temperature: RT; back pressure: 100 bar, injection volume: 8.0 mL; cycle time: 9.5 min) to obtain two isomers: compound 413-1A and compound 413-1B:

413-1A：峰1，Chiral HPLC：1.759min；(5.30g，10.31mmol，收率：48.2％)，LCSM m/z：536[M+Na]+.413-1A: Peak 1, Chiral HPLC: 1.759 min; (5.30 g, 10.31 mmol, yield: 48.2%), LCSM m/z: 536 [M+Na] + .

413-1B：峰2，Chiral HPLC：4.766min；(5.39g，10.48mmol，收率：49.0％)，LCMS m/z：536[M+Na]+.413-1B: Peak 2, Chiral HPLC: 4.766 min; (5.39 g, 10.48 mmol, yield: 49.0%), LCMS m/z: 536 [M+Na] + .

2)、(R，E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲亚胺酰氯或对映体的合成

Figure PCTCN2024113428-ftappb-I100402
2) Synthesis of (R, E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or enantiomer
Figure PCTCN2024113428-ftappb-I100402

在室温下，向溶有413-1A(1.00g，1.95mmol)的DCM(20mL)溶液中，加入DMAP(1.19g，9.75mmol)和POCl3(0.60g，3.90mmol)，加热50℃搅拌2小时。LCMS显示反应完成。然后将LiCl(0.85g，19.5mmol)加入上述混合反应液中，搅拌16小时。并用EA(50mL)稀释，再用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥，过滤、减压浓缩得到残余物。残余物通过硅胶柱色谱法(PE/DCM＝2/3)纯化得到(R，E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲亚胺酰氯或对映体413-2A(0.36g，0.67mmol，收率：36.2％)，LCMS m/z：532[M+H]+ At room temperature, DMAP (1.19 g, 9.75 mmol) and POCl 3 (0.60 g, 3.90 mmol) were added to a solution of 413-1A (1.00 g, 1.95 mmol) in DCM (20 mL), and the mixture was heated at 50°C and stirred for 2 hours. LCMS showed that the reaction was complete. LiCl (0.85 g, 19.5 mmol) was then added to the mixed reaction solution and stirred for 16 hours. The mixture was diluted with EA (50 mL), washed with saturated brine (50 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE/DCM=2/3) to give (R,E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or enantiomer 413-2A (0.36 g, 0.67 mmol, yield: 36.2%), LCMS m/z: 532 [M+H] +

3)、(R)-4-(((E)-2-(Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵三氟乙酸盐或对映体(MDR01-413-1)和(E)-4-(((E)-2-(Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-氨基三氟乙酸盐或对映体(MDR01-413de-1)的合成

Figure PCTCN2024113428-ftappb-I100403
3), (R)-4-(((E)-2-(Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium trifluoroacetate or enantiomer (MDR01-413-1) and Synthesis of (E)-4-(((E)-2-(Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene-1-amino trifluoroacetate or enantiomer (MDR01-413de-1)
Figure PCTCN2024113428-ftappb-I100403

在室温下，向溶有413-2A(360mg，0.67mmol)的干燥DMF(10mL)溶液中，加入(R)-2-乙酰氧基-4-胍-N，N-二甲基-4-氧代丁-1-胺(328mg，1.34mmol)，搅拌0.5小时后，加入三乙胺(203mg，2.01mmol)后，室温搅拌16小时。将混合物浓缩并通过反相柱色谱(条件如下(柱：Spherical C18，20-40μm，80g；流动相A：0.03％TFA的水；流动相B：乙腈；流速：50mL/min；梯度：5％B 10分钟，5-30％B 5分钟，30-40％B 3分钟；检测器：214nm)纯化，在40％B下，收集含有所需产物的级分，减压浓缩得到粗产物(50mg)。粗产品通过pre-HPLC(Waters 2767/Qda：Sunfire C18，19×250×10um；流动相A：0.05％TFA的水；B：ACN；流速：20mL/min；梯度：38％B-38％；保留时间：7.0-11.0分钟，16分钟)进一步纯化得到两个异构体：MDR01-413-1和MDR01-413de-1：At room temperature, (R)-2-acetoxy-4-guanidine-N,N-dimethyl-4-oxobutan-1-amine (328 mg, 1.34 mmol) was added to a solution of 413-2A (360 mg, 0.67 mmol) in dry DMF (10 mL). After stirring for 0.5 h, triethylamine (203 mg, 2.01 mmol) was added and stirred at room temperature for 16 h. The mixture was concentrated and purified by reverse phase column chromatography (column: Spherical C18, 20-40 μm, 80 g; mobile phase A: 0.03% TFA in water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B for 10 min, 5-30% B for 5 min, 30-40% B for 3 min; detector: 214 nm). At 40% B, fractions containing the desired product were collected and concentrated under reduced pressure to give a crude product (50 The crude product was further purified by pre-HPLC (Waters 2767/Qda: Sunfire C18, 19×250×10um; mobile phase A: 0.05% TFA in water; B: ACN; flow rate: 20mL/min; gradient: 38%B-38%; retention time: 7.0-11.0 min, 16 min) to obtain two isomers: MDR01-413-1 and MDR01-413de-1:

MDR-001-413-1：(R)-4-(((E)-2-(Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵三氟乙酸盐或对映体(22.85mg，0.033mmol，收率：4.9％)，tR＝8.606min，LCMS m/z：698[M]+.MDR-001-413-1: (R)-4-(((E)-2-(Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium trifluoroacetate or enantiomer (22.85 mg, 0.033 mmol, yield: 4.9%), t R =8.606 min, LCMS m/z: 698 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.66(s，1H)，δ8.02(d，J＝8.0Hz，2H)，7.83(d，J＝8.4Hz，2H)，7.58(d，J＝8.8Hz，2H)，7.44-7.40(m，3H)，6.96-6.94(m，2H)，5.75(d，J＝6.0Hz，1H)，5.41(dd，J＝11.2，4.8Hz，1H)，4.51-4.42(m，2H)，3.95(dd，J＝11.6，5.2Hz，1H)，3.43-3.38(m，2H)，3.15(s，9H)，2.62-2.58(m，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.66 (s, 1H), δ8.02 (d, J=8.0Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 7.58 (d, J=8.8Hz, 2H), 7.44-7.40 (m, 3H), 6.96-6.94 (m, 2H), 5.75 (d, J=6. 0Hz, 1H), 5.41 (dd, J=11.2, 4.8Hz, 1H), 4.51-4.42 (m, 2H), 3.95 (dd, J=11.6, 5.2Hz, 1H), 3.43-3.38 (m, 2H), 3.15 (s, 9H), 2.62-2.58 (m, 2H).

19F NMR(377MHz，DMSO-d6)：δ-61.265，-73.452. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.265, -73.452.

MDR-001-413de-1：(E)-4-(((E)-2-(Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-氨基三氟乙酸盐或对映体(4.67mg，0.0068mmol，收率：1.0％)，tR＝8.606min，LCMS m/z：680[M]+.MDR-001-413de-1: (E)-4-(((E)-2-(Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene-1-amino trifluoroacetate or enantiomer (4.67 mg, 0.0068 mmol, yield: 1.0%), t R =8.606 min, LCMS m/z: 680 [M] + .

1H NMR(400MHz，DMSO-d6)：δ8.01(d，J＝8.8Hz，2H)，7.82(d，J＝8.0Hz，2H)，7.59(d，J＝8.4Hz，2H)，7.45-7.40(m，3H)，6.98-6.94(m，3H)，5.76(s，1H)，5.55(d，J＝14.8Hz，1H)，4.43(dd，J＝11.6，5.6Hz，1H)，4.46(t，J＝14.0Hz，1H)，4.19(t，J＝7.2Hz，2H)，3.99-3.94(m，1H)，3.10(s，9H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.01 (d, J=8.8Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7.59 (d, J=8.4Hz, 2H), 7.45-7.40 (m, 3H), 6.98-6.94 (m, 3H), 5.76 (s, 1H), 5.55 (d, J=14.8Hz, 1H), 4.43 (dd, J=11.6, 5.6Hz, 1H), 4.46 (t, J=14.0Hz, 1H), 4.19 (t, J=7.2Hz, 2H), 3.99-3.94 (m, 1H), 3.10 (s, 9H).

19F NMR(377MHz，DMSO-d6)：δ-61.305，-73.404. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.305, -73.404.

4)、(R，E)-3-(4-氯苯基)-4-(噻吩-2-基)-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲亚胺酰氯或对映体的合成

Figure PCTCN2024113428-ftappb-I100404
4) Synthesis of (R, E)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or enantiomer
Figure PCTCN2024113428-ftappb-I100404

在室温下，向溶有413-1B(1.00g，1.95mmol)的DCM(20mL)溶液中，加入DMAP(1.19g，9.75mmol)和POCl3(0.90g，5.85mmol)，加热50℃搅拌2小时。LCMS显示反应完成。然后将LiCl(0.85g，19.5mmol)加入上述混合物中，搅拌16小时。将混合反应液用EA(50mL)稀释，并用饱和食盐水(50mL×3)洗涤，无水Na2SO4干燥。过滤、减压浓缩。残余物通过硅胶柱色谱法(PE/DCM＝2/3)纯化得化合物413-2B(0.46g，0.86mmol，收率：44.1％)，LCMS m/z：532[M+H]+ At room temperature, DMAP (1.19 g, 9.75 mmol) and POCl 3 (0.90 g, 5.85 mmol) were added to a solution of 413-1B (1.00 g, 1.95 mmol) in DCM (20 mL), and the mixture was heated at 50°C and stirred for 2 hours. LCMS showed that the reaction was complete. LiCl (0.85 g, 19.5 mmol) was then added to the mixture and stirred for 16 hours. The mixed reaction solution was diluted with EA (50 mL), washed with saturated brine (50 mL×3), and dried over anhydrous Na 2 SO 4. Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/DCM=2/3) to give compound 413-2B (0.46 g, 0.86 mmol, yield: 44.1%), LCMS m/z: 532 [M+H] +

5)、(R)-4-(((E)-2-(Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体的三氟乙酸盐和(E)-4-(((E)-2-(Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-氨基或对映体的三氟乙酸盐的合成

Figure PCTCN2024113428-ftappb-I100405
5) Synthesis of (R)-4-(((E)-2-(Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or its enantiomer trifluoroacetate and (E)-4-(((E)-2-(Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobutan-2-ene-1-amino or its enantiomer trifluoroacetate
Figure PCTCN2024113428-ftappb-I100405

在室温下，向溶有413-2B(460mg，0.86mmol)的干燥DMF(10mL)溶液中，加入(R)-2-乙酰氧基-4-胍-N，N-二甲基-4-氧代丁-1-胺(420mg，1.72mmol)，室温搅拌0.5小时，加入三乙胺(260mg，2.58mmol)后，室温搅拌16小时。将混合物浓缩并通过反相柱色谱(条件如下(柱：Spherical C18，20-40um，80g；流动相A：水中0.03％TFA；流动相B：乙腈；流速：50mL/min；梯度：5％B10min，5-30％B5min，30-40％B3min；检测器：214nm)纯化。在40％B下，收集含有所需产物的级分，减压浓缩的得到粗产物(150mg)。粗产物通过pre-HPLC(Waters 2767/Qda柱：Sunfire C18，19×250×10um；流动相A：0.05％TFA/水；B：ACN；流速：20mL/min；梯度：38％B-38％；保留时间：7.0-11.0分钟(16分钟)纯化得到两个化合物：MDR-001-413-2和MDR-001-413de-2：At room temperature, (R)-2-acetoxy-4-guanidine-N,N-dimethyl-4-oxobutan-1-amine (420 mg, 1.72 mmol) was added to a solution of 413-2B (460 mg, 0.86 mmol) in dry DMF (10 mL), and the mixture was stirred at room temperature for 0.5 hours. After adding triethylamine (260 mg, 2.58 mmol), the mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by reverse phase column chromatography (conditions as follows (column: Spherical C18, 20-40 um, 80 g; mobile phase A: 0.03% TFA in water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B10 min, 5-30% B5 min, 30-40% B3 min; detector: 214 nm). At 40% B, fractions containing the desired product were collected and concentrated under reduced pressure to give a crude product (150 The crude product was purified by pre-HPLC (Waters 2767/Qda column: Sunfire C18, 19×250×10um; mobile phase A: 0.05% TFA/water; B: ACN; flow rate: 20 mL/min; gradient: 38% B-38%; retention time: 7.0-11.0 min (16 min) to obtain two compounds: MDR-001-413-2 and MDR-001-413de-2:

MDR-001-413-2：(R)-4-(((E)-2-(Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体的三氟乙酸盐(84.68mg，0.12mmol，收率：13.9％)，tR＝8.623min，LCMS m/z：698[M]+，MDR-001-413-2: (R)-4-(((E)-2-(Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer trifluoroacetate salt (84.68 mg, 0.12 mmol, yield: 13.9%), t R =8.623 min, LCMS m/z: 698 [M] + ,

1H NMR(400MHz，DMSO-d6)：δ10.66(s，1H)，δ8.02(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.59(d，J＝8.8Hz，2H)，7.44-7.40(m，3H)，6.98-6.93(m，2H)，5.74(d，J＝4.4Hz，1H)，5.41(dd，J＝11.6，4.8Hz，1H)，4.52-4.41(m，2H)，3.95(dd，J＝12.0，5.2Hz，1H)，3.40-3.34(m，2H)，3.15(s，9H)，2.62-2.59(m，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.66 (s, 1H), δ8.02 (d, J=8.0Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.59 (d, J=8.8Hz, 2H), 7.44-7.40 (m, 3H), 6.98-6.93 (m, 2H), 5.74 (d, J=4. 4Hz, 1H), 5.41 (dd, J=11.6, 4.8Hz, 1H), 4.52-4.41 (m, 2H), 3.95 (dd, J=12.0, 5.2Hz, 1H), 3.40-3.34 (m, 2H), 3.15 (s, 9H), 2.62-2.59 (m, 2H).

19F NMR(377MHz，DMSO-d6)：δ-61.265，-73.868. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.265, -73.868.

MDR-001-413de-2：(E)-4-(((E)-2-(Z)-((S)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体的三氟乙酸盐(28.01mg，0.04mmol，收率：4.6％)。tR＝8.653min，LCMS m/z：680[M]+ MDR-001-413de-2: (E)-4-(((E)-2-(Z)-((S)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer trifluoroacetate salt (28.01 mg, 0.04 mmol, yield: 4.6%). t R =8.653 min, LCMS m/z: 680 [M] +

1H NMR(400MHz，DMSO-d6)：δ10.95(s，1H)，8.01(d，J＝8.0Hz，2H)，7.82(d，J＝12.0Hz，2H)，7.61-7.58(m，2H)，7.45-7.40(m，3H)，6.99-6.95(m，3H)，6.55(d，J＝15.2Hz，1H)，5.45-5.41(m，1H)，4.46(t，J＝11.6Hz，1H)，4.20(t，J＝7.2Hz，2H)，3.99-3.94(m，1H)，3.10(s，9H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.95 (s, 1H), 8.01 (d, J=8.0Hz, 2H), 7.82 (d, J=12.0Hz, 2H), 7.61-7.58 (m, 2H), 7.45-7.40 (m, 3H), 6.99-6.95 (m, 3H), 6.55 (d, J=15.2Hz, 1H), 5.45-5.41 (m, 1H), 4.46 (t, J=11.6Hz, 1H), 4.20 (t, J=7.2Hz, 2H), 3.99-3.94 (m, 1H), 3.10 (s, 9H).

19F NMR(377MHz，DMSO-d6)：δ-61.309，-73.625. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.309, -73.625.

实施例42、N-((E)-N′-(Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MDR-001-703-1、MDR-001-703-1B、MDR-001-703-2A和MDR-001-703-2B)的合成：Example 42, Synthesis of N-((E)-N′-(Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (MDR-001-703-1, MDR-001-703-1B, MDR-001-703-2A and MDR-001-703-2B):

1)4，4-二氟哌啶-1-磺酰胺的合成

Figure PCTCN2024113428-ftappb-I100406
1) Synthesis of 4,4-difluoropiperidine-1-sulfonamide
Figure PCTCN2024113428-ftappb-I100406

在室温下，向溶有4，4-二氟哌啶盐酸盐(5g，31.64mmol)的乙酸丁酯(100mL)溶液中，加入硫酸二酰胺(3.0g，31.64mmol)和N，N-二异丙基乙胺(4.5g，34.80mmol)，加热140℃搅拌16小时。将混合反应液减压浓缩，并用乙酸乙酯(100mL)稀释，再用HCl(20mL，1M)，饱和食盐水(50mL)洗涤。收集有机相无水硫酸钠干燥，过滤、减压浓缩。残余物用甲基叔丁醚(10mL)打浆得到4，4-二氟哌啶-1-磺酰胺(4.2g，21mmol，收率：66.4％)，At room temperature, sulfuric acid diamide (3.0 g, 31.64 mmol) and N, N-diisopropylethylamine (4.5 g, 34.80 mmol) were added to a solution of 4,4-difluoropiperidine hydrochloride (5 g, 31.64 mmol) in butyl acetate (100 mL), and the mixture was heated at 140°C and stirred for 16 hours. The mixed reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), and then washed with HCl (20 mL, 1 M) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether (10 mL) to obtain 4,4-difluoropiperidine-1-sulfonamide (4.2 g, 21 mmol, yield: 66.4%).

1H NMR(400MHz，DMSO-d6)δ6.91(s，2H)，3.15-3.12(m，4H)，2.13-2.03(m，4H). 1 H NMR (400MHz, DMSO-d 6 ) δ6.91 (s, 2H), 3.15-3.12 (m, 4H), 2.13-2.03 (m, 4H).

2)、((4，4-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100407
2) Synthesis of methyl ((4,4-difluoropiperidin-1-yl)sulfonyl)carbamate
Figure PCTCN2024113428-ftappb-I100407

在0℃下，向溶有4，4-(三氟甲基)哌啶-1-磺酰胺(1g，5.0mmol)的乙腈(20mL)溶液中，加入三乙胺(1.26g，12.5mmol)和氯甲酸甲酯(705mg，7.5mmol)，室温搅拌2小时。将混合反应液减压浓缩并用乙酸乙酯(40mL)稀释，再用饱和碳酸氢钠NaHCO3(40mL)洗涤。收集水相加入浓盐酸得到油状物，再用乙酸乙酯(30mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩得到((4，4-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯(850mg，3.29mmol，收率：65.9％)，At 0°C, triethylamine (1.26 g, 12.5 mmol) and methyl chloroformate (705 mg, 7.5 mmol) were added to a solution of 4,4-(trifluoromethyl)piperidine-1-sulfonamide (1 g, 5.0 mmol) in acetonitrile (20 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (40 mL), and then washed with saturated sodium bicarbonate NaHCO3 (40 mL). The aqueous phase was collected and concentrated hydrochloric acid was added to obtain an oil, which was then extracted with ethyl acetate (30 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl ((4,4-difluoropiperidin-1-yl)sulfonyl)carbamate (850 mg, 3.29 mmol, yield: 65.9%).

1H NMR(400MHz，DMSO-d6)δ11.52(s，1H)，3.67(s，3H)，3.39-3.33(s，4H)，2.11-1.98(m，4H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 3.67 (s, 3H), 3.39-3.33 (s, 4H), 2.11-1.98 (m, 4H).

3)、反式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体和顺式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100408
3) Synthesis of trans-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers and cis-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers
Figure PCTCN2024113428-ftappb-I100408

在室温下，向溶有((4，4-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯(850mg，3.29mmol)的甲苯(20mL)溶液中，加入3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(1.12g，4.12mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱法(石油醚/乙酸乙酯＝3/1)纯化得到粗品。粗品通过制备级高效液相色谱法(色谱条件：色谱柱：Waters 2767/Qda，柱：XBridge，19*250mm，10μm；流动相A：10mmol NH4HCO3/H2O，流动相B：ACN；流速：20mL/min；梯度：50％-58％；保留时间：5.50-9.00min和10.25-12.75min的18min)纯化得到两个异构体：703-7-1和703-7-2：At room temperature, 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (1.12 g, 4.12 mmol) was added to a solution of methyl ((4,4-difluoropiperidin-1-yl)sulfonyl)carbamate (850 mg, 3.29 mmol) in toluene (20 mL), and the mixture was heated at 110° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain a crude product. The crude product was purified by preparative HPLC (chromatographic conditions: chromatographic column: Waters 2767/Qda, column: XBridge, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH 4 HCO 3 /H 2 O, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 50%-58%; retention time: 5.50-9.00 min and 10.25-12.75 min for 18 min) to obtain two isomers: 703-7-1 and 703-7-2:

化合物703-7-1：反式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(170mg，0.342mmol，收率：10.3％)。tR＝12.77min，LCMS：m/z：497[M+H]+；Compound 703-7-1: trans-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (170 mg, 0.342 mmol, yield: 10.3%). t R =12.77 min, LCMS: m/z: 497 [M+H] + ;

化合物703-7-2：顺式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(100mg，0.20mmol，收率：6.11％)，tR＝12.886min；LCMS：m/z：497[M+H]+。Compound 703-7-2: cis-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (100 mg, 0.20 mmol, yield: 6.11%), t R =12.886 min; LCMS: m/z: 497 [M+H] + .

4)、1-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100409
4) Synthesis of 1-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100409

在室温下，向溶有反式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(170mg，0.342mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(105mg，0.684mmol)和4-二甲氨基吡啶(208mg，1.71mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(205mg，0.342mmol，收率：＞99％)，LCMS m/z：601[M]+.To a solution of trans-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (170 mg, 0.342 mmol) in dichloromethane (20 mL) were added phosphorus oxychloride (105 mg, 0.684 mmol) and 4-dimethylaminopyridine (208 mg, 1.71 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (205 mg, 0.342 mmol, yield: >99%), LCMS m/z: 601 [M] + .

5)、N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100410
5) Synthesis of N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers
Figure PCTCN2024113428-ftappb-I100410

在室温下，向溶有1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(205mg，0.342mmol)的N，N-二甲基甲酰胺(10mL)溶液中，加入N-氨基甲亚胺酰基乙酰胺(345mg，3.42mmol)和三乙胺(345mg，3.42mmol)，室温搅拌16小时。将混合反应液加乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过反相柱快速柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：在12分钟内5％B-75％B；检测器：254nm)纯化，，在70％B下，收集含有产物的级分，减压浓缩得到N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(80mg，0.138mmol，收率：40.3％)，LCMS m/z：580[M+H]+.At room temperature, N-aminomethylimidoacetamide (345 mg, 3.42 mmol) and triethylamine (345 mg, 3.42 mmol) were added to a solution of 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (205 mg, 0.342 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-75% B in 12 minutes; detector: 254 nm), at 70% B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (80 mg, 0.138 mmol, yield: 40.3%), LCMS m/z: 580 [M+H] + .

6)、N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺和N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-703-1A和MDR-001-703-1B)的合成

Figure PCTCN2024113428-ftappb-I100411
6) Synthesis of N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide and N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-703-1A and MDR-001-703-1B)
Figure PCTCN2024113428-ftappb-I100411

将化合物N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(80mg，0.138mmol)通过制备级超临界流体色谱(色谱条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100412
柱尺寸：250*30mm10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/L氨/甲醇)，A：B＝70：30，检测波长：214nm；流量：120mL/min；柱温：室温；柱压：100bar；进样量：5.0mL；循环时间：8.4min)得到两种异构体：MDR-001-703-1A和MDR-001-703-1B：Compound N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (80 mg, 0.138 mmol) was subjected to preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100412
Column size: 250*30mm10μm; mobile phase A: supercritical CO 2 ; mobile phase B: IPA (+0.1% 7.0mol/L ammonia/methanol), A:B=70:30, detection wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar; injection volume: 5.0mL; cycle time: 8.4min) to obtain two isomers: MDR-001-703-1A and MDR-001-703-1B:

MDR-001-703-1A：峰1，Chiral HPLC：0.933min；N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(25.74mg，0.044mmol，收率：32.16％)LCMS m/z：580[M+H]+.MDR-001-703-1A: Peak 1, Chiral HPLC: 0.933 min; N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (25.74 mg, 0.044 mmol, yield: 32.16%) LCMS m/z: 580 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.71(s，1H)，7.79-7.58(m，3H)，7.42(d，J＝8.8Hz，2H)，7.34-7.30(m，2H)，7.27-7.23(m，3H)，4.61-4.60(m，1H)，4.30-4.26(m，1H)，3.18(s，4H)，2.11-2.04(m，7H)，1.52(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.71(s, 1H), 7.79-7.58(m, 3H), 7.42(d, J=8.8Hz, 2H), 7.34-7.30(m, 2H), 7.27-7.23( m, 3H), 4.61-4.60 (m, 1H), 4.30-4.26 (m, 1H), 3.18 (s, 4H), 2.11-2.04 (m, 7H), 1.52 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-97.097. 19 F NMR (377MHz, DMSO-d 6 ) δ-97.097.

MDR-001-703-1B：峰2，Chiral HPLC：2.190min；N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基) -5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(34.18mg，0.059mmol，收率：42.7％)，LCMS m/z：580[M+H]+ MDR-001-703-1B: Peak 2, Chiral HPLC: 2.190 min; N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl) -5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (34.18 mg, 0.059 mmol, yield: 42.7%), LCMS m/z: 580 [M+H] +

1H NMR(400MHz，DMSO-d6)δ10.71(s，1H)，7.77-7.58(m，3H)，7.42(d，J＝8.8Hz，2H)，7.34-7.30(m，2H)，7.27-7.23(m，3H)，4.61-4.60(m，1H)，4.30-4.26(m，1H)，3.18(s，4H)，2.11-2.04(m，7H)，1.52(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.71(s, 1H), 7.77-7.58(m, 3H), 7.42(d, J=8.8Hz, 2H), 7.34-7.30(m, 2H), 7.27-7.23( m, 3H), 4.61-4.60 (m, 1H), 4.30-4.26 (m, 1H), 3.18 (s, 4H), 2.11-2.04 (m, 7H), 1.52 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-96.887. 19 F NMR (377MHz, DMSO-d 6 ) δ-96.887.

7)、1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成
7) Synthesis of 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof

在室温下，向溶有顺式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(100mg，0.2mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(62mg，0.4mmol)和4-二甲氨基吡啶(122mg，1.0mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(120mg，0.2mmol，收率：＞99％)，LCMS：m/z：601.1[M]+.To a solution of cis-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (100 mg, 0.2 mmol) in dichloromethane (20 mL) were added phosphorus oxychloride (62 mg, 0.4 mmol) and 4-dimethylaminopyridine (122 mg, 1.0 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (120 mg, 0.2 mmol, yield: >99%), LCMS: m/z: 601.1 [M] + .

8)、N-((E)-N′-(Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成
8) Synthesis of N-((E)-N′-(Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers

在室温下，向溶有1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(120mg，0.2mmol)的N，N-二甲基甲酰胺(10mL)溶液中，加入N-氨基甲亚胺酰基乙酰胺(202mg，2.0mmol)和三乙胺(202mg、2.0mmol)。将混合反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快色柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：在12分钟内5％B-75％B；检测器：254nm)纯化，再75％B下，收集含有产物的级分，减压浓缩得到N-((E)-N′-(Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(30mg，0.051mmol，收率：25.8％)，LCMS m/z：580[M+H]+。At room temperature, N-aminomethylimidoacetamide (202 mg, 2.0 mmol) and triethylamine (202 mg, 2.0 mmol) were added to a solution of 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (120 mg, 0.2 mmol) in N,N-dimethylformamide (10 mL). The mixed reaction liquid was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40 um, 80 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-75% B in 12 minutes; detector: 254 nm), and the fractions containing the product were collected at 75% B and concentrated under reduced pressure to give N-((E)-N′-(Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (30 mg, 0.051 mmol, yield: 25.8%), LCMS m/z: 580 [M+H] + .

9)、N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺和N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-703-2A和MDR-001-703-2B)的合成

Figure PCTCN2024113428-ftappb-I100415
9) Synthesis of N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide and N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-703-2A and MDR-001-703-2B)
Figure PCTCN2024113428-ftappb-I100415

化合物N-((E)-N′-(Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(30mg，0.051mmol)通过制备级超临界流体色谱(色谱条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100416
柱尺寸：250*25mm10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/l氨/甲醇)，A：B＝70：30；检测波长：214nm；流量：120mL/min；柱温：RT；柱压：100bar；进样量：2.0mL；循环时间：5.2min)得两种异构体：MDR-001-703-2A和MDR-001-703-2B：Compound N-((E)-N′-(Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (30 mg, 0.051 mmol) was purified by preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100416
Column size: 250*25mm10μm; mobile phase A; supercritical CO2; mobile phase B: IPA (+0.1% 7.0mol/l ammonia/methanol), A:B=70:30; detection wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; column pressure: 100bar; injection volume: 2.0mL; cycle time: 5.2min) to obtain two isomers: MDR-001-703-2A and MDR-001-703-2B:

MDR-001-703-2A：峰1，chiralHPLC：1.796min；N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(4.93mg，0.0085mmol，收率：16.67％)，LCMS m/z：580[M+H]+.MDR-001-703-2A: Peak 1, chiralHPLC: 1.796 min; N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (4.93 mg, 0.0085 mmol, yield: 16.67%), LCMS m/z: 580 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，8.14-7.59(m，1H)，7.45(d，J＝8.8Hz，2H)，7.38(d，J＝8.8Hz，2H)，7.33-7.23(m，3H)，7.12(s，2H)，5.16(d，J＝11.2Hz，1H)，4.79-4.71(m，1H)，3.20-3.14(m，4H)，2.11(s，3H)，2.09-2.00(m，4H)，0.99(d，J＝6.4Hz，，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.63 (s, 1H), 8.14-7.59 (m, 1H), 7.45 (d, J = 8.8Hz, 2H), 7.38 (d, J = 8.8Hz, 2H), 7.33-7.23 (m, 3H), 7.12 (s, 2H), 5. 16 (d, J=11.2Hz, 1H), 4.79-4.71 (m, 1H), 3.20-3.14 (m, 4H), 2.11 (s, 3H), 2.09-2.00 (m, 4H), 0.99 (d, J=6.4Hz,, 3H).

19F NMR(377MHz，DMSO-d6)δ-96.846，-96.872. 19 F NMR (377MHz, DMSO-d 6 ) δ -96.846, -96.872.

MDR-001-703-2B：峰2，chiral HPLC：2.295min；N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(5.57mg，0.0096mmol，收率：18.8％)，LCMS：m/z：584[M+H]+.MDR-001-703-2B: Peak 2, chiral HPLC: 2.295 min; N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (5.57 mg, 0.0096 mmol, yield: 18.8%), LCMS: m/z: 584 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，8.14-7.59(m，1H)，7.45(d，J＝8.8Hz，2H)，7.38(d，J＝8.8Hz，2H)，7.33-7.23(m，3H)，7.12(s，2H)，5.16(d，J＝11.2Hz，1H)，4.77-4.73(m，1H)，3.32-3.20(m，4H)，2.11(s，3H)，2.09-2.02(m，4H)，0.99(d，J＝6.4Hz，，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.63 (s, 1H), 8.14-7.59 (m, 1H), 7.45 (d, J = 8.8Hz, 2H), 7.38 (d, J = 8.8Hz, 2H), 7.33-7.23 (m, 3H), 7.12 (s, 2H), 5. 16 (d, J=11.2Hz, 1H), 4.77-4.73 (m, 1H), 3.32-3.20 (m, 4H), 2.11 (s, 3H), 2.09-2.02 (m, 4H), 0.99 (d, J=6.4Hz,, 3H).

19F NMR(377MHz，DMSO-d6)δ-96.861，-96.972. 19 F NMR (377MHz, DMSO-d 6 ) δ -96.861, -96.972.

实施例43、N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其对映体(MDR-001-704-1A、MDR-001-704-1B、MDR-001-704-2A和MDR-001-704-2B)的合成：Example 43. Synthesis of N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide and its enantiomers (MDR-001-704-1A, MDR-001-704-1B, MDR-001-704-2A and MDR-001-704-2B):

1)、4-(三氟甲基)哌啶-1-磺酰胺的合成

Figure PCTCN2024113428-ftappb-I100417
1) Synthesis of 4-(trifluoromethyl)piperidine-1-sulfonamide
Figure PCTCN2024113428-ftappb-I100417

在室温下，向溶有4-(三氟甲基)哌啶盐酸盐(5g，26.32mmol)的乙酸丁酯(100mL)溶液中，加入硫酸二酰胺(2.53g，26.32mmol)和N，N-二异丙基乙胺(4.07g，31.58mmol)，加热140℃搅拌16小时。将混合反应液减压浓缩并用乙酸乙酯(100mL)稀释。有机相用盐酸(20mL，1M)，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物甲基叔丁基醚(10mL)打浆得到4-(三氟甲基)哌啶-1-磺酰胺(4.90g，21.12mmol，收率：80.32％)。At room temperature, sulfuric acid diamide (2.53 g, 26.32 mmol) and N, N-diisopropylethylamine (4.07 g, 31.58 mmol) were added to a solution of 4-(trifluoromethyl)piperidine hydrochloride (5 g, 26.32 mmol) in butyl acetate (100 mL), and the mixture was heated at 140°C and stirred for 16 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic phase was washed with hydrochloric acid (20 mL, 1 M) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether (10 mL) to give 4-(trifluoromethyl)piperidine-1-sulfonamide (4.90 g, 21.12 mmol, yield: 80.32%).

1H NMR(400MHz，DMSO-d6)δ6.82(s，2H)，3.57-3.54(m，2H)，2.58-2.52(m，2H)，2.46-2.42(m，1H)，1.91-1.88(m，2H)，1.53-1.43(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 6.82 (s, 2H), 3.57-3.54 (m, 2H), 2.58-2.52 (m, 2H), 2.46-2.42 (m, 1H), 1.91-1.88 (m, 2H), 1.53-1.43 (m, 2H).

2)、((4-(三氟甲基)哌啶-1-基)磺酰基)氨基甲酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100418
2) Synthesis of methyl ((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)carbamate
Figure PCTCN2024113428-ftappb-I100418

在0℃下，向溶有4-(三氟甲基)哌啶-1-磺酰胺(1g，4.31mmol)的乙腈(20mL)溶液中，加入三乙胺(1.09g，10.78mmol)和氯甲酸甲酯(608mg，6.47mmol)，室温搅拌2小时。将混合反应液减压浓缩并用乙酸乙酯(40mL)稀释。有机相用饱和碳酸氢钠水溶液(40mL)洗涤。收集水相加入浓盐酸析出油状物，并用乙酸乙酯(30mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩得到((4-(三氟甲基)哌啶-1-基)磺酰基)氨基甲酸甲酯(720mg，2.48mmol，收率：57.60％)。At 0°C, triethylamine (1.09 g, 10.78 mmol) and methyl chloroformate (608 mg, 6.47 mmol) were added to a solution of 4-(trifluoromethyl)piperidine-1-sulfonamide (1 g, 4.31 mmol) in acetonitrile (20 mL), and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (40 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution (40 mL). The aqueous phase was collected and concentrated hydrochloric acid was added to precipitate an oily substance, which was extracted with ethyl acetate (30 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl ((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)carbamate (720 mg, 2.48 mmol, yield: 57.60%).

1H NMR(400MHz，DMSO-d6)δ11.40(s，1H)，4.06-4.00(m，2H)，3.65(s，3H)，2.93-2.86(m，2H)，2.60-2.55(m，1H)，1.91-1.87(m，2H)，1.48-1.35(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ11.40 (s, 1H), 4.06-4.00 (m, 2H), 3.65 (s, 3H), 2.93-2.86 (m, 2H), 2.60-2.55 (m, 1H), 1.91-1.87 (m, 2H), 1.48-1.35 (m, 2H).

3)、反式-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)哌啶-1-基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体和顺式-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)哌啶-1-基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100419
3) Synthesis of trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers and cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers
Figure PCTCN2024113428-ftappb-I100419

在室温下，向溶有((4-(三氟甲基)哌啶-1-基)磺酰基)氨基甲酸甲酯(720mg，2.48mmol)的甲苯(20mL)溶液中，加入3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(869mg，3.22mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱纯化(石油醚/乙酸乙酯＝3/1)得到粗品。粗品通过制备级高效液相色谱(色谱条件：色谱柱：Waters 2767/Qda，色谱柱：XBridge，19*250mm，10μm；流动相A：10mmol NH4HCO3/H2O，B：乙腈；流速：20mL/min；梯度：52％-56％；保留时间：5.50-9.00分钟和10.30-12.30分钟(18分钟)纯化得到两个异构体：704-7-1和704-7-2：At room temperature, 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (869 mg, 3.22 mmol) was added to a solution of methyl ((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)carbamate (720 mg, 2.48 mmol) in toluene (20 mL), and the mixture was heated at 110° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to give a crude product. The crude product was purified by preparative HPLC (chromatographic conditions: chromatographic column: Waters 2767/Qda, chromatographic column: XBridge, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH 4 HCO 3 /H 2 O, B: acetonitrile; flow rate: 20 mL/min; gradient: 52%-56%; retention time: 5.50-9.00 minutes and 10.30-12.30 minutes (18 minutes) to obtain two isomers: 704-7-1 and 704-7-2:

704-7-1：反式-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)哌啶-1-基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(200mg，0.38mmol，收率：15.26％)，tR＝13.187min；LCMS m/z：529[M+H]+；704-7-1: trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (200 mg, 0.38 mmol, yield: 15.26%), t R =13.187 min; LCMS m/z: 529 [M+H] + ;

704-7-2：顺式-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)哌啶-1-基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(180mg，0.34mmol，收率：13.74％)，tR＝13.272min；LCMS m/z：529[M+H]+.704-7-2: cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (180 mg, 0.34 mmol, yield: 13.74%), t R =13.272 min; LCMS m/z: 529 [M+H] + .

4)、1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100420
4) Synthesis of 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100420

室温下，向溶有反式-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)哌啶-1-基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(200mg，0.38mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(291mg，1.90mmol)和4-二甲氨基吡啶(232mg，1.90mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(241mg，0.38mmol，收率：＞99％)。LCMS m/z：633[M]+。 To a solution of trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (200 mg, 0.38 mmol) in dichloromethane (20 mL) at room temperature were added phosphorus oxychloride (291 mg, 1.90 mmol) and 4-dimethylaminopyridine (232 mg, 1.90 mmol), and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction liquid was concentrated under reduced pressure to obtain 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (241 mg, 0.38 mmol, yield: >99%). LCMS m/z: 633 [M] + .

5)、N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100421
5) Synthesis of N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers
Figure PCTCN2024113428-ftappb-I100421

室温下，向溶有1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(241mg，0.38mmol)的N，N二甲基甲酰胺(10mL)溶液中，加入N-氨基甲酰氨基乙酰胺(384mg，3.80mmol)和三乙胺(384mg，3.80mmol)，室温搅拌16小时。将混合反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过快速反相柱色谱(色谱条件：色谱柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：5％B-75％B，12min；检测器：254nm)纯化。在73％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(180mg，0.29mmol，收率：77.58％)，LCMS m/z：612[M+H]+.At room temperature, N-carbamoylaminoacetamide (384 mg, 3.80 mmol) and triethylamine (384 mg, 3.80 mmol) were added to a solution of 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (241 mg, 0.38 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 16 hours. The mixed reaction liquid was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-75%B, 12min; detector: 254nm). At 73%B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (180mg, 0.29mmol, yield: 77.58%), LCMS m/z: 612[M+H] + .

6)、N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-704-1A和MDR-001-704-1B)的合成

Figure PCTCN2024113428-ftappb-I100422
6) Synthesis of N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-704-1A and MDR-001-704-1B)
Figure PCTCN2024113428-ftappb-I100422

将化合物N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(90mg，0.15mmol)通过制备级超临界流体色谱(色谱条件：系统：Waters SFC 80；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100423
色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨/甲醇)，A：B＝55：45；波长：214nm；流速：70mL/min；柱温：室温；柱压：100bar，进样量：4.0mL；循环时间：5.68min)纯化得到两个异构体：MDR-001-704-1A和MDR-001-704-1B：Compound N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (90 mg, 0.15 mmol) was subjected to preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 80; column name:
Figure PCTCN2024113428-ftappb-I100423
Column size: 250*25mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia/methanol), A:B=55:45; wavelength: 214nm; flow rate: 70mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 4.0mL; cycle time: 5.68min) was purified to obtain two isomers: MDR-001-704-1A and MDR-001-704-1B:

MDR-001-704-1A：Peak 1 Chiral HPLC：0.696min；N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(39.53mg，0.06mmol，收率：43.92％)，LCMS m/z：612[M+H]+.MDR-001-704-1A: Peak 1 Chiral HPLC: 0.696 min; N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (39.53 mg, 0.06 mmol, yield: 43.92%), LCMS m/z: 612 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.69(s，1H)，7.58(s，2H)，7.43-7.41(m，2H)，7.34-7.30(m，2H)，7.26-7.23(m，3H)，4.60(s，1H)，4.32(s，1H)，3.66-3.60(m，2H)，2.61-2.55(m，2H)，2.40-2.36(m，1H)，2.11(s，3H)，1.88-1.84(m，2H)，1.52-1.45(m，5H). 1 H NMR (400MHz, DMSO-d 6 )δ10.69(s, 1H), 7.58(s, 2H), 7.43-7.41(m, 2H), 7.34-7.30(m, 2H), 7.26-7.23(m, 3H), 4.60(s, 1H), 4.32(s, 1H ), 3.66-3.60(m, 2H), 2.61-2.55(m, 2H), 2.40-2.36(m, 1H), 2.11(s, 3H), 1.88-1.84(m, 2H), 1.52-1.45(m, 5H).

19F NMR(377MHz，DMSO-d6)δ-72.272. 19 F NMR (377MHz, DMSO-d 6 ) δ-72.272.

MDR-001-704-1B：Peak 2 Chiral HPLC：1.259min；N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(35.80mg，0.06mmol，收率：39.78％)，LCMS：m/z：612[M+H]+.MDR-001-704-1B: Peak 2 Chiral HPLC: 1.259 min; N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (35.80 mg, 0.06 mmol, yield: 39.78%), LCMS: m/z: 612 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.69(s，1H)，7.58(s，2H)，7.43-7.41(m，2H)，7.34-7.30(m，2H)，7.26-7.23(m，3H)，4.60(s，1H)，4.34-4.31(m，1H)，3.66-3.59(m，2H)，2.61-2.55(m，2H)，2.40-2.33(m，1H)，2.11(s，3H)，1.87-1.84(m，2H)，1.52-1.45(m，5H). 1 H NMR (400MHz, DMSO-d 6 )δ10.69(s, 1H), 7.58(s, 2H), 7.43-7.41(m, 2H), 7.34-7.30(m, 2H), 7.26-7.23(m, 3H), 4.60(s, 1H), 4.34-4.31(m , 1H), 3.66-3.59(m, 2H), 2.61-2.55(m, 2H), 2.40-2.33(m, 1H), 2.11(s, 3H), 1.87-1.84(m, 2H), 1.52-1.45(m, 5H).

19F NMR(377MHz，DMSO-d6)δ-72.272. 19 F NMR (377MHz, DMSO-d 6 ) δ-72.272.

7)、1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100424
7) Synthesis of 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100424

室温下，向溶有顺式-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)哌啶-1-基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(200mg，0.38mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(291mg，1.90mmol)和4-二甲氨基吡啶(232mg，1.90mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(241mg，0.38mmol，收率：＞99％)。LCMS m/z：633[M]+.To a solution of cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (200 mg, 0.38 mmol) in dichloromethane (20 mL) at room temperature were added phosphorus oxychloride (291 mg, 1.90 mmol) and 4-dimethylaminopyridine (232 mg, 1.90 mmol), and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (241 mg, 0.38 mmol, yield: >99%). LCMS m/z: 633 [M] + .

8)、N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100425
8) Synthesis of N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers
Figure PCTCN2024113428-ftappb-I100425

室温下，向溶有1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(241mg，0.38mmol)的N，N-二甲基甲酰胺(10mL)溶液中，加入N-氨基甲酰氨基乙酰胺(384mg，3.80mmol)和三乙胺(384mg，3.80mmol)，室温搅拌混合物16小时。将混合反应液用乙酸乙酯(50mL)稀释。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过快速反相柱色谱(色谱条件：色谱柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：5％B-75％B，12min；检测器：254nm)纯化，在73％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(100mg，0.16mmol，收率：43.0％)。LCMS：m/z：612[M+H]+.To a solution of 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (241 mg, 0.38 mmol) in N,N-dimethylformamide (10 mL) at room temperature, N-carbamoylaminoacetamide (384 mg, 3.80 mmol) and triethylamine (384 mg, 3.80 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-75%B, 12min; detector: 254nm). At 73%B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (100mg, 0.16mmol, yield: 43.0%). LCMS: m/z: 612[M+H] + .

9)、N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或其异构体N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-704-2A和MDR-001-704-2B)的合成

Figure PCTCN2024113428-ftappb-I100426
9) Synthesis of N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or its isomer N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-704-2A and MDR-001-704-2B)
Figure PCTCN2024113428-ftappb-I100426

将化合物N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(100mg，0.16mmol)通过制备级超临界流体色谱(色谱条件：系统：Waters SFC 80；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100427
色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝60：40；波长：214nm；流速：70mL/min；柱温：室温；柱压：100bar，进样量：2.0mL；循环时间：4.83min)纯化得到两个异构体：MDR-001-704-2A和MDR-001-704-2B。Compound N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (100 mg, 0.16 mmol) was subjected to preparative supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 80; column name:
Figure PCTCN2024113428-ftappb-I100427
Chromatographic column size: 250*25mm 10μm; mobile phase A; supercritical CO2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=60:40; wavelength: 214nm; flow rate: 70mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 2.0mL; cycle time: 4.83min) was purified to obtain two isomers: MDR-001-704-2A and MDR-001-704-2B.

MDR-001-704-2A：峰1：Chira1HPLC：1.012min；N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(49.45mg，0.08mmol，收率：49.45％)，LCMS m/z：612[M+H]+.MDR-001-704-2A: Peak 1: Chira1 HPLC: 1.012 min; N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (49.45 mg, 0.08 mmol, yield: 49.45%), LCMS m/z: 612 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.60(s，1H)，7.47-7.45(m，2H)，7.40-7.38(m，2H)，7.33-7.12(m，5H)，5.18-5.15(m，1H)，4.81-4.73(m，1H)，3.66-3.62(m，2H)，2.66-2.55(m，2H)，2.45-2.37(m，1H)，2.11(s，3H)，1.88-1.84(m，2H)，1.53-1.44(m，2H)，1.00(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.60(s, 1H), 7.47-7.45(m, 2H), 7.40-7.38(m, 2H), 7.33-7.12(m, 5H), 5.18-5.15(m, 1H), 4.81-4.73(m, 1H), 3.66-3.6 2 (m, 2H), 2.66-2.55 (m, 2H), 2.45-2.37 (m, 1H), 2.11 (s, 3H), 1.88-1.84 (m, 2H), 1.53-1.44 (m, 2H), 1.00 (d, J=6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-72.232. 19 F NMR (377MHz, DMSO-d 6 ) δ-72.232.

MDR-001-704-2B：峰2：Chiral HPLC：1.728min；N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(44.77mg，0.07mmol，44.77％yield)，LCMS m/z：612[M+H]+.MDR-001-704-2B: Peak 2: Chiral HPLC: 1.728 min; N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (44.77 mg, 0.07 mmol, 44.77% yield), LCMS m/z: 612 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.61(s，1H)，7.47-7.45(m，2H)，7.40-7.38(m，2H)，7.33-7.12(m，5H)，5.18-5.15(m，1H)，4.79-4.74(m，1H)，3.64-6.63(m，2H)，2.67-2.58(m，2H)，2.41-2.36(m，1H)，2.11(s，3H)，1.87-1.84(m，2H)，1.53-1.44(m，2H)，1.00(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.61 (s, 1H), 7.47-7.45 (m, 2H), 7.40-7.38 (m, 2H), 7.33-7.12 (m, 5H), 5.18-5.15 (m, 1H), 4.79-4.74 (m, 1H), 3.64-6.6 3(m, 2H), 2.67-2.58(m, 2H), 2.41-2.36(m, 1H), 2.11(s, 3H), 1.87-1.84(m, 2H), 1.53-1.44(m, 2H), 1.00(d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-72.236. 19 F NMR (377MHz, DMSO-d 6 ) δ-72.236.

实施例44、N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MDR-001-705-1A、MDR-001-705-1B、MDR-001-705-2A和MDR-001-705-2B)的合成：Example 44. Synthesis of N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (MDR-001-705-1A, MDR-001-705-1B, MDR-001-705-2A and MDR-001-705-2B):

1)、3，3-二氟哌啶-1-磺酰胺的合成

Figure PCTCN2024113428-ftappb-I100428
1) Synthesis of 3,3-difluoropiperidine-1-sulfonamide
Figure PCTCN2024113428-ftappb-I100428

室温下，向溶有3，3-二氟哌啶盐酸盐(5g，31.65mmol)的乙酸丁酯(100mL)溶液中，加入硫酸二酰胺(3.04g，31.65mmol)和N，N-二异丙基乙胺(4.49g，34.82mmol)，加热140℃搅拌16小时。将混合反应液减压浓缩并用乙酸乙酯(100mL)稀释。有机相盐酸(20mL，1M)，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过甲基叔丁基醚(10mL)打浆得到3，3-二氟哌啶-1-磺酰胺(4.4g，22.00mmol，收率：69.84％)。At room temperature, sulfuric acid diamide (3.04g, 31.65mmol) and N, N-diisopropylethylamine (4.49g, 34.82mmol) were added to a solution of butyl acetate (100mL) containing 3,3-difluoropiperidine hydrochloride (5g, 31.65mmol), and heated at 140°C with stirring for 16 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (100mL). The organic phase was washed with hydrochloric acid (20mL, 1M) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with methyl tert-butyl ether (10mL) to obtain 3,3-difluoropiperidine-1-sulfonamide (4.4g, 22.00mmol, yield: 69.84%).

1H NMR(400MHz，DMSO-d6)δ6.98(s，2H)，3.20(t，J＝12.0Hz，2H)，3.02-2.99(m，2H)，2.03-1.93(m，2H)， 1.77-1.71(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ6.98 (s, 2H), 3.20 (t, J=12.0Hz, 2H), 3.02-2.99 (m, 2H), 2.03-1.93 (m, 2H), 1.77-1.71 (m, 2H).

2)、((3，3-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯的合成

Figure PCTCN2024113428-ftappb-I100429
2) Synthesis of methyl ((3,3-difluoropiperidin-1-yl)sulfonyl)carbamate
Figure PCTCN2024113428-ftappb-I100429

在0℃下，向溶有3，3-二氟哌啶-1-磺酰胺(1g，5.00mmol)的乙腈(20mL)溶液中，加入三乙胺(1.26g，12.50mmol)和氯甲酸甲酯(713mg，7.50mmol)，室温搅拌2小时。将混合反应液减压浓缩，并用乙酸乙酯(50mL)稀释。有机相用饱和碳酸氢钠水溶液(50mL)洗涤。收集水相加入浓盐酸析出油状物，并用乙酸乙酯(50mL×2)萃取。合并的有机相用无水硫酸钠干燥，过滤、减压浓缩((3，3-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯(1.0g，3.88mmol，收率：77.51％)，At 0°C, triethylamine (1.26 g, 12.50 mmol) and methyl chloroformate (713 mg, 7.50 mmol) were added to a solution of 3,3-difluoropiperidine-1-sulfonamide (1 g, 5.00 mmol) in acetonitrile (20 mL), and stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (50 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL). The aqueous phase was collected and concentrated hydrochloric acid was added to precipitate an oily substance, which was extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl ((3,3-difluoropiperidin-1-yl)sulfonyl)carbamate (1.0 g, 3.88 mmol, yield: 77.51%).

1H NMR(400MHz，DMSO-d6)δ11.55(s，1H)，3.66(s，3H)，3.52(t，J＝11.6Hz，2H)，3.28-3.25(m，2H)，2.05-2.00(m，2H)，1.76-1.71(m，2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 11.55 (s, 1H), 3.66 (s, 3H), 3.52 (t, J=11.6Hz, 2H), 3.28-3.25 (m, 2H), 2.05-2.00 (m, 2H), 1.76-1.71 (m, 2H).

3)、反式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体和顺式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100430
3) Synthesis of trans-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers and cis-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers
Figure PCTCN2024113428-ftappb-I100430

室温下，向溶有((3，3-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯(1.0g，3.88mmol)的甲苯(30mL)溶液中，加入3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(1.37g，5.04mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱(石油醚/乙酸乙酯＝3/1)纯化得粗品。粗品通制备级高效液相色谱纯(色谱条件：色谱柱：Waters 2767/Qda，色谱柱：XBridge，19*250mm，10μm；流动相A：10mmol NH4HCO3/H2O，流动相B：乙腈；流速：20mL/min；梯度：48％-48％；保留时间：6.50-9.10min和10.80-12.70min(18min))纯化得到两个异构体：705-7-1和705-7-2：At room temperature, 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (1.37 g, 5.04 mmol) was added to a solution of methyl ((3,3-difluoropiperidin-1-yl)sulfonyl)carbamate (1.0 g, 3.88 mmol) in toluene (30 mL), and the mixture was heated to 110° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain a crude product. The crude product was purified by preparative HPLC (chromatographic conditions: chromatographic column: Waters 2767/Qda, chromatographic column: XBridge, 19*250 mm, 10 μm; mobile phase A: 10 mmol NH 4 HCO 3 /H 2 O, mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: 48%-48%; retention time: 6.50-9.10 min and 10.80-12.70 min (18 min)) to obtain two isomers: 705-7-1 and 705-7-2:

705-7-1：反式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(280mg，0.56mmol，收率：14.58％)，tR＝12.755min，LCMS m/z：497[M+H]+；705-7-1: trans-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (280 mg, 0.56 mmol, yield: 14.58%), t R =12.755 min, LCMS m/z: 497 [M+H] + ;

705-7-2：顺式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(180mg，0.36mmol，收率：9.37％)，tR＝12.849min，LCMS m/z：497[M+H]+.705-7-2: cis-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (180 mg, 0.36 mmol, yield: 9.37%), t R =12.849 min, LCMS m/z: 497 [M+H] + .

4)、1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100431
4) Synthesis of 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100431

室温下，向溶有反式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(280mg，0.56mmol)的二氯甲烷(20mL)溶液中加入三氯氧磷(428mg，2.80mmol)和4-二甲氨基吡啶(342mg，2.80mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到1-((Z) -(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(339mg，0.56mmol，收率：＞99％)，LCMS m/z：601[M]+。Phosphorus oxychloride (428 mg, 2.80 mmol) and 4-dimethylaminopyridine (342 mg, 2.80 mmol) were added to a solution of trans-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (280 mg, 0.56 mmol) in dichloromethane (20 mL) at room temperature, and the mixture was heated at 50°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain 1-((Z) -(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (339 mg, 0.56 mmol, yield: >99%), LCMS m/z: 601 [M] + .

5)、N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100432
5) Synthesis of N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers
Figure PCTCN2024113428-ftappb-I100432

室温下，向溶有1-((Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(339mg，0.56mmol)的N，N二甲基甲酰胺(20mL)溶液中，加入N-氨基甲酰氨基乙酰胺(566mg，5.60mmol)和三乙胺(566mg，5.60mmol)，室温搅拌16小时。将混合反应液减压浓缩并用乙酸乙酯(50mL)稀释。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过快速反相柱色谱柱(色谱条件：色谱柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：5％B-70％B，12min；检测器：254nm))纯化，在70％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(140mg，0.24mmol，收率：42.85％)，LCMSm/z：580[M+H]+.At room temperature, N-carbamoylaminoacetamide (566 mg, 5.60 mmol) and triethylamine (566 mg, 5.60 mmol) were added to a solution of 1-((Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (339 mg, 0.56 mmol) in N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-70%B, 12min; detector: 254nm)). At 70%B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (140mg, 0.24mmol, yield: 42.85%), LCMSm/z: 580[M+H] + .

6)、N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或其对映体N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-705-1A和MDR-001-705-1B)的合成

Figure PCTCN2024113428-ftappb-I100433
6) Synthesis of N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or its enantiomer N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-705-1A and MDR-001-705-1B)
Figure PCTCN2024113428-ftappb-I100433

将化合物N-((E)-N′-(Z)-(反式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(90mg，0.16mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100434
色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝65：35；波长：214nm；流速：100mL/min；柱温：室温；柱压：100bar，进样量：6.0mL；循环时间：6.26min)纯化得到两个异构体：MDR-001-705-1A和MDR-001-705-1B：Compound N-((E)-N′-(Z)-(trans-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (90 mg, 0.16 mmol) was subjected to supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100434
Column size: 250*25mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=65:35; wavelength: 214nm; flow rate: 100mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 6.0mL; cycle time: 6.26min) was purified to obtain two isomers: MDR-001-705-1A and MDR-001-705-1B:

MDR-001-705-1A：Peak 1 Chiral HPLCL：0.920min；N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(41.90mg，0.07mmol，收率：46.55％)，LCMS m/z：580[M+H]+.MDR-001-705-1A: Peak 1 Chiral HPLC: 0.920 min; N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (41.90 mg, 0.07 mmol, yield: 46.55%), LCMS m/z: 580 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.73(s，1H)，7.58(s，2H)，7.44-7.42(m，2H)，7.34-7.30(m，2H)，7.26-7.23 (m，3H)，4.07(s，1H)，4.35-4.34(m，1H)，3.26-3.21(m，2H)，3.04(s，2H)，2.12(s，3H)，2.01-1.90(m，2H)，1.70(s，2H)，1.52(s，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.73 (s, 1H), 7.58 (s, 2H), 7.44-7.42 (m, 2H), 7.34-7.30 (m, 2H), 7.26-7.23 (m, 3H), 4.07 (s, 1H), 4.35-4.34 (m, 1H), 3.26-3.21 (m, 2H), 3.04 (s, 2H), 2.12 (s, 3H), 2.01-1.90 (m, 2H), 1.70 (s, 2H), 1.52 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-98.953. 19 F NMR (377MHz, DMSO-d 6 ) δ-98.953.

MDR-001-705-1B：Peak 2 Chiral HPLC：3.993min；N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(39.33mg，0.07mmol，收率：43.70％)，LCMS m/z：580[M+H]+.MDR-001-705-1B: Peak 2 Chiral HPLC: 3.993 min; N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (39.33 mg, 0.07 mmol, yield: 43.70%), LCMS m/z: 580 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.72(s，1H)，7.58(s，2H)，7.44-7.41(m，2H)，7.34-7.30(m，2H)，7.25-7.23(m，3H)，4.61(s，1H)，4.34-4.33(m，1H)，3.26-3.21(m，2H)，3.04(s，2H)，2.12(s，3H)，1.95(s，2H)，1.70(s，2H)，1.52(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.72(s, 1H), 7.58(s, 2H), 7.44-7.41(m, 2H), 7.34-7.30(m, 2H), 7.25-7.23(m, 3H), 4.61(s, 1H), 4 .34-4.33(m, 1H), 3.26-3.21(m, 2H), 3.04(s, 2H), 2.12(s, 3H), 1.95(s, 2H), 1.70(s, 2H), 1.52(s, 3H).

19F NMR(377MHz，DMSO-d6)δ-98.950. 19 F NMR (377MHz, DMSO-d 6 ) δ-98.950.

7)、1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100435
7) Synthesis of 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100435

室温下，向溶有顺式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(180mg，0.36mmol)的二氯甲烷(20mL)溶液中，加入三氯氧磷(275mg，1.80mmol)和4-二甲氨基吡啶(220mg，1.80mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩得到1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(218mg，0.36mmol，收率：＞99％)。LCMS m/z：601[M]+.To a solution of cis-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (180 mg, 0.36 mmol) in dichloromethane (20 mL) at room temperature were added phosphorus oxychloride (275 mg, 1.80 mmol) and 4-dimethylaminopyridine (220 mg, 1.80 mmol), and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure to obtain 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (218 mg, 0.36 mmol, yield: >99%). LCMS m/z: 601[M] + .

8)、N-((E)-N′-(Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100436
8) Synthesis of N-((E)-N′-(Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers
Figure PCTCN2024113428-ftappb-I100436

室温下，向溶有1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(218mg，0.36mmol)的N，N二甲基甲酰胺(15mL)溶液中，加入N-氨基甲酰氨基乙酰胺(364mg，3.60mmol)和三乙胺(364mg，3.60mmol)，室温搅拌混合物16小时。将混合反应液加乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速色谱柱(色谱条件：色谱柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：5％B-70％B，12min；检测器：254nm))纯化，在70％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(90mg，0.16mmol，收率：42.85％)，LCMS m/z：580[M+H]+.At room temperature, N-carbamoylaminoacetamide (364 mg, 3.60 mmol) and triethylamine (364 mg, 3.60 mmol) were added to a solution of 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (218 mg, 0.36 mmol) in N,N-dimethylformamide (15 mL), and the mixture was stirred at room temperature for 16 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-70%B, 12min; detector: 254nm)). At 70%B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (90mg, 0.16mmol, yield: 42.85%), LCMS m/z: 580[M+H] + .

9)、N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体N-((E)-N′-(Z)-((4R， 5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(MDR-001-705-2A和MDR-001-705-2B)的合成

Figure PCTCN2024113428-ftappb-I100437
9), N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or the enantiomer N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide Synthesis of (5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide (MDR-001-705-2A and MDR-001-705-2B)
Figure PCTCN2024113428-ftappb-I100437

将化合物N-((E)-N′-(Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(90mg，0.16mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100438
色谱柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝60：40；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：3.7mL；循环时间：7.0min)纯化得到两个异构体：MDR-001-705-2A和MDR-001-705-2B：Compound N-((E)-N′-(Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomer (90 mg, 0.16 mmol) was subjected to supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100438
Column size: 250*25mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=60:40; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 3.7mL; cycle time: 7.0min) was purified to obtain two isomers: MDR-001-705-2A and MDR-001-705-2B:

MDR-001-705-2A：Peak 1 Chiral HPLC：2.354min；N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(22.71mg，0.04mmol，收率：25.23％)，LCMS m/z：580[M+H]+.MDR-001-705-2A: Peak 1 Chiral HPLC: 2.354 min; N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (22.71 mg, 0.04 mmol, yield: 25.23%), LCMS m/z: 580 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.64(s，1H)，7.47-7.45(m，2H)，7.40-7.38(m，2H)，7.33-7.12(m，5H)，5.18-5.15(m，1H)，4.83-4.77(m，1H)，3.29-3.23(m，2H)，3.12-3.01(m，2H)，2.11(s，3H)，2.01-1.93(m，2H)，1.74-1.70(m，2H)，1.01-1.00(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.64(s, 1H), 7.47-7.45(m, 2H), 7.40-7.38(m, 2H), 7.33-7.12(m, 5H), 5.18-5.15(m, 1H), 4.83-4.77(m, 1H ), 3.29-3.23(m, 2H), 3.12-3.01(m, 2H), 2.11(s, 3H), 2.01-1.93(m, 2H), 1.74-1.70(m, 2H), 1.01-1.00(m, 3H).

19F NMR(377MHz，DMSO-d6)δ-98.975. 19 F NMR (377MHz, DMSO-d 6 ) δ-98.975.

MDR-001-705-2B：Peak 2 Chiral HPLC：3.499min；N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(20.08mg，0.03mmol，收率：22.31％)，LCMS m/z：580[M+H]+.MDR-001-705-2B: Peak 2 Chiral HPLC: 3.499 min; N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (20.08 mg, 0.03 mmol, yield: 22.31%), LCMS m/z: 580 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.64(s，1H)，7.47-7.45(m，2H)，7.40-7.38(m，2H)，7.33-7.12(m，5H)，5.18-5.15(m，1H)，4.83-4.75(m，1H)，3.29-3.23(m，2H)，3.13-3.01(m，2H)，2.11(s，3H)，2.00-1.91(m，2H)，1.73-1.70(m，2H)，1.01-1.00(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.64(s, 1H), 7.47-7.45(m, 2H), 7.40-7.38(m, 2H), 7.33-7.12(m, 5H), 5.18-5.15(m, 1H), 4.83-4.75(m, 1H ), 3.29-3.23(m, 2H), 3.13-3.01(m, 2H), 2.11(s, 3H), 2.00-1.91(m, 2H), 1.73-1.70(m, 2H), 1.01-1.00(m, 3H).

19F NMR(377MHz，DMSO-d6)δ-98.979. 19 F NMR (377MHz, DMSO-d 6 ) δ-98.979.

实施例45、(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺酰基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺及其异构体(MDR-001-804-1A、MDR-001-804-1B、MDR-001-804-2A和MDR-001-804-2B)的合成：Example 45, Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-N-(2-sulfamoylethyl)-4-(thiophen-2-yl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide and its isomers (MDR-001-804-1A, MDR-001-804-1B, MDR-001-804-2A and MDR-001-804-2B):

1)、1-(4-氯苯基)-2-(噻吩-2-基)乙烷-1-酮的合成

Figure PCTCN2024113428-ftappb-I100439
1) Synthesis of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethane-1-one
Figure PCTCN2024113428-ftappb-I100439

在0℃下，向溶有1-甲基4-氯苯甲酸甲酯(20.00g，140.85mmol)的DMF(200mL)溶液中，加入2-(噻吩-2-基)乙酸(24.09g，169mmol)，LiHMDS(1M的四氢呋喃溶液，437mL，436.64mmol)，室温搅拌1小时。将混合反应液用饱和氯化铵溶液(200mL)淬灭，并用乙酸乙酯(300mL×2)萃取。合并的有机相用饱和食盐水(200mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到1-(4-氯苯基)-2-(噻吩-2-基)乙烷-1-酮(29.20g，123.21mmol，收率：87.4％)，LCMS m/z：237[M+H]+。 At 0°C, 2-(thiophene-2-yl)acetic acid (24.09 g, 169 mmol) and LiHMDS (1M tetrahydrofuran solution, 437 mL, 436.64 mmol) were added to a DMF (200 mL) solution containing 1-methyl 4-chlorobenzoic acid methyl ester (20.00 g, 140.85 mmol) and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (300 mL×2). The combined organic phase was washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-chlorophenyl)-2-(thiophene-2-yl)ethane-1-one (29.20 g, 123.21 mmol, yield: 87.4%), LCMS m/z: 237 [M+H] + .

2)、1-(4-氯苯基)-3-羟基-2-(噻吩-2-基)丁-1-酮的合成

Figure PCTCN2024113428-ftappb-I100440
2) Synthesis of 1-(4-chlorophenyl)-3-hydroxy-2-(thiophen-2-yl)butan-1-one
Figure PCTCN2024113428-ftappb-I100440

在室温下，向溶有1-(4-氯苯基)-2-(噻吩-2-基)乙烷-1-酮(5.00g，21.09mmol)的THF(50mL)溶液中加入乙醛(9.28g，210.90mmol)，无水碳酸钾(8.73g，63.27mmol)，加热40℃搅拌16小时。将混合物用饱和氯化铵溶液(100mL)淬灭，并用乙酸乙酯(100mL×2)萃取。合并的有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(PE；EA＝50；1)纯化得到1-(4-氯苯基)-3-羟基-2-(噻吩-2-基)丁-1-酮(3.20g，12.17mmol，收率：54％)，LCMSm/z：263[M-H2O]+ At room temperature, acetaldehyde (9.28 g, 210.90 mmol) and anhydrous potassium carbonate (8.73 g, 63.27 mmol) were added to a solution of 1-(4-chlorophenyl)-2-(thiophen-2-yl)ethane-1-one (5.00 g, 21.09 mmol) in THF (50 mL), and the mixture was heated at 40°C and stirred for 16 hours. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE; EA=50; 1) to give 1-(4-chlorophenyl)-3-hydroxy-2-(thiophen-2-yl)butan-1-one (3.20 g, 12.17 mmol, yield: 54%), LCMS m/z: 263 [MH 2 O] +

3)、3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑的合成

Figure PCTCN2024113428-ftappb-I100441
3) Synthesis of 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole
Figure PCTCN2024113428-ftappb-I100441

在室温下，向溶有1-(4-氯苯基)-3-羟基-2-(噻吩-2-基)丁-1-酮(3.20g，12.17mmol)的乙醇(30mL)溶液中，加入水合肼(4.87g，97.36mmol)，加热80℃搅拌2小时。将混合反应液用饱和氯化铵溶液(50mL)淬灭，并用乙酸乙酯(100mL×2)萃取。合并的有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤、减压浓缩纯化得到3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(3.37g，粗品)，LCMS m/z：277[M+H]+。At room temperature, hydrazine hydrate (4.87 g, 97.36 mmol) was added to a solution of 1-(4-chlorophenyl)-3-hydroxy-2-(thiophen-2-yl)butan-1-one (3.20 g, 12.17 mmol) in ethanol (30 mL), and the mixture was heated at 80°C and stirred for 2 hours. The mixed reaction solution was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (3.37 g, crude product), LCMS m/z: 277 [M+H] + .

4)、顺式-3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺和反式异构体的合成

Figure PCTCN2024113428-ftappb-I100442
4) Synthesis of cis-3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide and trans isomer
Figure PCTCN2024113428-ftappb-I100442

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑(3.37g，12.17mmol)的甲苯溶液(20mL)溶液中，加入((4-(三氟甲基)苯基)磺酰基)氨基甲酸甲酯(5.17g，18.26mmol)，加热110℃搅拌3小时。将混合反应液减压浓缩并通过反相快速色谱法(色谱条件：色谱柱：球形C18，20- 40um，40g；流动相A：水(碳酸氢铵)；流动相B：乙腈；流速：50mL/min；梯度：20min内5％B-50％B；检测器：214nm)纯化，在为41％B下，收集含有所需产物的馏分，减压浓缩得到两个异构体：804-8-1和804-8-2：At room temperature, methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (5.17 g, 18.26 mmol) was added to a toluene solution (20 mL) containing 3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole (3.37 g, 12.17 mmol), and the mixture was heated to 110° C. and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash chromatography (chromatographic conditions: chromatographic column: spherical C18, 20- 40um, 40g; mobile phase A: water (ammonium bicarbonate); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5% B-50% B in 20min; detector: 214nm) purification, at 41% B, collect the fractions containing the desired product, and concentrate under reduced pressure to obtain two isomers: 804-8-1 and 804-8-2:

804-8-1：(356mg，0.67mmol，收率：5.5％)，tR＝13.078min，LCMS m/z：528[M+H]+ 804-8-1: (356 mg, 0.67 mmol, yield: 5.5%), t R =13.078 min, LCMS m/z: 528 [M+H] +

804-8-2：(368mg，0.70mmol，收率：5.7％)，tR＝13.192min，LCMS m/z：528[M+H]+。804-8-2: (368 mg, 0.70 mmol, yield: 5.7%), t R =13.192 min, LCMS m/z: 528 [M+H] + .

5)、1-((Z)-((顺式-3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成

Figure PCTCN2024113428-ftappb-I100443
5) Synthesis of 1-((Z)-((cis-3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium
Figure PCTCN2024113428-ftappb-I100443

在室温下，向溶有804-8-1(380mg，0.72mmol)的二氯甲烷(5mL)溶液中，加入4-二甲基氨基吡啶(439mg，3.60mmol)，POCl3(330mg，2.16mmol)，氮气氛围加热50℃搅拌1小时。残余物通过反相快速柱色谱法(色谱柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20min内5％B-50％B；检测器：214nm)纯化，在38.2％B下，收集含有所需产物的馏分，并减压浓缩的得到1-((Z)-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(300mg，0.47mmol，收率：65.7％)，LCMS m/z：632[M]+。To a solution of 804-8-1 (380 mg, 0.72 mmol) in dichloromethane (5 mL) were added 4-dimethylaminopyridine (439 mg, 3.60 mmol) and POCl 3 (330 mg, 2.16 mmol) at room temperature, and the mixture was heated at 50° C. and stirred for 1 hour under a nitrogen atmosphere. The residue was purified by reverse phase flash column chromatography (chromatographic column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-50%B in 20min; detector: 214nm), and the fractions containing the desired product were collected at 38.2%B and concentrated under reduced pressure to give 1-((Z)-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (300mg, 0.47mmol, yield: 65.7%), LCMS m/z: 632[M] + .

6)、(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺酰基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺及其异构体的合成

Figure PCTCN2024113428-ftappb-I100444
6) Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-N-(2-sulfamoylethyl)-4-(thiophen-2-yl)-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide and its isomers
Figure PCTCN2024113428-ftappb-I100444

在室温下，向溶有1-((Z)-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(300mg，0.47mmol)的DMF(5mL)溶液中，加入2-氨基乙烷-1-磺酰胺(117mg，0.94mmol)，TEA(95mg，0.94mmol)，氮气氛围加热60℃搅拌2小时。残余物通过反相快速色谱法(色谱柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：5％B-100％B，20min；检测器：214nm。)纯化，在59％B下，收集所需产物的馏分，减压浓缩得到顺式-(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺或异构体(200mg，0.32mmol，收率：66.6％)，LCMS m/z：634[M+H]+。At room temperature, 2-aminoethane-1-sulfonamide (117 mg, 0.94 mmol) and TEA (95 mg, 0.94 mmol) were added to a solution of 1-((Z)-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (300 mg, 0.47 mmol) in DMF (5 mL), and the mixture was heated at 60° C. under nitrogen atmosphere and stirred for 2 hours. The residue was purified by reverse phase flash chromatography (chromatographic column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-100%B, 20min; detector: 214nm. ) was purified, and the fractions of the desired product were collected at 59%B, and concentrated under reduced pressure to obtain cis-(Z)-3-(4-chlorophenyl)-5-methyl-N-(2-aminosulfonylethyl)-4-(thiophen-2-yl)-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide or isomer (200mg, 0.32mmol, yield: 66.6%), LCMS m/z: 634[M+H] + .

将(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺或异构体(200mg，0.32mmol)通过SFC纯化(条件：系统：Waters SFC 150；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100445
色谱柱尺寸：250*40mm 10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/l氨水，MeOH溶液)，流动相A：B＝60：40；波长：214nm；流量：140mL/min；色谱柱温度：RT；背压：100bar，进样量：2.0mL；循环时间：14.33min)得到两种异构体：MDR-001-804-1A和MDR-001-804-1B： (Z)-3-(4-chlorophenyl)-5-methyl-N-(2-sulfamoylethyl)-4-(thiophen-2-yl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide or isomer (200 mg, 0.32 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100445
Column size: 250*40mm 10μm; mobile phase A; supercritical CO 2 ; mobile phase B: IPA (+0.1% 7.0mol/l ammonia water, MeOH solution), mobile phase A:B=60:40; wavelength: 214nm; flow rate: 140mL/min; column temperature: RT; back pressure: 100bar, injection volume: 2.0mL; cycle time: 14.33min) to obtain two isomers: MDR-001-804-1A and MDR-001-804-1B:

MDR-001-804-1A：峰1：chiral HPLC：3.204min；(68.97mg，0.109mmol，收率：34.4％)。LCMS m/z：634[M+H]+。MDR-001-804-1A: Peak 1: chiral HPLC: 3.204 min; (68.97 mg, 0.109 mmol, yield: 34.4%). LCMS m/z: 634 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.30(d，J＝5.2Hz，1H)，8.01(d，J＝8.0Hz，2H)，7.84(t，J＝10.0Hz，4H)，7.51(d，J＝8.8Hz，2H)，7.41(d，J＝4.0Hz，1H)，7.06(s，2H)，6.98-6.93(m，2H)，5.09(d，J＝2.0Hz，1H)4.57-4.55(m，1H)，3.83-3.79(m，2H)，3.33-3.29(m，2H)，1.27(t，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.30 (d, J=5.2Hz, 1H), 8.01 (d, J=8.0Hz, 2H), 7.84 (t, J=10.0Hz, 4H), 7.51 (d, J=8.8Hz, 2H), 7.41 (d, J=4.0Hz, 1H), 7.06 (s, 2H), 6.98-6.93 (m, 2H), 5.09 (d, J=2.0Hz, 1H) 4.57-4.55 (m, 1H), 3.83-3.79 (m, 2H), 3.33-3.29 (m, 2H), 1.27 (t, J=6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.331.19F NMR(377MHz, DMSO-d6)δ-61.331.

MDR-001-804-1B：峰2：chiralHPLC：4.336min；(63.83mg，0.1007mmol，收率：31.9％LCMS：m/z：634[M+H]+。MDR-001-804-1B: Peak 2: chiralHPLC: 4.336 min; (63.83 mg, 0.1007 mmol, yield: 31.9%LCMS: m/z: 634 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.31(s，1H)，8.01(d，J＝8.4Hz，2H)，7.84(t，J＝9.2Hz，4H)，7.51(d，J＝8.0Hz，2H)，7.41(d，J＝5.2Hz，1H)，7.06(s，2H)，6.98-6.93(m，2H)，5.09(s，1H)，4.58-4.55(m，1H)，3.83-3.79(m，2H)，3.35-3.29(m，2H)，1.27(t，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.31 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7.84 (t, J = 9.2Hz, 4H), 7.51 (d, J = 8.0Hz, 2H), 7.41 (d, J = 5.2Hz, 1H), 7.06 (s, 2 H), 6.98-6.93 (m, 2H), 5.09 (s, 1H), 4.58-4.55 (m, 1H), 3.83-3.79 (m, 2H), 3.35-3.29 (m, 2H), 1.27 (t, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.331.19F NMR(377MHz, DMSO-d6)δ-61.331.

7)、1-((Z)-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100446
7) Synthesis of 1-((Z)-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100446

在室温下，向溶有804-8-2(200mg，0.38mmol，1.0eq)的二氯甲烷(5mL)溶液中，加入DMAP(232mg，1.90mmol)，POCl3(174mg，1.14mmol)，氮气氛围加热50℃拌1小时。残余物通过反相快速柱色谱(色谱条件：色谱柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：20min内5％B-50％B；检测器：214nm。)纯化，在38.2％B下，收集含有所需产物的馏分，并减压浓缩得到1-((Z)-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(80mg，0.13mmol，收率：33.3％)，LCMS m/z：632[M+H]+。To a solution of 804-8-2 (200 mg, 0.38 mmol, 1.0 eq) in dichloromethane (5 mL) were added DMAP (232 mg, 1.90 mmol) and POCl 3 (174 mg, 1.14 mmol) at room temperature, and the mixture was heated at 50° C. under nitrogen atmosphere and stirred for 1 hour. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: chromatographic column: spherical C18, 20-40 um, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-50% B in 20 min; detector: 214 nm.), and the fractions containing the desired product were collected at 38.2% B and concentrated under reduced pressure to give 1-((Z)-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (80 mg, 0.13 mmol, yield: 33.3%), LCMS m/z: 632 [M+H] + .

8)、(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺酰基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺及其异构体的合成

Figure PCTCN2024113428-ftappb-I100447
8) Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-N-(2-sulfamoylethyl)-4-(thiophen-2-yl)-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide and its isomers
Figure PCTCN2024113428-ftappb-I100447

在室温下，向溶有1-((Z)-((3-(4-氯苯基)-5-甲基-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(80mg，0.13mmol)的DMF(5mL)溶液中，加入2-氨基乙烷-1-磺酰胺(32mg，0.26mmol)，TEA(26mg，0.26mmol)，氮气氛围加热60℃搅拌2小时。残余物通过反相快速色谱法在以下条件下纯化：色谱柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：5％B-100％B，20min；检测器：214nm。收集含有所需产物的馏分，浓度为59％B，减压浓缩得(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺或异构体(30mg，0.047mmol， 收率：37.5％)，LCMS：m/z：634.3[M+H]+。At room temperature, 2-aminoethane-1-sulfonamide (32 mg, 0.26 mmol) and TEA (26 mg, 0.26 mmol) were added to a solution of 1-((Z)-((3-(4-chlorophenyl)-5-methyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (80 mg, 0.13 mmol) in DMF (5 mL), and the mixture was heated at 60° C. under nitrogen atmosphere and stirred for 2 hours. The residue was purified by reverse phase flash chromatography at 400 nm. Purification under the following conditions: chromatographic column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-100%B, 20min; detector: 214nm. The fractions containing the desired product were collected, with a concentration of 59%B, and concentrated under reduced pressure to obtain (Z)-3-(4-chlorophenyl)-5-methyl-N-(2-aminosulfonylethyl)-4-(thiophen-2-yl)-N'-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide or isomer (30mg, 0.047mmol, Yield: 37.5%), LCMS: m/z: 634.3 [M+H] + .

将(Z)-3-(4-氯苯基)-5-甲基-N-(2-氨磺基乙基)-4-(噻吩-2-基)-N’-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酸酰胺或异构体(30mg，0.047mmol)通过SFC纯化(条件：系统：Waters SFC 80；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100448
色谱柱尺寸：250*25mm 10m；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨水，MEOH溶液)，A：B＝52：48；波长：214nm；流量：70mL/min；色谱柱温度：RT；背压：100bar，进样：2.5mL；循环时间：7.88min)纯化得到两种异构体：MDR-001-804-2A和MDR-001-804-2B：(Z)-3-(4-chlorophenyl)-5-methyl-N-(2-sulfamoylethyl)-4-(thiophen-2-yl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amide or isomer (30 mg, 0.047 mmol) was purified by SFC (conditions: system: Waters SFC 80; column name:
Figure PCTCN2024113428-ftappb-I100448
Column size: 250*25mm 10m; mobile phase A: supercritical CO 2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia water, MEOH solution), A:B=52:48; wavelength: 214nm; flow rate: 70mL/min; column temperature: RT; back pressure: 100bar, injection: 2.5mL; cycle time: 7.88min) was purified to obtain two isomers: MDR-001-804-2A and MDR-001-804-2B:

MDR-001-804-2A：峰1：Chiral-HPLC：2.953min；(12.62mg，0.02mmol，收率：42.0％)，LCMS m/z：634[M+H]+。MDR-001-804-2A: Peak 1: Chiral-HPLC: 2.953 min; (12.62 mg, 0.02 mmol, yield: 42.0%), LCMS m/z: 634 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.14(d，J＝4.4Hz，1H)，8.05(d，J＝8.4Hz，2H)，7.91(d，J＝8.4Hz，2H)，7.62(d，J＝8.4Hz，2H)，7.46-7.43(m，3H)，7.08(s，2H)，6.97-6.95(m，1H)，6.88(d，J＝2.8Hz，1H)，5.48(d，J＝10.4Hz，1H)，4.73-4.69(m，1H)，3.86(d，J＝1.6Hz，2H)，3.32(s，2H)，0.86(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.14 (d, J=4.4Hz, 1H), 8.05 (d, J=8.4Hz, 2H), 7.91 (d, J=8.4Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.46-7.43 (m, 3H), 7.08 (s, 2H), 6.97-6. 95 (m, 1H), 6.88 (d, J = 2.8Hz, 1H), 5.48 (d, J = 10.4Hz, 1H), 4.73-4.69 (m, 1H), 3.86 (d, J = 1.6Hz, 2H), 3.32 (s, 2H), 0.86 (d, J = 6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.36119F NMR (377MHz, DMSO-d6): δ-61.361

MDR-001-804-2B：峰2：Chiral-HPLC：4.285min；(3.94mg，0.006mmol，收率：13.1％)，LCMS m/z：634[M+H]+。MDR-001-804-2B: Peak 2: Chiral-HPLC: 4.285 min; (3.94 mg, 0.006 mmol, yield: 13.1%), LCMS m/z: 634 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.15(s，1H)，8.05(d，J＝8.4Hz，2H)，7.91(d，J＝8.4Hz，2H)，7.64(d，J＝8.4Hz，2H)，7.46-7.43(m，3H)，7.08(s，2H)，6.97-6.95(m，1H)，6.88(d，J＝2.8Hz，1H)，5.48(d，J＝10.4Hz，1H)，4.73-4.68(m，1H)，3.85(d，J＝4.4Hz，2H)，3.32(s，2H)，0.86(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d6) δ 8.15 (s, 1H), 8.05 (d, J = 8.4Hz, 2H), 7.91 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 7.46-7.43 (m, 3H), 7.08 (s, 2H), 6. 97-6.95 (m, 1H), 6.88 (d, J=2.8Hz, 1H), 5.48 (d, J=10.4Hz, 1H), 4.73-4.68 (m, 1H), 3.85 (d, J=4.4Hz, 2H), 3.32 (s, 2H), 0.86 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.36119F NMR (377MHz, DMSO-d6): δ-61.361

实施例46、(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺及其异构体(MDR-001-805-1A、MDR-001-805-1B、MDR-001-805-2A和MDR-001-805-2B)的合成：Example 46, Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide and its isomers (MDR-001-805-1A, MDR-001-805-1B, MDR-001-805-2A and MDR-001-805-2B):

1)、1-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100449
1) Synthesis of 1-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100449

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(250mg，0.478mmol)的二氯甲烷(10mL)溶液中，加入POCl3(146mg，0.957mmol)和DMAP(291mg，2.39mmol)，加热50℃搅拌2小时。混合反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：5％B-75％B，12分钟；检测器：254nm)纯化，在75％B下，收集含有产物的级分，减压浓缩得到1-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成(140mg，0.22mmol，收率：46.66％)，LCMS m/z：626[M+H]+ To a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (250 mg, 0.478 mmol) in dichloromethane (10 mL) was added POCl 3 (146 mg, 0.957 mmol) and DMAP (291 mg, 2.39 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction liquid was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-75%B, 12 minutes; detector: 254nm), and the fractions containing the product were collected at 75%B and concentrated under reduced pressure to give 1-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer synthesis (140mg, 0.22mmol, yield: 46.66%), LCMS m/z: 626[M+H] +

2)、(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100450
2) Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomers
Figure PCTCN2024113428-ftappb-I100450

在室温下，向溶有1-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(140mg，0.22mmol)的DMF(3mL)溶液中，加入2-氨基乙烷-1-磺酰胺(55mg，0.44mmol)和TEA(45mg，0.44mmol)，加热60℃搅拌2小时。将混合反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：在12分钟内5％B-75％B；检测器：254nm)纯化，在60％B下，收集含有产物的级分，减压浓缩得到反式-(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(75mg，0.12mmol，收率：53.57％)，LCMS m/z：628[M+H]+.To a solution of 1-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (140 mg, 0.22 mmol) in DMF (3 mL) at room temperature, 2-aminoethane-1-sulfonamide (55 mg, 0.44 mmol) and TEA (45 mg, 0.44 mmol) were added, and the mixture was heated at 60° C. and stirred for 2 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-75%B in 12 minutes; detector: 254nm), and the fractions containing the product were collected at 60%B and concentrated under reduced pressure to give trans-(Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (75mg, 0.12mmol, yield: 53.57%), LCMS m/z: 628[M+H] + .

3)、(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺及其异构体(MDR-001-805-1A和MDR-001-805-1B)的制备：

Figure PCTCN2024113428-ftappb-I100451
3) Preparation of (Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide and its isomers (MDR-001-805-1A and MDR-001-805-1B):
Figure PCTCN2024113428-ftappb-I100451

将(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(75mg，0.12mmol)通过超临界流体色谱(色谱条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100452
柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：IPA(在MEOH中+0.1％7.0mol/l氨)，A：B＝60：40波长：214nm；流量：120mL/min柱温：RT背压：100bar，进样量：5.0mL；循环时间：8.0min)得到两个异构体：MDR-001-805-1A和MDR-001-806-1B：(Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (75 mg, 0.12 mmol) was subjected to supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100452
Column size: 250*30mm 10μm; mobile phase A; supercritical CO2; mobile phase B: IPA (in MEOH + 0.1% 7.0mol/l ammonia), A: B = 60:40 wavelength: 214nm; flow rate: 120mL/min column temperature: RT back pressure: 100bar, injection volume: 5.0mL; cycle time: 8.0min) to obtain two isomers: MDR-001-805-1A and MDR-001-806-1B:

MDR-001-805-1A：峰1：Chiral HPLC：2.498min；25.73mg，0.041mmol，收率：34.30％)LCMS m/z：628[M+H]+.MDR-001-805-1A: Peak 1: Chiral HPLC: 2.498 min; 25.73 mg, 0.041 mmol, yield: 34.30%) LCMS m/z: 628 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.17-8.08(m，1H)，8.04(d，J＝8.4Hz，2H)，7.90(d，J＝8.2Hz，2H)，7.55(d，J＝8.6Hz，2H)，7.40(d，J＝8.8Hz，2H)，7.33-7.20(m，3H)，7.15-7.01(m，4H)，5.13(d，J＝10.8Hz，1H)，4.82-4.72(m，1H)，3.95-3.79(m，2H)，3.38-3.26(m，2H)，0.73(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.17-8.08 (m, 1H), 8.04 (d, J=8.4Hz, 2H), 7.90 (d, J=8.2Hz, 2H), 7.55 (d, J=8.6Hz, 2H), 7.40 (d, J=8.8Hz, 2H), 7.33-7.20 (m, 3H), 7.15-7.01 (m, 4H), 5.13 (d, J=10.8Hz, 1H), 4.82-4.72 (m, 1H), 3.95-3.79 (m, 2H), 3.38-3.26 (m, 2H), 0.73 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.354. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.354.

MDR-001-805-1B：峰2：ChiralHPLC：3.258min；(35.18mg，0.056mmol，收率：46.90％)，LCMS  m/z：628[M+H]+.MDR-001-805-1B: Peak 2: ChiralHPLC: 3.258 min; (35.18 mg, 0.056 mmol, yield: 46.90%), LCMS m/z：628[M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.17-8.08(m，1H)，8.04(d，J＝8.4Hz，2H)，7.90(d，J＝8.2Hz，2H)，7.55(d，J＝8.6Hz，2H)，7.40(d，J＝8.8Hz，2H)，7.33-7.20(m，3H)，7.15-7.01(m，4H)，5.13(d，J＝10.8Hz，1H)，4.82-4.72(m，1H)，3.95-3.79(m，2H)，3.38-3.26(m，2H)，0.73(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.17-8.08 (m, 1H), 8.04 (d, J=8.4Hz, 2H), 7.90 (d, J=8.2Hz, 2H), 7.55 (d, J=8.6Hz, 2H), 7.40 (d, J=8.8Hz, 2H), 7.33-7.20 (m, 3H), 7.15-7.01 (m, 4H), 5.13 (d, J=10.8Hz, 1H), 4.82-4.72 (m, 1H), 3.95-3.79 (m, 2H), 3.38-3.26 (m, 2H), 0.73 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.355. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.355.

4)、1-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体的合成

Figure PCTCN2024113428-ftappb-I100453
4) Synthesis of 1-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomers thereof
Figure PCTCN2024113428-ftappb-I100453

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(250mg，0.478mmol)的二氯甲烷(10mL)溶液中，加入POCl3(146mg，0.957mmol)和DMAP(291mg，2.39mmol)，加热50℃搅拌2小时。混合反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(色谱条件：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：5％B-75％B，12分钟；检测器：254nm)纯化，在75％B下，收集含有产物的级分，减压浓缩得到1-((Z)-(顺式-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(140mg，0.22mmol，收率：46.66％)，LCMS m/z：626[M+H]+ To a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (250 mg, 0.478 mmol) in dichloromethane (10 mL) was added POCl 3 (146 mg, 0.957 mmol) and DMAP (291 mg, 2.39 mmol) at room temperature, and the mixture was heated at 50°C with stirring for 2 hours. The mixed reaction liquid was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-75%B, 12 minutes; detector: 254nm), and the fractions containing the product were collected at 75%B and concentrated under reduced pressure to give 1-((Z)-(cis-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (140mg, 0.22mmol, yield: 46.66%), LCMS m/z: 626[M+H] +

5)、(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100454
5) Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomers
Figure PCTCN2024113428-ftappb-I100454

在室温下，向溶有1-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓或异构体(140mg，0.22mmol)的DMF(3mL)溶液中，加入2-氨基乙烷-1-磺酰胺(55mg，0.44mmol)和TEA(45mg，0.44mmol)，加热60℃搅拌2小时。将混合反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：在12分钟内5％B-75％B；检测器：254nm)纯化，在60％B下，收集含有产物的级分，减压浓缩得到(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(120mg，0.19mmol，收率：85.71％)，LCMS m/z：628[M+H]+.To a solution of 1-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium or isomer (140 mg, 0.22 mmol) in DMF (3 mL) at room temperature, 2-aminoethane-1-sulfonamide (55 mg, 0.44 mmol) and TEA (45 mg, 0.44 mmol) were added, and the mixture was heated at 60° C. and stirred for 2 hours. The mixed reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (column: spherical C18, 20-40um, 80g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-75%B in 12 minutes; detector: 254nm), and the fractions containing the product were collected at 60%B and concentrated under reduced pressure to give (Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (120mg, 0.19mmol, yield: 85.71%), LCMS m/z: 628[M+H] + .

6)、(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺及其异构体(MDR-001-805-2A和MDR-001-805-2B)的合成

Figure PCTCN2024113428-ftappb-I100455
6) Synthesis of (Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide and its isomers (MDR-001-805-2A and MDR-001-805-2B)
Figure PCTCN2024113428-ftappb-I100455

将(Z)-3-(4-氯苯基)-5-甲基-4-苯基-N-(2-氨磺酰基乙基)-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(120mg，0.19mmol)通过超临界流体色谱(条件：系统：SHIMADZU LC-20AP；柱名：

Figure PCTCN2024113428-ftappb-I100456
柱尺寸：250*30mm 10μm；流动相A；正己烷；流动相B：IPA(+0.1％7.0mol/l氨在甲醇中)，A：B＝60：40波长：254nm流量：50mL/min柱温：RT；柱压：100bar，进样量：4.0mL；循环时间：9.0min)制备分离得到两种异构体：MDR-001-805-2A和MDR-001-805-2B：(Z)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(2-sulfamoylethyl)-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (120 mg, 0.19 mmol) was subjected to supercritical fluid chromatography (conditions: system: SHIMADZU LC-20AP; column name:
Figure PCTCN2024113428-ftappb-I100456
Column size: 250*30mm 10μm; mobile phase A: n-hexane; mobile phase B: IPA (+0.1% 7.0mol/l ammonia in methanol), A:B=60:40 wavelength: 254nm flow rate: 50mL/min column temperature: RT; column pressure: 100bar, injection volume: 4.0mL; cycle time: 9.0min) preparation and separation to obtain two isomers: MDR-001-805-2A and MDR-001-805-2B:

MDR-001-805-2A：峰1：Chiral HPLC：6.600min；(28.86mg，0.045mmol，收率：24.05％)，LCMS m/z：628[M+H]+.MDR-001-805-2A: Peak 1: Chiral HPLC: 6.600 min; (28.86 mg, 0.045 mmol, yield: 24.05%), LCMS m/z: 628 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.31(s，1H)，7.99(d，J＝8.2Hz，2H)，7.81(d，J＝8.4Hz，2H)，7.75(d，J＝8.6Hz，2H)，7.46(d，J＝8.6Hz，2H)，7.36-7.25(m，3H)，7.20(d，J＝7.2Hz，2H)，7.06(s，2H)，4.67(d，J＝2.4Hz，1H)，4.53-4.44(m，1H)，3.82(d，J＝4.8Hz，2H)，3.40-3.32(m，2H)，1.29(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.31 (s, 1H), 7.99 (d, J = 8.2Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.75 (d, J = 8.6Hz, 2H), 7.46 (d, J = 8.6Hz, 2H), 7.36-7.25 (m, 3H), 7.20 (d, J=7.2Hz, 2H), 7.06 (s, 2H), 4.67 (d, J=2.4Hz, 1H), 4.53-4.44 (m, 1H), 3.82 (d, J=4.8Hz, 2H), 3.40-3.32 (m, 2H), 1.29 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.344. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.344.

MDR-001-805-2B：峰2：chiral HPLC：7.284min；(25.12mg，0.04mmol，收率：20.93％)，LCMS m/z：628[M+H]+.MDR-001-805-2B: Peak 2: chiral HPLC: 7.284 min; (25.12 mg, 0.04 mmol, yield: 20.93%), LCMS m/z: 628 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.31(s，1H)，7.99(d，J＝8.2Hz，2H)，7.81(d，J＝8.4Hz，2H)，7.75(d，J＝8.6Hz，2H)，7.46(d，J＝8.6Hz，2H)，7.36-7.25(m，3H)，7.20(d，J＝7.2Hz，2H)，7.06(s，2H)，4.67(d，J＝2.4Hz，1H)，4.53-4.44(m，1H)，3.82(d，J＝4.8Hz，2H)，3.40-3.32(m，2H)，1.29(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.31 (s, 1H), 7.99 (d, J = 8.2Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.75 (d, J = 8.6Hz, 2H), 7.46 (d, J = 8.6Hz, 2H), 7.36-7.25 (m, 3H), 7.20 (d, J=7.2Hz, 2H), 7.06 (s, 2H), 4.67 (d, J=2.4Hz, 1H), 4.53-4.44 (m, 1H), 3.82 (d, J=4.8Hz, 2H), 3.40-3.32 (m, 2H), 1.29 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-61.341. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.341.

实施例47、(E)-4-((R，Z)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺基)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺鎓三氟乙酸盐或对映体(MDR-001-808-1)的合成：Example 47, Synthesis of (E)-4-((R,Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine trifluoroacetate or enantiomer (MDR-001-808-1):

1)、(E)-4-溴丁-2-烯酰氯的合成

Figure PCTCN2024113428-ftappb-I100457
1) Synthesis of (E)-4-bromobut-2-enoyl chloride
Figure PCTCN2024113428-ftappb-I100457

在室温下，向溶有(E)-4-溴丁-2-烯酸(10g，60.61mmol)的二氯甲烷(200mL)溶液中，加入草酰氯(9.24g，72.73mmol)和N，N二甲基甲酰胺(442mg，6.06mmol)，室温搅拌2小时。混合反应液直接用于一下步，无需进一步纯化。At room temperature, oxalyl chloride (9.24 g, 72.73 mmol) and N,N-dimethylformamide (442 mg, 6.06 mmol) were added to a solution of (E)-4-bromobut-2-enoic acid (10 g, 60.61 mmol) in dichloromethane (200 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was used directly in the next step without further purification.

2)、(E)-4-溴丁-2-烯酰胺的合成

Figure PCTCN2024113428-ftappb-I100458
2) Synthesis of (E)-4-bromobut-2-enamide
Figure PCTCN2024113428-ftappb-I100458

将溶有(E)-4-溴丁-2-烯酰氯(200mL，60.61mmol)的氨-二氧六环(455mL，181.83mmol，0.4M)溶液，室温搅拌1小时。将反应液过滤并减压浓缩。残余物通过反相快速柱色谱(条件如下：色谱柱：球形C18，20-40um，330g；流动相A：水；流动相B：乙腈；流速：100mL/min；梯度：2分钟内5％B-20％B；检测 器：214nm)纯化。在10％B下，收集含有产物的馏分，减压浓缩得到(E)-4-溴丁-2-烯酰胺(10g，粗品)，LCMS m/z：164[M+H]+.A solution of (E)-4-bromobut-2-enoyl chloride (200 mL, 60.61 mmol) in ammonia-dioxane (455 mL, 181.83 mmol, 0.4 M) was stirred at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions are as follows: chromatographic column: spherical C18, 20-40 um, 330 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 5% B-20% B in 2 minutes; detection The product was purified by HPLC (HPLC: 214 nm). At 10% B, the fractions containing the product were collected and concentrated under reduced pressure to give (E)-4-bromobut-2-enamide (10 g, crude product), LCMS m/z: 164 [M+H] + .

3)、(E)-4-(甲基氨基)丁-2-烯酰胺的合成

Figure PCTCN2024113428-ftappb-I100459
3) Synthesis of (E)-4-(methylamino)but-2-enamide
Figure PCTCN2024113428-ftappb-I100459

在室温下，向溶有(E)-4-溴丁-2-烯酰胺(10g，60.97mmol)的四氢呋喃(100mL)溶液中，加入甲胺(2M在四氢呋喃，152.43mL，304.85mmol)溶液，室温搅拌1小时。将混合反应液减压浓缩并通过反相快速柱色谱纯化(条件如下：柱：球形C18，20-40um，330g；流动相A：水；流动相B：乙腈；流速：100mL/min；梯度：2分钟内5％B-20％B；探测器：214nm)纯化，在10％B下，收集含有你产物的馏分，减压浓缩得到(E)-4-(甲基氨基)丁-2-烯酰胺(9g，粗品)，LCMS m/z：229[2M+H]+.At room temperature, a solution of methylamine (2M in tetrahydrofuran, 152.43 mL, 304.85 mmol) was added to a solution of (E)-4-bromobut-2-enamide (10 g, 60.97 mmol) in tetrahydrofuran (100 mL), and stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40 um, 330 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 5% B-20% B in 2 minutes; detector: 214 nm). At 10% B, the fractions containing the product were collected and concentrated under reduced pressure to obtain (E)-4-(methylamino)but-2-enamide (9 g, crude product), LCMS m/z: 229 [2M+H] + .

4)、(E)-(4-氨基-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯的合成

Figure PCTCN2024113428-ftappb-I100460
4) Synthesis of tert-butyl (E)-(4-amino-4-oxobut-2-en-1-yl)(methyl)carbamate
Figure PCTCN2024113428-ftappb-I100460

在室温下，向溶有(E)-4-(甲基氨基)丁-2-烯酰胺(9g，78.95mmol)的四氢呋喃(100mL)和水(100mL)溶液中，加入三乙胺(15.95g，157.9mmol)和二碳酸二叔丁酯(20.65g，94.74mmol)，室温搅拌2小时。将混合反应液减压浓缩，并用乙酸乙酯(100mL)稀释。收集有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱层析(DCM/MeOH＝50/1)纯化得到(E)-(4-氨基-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯(900mg，4.20mmol，收率：5.35％)，LCMS m/z：237[M+Na]+.At room temperature, triethylamine (15.95 g, 157.9 mmol) and di-tert-butyl dicarbonate (20.65 g, 94.74 mmol) were added to a solution of (E)-4-(methylamino)but-2-enamide (9 g, 78.95 mmol) in tetrahydrofuran (100 mL) and water (100 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The collected organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=50/1) to give tert-butyl (E)-(4-amino-4-oxobut-2-ene-1-yl)(methyl)carbamate (900 mg, 4.20 mmol, yield: 5.35%), LCMS m/z: 237 [M+Na] + .

5)、(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100461
5) Synthesis of (R, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomers
Figure PCTCN2024113428-ftappb-I100461

在室温下，向溶有(R)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(1g，1.97mmol)的甲苯(20mL)溶液中，加入五氯化磷(1.64g，7.88mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱层析(PE/DCM＝1/4)纯化得到(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(450mg，0.85mmol，收率：43.68％)。LCMS：m/z：526[M+H]+.Phosphorus pentachloride (1.64 g, 7.88 mmol) was added to a toluene (20 mL) solution of (R)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (1 g, 1.97 mmol) at room temperature, and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/4) to obtain (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide chloride or isomer (450 mg, 0.85 mmol, yield: 43.68%). LCMS: m/z: 526[M+H] + .

6)、((E)-4-((R，Z)-3-(4-氯苯基)-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺基)-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯或异构体的合成

Figure PCTCN2024113428-ftappb-I100462
6) Synthesis of tert-butyl ((E)-4-((R,Z)-3-(4-chlorophenyl)-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-4-oxobut-2-en-1-yl)(methyl)carbamate or isomer
Figure PCTCN2024113428-ftappb-I100462

在-30℃下，向溶有(E)-(4-氨基-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯(150mg，0.70mmol)的四氢呋喃(10mL)溶液中，加入双三甲基硅基胺基锂(1M的四氢呋喃溶液，700μL，0.70mmol)，-30℃搅拌0.5小时，然后加入(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(368mg，0.70mmol)，在-30℃继续搅拌1小时。混合反应液用饱和氯化铵水溶液(2mL)淬灭，并用用乙酸乙酯(20mL)萃取。合并的有机相用饱和食盐水(10mL)，无水硫酸钠干燥，过滤、减压浓缩。残余我通过反相快速柱(条件如下：柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：40mL/min；梯度：12分钟内5％B-80％B；检测波长：214nm)纯化。在75％B下，收集含有的产物的馏分，减压浓缩得到化合物((E)-4-((R，Z)-3-(4-氯苯基)-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺基)-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯或异构体(110mg，0.15mmol，收率：22.35％)，LCMS m/z：704[M+H]+.To a solution of tert-butyl (E)-(4-amino-4-oxobut-2-en-1-yl)(methyl)carbamate (150 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 700 μL, 0.70 mmol) at -30°C, and the mixture was stirred at -30°C for 0.5 hours, and then (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (368 mg, 0.70 mmol) was added, and stirring was continued at -30°C for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (2 mL) and extracted with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column (conditions as follows: column: spherical C18, 20-40 um, 40 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-80% B in 12 minutes; detection wavelength: 214 nm). At 75% B, the fractions containing the product were collected and concentrated under reduced pressure to give the compound ((E)-4-((R,Z)-3-(4-chlorophenyl)-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-4-oxobut-2-en-1-yl)(methyl)carbamic acid tert-butyl ester or isomer (110 mg, 0.15 mmol, yield: 22.35%), LCMS m/z: 704 [M+H] + .

7)、(E)-N-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(甲基氨基)丁-2-烯酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100463
7) Synthesis of (E)-N-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(methylamino)but-2-enamide or isomers
Figure PCTCN2024113428-ftappb-I100463

在室温下，向溶有((E)-4-((R，Z)-3-(4-氯苯基)-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺基)-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯或异构体(50mg，0.07mmol)的二氯甲烷(6mL)溶液中，加入TFA(2mL)，室温搅拌1小时。将混合反应液减压浓缩得到化合物(E)-N-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(甲基氨基)丁-2-烯酰胺或异构体(43mg，粗品)，LCMS m/z：604[M+H]+.To a solution of tert-butyl ((E)-4-((R,Z)-3-(4-chlorophenyl)-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-4-oxobut-2-en-1-yl)(methyl)carbamate or isomer (50 mg, 0.07 mmol) in dichloromethane (6 mL) was added TFA (2 mL) at room temperature and stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure to obtain compound (E)-N-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(methylamino)but-2-enamide or isomer (43 mg, crude product), LCMS m/z: 604 [M+H] + .

8)、(E)-4-((R，Z)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺基)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺鎓三氟乙酸盐或对映体(MDR-001-808-1)的合成

Figure PCTCN2024113428-ftappb-I100464
8) Synthesis of (E)-4-((R,Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine trifluoroacetate or enantiomer (MDR-001-808-1)
Figure PCTCN2024113428-ftappb-I100464

在室温下，向溶有(E)-N-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三 氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(甲基氨基)丁-2-烯酰胺或异构体(43mg，0.07mmol)的四氢呋喃(10mL)溶液中，加入N，N-二异丙基乙胺(90mg，0.70mmol)和碘甲烷(50mg，0.35mmol)，室温搅拌2小时。将混合反应液减压浓缩。残余物通过prep-HPLC(色谱柱：Waters 2767/Qda，色谱柱：Sunfire C18，19*250mm，10μm；流动相A：0.1％TFA/H2O，B：乙腈；流速：20mL/min；梯度：36％-36％；保留时间：6.2-9.6min，16min)纯化得到(E)-4-((R，Z)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺基)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺鎓三氟乙酸盐或对映体(7.69mg，收率：14.5％)。LCMS m/z：632[M]+.At room temperature, a solution of (E)-N-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(triphenyl)phenyl)-1H-pyrazol-1-yl)- To a solution of 4-( ... The residue was purified by prep-HPLC (chromatographic column: Waters 2767/Qda, chromatographic column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% TFA/H2O, B: acetonitrile; flow rate: 20 mL/min; gradient: 36%-36%; retention time: 6.2-9.6 min, 16 min) to give (E)-4-((R,Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine trifluoroacetate or enantiomer (7.69 mg, yield: 14.5%). LCMS m/z: 632 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.07(s，1H)，8.01-7.99(m，2H)，7.88-7.86(m，2H)，7.63-7.61(m，2H)，7.44-7.42(m，2H)，7.33-7.23(m，5H)，6.97(s，1H)，6.62(s，1H)，5.10-5.08(m，1H)，4.54-4.49(m，1H)，4.22(s，2H)，3.86-3.82(m，1H)，3.11(s，9H). 1 H NMR (400MHz, DMSO-d 6 )δ11.07(s, 1H), 8.01-7.99(m, 2H), 7.88-7.86(m, 2H), 7.63-7.61(m, 2H), 7.44-7.42(m, 2H), 7.33-7.23(m, 5H) , 6.97 (s, 1H), 6.62 (s, 1H), 5.10-5.08 (m, 1H), 4.54-4.49 (m, 1H), 4.22 (s, 2H), 3.86-3.82 (m, 1H), 3.11 (s, 9H).

19F NMR(377MHz，DMSO-d6)δ-61.440，-73.404. 19 F NMR (377MHz, DMSO-d 6 ) δ -61.440, -73.404.

实施例48、(E)-4-((S，Z)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺基)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺鎓三氟乙酸盐或对映体(MDR-001-808-2)的合成：Example 48, Synthesis of (E)-4-((S,Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine trifluoroacetate or enantiomer (MDR-001-808-2):

1)、(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体

Figure PCTCN2024113428-ftappb-I100465
1), (S, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomers
Figure PCTCN2024113428-ftappb-I100465

在室温下，向溶有(S)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(1g，1.97mmol)的甲苯(20mL)溶液中，加入五氯化磷(1.64g，7.88mmol)，加分100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱层析(PE/DCM＝1/4)纯化得到(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体((450mg，0.85mmol，收率：43.68％)，LCMS m/z：526[M+H]+.Phosphorus pentachloride (1.64 g, 7.88 mmol) was added to a toluene (20 mL) solution of (S)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (1 g, 1.97 mmol) at room temperature, and the mixture was stirred at 100°C for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/4) to obtain (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide chloride or isomer ((450 mg, 0.85 mmol, yield: 43.68%), LCMS m/z: 526 [M+H] + .

2)、((E)-4-((S，Z)-3-(4-氯苯基)-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺基)-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯或异构体的合成

Figure PCTCN2024113428-ftappb-I100466
2) Synthesis of tert-butyl ((E)-4-((S,Z)-3-(4-chlorophenyl)-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-4-oxobut-2-en-1-yl)(methyl)carbamate or isomer
Figure PCTCN2024113428-ftappb-I100466

在-30℃下，向溶有(E)-(4-氨基-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯(150mg，0.70mmol)的四氢呋喃(10mL)溶液中，加入双三甲基硅基胺基锂(1M四氢呋喃中，700μL，0.70mmol)，在-30℃搅拌0.5小时，然后加入(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(368mg，0.70mmol)，在-30℃继续搅拌1小时。将混合反应液用饱和氯化铵水溶液(2mL)淬灭，并用乙酸乙酯(20mL)稀释。合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物通过反相柱色谱纯化(条件如下(柱：球形C18，20-40um，40g；流动相A：水；流动相B：乙腈；流速：40mL/min；梯度：12min内5％B-80％B；检测波长：214nm)纯化，在75％B下，收集含有产物的馏分减压浓缩得到((E)-4-((S，Z)-3-(4-氯苯基)-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺基)-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯或异构体(110mg，0.15mmol，收率：22.35％)，LCMS m/z：704[M+H]+. To a solution of tert-butyl (E)-(4-amino-4-oxobut-2-en-1-yl)(methyl)carbamate (150 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added lithium bistrimethylsilylamide (1 M in tetrahydrofuran, 700 μL, 0.70 mmol) at -30°C, and the mixture was stirred at -30°C for 0.5 hours, and then (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (368 mg, 0.70 mmol) was added, and stirring was continued at -30°C for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride (2 mL) and diluted with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (conditions as follows (column: spherical C18, 20-40um, 40g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 5%B-80%B in 12min; detection wavelength: 214nm), and the fractions containing the product were collected and concentrated under reduced pressure at 75%B to give tert-butyl ((E)-4-((S,Z)-3-(4-chlorophenyl)-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-4-oxobut-2-ene-1-yl)(methyl)carbamate or isomer (110mg, 0.15mmol, yield: 22.35%), LCMS m/z: 704[M+H] + .

3)、(E)-N-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(甲基氨基)丁-2-烯酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100467
3) Synthesis of (E)-N-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(methylamino)but-2-enamide or isomers
Figure PCTCN2024113428-ftappb-I100467

在室温下，向溶有((E)-4-((S，Z)-3-(4-氯苯基)-4-苯基-N′-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰亚胺基)-4-氧代丁-2-烯-1-基)(甲基)氨基甲酸叔丁酯或异构体(50mg，0.07mmol)的二氯甲烷(6mL)溶液中，加入TFA(2mL)，室温搅拌1小时。将混合反应液减压浓缩得到(E)-N-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(甲基氨基)丁-2-烯酰胺或异构体(43mg，粗品)，LCMS m/z：604[M+H]+.To a solution of tert-butyl ((E)-4-((S,Z)-3-(4-chlorophenyl)-4-phenyl-N′-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-4-oxobut-2-en-1-yl)(methyl)carbamate or isomer (50 mg, 0.07 mmol) in dichloromethane (6 mL) was added TFA (2 mL) at room temperature and stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure to obtain (E)-N-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(methylamino)but-2-enamide or isomer (43 mg, crude product), LCMS m/z: 604 [M+H] + .

4)、(E)-4-((S，Z)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺基)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺鎓三氟乙酸盐或对映体(MDR-001-808-2)的合成

Figure PCTCN2024113428-ftappb-I100468
4) Synthesis of (E)-4-((S,Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine trifluoroacetate or enantiomer (MDR-001-808-2)
Figure PCTCN2024113428-ftappb-I100468

在室温下，向溶有(E)-N-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(甲基氨基)丁-2-烯酰胺或异构体(43mg，0.07mmol)的四氢呋喃(10mL)溶液中，加入N，N-二异丙基乙胺(90mg，0.70mmol)和碘甲烷(50mg，0.35mmol)，室温搅拌2小时。将混合反应液减压浓缩。残余物残通过prep-HPLC(色谱柱：Waters 2767/Qda，色谱柱：Sunfire C18，19*250mm，10μm；流动相A：0.1％TFA/H2O，B：乙腈；流速：20mL/min；梯度：36％-36％；保留时间：6.2-9.6min，16min)纯化得到化合物(E)-4-((S，Z)-3-(4-氯苯基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺基)-N，N，N-三甲基-4-氧代丁-2-烯-1-胺鎓三氟乙酸盐或对映体(13.49mg，0.021mmol，收率：25％)，LCMS m/z：632[M]+.To a solution of (E)-N-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(methylamino)but-2-enamide or isomer (43 mg, 0.07 mmol) in tetrahydrofuran (10 mL) was added N,N-diisopropylethylamine (90 mg, 0.70 mmol) and iodomethane (50 mg, 0.35 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by prep-HPLC (chromatographic column: Waters 2767/Qda, chromatographic column: Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% TFA/H 2 O, B: acetonitrile; flow rate: 20 mL/min; gradient: 36%-36%; retention time: 6.2-9.6 min, 16 min) to obtain compound (E)-4-((S,Z)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximido)-N,N,N-trimethyl-4-oxobut-2-ene-1-amine trifluoroacetate or enantiomer (13.49 mg, 0.021 mmol, yield: 25%), LCMS m/z: 632 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.07(s，1H)，8.00-7.98(m，2H)，7.86-7.84(m，2H)，7.61-7.59(m，2H)，7.43-7.41(m，2H)，7.33-7.23(m，5H)，6.93(s，1H)，6.58(s，1H)，5.09-5.04(m，1H)，4.51-4.44(m，1H)，4.19(s，2H)，3.85-3.81(m，1H)，3.09(s，9H). 1 H NMR (400MHz, DMSO-d 6 )δ11.07(s, 1H), 8.00-7.98(m, 2H), 7.86-7.84(m, 2H), 7.61-7.59(m, 2H), 7.43-7.41(m, 2H), 7.33-7.23(m, 5H) , 6.93 (s, 1H), 6.58 (s, 1H), 5.09-5.04 (m, 1H), 4.51-4.44 (m, 1H), 4.19 (s, 2H), 3.85-3.81 (m, 1H), 3.09 (s, 9H).

19F NMR(377MHz，DMSO-d6)δ-61.396，-73.412. 19 F NMR (377MHz, DMSO-d 6 ) δ -61.396, -73.412.

实施例49、(E)-N-((E)-N′-(Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-4-(二甲基氨基)丁-2-烯酰胺或对映体(MDR-001-810-1和MDR-001-810-2)的合成：Example 49, Synthesis of (E)-N-((E)-N′-(Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-4-(dimethylamino)but-2-enamide or enantiomers (MDR-001-810-1 and MDR-001-810-2):

1)、(E)-4-溴丁-2-烯酰氯的合成

Figure PCTCN2024113428-ftappb-I100469
1) Synthesis of (E)-4-bromobut-2-enoyl chloride
Figure PCTCN2024113428-ftappb-I100469

在室温下，向溶有(E)-4-溴丁-2-烯酸(3g，18.18mmol)的二氯甲烷(90mL)溶液中，加入草酰氯(2.77g，21.82mmol)和N，N二甲基甲酰胺(133mg，1.82mmol)，室温搅拌2小时。将混合反应液直接用于下一步，无需进行进一步纯化。At room temperature, oxalyl chloride (2.77 g, 21.82 mmol) and N,N-dimethylformamide (133 mg, 1.82 mmol) were added to a solution of (E)-4-bromobut-2-enoic acid (3 g, 18.18 mmol) in dichloromethane (90 mL), and stirred at room temperature for 2 hours. The mixed reaction solution was used directly in the next step without further purification.

2)、810-4的合成

Figure PCTCN2024113428-ftappb-I100470
2) Synthesis of 810-4
Figure PCTCN2024113428-ftappb-I100470

在室温下，向溶有1-(叔丁氧羰基)胍(2.89g，18.18mmol)的四氢呋喃(40mL)溶液中，加入三乙胺(5.45g，54.00mmol)和(E)-4-溴丁-2-烯酰氯(90mL，18.00mmol)。室温搅拌1小时。将混合反应液加水(20mL)淬灭，并用乙酸乙酯(100mL)萃取。合并有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过硅胶柱层析(二氯甲烷/甲醇＝50/1)纯化得到810-4(3.2g，10.46mmol，收率：58.11％)，LCMS m/z：306[M+H]+。At room temperature, triethylamine (5.45 g, 54.00 mmol) and (E)-4-bromobut-2-enoyl chloride (90 mL, 18.00 mmol) were added to a solution of 1-(tert-butyloxycarbonyl)guanidine (2.89 g, 18.18 mmol) in tetrahydrofuran (40 mL). Stir at room temperature for 1 hour. The mixed reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=50/1) to give 810-4 (3.2 g, 10.46 mmol, yield: 58.11%), LCMS m/z: 306 [M+H] + .

3)、(E)-4-溴-N-甲酰氨基丁-2-烯酰胺的合成

Figure PCTCN2024113428-ftappb-I100471
3) Synthesis of (E)-4-bromo-N-formylaminobut-2-enamide
Figure PCTCN2024113428-ftappb-I100471

在室温下，向溶有810-4(3.2g，10.46mmol)的二氯甲烷(60mL)溶液中，加入2，2，2-三氟乙酸(20mL)。室温搅拌16小时。将混合反应液减压浓缩得到(E)-4-溴-N-甲酰氨基丁-2-烯酰胺(4.5g，21.84mmol，粗品)。LCMS m/z：206[M+H]+。At room temperature, 2,2,2-trifluoroacetic acid (20 mL) was added to a solution of 810-4 (3.2 g, 10.46 mmol) in dichloromethane (60 mL). The mixture was stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure to give (E)-4-bromo-N-formylaminobut-2-enamide (4.5 g, 21.84 mmol, crude product). LCMS m/z: 206 [M+H] + .

4)、(E)-N-((E)-N’-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-4-(二甲基氨基)丁-2-烯酰胺的合成

Figure PCTCN2024113428-ftappb-I100472
4) Synthesis of (E)-N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-4-(dimethylamino)but-2-enamide
Figure PCTCN2024113428-ftappb-I100472

在室温下，向溶有(Z)-1-((3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(1.1g，1.78mmol)的N，N二甲基甲酰胺(20mL)溶液中，加入(E)-4-溴-N-甲酰氨基丁-2-烯酰胺(3.67g，17.80mmol)和N，N-二异丙基乙胺(2.30g，17.80mmol)，室温搅拌1小时，然后加入二甲胺(2M的四氢呋喃溶液，8.88mL，17.80mmol)，室温搅拌1小时。将混合反应液用乙酸乙酯(100mL)稀释，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相柱色谱(色谱柱：球形C18，20-40um，330g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：100mL/min；梯度：5％B-60％B在12分钟内；检测器：254nm)纯化。在49％B下，收集含有所需产物的馏分，减压浓缩得到(E)-N-((E)-N’-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-4-(二甲基氨基)丁-2-烯酰胺(220mg，0.33mmol，收率：18.6％)。LCMS m/z：666[M+H]+。To a solution of (Z)-1-((3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (1.1 g, 1.78 mmol) in N,N-dimethylformamide (20 mL) at room temperature were added (E)-4-bromo-N-formylaminobut-2-enamide (3.67 g, 17.80 mmol) and N,N-diisopropylethylamine (2.30 g, 17.80 mmol), and the mixture was stirred at room temperature for 1 hour. Then, dimethylamine (2M solution in tetrahydrofuran, 8.88 mL, 17.80 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (chromatographic column: spherical C18, 20-40 um, 330 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 5% B-60% B in 12 minutes; detector: 254 nm). At 49% B, the fractions containing the desired product were collected and concentrated under reduced pressure to give (E)-N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-4-(dimethylamino)but-2-enamide (220 mg, 0.33 mmol, yield: 18.6%). LCMS m/z: 666 [M+H] + .

5)、(E)-N-((E)-N′-(Z)-((R)-3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-4-(二甲基氨基)丁-2-烯酰胺或对映体(MDR-001-810-1和MDR-001-810-2)的合成

Figure PCTCN2024113428-ftappb-I100473
5) Synthesis of (E)-N-((E)-N′-(Z)-((R)-3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-4-(dimethylamino)but-2-enamide or enantiomers (MDR-001-810-1 and MDR-001-810-2)
Figure PCTCN2024113428-ftappb-I100473

将化合物(E)-N-((E)-N’-((Z)-(3-(4-氯苯基)-4-(噻吩-2-基)-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-4-(二甲基氨基)丁-2-烯酰胺(100mg，0.15mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 80；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100474
色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0M氨甲醇)，A：B＝75：25；波长：214nm；流速：140mL/min；柱温：室温；柱压：100bar，进样量：8.0mL；循环时间；17.0min)纯化得到两个异构体：MDR-001-810-1和MDR-001-810-2：Compound (E)-N-((E)-N'-((Z)-(3-(4-chlorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-4-(dimethylamino)but-2-enamide (100 mg, 0.15 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 80; column name:
Figure PCTCN2024113428-ftappb-I100474
Chromatographic column size: 250*30mm 10μm; mobile phase A: supercritical CO2; mobile phase B: isopropanol (+0.1% 7.0M ammonia methanol), A: B = 75:25; wavelength: 214nm; flow rate: 140mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 17.0min) was purified to obtain two isomers: MDR-001-810-1 and MDR-001-810-2:

MDR-001-810-1：Peak 1：Chiral HPLC：2.528min；(26.84mg，0.04mmol，收率：26.84％)，LCMS m/z：666[M+H]+.MDR-001-810-1: Peak 1: Chiral HPLC: 2.528 min; (26.84 mg, 0.04 mmol, yield: 26.84%), LCMS m/z: 666 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.53(s，1H)，8.02-8.00(m，2H)，7.82-7.80(m，2H)，7.58-7.56(m，2H)，7.44-7.40(m，3H)，6.98-6.94(m，2H)，6.89-6.82(m，1H)，6.37-6.33(m，1H)，5.43-5.39(m，1H)，4.45(t，J＝12.0Hz，1H)，3.98-3.94(m，1H)，3.06-3.04(m，2H)，2.15(s，6H). 1 H NMR (400MHz, DMSO-d 6 )δ10.53 (s, 1H), 8.02-8.00 (m, 2H), 7.82-7.80 (m, 2H), 7.58-7.56 (m, 2H), 7.44-7.40 (m, 3H), 6.98-6.94 (m, 2H), 6.89-6.8 2(m, 1H), 6.37-6.33(m, 1H), 5.43-5.39(m, 1H), 4.45(t, J=12.0Hz, 1H), 3.98-3.94(m, 1H), 3.06-3.04(m, 2H), 2.15(s, 6H).

19F NMR(377MHz，DMSO-d6)δ-61.341. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.341.

MDR-001-810-2：Peak 2：Chiral HPLC：5.138min；(25.84mg，0.04mmol，收率：25.84％)，LCMS m/z：666[M+H]+.MDR-001-810-2: Peak 2: Chiral HPLC: 5.138 min; (25.84 mg, 0.04 mmol, yield: 25.84%), LCMS m/z: 666 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.58(s，1H)，8.02-8.00(m，2H)，7.82-7.80(m，2H)，7.58-7.56(m，2H)，7.44-7.40(m，3H)，6.98-6.93(m，2H)，6.89-6.82(m，1H)，6.37-6.34(m，1H)，5.43-5.39(m，1H)，4.45(t，J＝11.6Hz，1H)，3.98-3.94(m，1H)，3.06-3.05(m，2H)，2.15(s，6H). 1 H NMR (400MHz, DMSO-d 6 )δ10.58 (s, 1H), 8.02-8.00 (m, 2H), 7.82-7.80 (m, 2H), 7.58-7.56 (m, 2H), 7.44-7.40 (m, 3H), 6.98-6.93 (m, 2H), 6.89-6.8 2 (m, 1H), 6.37-6.34 (m, 1H), 5.43-5.39 (m, 1H), 4.45 (t, J=11.6Hz, 1H), 3.98-3.94 (m, 1H), 3.06-3.05 (m, 2H), 2.15 (s, 6H).

19F NMR(377MHz，DMSO-d6)δ-61.345. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.345.

实施例50、(R)-4-(((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或其异构体三氟乙酸盐(MDR-001-1001A～D)和(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1002A～D)的合成：Example 50, (R)-4-(((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (MDR-001-1001A～ D) and (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (MDR-001-1002A to D):

1)、3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺异构体的制备：

Figure PCTCN2024113428-ftappb-I100475
1) Preparation of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide isomers:
Figure PCTCN2024113428-ftappb-I100475

化合物3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(2.0g，3.83mmol)通过SFC制备(条件：系统：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100476
柱尺寸：250×25mm 10μm；流动相A；超临界CO2；流动相B：MeOH(+0.1％，7.0mol/L的氨甲醇)，A：B＝50：50；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar，进样量：3.0mL；循环时间：4.0min)纯化得到两个异构体：单体407-2D和混合物407-2M(1.47g)：Compound 3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (2.0 g, 3.83 mmol) was prepared by SFC (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100476
Column size: 250×25 mm 10 μm; mobile phase A: supercritical CO 2 ; mobile phase B: MeOH (+0.1%, 7.0 mol/L ammonia methanol), A: B = 50:50; wavelength: 214 nm; flow rate: 120 mL/min; column temperature: RT; back pressure: 100 bar, injection volume: 3.0 mL; cycle time: 4.0 min) was purified to obtain two isomers: monomer 407-2D and mixture 407-2M (1.47 g):

407-2D：Peak 1：Chiral HPLC：3.030min；(500mg，0.96mmol，收率：25.0％).

Figure PCTCN2024113428-ftappb-I100477
407-2D: Peak 1: Chiral HPLC: 3.030 min; (500 mg, 0.96 mmol, yield: 25.0%).
Figure PCTCN2024113428-ftappb-I100477

混合物407-2M(1.47g，2.82mmol)通过SFC制备(条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100478
柱尺寸：250×25mm 10μm；流动相A；超临界CO2；流动相B：MEOH(添加0.1％，7.0mol/L的甲醇氨)，A：B＝75：25；波长：214nm；流量：150mL/min；柱温：RT；背压：100bar，进样量：5.0mL；循环时间：7.8min)再次纯化得到两个异构体：单体407-2A和混合物407-2M’(1.06g)。Mixture 407-2M (1.47 g, 2.82 mmol) was prepared by SFC (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100478
Column size: 250×25 mm 10 μm; mobile phase A; supercritical CO 2 ; mobile phase B: MEOH (added with 0.1%, 7.0 mol/L methanolic ammonia), A:B=75:25; wavelength: 214 nm; flow rate: 150 mL/min; column temperature: RT; back pressure: 100 bar, injection volume: 5.0 mL; cycle time: 7.8 min) was purified again to obtain two isomers: monomer 407-2A and mixture 407-2M' (1.06 g).

407-2A：Peak 1：Chiral HPLC：0.627min；(400mg，0.766mmol，收率：27.2％).

Figure PCTCN2024113428-ftappb-I100479
407-2A: Peak 1: Chiral HPLC: 0.627 min; (400 mg, 0.766 mmol, yield: 27.2%).
Figure PCTCN2024113428-ftappb-I100479

混合物407-2M’(1.06g，2.0mmol)通过SFC纯化(条件：体系：Waters SFC 150；柱名：

Figure PCTCN2024113428-ftappb-I100480
柱尺寸：250×30mm 10μm；流动相A；超临界CO2；流动相B：MEOH(添加0.1％，7.0mol/L的氨甲醇)，A：B＝85：15；波长：214nm；流量：140mL/min；柱温：RT；背压：100bar，进样量：4.0mL；循环时间：4.5min)纯化得到两个异构体：单体407-2B和单体407-2C：The mixture 407-2M' (1.06 g, 2.0 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name:
Figure PCTCN2024113428-ftappb-I100480
Column size: 250×30 mm 10 μm; mobile phase A: supercritical CO 2 ; mobile phase B: MEOH (added with 0.1%, 7.0 mol/L ammonia methanol), A: B = 85:15; wavelength: 214 nm; flow rate: 140 mL/min; column temperature: RT; back pressure: 100 bar, injection volume: 4.0 mL; cycle time: 4.5 min) was purified to obtain two isomers: monomer 407-2B and monomer 407-2C:

407-2B：Peak 1：Chiral HPLC：0.899min；(600mg，1.15mmol，收率：57.5％).407-2B: Peak 1: Chiral HPLC: 0.899 min; (600 mg, 1.15 mmol, yield: 57.5%).

407-2C：Peak 2：Chiral HPLC：0.799min；(400mg，0.766mmol，收率：38.3％).407-2C: Peak 2: Chiral HPLC: 0.799 min; (400 mg, 0.766 mmol, yield: 38.3%).

2)、(E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯及其异构体的合成：

Figure PCTCN2024113428-ftappb-I100481
2) Synthesis of (E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride and its isomers:
Figure PCTCN2024113428-ftappb-I100481

在室温下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺异构体407-2A(400mg，0.766mmol)的氯苯(20mL)溶液中，加入PCl5(319mg，1.53mmol)，加热100℃搅拌反应3小时。反应完全后，冷却至室温，将反应溶液浓缩，并通过硅胶柱色谱法(PE/DCM＝1/5)纯化得到3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯异构体407-3A(250mg，0.463mmol，收率：60.4％)，LCMS m/z：540[M+H]+。.To a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide isomer 407-2A (400 mg, 0.766 mmol) in chlorobenzene (20 mL) was added PCl 5 (319 mg, 1.53 mmol) at room temperature, and the mixture was heated at 100° C. with stirring for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated, and purified by silica gel column chromatography (PE/DCM=1/5) to obtain 3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride isomer 407-3A (250 mg, 0.463 mmol, yield: 60.4%), LCMS m/z: 540 [M+H] + .

3)、(R)-4-(((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或其异构体三氟乙酸盐((MDR-001-1001A))和(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1002A)的合成

Figure PCTCN2024113428-ftappb-I100482
3), (R)-4-(((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate ((MDR-001-1001A )) and (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (MDR-001-1002A)
Figure PCTCN2024113428-ftappb-I100482

在室温下，向溶有(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(188mg，0.926mmol)的DMF(20mL)溶液中，加入(4R，5R，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或其异构体(250mg，0.463mmol)，25℃搅拌10分钟，然后加入TEA(140mg，1.39mmol)，25℃继续搅拌20小时。反应完全后，将混合反应液直接通过反相快速柱色谱(条件如下：柱：球形C18，20-40μm，120g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：5％-100％B，30min，检测器：214nm)纯化，在62％B下收集含有产物的馏分得到粗产物(200mg)。粗产物再通过制备级高效液相色谱(Waters 2767/Qda：柱：Sunfire C18 19×250×10μm，流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：39-40％；保留时间：8.5-13.0min，16min)纯化得到两个异构体：MDR-001-1001A和白色固体MDR-001-1002A：To a solution of (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (188 mg, 0.926 mmol) in DMF (20 mL) was added (4R,5R,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or its isomer (250 mg, 0.463 mmol) at room temperature, the mixture was stirred at 25°C for 10 minutes, and then TEA (140 mg, 1.39 mmol) was added and stirring was continued at 25°C for 20 hours. After the reaction was completed, the mixed reaction solution was directly purified by reverse phase flash column chromatography (conditions were as follows: column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5%-100% B, 30 min, detector: 214 nm), and the fractions containing the product were collected at 62% B to give a crude product (200 mg). The crude product was then purified by preparative HPLC (Waters 2767/Qda: column: Sunfire C18 19×250×10 μm, mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39-40%; retention time: 8.5-13.0 min, 16 min) to obtain two isomers: MDR-001-1001A and white solid MDR-001-1002A:

MDR-001-1001A：(R)-4-(((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或对映体三氟乙酸盐(44.45mg，0.063mmol，产率13.5％)，tR＝9.020min；LCMS m/z：706[M]+.MDR-001-1001A: (R)-4-(((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer trifluoroacetate salt (44.45 mg, 0.063 mmol, 13.5% yield), t R =9.020 min; LCMS m/z: 706 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.74(s，1H)，7.99(d，J＝8.0Hz，2H)，7.84(d，J＝7.6Hz，2H)，7.56(d，J＝7.6Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.32-7.22(m，5H)，5.79(d，J＝4.8Hz，1H)，4.63(s，1H)，4.54(s，1H)，4.34-4.32(m，1H)，3.41-3.38(m，2H)，3.08(s，9H)，2.67-2.61(m，2H)，1.45(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.74 (s, 1H), 7.99 (d, J = 8.0Hz, 2H), 7.84 (d, J = 7.6Hz, 2H), 7.56 (d, J = 7.6Hz, 2H), 7.40 (d, J = 8.4Hz, 2H), 7.32-7.22 (m, 5H), 5.79 (d .

19F NMR(377MHz，DMSO-d6)：δ-61.272，-73.400. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.272, -73.400.

MDR-001-1002A：(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯 -1-铵或对映体三氟乙酸盐(35.27mg，0.051mmol，收率：11.1％)，tR＝9.096min，LCMS m/z：688[M]+.MDR-001-1002A: (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene -1-ammonium or enantiomer trifluoroacetate (35.27 mg, 0.051 mmol, yield: 11.1%), t R =9.096 min, LCMS m/z: 688 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.99(s，1H)，8.03(d，J＝8.8Hz，2H)，7.83(d，J＝8.0Hz，2H)，7.55(d，J＝8.0Hz，2H)，7.41(d，J＝8.4Hz，2H)，7.33-7.22(m，5H)，7.00-6.94(m，1H)，6.57(d，J＝14.8Hz，1H)，4.65(s，1H)，4.34-4.30(m，1H)，4.21(d，J＝6.8Hz，2H)，3.10(s，9H)，1.47(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.99 (s, 1H), 8.03 (d, J=8.8Hz, 2H), 7.83 (d, J=8.0Hz, 2H), 7.55 (d, J=8.0Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.33-7.22 (m, 5H), 7. 00-6.94 (m, 1H), 6.57 (d, J=14.8Hz, 1H), 4.65 (s, 1H), 4.34-4.30 (m, 1H), 4.21 (d, J=6.8Hz, 2H), 3.10 (s, 9H), 1.47 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.302，-73.400. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.302, -73.400.

4)、(E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯异构体的合成

Figure PCTCN2024113428-ftappb-I100483
4) Synthesis of (E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride isomers
Figure PCTCN2024113428-ftappb-I100483

在室温下，向溶有(4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺异构体407-2B(620mg，1.19mmol)的氯苯(15mL)溶液中，加入PCl5(990mg，4.76mmol)，加热100℃搅拌2小时。将混合反应溶液浓缩并通过硅胶柱色谱法(PE/DCM＝1/2)纯化得到(E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体407-3B(440mg，0.81mmol，收率：68.1％)，LCMS m/z：540[M+H]+.To a solution of (4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide isomer 407-2B (620 mg, 1.19 mmol) in chlorobenzene (15 mL) was added PCl 5 (990 mg, 4.76 mmol) at room temperature, and the mixture was heated at 100° C. with stirring for 2 hours. The mixed reaction solution was concentrated and purified by silica gel column chromatography (PE/DCM=1/2) to give (E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer 407-3B (440 mg, 0.81 mmol, yield: 68.1%), LCMS m/z: 540 [M+H] + .

5)、(R)-4-(((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或异构体的三氟乙酸盐(MDR-001-1001B)和(E)-4-((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或异构体的三氟乙酸盐(MDR-001-1002B)的合成

Figure PCTCN2024113428-ftappb-I100484
5), (R)-4-(((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or isomer trifluoroacetate (MDR-001-1001B ) and (E)-4-((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or isomer trifluoroacetate (MDR-001-1002B)
Figure PCTCN2024113428-ftappb-I100484

在室温下，向溶有(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(570mg，2.02mmol)的DMF(10mL)溶液中，加入(4R，5S，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(440mg，0.81mmol)，25℃搅拌10分钟，然后加入TEA(327mg，3.24mmol)。25℃继续搅拌20小时。将混合反应液通过反相柱色谱纯(柱：球形C18，20-40um，120g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：5％-100％B，30min，检测器：214nm)。在50％B下收集含有所需产物的级分，得到白色固体的粗产物(50mg)。粗产物通过制备级高效液相色谱(Waters 2767/Qda：柱：Sunfire C18 19×250×10μm，流动相A：0.1％FA/水；流动相B：ACN；流速：20mL/min；梯度：36-36％；保留时间：7.0-10.0min，16min)纯化得到两个异构体：MDR-001-1001B和MDR-001-1002B：To a solution of (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (570 mg, 2.02 mmol) in DMF (10 mL) was added (4R,5S,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (440 mg, 0.81 mmol) at room temperature, stirred at 25°C for 10 minutes, and then TEA (327 mg, 3.24 mmol) was added. Stirring was continued at 25°C for 20 hours. The mixed reaction solution was purified by reverse phase column chromatography (column: spherical C18, 20-40um, 120g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80mL/min; gradient: 5%-100% B, 30min, detector: 214nm). The fractions containing the desired product were collected at 50% B to obtain a crude product (50mg) of a white solid. The crude product was purified by preparative HPLC (Waters 2767/Qda: column: Sunfire C18 19×250×10μm, mobile phase A: 0.1% FA/water; mobile phase B: ACN; flow rate: 20mL/min; gradient: 36-36%; retention time: 7.0-10.0min, 16min) to obtain two isomers: MDR-001-1001B and MDR-001-1002B:

MDR-001-1001B：(R)-4-(((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或其异构体的三氟乙酸盐(16.33mg，0.023mmol，收率：2.8％)；tR＝8.688min.LCMS m/z：706[M]+.MDR-001-1001B: (R)-4-(((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (16.33 mg, 0.023 mmol, yield: 2.8%); t R =8.688 min. LCMS m/z: 706 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.72(s，1H)，7.99(d，J＝8.4Hz，2H)，7.84(d，J＝7.6Hz，2H)，7.56(d，J＝7.6Hz，2H)，7.40(d，J＝8.4Hz，2H)，7.32-7.20(m，5H)，5.77(d，J＝5.2Hz，1H)，4.63(s，1H)，4.54(s，1H)，4.34-4.31(m，1H)，3.42-3.39(m，2H)，3.16(s，9H)，2.67-2.62(m，2H)，1.46(d，J＝6.0Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.72 (s, 1H), 7.99 (d, J = 8.4Hz, 2H), 7.84 (d, J = 7.6Hz, 2H), 7.56 (d, J = 7.6Hz, 2H), 7.40 (d, J = 8.4Hz, 2H), 7.32-7.20 (m, 5H), 5.77 (d .

19F NMR(377MHz，DMSO-d6)：δ-61.275，-73.412. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.275, -73.412.

MDR-001-1002B：(E)-4-((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体的三氟乙酸盐(20.98mg，0.030mmol，收率：3.7％)；tR＝8.752min.LCMS m/z：688[M]+.MDR-001-1002B: (E)-4-((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or its isomer trifluoroacetate (20.98 mg, 0.030 mmol, yield: 3.7%); t R =8.752 min. LCMS m/z: 688 [M] + .

1H NMR(400MHz，DMSO-d6)：δ11.02(s，1H)，7.98(d，J＝8.0Hz，2H)，7.83(d，J＝8.0Hz，2H)，7.55(d，J＝8.4Hz，2H)，7.41(d，J＝8.4Hz，2H)，7.33-7.22(m，5H)，7.01-6.96(m，1H)，6.57(d，J＝15.2Hz，1H)， 4.65(s，1H)，4.34-4.30(m，1H)，4.21(d，J＝6.8Hz，2H)，3.10(s，9H)，1.48(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.02 (s, 1H), 7.98 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.0Hz, 2H), 7.55 (d, J = 8.4Hz, 2H) , 7.41 (d, J = 8.4Hz, 2H), 7.33-7.22 (m, 5H), 7.01-6.96 (m, 1H), 6.57 (d, J = 15.2Hz, 1H), 4.65 (s, 1H), 4.34-4.30 (m, 1H), 4.21 (d, J=6.8Hz, 2H), 3.10 (s, 9H), 1.48 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.304，-73.398. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.304, -73.398.

6)、(4S，5R，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100485
6) Synthesis of (4S,5R,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomers
Figure PCTCN2024113428-ftappb-I100485

室温下，向溶有(4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(440mg，0.84mmol)的氯苯(12mL)溶液中，加入PCl5(700mg，3.36mmol)，加热100℃搅拌2小时。将混合反应溶液减压浓缩并通过硅胶柱色谱法(PE/DCM＝1/2)纯化得到(4S，5R，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(160mg，0.296mmol，收率：35.2％)，LCMS m/z：540[M+H]+.To a solution of (4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (440 mg, 0.84 mmol) in chlorobenzene (12 mL) was added PCl5 (700 mg, 3.36 mmol) at room temperature, and the mixture was heated at 100°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/2) to give (4S,5R,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (160 mg, 0.296 mmol, yield: 35.2%), LCMS m/z: 540 [M+H] + .

7)、(R)-4-(((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或其异构体的三氟乙酸盐(MDR-001-1001C)和(E)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1002C)的合成

Figure PCTCN2024113428-ftappb-I100486
7), (R)-4-(((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers trifluoroacetate (MDR-001-1001 C) and (E)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (MDR-001-1002C)
Figure PCTCN2024113428-ftappb-I100486

在室温下，向溶有(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(207mg，0.74mmol)的DMF(5mL)溶液中，加入(4S，5R，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(160mg，0.296mmol)，25℃搅拌10min，然后加入TEA(120mg，1.18mmol)，25℃继续搅拌20小时。将混合反应液通过反相柱色谱(柱：球形C18，20-40μm，120g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：5％-100％B，30min，检测器：214nm)。在50％B下收集含有所需产物的级分得到粗产物(20mg)。粗产物再通过制备级HPLC(Waters 2767/Qda：柱：Sunfire C18 19×250×10μm，流动相A：0.1％FA/水；流动相B：ACN；流速：20mL/min；梯度：36-36％；保留时间：7.0-10.0分钟，16min)纯化得到两个异构体：MDR-001-1001C和MDR-001-1002C：To a solution of (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (207 mg, 0.74 mmol) in DMF (5 mL) was added (4S,5R,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (160 mg, 0.296 mmol) at room temperature, the mixture was stirred at 25°C for 10 min, and then TEA (120 mg, 1.18 mmol) was added and stirring was continued at 25°C for 20 hours. The mixed reaction solution was purified by reverse phase column chromatography (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5%-100% B, 30 min, detector: 214 nm). The fractions containing the desired product were collected at 50% B to obtain a crude product (20 mg). The crude product was further purified by preparative HPLC (Waters 2767/Qda: column: Sunfire C18 19×250×10 μm, mobile phase A: 0.1% FA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 36-36%; retention time: 7.0-10.0 min, 16 min) to obtain two isomers: MDR-001-1001C and MDR-001-1002C:

MDR-001-1001C：(R)-4-(((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或其异构体三氟乙酸盐(1.63mg，0.0023mmol，收率：0.77％)，LCMS m/z：706[M]+.MDR-001-1001C: (R)-4-(((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (1.63 mg, 0.0023 mmol, yield: 0.77%), LCMS m/z: 706 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.65(s，1H)，8.00(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.41-7.32(m，4H)，7.32-7.23(m，3H)，7.09(s，2H)，5.76(d，J＝6.8Hz，1H)，5.17(d，J＝11.2Hz，1H)，4.80-4.76(m，1H)，4.53-4.50(m，1H)，3.44-3.38(m，2H)，3.15(s，9H)，2.63-2.60(m，2H)，0.98(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.65 (s, 1H), 8.00 (d, J=8.0Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.41-7.32 (m, 4H), 7.32-7.23 (m, 3H), 7.09 (s, 2H), 5.76 (d, J=6.8Hz, 1H) , 5.17 (d, J=11.2Hz, 1H), 4.80-4.76 (m, 1H), 4.53-4.50 (m, 1H), 3.44-3.38 (m, 2H), 3.15 (s, 9H), 2.63-2.60 (m, 2H), 0.98 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.253，-73.412. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.253, -73.412.

MDR-001-1002C：(E)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对其异构体三氟乙酸盐(7.79mg，0.011mmol，收率：3.7％)，LCMS m/z：688[M]+.MDR-001-1002C: (E)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (7.79 mg, 0.011 mmol, yield: 3.7%), LCMS m/z: 688 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.92(s，1H)，7.99(d，J＝8.4Hz，2H)，7.82(d，J＝8.0Hz，2H)，7.41-7.32(m，4H)，7.30-7.24(m，3H)，7.10-7.07(m，2H)，7.00-6.92(m，1H)，6.57(d，J＝15.6Hz，1H)，5.19(d，J＝10.8Hz，1H)，4.84-4.80(m，1H)，4.20(d，J＝7.2Hz，2H)，3.11(s，9H)，0.98(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.92 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7.41-7.32 (m, 4H), 7.30-7.24 (m, 3H), 7.10-7.07 (m, 2H), 7.00-6.92 ( m, 1H), 6.57 (d, J = 15.6Hz, 1H), 5.19 (d, J = 10.8Hz, 1H), 4.84-4.80 (m, 1H), 4.20 (d, J = 7.2Hz, 2H), 3.11 (s, 9H), 0.98 (d, J = 6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.296，-73.427. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.296, -73.427.

8)、(4S，5S，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或其异构体的合成

Figure PCTCN2024113428-ftappb-I100487
8) Synthesis of (4S,5S,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or its isomers
Figure PCTCN2024113428-ftappb-I100487

室温下，向溶有(4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或异构体407-2D(500mg，0.96mmol)的氯苯(20mL)溶液中，加入PCl5(398mg，1.92mmol)，加热100℃搅拌3小时。将混合反应液浓缩，并通过硅胶柱色谱法(PE/DCM＝1/5)纯化得到(4S，5S，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(300mg，0.556mmol，收率：57.8％)，LCMS m/z：540[M+H]+。To a solution of (4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer 407-2D (500 mg, 0.96 mmol) in chlorobenzene (20 mL) was added PCl5 (398 mg, 1.92 mmol) at room temperature, and the mixture was heated at 100°C with stirring for 3 hours. The mixed reaction liquid was concentrated and purified by silica gel column chromatography (PE/DCM=1/5) to give (4S,5S,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (300 mg, 0.556 mmol, yield: 57.8%), LCMS m/z: 540 [M+H] + .

9)、(R)-4-(((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或其异构体三氟乙酸盐(MDR-001-1001D)和(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1002D)的合成

Figure PCTCN2024113428-ftappb-I100488
9), (R)-4-(((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (MDR-001-1001D ) and (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (MDR-001-1002D)
Figure PCTCN2024113428-ftappb-I100488

室温下，向溶有(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(226mg，1.11mmol)的DMF(20mL)溶液中，加入(4S，5S，E)-3-(4-氯苯基)-5-甲基-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体407-3D(300mg，0.556mmol)，25℃搅拌10min，然后加入TEA(169mg，1.67mmol)。25℃继续搅拌20小时。将混合反应液通过反相柱色谱(柱：球形C18，20-40μm，120g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：80mL/min；梯度：5％-100％B，30min，检测器：214nm)纯化，在62％B下收集含有所需产物的级分，得到白色固体的粗产物(220mg)。粗产物再通过制备级HPLC(Waters 2767/Qda：柱：Sunfire C18 19×250×10μm，流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：39-40％；保留时间：8.5-13.0min，16min)纯化得两个异构体：MDR-001-1001D和MDR-001-1002D：At room temperature, (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (226 mg, 1.11 mmol) was dissolved in DMF (20 mL), (4S,5S,E)-3-(4-chlorophenyl)-5-methyl-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer 407-3D (300 mg, 0.556 mmol) was added, stirred at 25°C for 10 min, and then TEA (169 mg, 1.67 mmol) was added. Stirring was continued at 25°C for 20 hours. The mixed reaction solution was purified by reverse phase column chromatography (column: spherical C18, 20-40 μm, 120 g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 80 mL/min; gradient: 5%-100% B, 30 min, detector: 214 nm), and the fractions containing the desired product were collected at 62% B to obtain a crude product (220 mg) as a white solid. The crude product was further purified by preparative HPLC (Waters 2767/Qda: column: Sunfire C18 19×250×10 μm, mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 39-40%; retention time: 8.5-13.0 min, 16 min) to obtain two isomers: MDR-001-1001D and MDR-001-1002D:

MDR-001-1001D：(R)-4-(((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵鎓或对映体三氟乙酸盐(24.29mg，0.034mmol，收率：6.2％)；LCMS m/z：706[M]+.MDR-001-1001D: (R)-4-(((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or enantiomer trifluoroacetate (24.29 mg, 0.034 mmol, yield: 6.2%); LCMS m/z: 706 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.62(s，1H)，8.00(d，J＝8.0Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.41-7.35(m，4H)，7.32-7.23(m，3H)，7.09(s，2H)，5.76(d，J＝6.0Hz，1H)，5.17(d，J＝11.2Hz，1H)，4.82-4.78(m，1H)，4.53-4.50(m，1H)，3.44-3.38(m，2H)，3.15(s，9H)，2.67-2.60(m，2H)，0.97(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.62 (s, 1H), 8.00 (d, J=8.0Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.41-7.35 (m, 4H), 7.32-7.23 (m, 3H), 7.09 (s, 2H), 5.76 (d, J=6.0Hz, 1H) , 5.17 (d, J=11.2Hz, 1H), 4.82-4.78 (m, 1H), 4.53-4.50 (m, 1H), 3.44-3.38 (m, 2H), 3.15 (s, 9H), 2.67-2.60 (m, 2H), 0.97 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.250，-73.404. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.250, -73.404.

MDR-001-1002D：(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体三氟乙酸盐(7.3mg，0.011mmol，收率：1.9％)；LCMS m/z：688[M]+.MDR-001-1002D: (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or enantiomer trifluoroacetate (7.3 mg, 0.011 mmol, yield: 1.9%); LCMS m/z: 688 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.92(s，1H)，7.99(d，J＝8.4Hz，2H)，7.82(d，J＝8.0Hz，2H)，7.42-7.35(m，4H)，7.32-7.24(m，3H)，7.09(s，2H)，7.00-6.93(m，1H)，6.57(d，J＝15.2Hz，1H)，5.20(d，J＝10.8Hz，1H)，4.84-4.81(m，1H)，4.20(d，J＝7.2Hz，2H)，3.11(s，9H)，0.98(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.92 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.82 (d, J=8.0Hz, 2H), 7.42-7.35 (m, 4H), 7.32-7.24 (m, 3H), 7.09 (s, 2H), 7.00-6.93 (m, 1H), 6.57 (d, J=15.2Hz, 1H), 5.20 (d, J=10.8Hz, 1H), 4.84-4.81 (m, 1H), 4.20 (d, J=7.2Hz, 2H), 3.11 (s, 9H), 0.98 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)：δ-61.298，-73.647. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.298, -73.647.

实施例51、(R)-4-((E)-2-((Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体(MDR-001-1007-A和MDR-001-1007-B)和(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体(MDR-001-1007-Ade和MDR-001-1007-Bde)的合成： Example 51, (R)-4-((E)-2-((Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers (MDR-001-1007-A and MDR-001-1007-B) and (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-ene-1-ammonium or its isomers (MDR-001-1007-Ade and MDR-001-1007-Bde):

1)、(4R，5R)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体和(4S，5S)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或其异构体的合成

Figure PCTCN2024113428-ftappb-I100489
1) Synthesis of (4R,5R)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or its isomers and (4S,5S)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or its isomers
Figure PCTCN2024113428-ftappb-I100489

反式-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(420mg，0.85mmol)通过超临界流体色谱(条件：系统：SHIMADZU LC-20AP；色谱柱名称：

Figure PCTCN2024113428-ftappb-I100490
色谱柱尺寸：250×30mm 10μm；流动相A；超临界CO2；流动相B：MEOH(+0.1％7.0mol/L Ammonia in MEOH)，A：B＝90：10；波长：214nm；流量：120mL/min；色谱柱温度：室温；背压：100bar；进样：2.0mL；循环时间：4.5分钟)纯化得到两种异构体：1007-1A和1007-1B：Trans-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (420 mg, 0.85 mmol) was purified by supercritical fluid chromatography (conditions: system: SHIMADZU LC-20AP; column name:
Figure PCTCN2024113428-ftappb-I100490
Column size: 250×30 mm 10 μm; mobile phase A: supercritical CO 2 ; mobile phase B: MEOH (+0.1% 7.0 mol/L Ammonia in MEOH), A:B=90:10; wavelength: 214 nm; flow rate: 120 mL/min; column temperature: room temperature; back pressure: 100 bar; injection: 2.0 mL; cycle time: 4.5 minutes) was purified to obtain two isomers: 1007-1A and 1007-1B:

1007-1A：chiral HPLC峰1：2.559min；(4R，5R)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(190mg，0.38mmol，收率：44.7％)，LCMS：m/z：497[M+H]+。1007-1A: chiral HPLC peak 1: 2.559 min; (4R, 5R)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (190 mg, 0.38 mmol, yield: 44.7%), LCMS: m/z: 497 [M+H] + .

1007-1B：chiral HPLC峰2：3.786min；(4S，5S)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(223mg，0.45mmol，收率：52.9％)，LCMS：m/z：497.2[M+H]+。1007-1B: chiral HPLC peak 2: 3.786 min; (4S, 5S)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (223 mg, 0.45 mmol, yield: 52.9%), LCMS: m/z: 497.2 [M+H] + .

2)、(4R，5R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100491
2) Synthesis of (4R, 5R, E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or isomers
Figure PCTCN2024113428-ftappb-I100491

在室温下，向溶有(4R，5R)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(190mg，0.38mmol)的氯苯(4mL)溶液中，加入PCl5(316mg，1.52mmol)加热100℃搅拌2小时。将混合反应液浓减压浓缩，并通过硅胶柱层析(PE：DCM＝1：2)纯化得到(4R，5R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰氯或异构体(130mg，0.25mmol，收率：65.8％)，LCMS m/z：515.[M+H]+. To a solution of (4R,5R)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (190 mg, 0.38 mmol) in chlorobenzene (4 mL) was added PCl5 (316 mg, 1.52 mmol) at room temperature, and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:DCM=1:2) to obtain (4R,5R,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or isomer (130 mg, 0.25 mmol, yield: 65.8%), LCMS m/z: 515.[M+H] + .

3)、(R)-4-((E)-2-((Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体(MDR-001-1007-A)和(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体(MDR-001-1007-Ade)的合成

Figure PCTCN2024113428-ftappb-I100492
3), (R)-4-((E)-2-((Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers (MDR-001-1007-A) and (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers (MDR-001-1007-Ade)
Figure PCTCN2024113428-ftappb-I100492

在室温下，向溶有(S)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(93mg，0.46mmol)的DMF(2mL)溶液中，加入1(120mg，0.23mmol)和三乙胺(70mg，0.69mmol)，30℃搅拌16小时。混合反应液通过制备级高效液相色谱(Waters 2767/Qda：色谱柱：Sunfire C18 19×250×10μm：流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：40-40％；保留时间：7.0-11.0minof16min)纯化得到两个异构体：MDR-001-1007-A和MDR-001-1007-Ade：At room temperature, 1 (120 mg, 0.23 mmol) and triethylamine (70 mg, 0.69 mmol) were added to a DMF (2 mL) solution of (S)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium (93 mg, 0.46 mmol), and stirred at 30°C for 16 hours. The mixed reaction solution was purified by preparative HPLC (Waters 2767/Qda: chromatographic column: Sunfire C18 19×250×10 μm: mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 40-40%; retention time: 7.0-11.0 min of 16 min) to obtain two isomers: MDR-001-1007-A and MDR-001-1007-Ade:

MDR-001-1007-A：(R)-4-((E)-2-((Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(7.41mg，0.01mmoμ，收率：4.3％)，tR＝8.671min，LCMS m/z：681[M]+.MDR-001-1007-A: (R)-4-((E)-2-((Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer (7.41 mg, 0.01 mmol, yield: 4.3%), t R =8.671 min, LCMS m/z: 681 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.81(d，J＝3.2Hz，1H)，7.58(d，J＝5.2Hz，2H)，7.41(d，J＝8.4Hz，2H)，7.34-7.30(m，2H)，7.27-7.23(m，3H)，5.74-5.75(m，1H)，4.62-4.61(m，1H)，4.57-4.51(m，1H)，4.29-4.27(m，1H)，3.39-3.37(m，2H)，3.10-3.13(m，4H)，3.14(s，9H)，2.69-2.61(m，2H)，2.07-2.03(m，4H)，1.52(s，3H). 1 H NMR (400 MHz, DMSO-d 6 )δ10.81 (d, J=3.2Hz, 1H), 7.58 (d, J=5.2Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.34-7.30(m, 2H), 7.27-7.23(m, 3H), 5.74-5.75(m, 1H), 4.62-4.61(m, 1 H), 4.57-4.51(m, 1H), 4.29-4.27(m, 1H), 3.39-3.37(m, 2H), 3.10-3.13 (m, 4H), 3.14 (s, 9H), 2.69-2.61 (m, 2H), 2.07-2.03 (m, 4H), 1.52 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.887，-96.975. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.887, -96.975.

MDR-001-1007-Ade：(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体(11.24mg，0.02mmol，收率：7.2％)，tR＝8.414min，LCMS m/z：663[M]+.MDR-001-1007-Ade: (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer (11.24 mg, 0.02 mmol, yield: 7.2%), t R =8.414 min, LCMS m/z: 663 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.14(s，1H)，7.58(d，J＝6.4Hz，2H)，7.42(d，J＝8.4Hz，2H)，7.35-7.31(m，2H)，7.27-7.23(m，3H)，7.04-6.95(m，1H)，6.63(d，J＝14.0Hz，1H)，4.64(s，1H)，4.30-4.27(m，1H)，4.20(d，J＝6.8Hz，2H)，3.17-3.13(m，4H)，3.10(s，9H)，2.05-2.03(m，4H)，2.02(s，4)1.54(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ11.14 (s, 1H), 7.58 (d, J=6.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 3H), 7.04-6.95 (m, 1H), 6.63 (d, J=14.0H z, 1H), 4.64 (s, 1H), 4.30-4.27 (m, 1H), 4.20 (d, J=6.8Hz, 2H), 3.17-3.13 (m, 4H), 3.10 (s, 9H), 2.05-2.03 (m, 4H), 2.02 (s, 4) 1.54 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-74.141，-97.041. 19 F NMR (377MHz, DMSO-d 6 ) δ -74.141, -97.041.

4)、(4S，5S，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100493
4) Synthesis of (4S,5S,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or isomers
Figure PCTCN2024113428-ftappb-I100493

在室温下，向溶有(4S，5S)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(75mg，0.15mmol)的氯苯(2mL)溶液中，加入PCl5(125mg，0.60mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩。残余物通过硅胶柱层析(PE：DCM＝1：2)纯化得到(4S，5S，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰氯或异构体(67mg，0.13mmol，收率：86.6％)，LCMS m/z：515[M+H]+.PCl 5 (125 mg, 0.60 mmol) was added to a solution of (4S,5S)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (75 mg, 0.15 mmol) in chlorobenzene (2 mL) at room temperature , and the mixture was heated at 100° C. with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:DCM=1:2) to give (4S,5S,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or isomer (67 mg, 0.13 mmol, yield: 86.6%), LCMS m/z: 515 [M+H] + .

4)、(R)-4-((E)-2-((Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体(MDR-001-1007-B)和(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1铵或其异构体(MDR-001-1007-Bde)的合成

Figure PCTCN2024113428-ftappb-I100494
4), (R)-4-((E)-2-((Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers (MDR-001-1007-B) and (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1aminium or its isomers (MDR-001-1007-Bde)
Figure PCTCN2024113428-ftappb-I100494

在室温下，向溶有(S)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(81mg，0.40mmol，2.0eq)的DMF(2mL)中，加入(4R，5R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰氯或异构体(102mg，0.20mmol)，然后加入三乙胺(61mg，0.60mmol)，30℃搅拌16小时。将混合反应液通过制备级高效液相色谱(Waters 2767/Qda：色谱柱：Sunfire C18 19×250×10μm，流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：34-34％；保留时间：7.6-10.4min of 16 min)纯化得到两个异构体：MDR-001-1007-B和MDR-001-1007-Bde：To a solution of (S)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (81 mg, 0.40 mmol, 2.0 eq) in DMF (2 mL) was added (4R,5R,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonyl chloride or isomer (102 mg, 0.20 mmol) at room temperature, followed by addition of triethylamine (61 mg, 0.60 mmol) and stirring at 30°C for 16 hours. The mixed reaction solution was purified by preparative HPLC (Waters 2767/Qda: chromatographic column: Sunfire C18 19×250×10μm, mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20mL/min; gradient: 34-34%; retention time: 7.6-10.4min of 16 min) to obtain two isomers: MDR-001-1007-B and MDR-001-1007-Bde:

MDR-001-1007-B：(R)-4-((E)-2-((Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(4.82mg，0.01mmol，收率：5.0％)，LCMS m/z：681[M]+.MDR-001-1007-B: (R)-4-((E)-2-((Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer (4.82 mg, 0.01 mmol, yield: 5.0%), LCMS m/z: 681 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.81(d，J＝2.8Hz，1H)，7.59(d，J＝2.4Hz，2H)，7.41(d，J＝8.4Hz，2H)，7.34-7.30(m，2H)，7.27-7.22(m，3H)，5.74(s，1H)，4.62(s，1H)，4.54-4.52(m，1H)，4.29-4.27(m，1H)，3.41-3.38(m，2H)，3.23-3.20(m，4H)，3.15(s，9H)，2.06-2.02(m，4H)，1.52(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.81 (d, J=2.8Hz, 1H), 7.59 (d, J=2.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.34-7.30 (m, 2H), 7.27-7.22 (m, 3H), 5.74 (s, 1H), 4.62 ( s, 1H), 4.54-4.52 (m, 1H), 4.29-4.27 (m, 1H), 3.41-3.38 (m, 2H), 3.23-3.20 (m, 4H), 3.15 (s, 9H), 2.06-2.02 (m, 4H), 1.52 (s, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.447，-96.965. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.447, -96.965.

MDR-001-1007-Bde：(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体(9..51mg，0.014mmol，收率：7.0％)，LCMS m/z：663[M]+.MDR-001-1007-Bde: (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or enantiomer (9..51 mg, 0.014 mmol, yield: 7.0%), LCMS m/z: 663 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.14(s，1H)，7.58(d，J＝6.4Hz，2H)，7.42(d，J＝8.4Hz，2H)，7.35-7.31(m，2H)，7.27-7.23(m，3H)，7.03-6.95(m，1H)，6.62(d，J＝14.8Hz，1H)，4.63(s，1H)，4.30-4.27(m，1H)，4.19(d，J＝7.6Hz，2H)，3.17-3.13(m，4H)，3.10(s，9H)，2.06-2.02(m，4H)，1.54(d，J＝1.6Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ11.14 (s, 1H), 7.58 (d, J=6.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 3H), 7.03-6.95 (m, 1H), 6.62 (d, J=14.8H z, 1H), 4.63 (s, 1H), 4.30-4.27 (m, 1H), 4.19 (d, J = 7.6Hz, 2H), 3.17-3.13 (m, 4H), 3.10 (s, 9H), 2.06-2.02 (m, 4H), 1.54 (d, J = 1.6Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-74.407，-97.981. 19 F NMR (377MHz, DMSO-d 6 ) δ -74.407, -97.981.

实施例52、(R)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体的三氟乙酸盐(MDR-001-1008-A和MDR-001-1008-B)和(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体的三氟乙酸盐(MDR-001-1008-Ade和MDR-001-1008-Bde)的合成：Example 52, (R)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-A and MDR-001-1008-B) and Synthesis of (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-Ade and MDR-001-1008-Bde):

1)、(4R，5R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或其异构体的合成

Figure PCTCN2024113428-ftappb-I100495
1) Synthesis of (4R, 5R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or its isomers
Figure PCTCN2024113428-ftappb-I100495

化合物(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(1.4g，2.82mmol)通过超临界流体(条件：体系：Waters SFC 150；柱名：CHIRAL ART Collulose  SC，柱尺寸：250*30mm 10μm；流动相A：超临界CO2；流动相B：MeOH(添加0.1％，7.0mol/L的甲醇氨)，A：B＝70：30；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar，进样量：2.0mL；循环时间：2.8min)制备得到两种异构体：1008-1A和1008-1B：The compound (4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (1.4 g, 2.82 mmol) was passed through a supercritical fluid (conditions: system: Waters SFC 150; column name: CHIRAL ART Collulose SC, column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: MeOH (added with 0.1%, 7.0mol/L methanolic ammonia), A:B=70:30; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar, injection volume: 2.0mL; cycle time: 2.8min) to prepare two isomers: 1008-1A and 1008-1B:

1008-1A：Peak 1Chiral HPLC：0.857min；(4R，5R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(0.68g，1.37mmol，收率：48.6％).1008-1A: Peak 1Chiral HPLC: 0.857 min; (4R, 5R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (0.68 g, 1.37 mmol, yield: 48.6%).

1008-1B：Peak 2ChiralHPLC：1.427min；(4S，5S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(0.73g，1.47mmol，收率：52.1％).1008-1B: Peak 2ChiralHPLC: 1.427min; (4S, 5S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (0.73g, 1.47mmol, yield: 52.1%).

2)、(4R，5R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或其异构体的合成

Figure PCTCN2024113428-ftappb-I100496
2) Synthesis of (4R, 5R, E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or its isomers
Figure PCTCN2024113428-ftappb-I100496

在室温下，向化合物(4R，5R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(680mg，1.37mmol)的氯苯(20mL)溶液中加入PCl5(855mg，4.11mmol)，加热100℃搅拌2小时。将混合物反应液减压浓缩并通过硅胶柱层析(PE/DCM＝2/3)纯化得到(4R，5R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(0.48g，0.93mmol，收率：68％)，LCMS m/z：515[M+H]+。To a solution of compound (4R,5R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (680 mg, 1.37 mmol) in chlorobenzene (20 mL) was added PCl5 (855 mg, 4.11 mmol) at room temperature, and the mixture was heated at 100°C with stirring for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=2/3) to give (4R,5R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (0.48 g, 0.93 mmol, yield: 68%), LCMS m/z: 515 [M+H] + .

3)、(R)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体的三氟乙酸盐(MDR-001-1008-A)和(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体的三氟乙酸盐(MDR-001-1008-Ade)的合成

Figure PCTCN2024113428-ftappb-I100497
3), (R)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-A) and Synthesis of (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-Ade)
Figure PCTCN2024113428-ftappb-I100497

在室温下，向溶有(4R，5R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(480mg，0.93mmol)的DMF(15mL)溶液中，加入(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(650mg，2.32mmol)和三乙胺(376mg，3.72mmol)，25℃搅拌16小时。反应液通过制备级高效液相色谱(Waters 2767/Qda：Sunfire C18 19*250*10μm；流动相A：0.05％FA/H2O，流动相B：ACN；流速：20mL/min；梯度：40-40％；保留时间：6.6-10.2min，16min)纯化得到：MDR-001-1008-A和MDR-001-1008-Ade：To a solution of (4R,5R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (480 mg, 0.93 mmol) in DMF (15 mL) at room temperature were added (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (650 mg, 2.32 mmol) and triethylamine (376 mg, 3.72 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction solution was purified by preparative HPLC (Waters 2767/Qda: Sunfire C18 19*250*10 μm; mobile phase A: 0.05% FA/H 2 O, mobile phase B: ACN; flow rate: 20 mL/min; gradient: 40-40%; retention time: 6.6-10.2 min, 16 min) to obtain: MDR-001-1008-A and MDR-001-1008-Ade:

MDR-001-1008-A：(R)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体三氟乙酸盐(73.88mg，0.108mmol，收率：11.6％)；LCMS m/z：681[M]+ MDR-001-1008-A: (R)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer trifluoroacetate (73.88 mg, 0.108 mmol, yield: 11.6%); LCMS m/z: 681 [M] +

1H NMR(400MHz，DMSO-d6)：δ10.83(s，1H)，7.57(s，2H)，7.41(d，J＝8.4Hz，2H)，7.34-7.30(m，2H)，7.27-7.24(m，3H)，4.62(s，1H)，4.54(s，1H)，4.35-4.34(m，1H)，3.38(s，2H)，3.23(t，J＝8.4Hz，2H)，3.14(s，9H)，3.04(s，2H)，2.61(s，2H)，1.94(br，2H)，1.70(br，2H)，1.53(m，2H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.83 (s, 1H), 7.57 (s, 2H), 7.41 (d, J=8.4Hz, 2H), 7.34-7.30 (m, 2H), 7.27-7.24 (m, 3H), 4.62 (s, 1H), 4.54 (s, 1H), 4.35-4. 34 (m, 1H), 3.38 (s, 2H), 3.23 (t, J=8.4Hz, 2H), 3.14 (s, 9H), 3.04 (s, 2H), 2.61 (s, 2H), 1.94 (br, 2H), 1.70 (br, 2H), 1.53 (m, 2H).

19F NMR(377MHz，DMSO-d6)δ-74.11，-98.97. 19 F NMR (377MHz, DMSO-d 6 ) δ -74.11, -98.97.

MDR-001-1008-Ade：(E)-4-((E)-2-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体三氟乙酸盐(37.29mg，0.056mmol，收率：6.0％)；LCMS m/z：663[M]+.MDR-001-1008-Ade: (E)-4-((E)-2-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or enantiomer trifluoroacetate (37.29 mg, 0.056 mmol, yield: 6.0%); LCMS m/z: 663 [M] + .

1H NMR(400MHz，DMSO-d6)：δ11.15(s，1H)，δ7.61-7.57(m，2H)，7.42(d，J＝8.8Hz，2H)，7.35-7.31(m， 2H)，7.27-7.24(m，3H)，7.03-6.96(m，1H)，6.67-6.61(m，1H)，4.64(s，1H)，4.37-4.34(m，1H)，4.19(d，J＝7.6Hz，2H)，3.26(t，J＝10.4Hz，2H)，3.09(s，9H)，3.04(m，2H)，1.94(br，2H)，1.70(br，2H)，1.55-1.52(m，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.15 (s, 1H), δ7.61-7.57 (m, 2H), 7.42 (d, J=8.8Hz, 2H), 7.35-7.31 (m, 2H), 7.27-7.24(m, 3H), 7.03-6.96(m, 1H), 6.67-6.61(m, 1H), 4.64(s, 1H), 4.37-4.34(m, 1H), 4.19(d, J=7. 6Hz, 2H), 3.26 (t, J=10.4Hz, 2H), 3.09 (s, 9H), 3.04 (m, 2H), 1.94 (br, 2H), 1.70 (br, 2H), 1.55-1.52 (m, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.89，-98.97. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.89, -98.97.

4)、(4S，5S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100498
4) Synthesis of (4S,5S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer
Figure PCTCN2024113428-ftappb-I100498

在室温下，向溶有化合物(4S，5S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(730mg，1.47mmol)的氯苯(20mL)溶液中，加入PCl5(920mg，4.41mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱法(PE/DCM＝1/4)纯化得到化合物(4S，5S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(630mg，1.22mmol，收率：83.0％)，LCMS m/z：515[M+H]+.To a solution of the compound (4S,5S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (730 mg, 1.47 mmol) in chlorobenzene (20 mL) was added PCl5 (920 mg, 4.41 mmol) at room temperature, and the mixture was heated at 100°C with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/4) to obtain compound (4S,5S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (630 mg, 1.22 mmol, yield: 83.0%), LCMS m/z: 515 [M+H] + .

5)、(R)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体的三氟乙酸盐(MDR-001-1008-B)和(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体的三氟乙酸盐(MDR-001-1008-Bde)的合成

Figure PCTCN2024113428-ftappb-I100499
5), (R)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-B) and Synthesis of (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-Bde)
Figure PCTCN2024113428-ftappb-I100499

在25℃下，向溶有(4S，5S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(410mg，0.80mmol)的DMF(15mL)溶液中，加入(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(560mg，2.00mmol)和三乙胺(242mg，2.40mmol)，25℃搅拌16小时。将混合反应液通制备级高效液相色谱(Waters 2767/Qda：Sunfire C18 19*250*10μm；流动相A：0.05％TFA/H2O，B：ACN；流速：20mL/min；梯度：36-36％；保留时间：7.0-10.0min，16min)纯化得到两个化合物：MDR-001-1008-B和MDR-001-1008-B-de：To a solution of (4S,5S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (410 mg, 0.80 mmol) in DMF (15 mL) at 25°C, (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (560 mg, 2.00 mmol) and triethylamine (242 mg, 2.40 mmol) were added, and the mixture was stirred at 25°C for 16 hours. The mixed reaction solution was purified by preparative HPLC (Waters 2767/Qda: Sunfire C18 19*250*10 μm; mobile phase A: 0.05% TFA/H 2 O, B: ACN; flow rate: 20 mL/min; gradient: 36-36%; retention time: 7.0-10.0 min, 16 min) to obtain two compounds: MDR-001-1008-B and MDR-001-1008-B-de:

MDR-001-1008-B：(R)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体三氟乙酸盐(56.76mg，0.083mmol，收率：10.3％)，tR＝8.673min，，LCMS m/z：681[M]+.MDR-001-1008-B: (R)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer trifluoroacetate (56.76 mg, 0.083 mmol, yield: 10.3%), t R =8.673 min, LCMS m/z: 681 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.84(s，1H)，7.59(br，2H)，7.41(d，J＝8.4Hz，2H)，7.34-7.31(m，2H)，7.27-7.23(m，2H)，7.12(s，3H)，5.75(br，1H)，4.62(s，1H)，4.54(br，1H)，4.36-4.33(m，1H)，3.38(s，2H)，3.23(t，J＝8.8Hz，2H)，3.14(s，9H)，3.04(m，2H)，2.64(m，2H)，1.94(br，2H)，1.69(br，2H)，1.52(m，3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ10.84 (s, 1H), 7.59 (br, 2H), 7.41 (d, J=8.4Hz, 2H), 7.34-7.31 (m, 2H), 7.27-7.23 (m, 2H), 7.12 (s, 3H), 5.75 (br, 1H), 4.62 (s, 1H), 4.54 (br , 1H), 4.36-4.33 (m, 1H), 3.38 (s, 2H), 3.23 (t, J=8.8Hz, 2H), 3.14 (s, 9 H), 3.04(m, 2H), 2.64(m, 2H), 1.94(br, 2H), 1.69(br, 2H), 1.52(m, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.86，-98.96. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.86, -98.96.

MDR-001-1008-Bde：(E)-4-((E)-2-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体三氟乙酸盐(18.99mg，0.028mmol，收率：3.5％)tR＝8.801min，LCMS m/z：663[M]+.MDR-001-1008-Bde: (E)-4-((E)-2-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or enantiomer trifluoroacetate (18.99 mg, 0.028 mmol, yield: 3.5%) t R =8.801 min, LCMS m/z: 663 [M] + .

1H NMR(400MHz，DMSO-d6)：δ11.15(s，1H)，7.57(d，J＝8.8Hz，2H)，7.42(d，J＝8.4Hz，2H)，7.35-7.31(m，2H)，7.26-7.24(m，3H)，7.02-6.96(m，1H)，6.63(d，J＝14.8Hz，1H)，4.64(s，1H)，4.37-4.34(m，1H)，4.19(d，J＝7.2Hz，2H)，3.23(t，J＝11.2Hz，2H)，3.10(s，9H)，1.94(br，2H)，1.70(br，2H)，1.55-1.54(m，3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ11.15 (s, 1H), 7.57 (d, J=8.8Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.35-7.31 (m, 2H), 7.26-7.24 (m, 3H), 7.02-6.96 (m, 1H), 6.63 (d, J=14.8Hz, 1H ), 4.64 (s, 1H), 4.37-4.34 (m, 1H), 4.19 (d, J=7.2Hz, 2H), 3.23 (t, J=11.2Hz, 2H), 3.10 (s, 9H), 1.94 (br, 2H), 1.70 (br, 2H), 1.55-1.54 (m, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.87，-98.97. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.87, -98.97.

实施例53、(R)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体三氟乙酸盐(MDR-001-1008-C和MDR-001-1008-D)和(E)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1008-Cde和MDR-001-1008- Dde)的合成：Example 53, (R)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (MDR-001-1008-C and MDR-001-1008 -D) and (E)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers trifluoroacetate (MDR-001-1008-Cde and MDR-001-1008- Synthesis of Dde):

1)、(4R，5S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体的合成

Figure PCTCN2024113428-ftappb-I100500
1) Synthesis of (4R, 5S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomers
Figure PCTCN2024113428-ftappb-I100500

化合物顺式-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(600mg，1.21mmol)通过超临界流体色谱(色谱条件：System：Waters SFC 150；柱：

Figure PCTCN2024113428-ftappb-I100501
色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：MEOH(+0.1％7.0mol/L氨溶液MeOH)，A：B＝70：30；波长：214nm；流量：120mL/min；柱温：RT；背压：100bar，进样：4.0mL；循环时间：4.3min)分离得到两种异构体：MDR-001-1008-1C和MDR-001-1008-1D：Compound cis-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (600 mg, 1.21 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: System: Waters SFC 150; column:
Figure PCTCN2024113428-ftappb-I100501
Column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: MEOH (+0.1% 7.0mol/L ammonia solution MeOH), A:B=70:30; wavelength: 214nm; flow rate: 120mL/min; column temperature: RT; back pressure: 100bar, injection: 4.0mL; cycle time: 4.3min) to separate two isomers: MDR-001-1008-1C and MDR-001-1008-1D:

MDR-001-1008-1C：(4R，5S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(237mg，0.48mmol)，MDR-001-1008-1C: (4R,5S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (237 mg, 0.48 mmol),

MDR-001-1008-1D：(4S，5R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体，(195mg，0.39mmol)。MDR-001-1008-1D: (4S,5R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer, (195 mg, 0.39 mmol).

2)、(4R，5S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100502
2) Synthesis of (4R, 5S, E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomers
Figure PCTCN2024113428-ftappb-I100502

在室温下，向溶有(4R，5S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(237mg，0.48mmol)的氯苯(5mL)溶液中，加入PCl5(200mg，0.96mmol)，氮气保护，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱(PE/EA＝2/1)减压浓缩纯化得到(4R，5S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(125mg，0.24mmol，收率：50.8％)，LCMS m/z：515[M+H]+。To a solution of (4R,5S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (237 mg, 0.48 mmol) in chlorobenzene (5 mL) was added PCl5 (200 mg, 0.96 mmol) at room temperature. The mixture was heated at 100°C with stirring for 2 hours under nitrogen protection. The mixed reaction liquid was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=2/1) to give (4R,5S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (125 mg, 0.24 mmol, yield: 50.8%), LCMS m/z: 515 [M+H] + .

3)、(R)-4-((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体三氟乙酸盐(MDR-001-1008-C)和(E)-4-((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1008-Cde)的合成

Figure PCTCN2024113428-ftappb-I100503
3), (R)-4-((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (MDR-001-1008-C) and Synthesis of (E)-4-((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (MDR-001-1008-Cde)
Figure PCTCN2024113428-ftappb-I100503

在室温下，向溶有(4R，5S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(125mg，0.24mmol)的DMF(2mL)溶液中，加入(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-氨(97mg，0.48mmol)和三乙胺(73mg，0.72mmol)，25℃搅拌16小时。将混合反应液通过制备级高效液相色谱(Waters 2767/Qda，柱：Sunfire C18 19*250*10μm；流动相A：0.1％FA/H2O，B：乙酸；流速：20mL/min；梯度：35-35％；保留时间：7.8-10.0min，每16min)纯化得到两个异构体：MDR-001-1008-C和MDR-001-1008-Cde：To a solution of (4R,5S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (125 mg, 0.24 mmol) in DMF (2 mL) at room temperature were added (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-amine (97 mg, 0.48 mmol) and triethylamine (73 mg, 0.72 mmol), and the mixture was stirred at 25°C for 16 hours. The mixed reaction solution was purified by preparative HPLC (Waters 2767/Qda, column: Sunfire C18 19*250*10 μm; mobile phase A: 0.1% FA/H 2 O, B: acetic acid; flow rate: 20 mL/min; gradient: 35-35%; retention time: 7.8-10.0 min, every 16 min) to obtain two isomers: MDR-001-1008-C and MDR-001-1008-Cde:

MDR-001-1008-C：(R)-4-((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体三氟乙酸盐(12.40mg，0.018mmol，收率：7.4％)，LCMS m/z：681[M]+ MDR-001-1008-C: (R)-4-((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer trifluoroacetate (12.40 mg, 0.018 mmol, yield: 7.4%), LCMS m/z: 681 [M] +

1H NMR(400MHz，DMSO-d6)：δ10.76(s，1H)，δ7.47(d，J＝8.4Hz，2H)，7.37(d，J＝8.4Hz，2H)，7.36-7.26(m，3H)，7.10(s，2H)，5.74(d，J＝6.4Hz，1H)，5.18(d，J＝11.2Hz，1H)，4.83-4.76(m，1H)，4.54(d，J＝5.6Hz，1H)，3.39(t，J＝10.4Hz，2H)，3.27(t，J＝11.6Hz，2H)，3.14(s，9H)，3.11-3.00(m，2H)，2.71-2.58(m，2H)，2.00-1.91(m，2H)，1.75-1.68(m，2H)，1.00(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.76 (s, 1H), δ7.47 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.36-7.26 (m, 3H), 7. 10 (s, 2H), 5.74 (d, J = 6.4Hz, 1H), 5.18 (d, J = 11.2Hz, 1H), 4.83-4.76 (m, 1H), 4.54 (d, J =5.6Hz, 1H), 3.39 (t, J = 10.4Hz, 2H), 3.27 (t, J = 11.6Hz, 2H), 3.14 (s, 9H), 3.11-3.00 ( m, 2H), 2.71-2.58 (m, 2H), 2.00-1.91 (m, 2H), 1.75-1.68 (m, 2H), 1.00 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.46，-98.96. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.46, -98.96.

MDR-001-1008-Cde：(E)-4-((E)-2-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体三氟乙酸盐(6.36mg，0.0096mmol，收率：3.9％)，LCMS m/z：663[M]+。MDR-001-1008-Cde: (E)-4-((E)-2-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer trifluoroacetate (6.36 mg, 0.0096 mmol, yield: 3.9%), LCMS m/z: 663 [M] + .

1H NMR(400MHz，DMSO-d6)：δ11.06(s，1H)，δ7.45(d，J＝8.8Hz，2H)，7.39(d，J＝8.8Hz，2H)，7.34-7.24(m，3H)，7.11(s，2H)，7.02-6.94(m，1H)，6.64(d，J＝15.2Hz，1H)，5.2(d，J＝11.2Hz，1H)，4.86-4.78(m，1H)，4.19(d，J＝7.6Hz，2H)，3.27(t，J＝11.6Hz，2H)，3.10(s，9H)，3.06-3.00(m，2H)，2.00-1.93(m，2H)，1.72(t，J＝5.2Hz，2H)，1.00(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.06 (s, 1H), δ7.45 (d, J=8.8Hz, 2H), 7.39 (d, J=8.8Hz, 2H), 7.34-7.24 (m, 3H ), 7.11 (s, 2H), 7.02-6.94 (m, 1H), 6.64 (d, J = 15.2Hz, 1H), 5.2 (d, J = 11.2Hz, 1H), 4.86-4.78 (m, 1H), 4.19 (d, J=7.6Hz, 2H), 3.27 (t, J=11.6Hz, 2H), 3.10 (s, 9H), 3. 06-3.00 (m, 2H), 2.00-1.93 (m, 2H), 1.72 (t, J=5.2Hz, 2H), 1.00 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.41，-98.97. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.41, -98.97.

4)、(4S，5R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体的合成

Figure PCTCN2024113428-ftappb-I100504
4) Synthesis of (4S,5R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer
Figure PCTCN2024113428-ftappb-I100504

在室温下，向溶有(4S，5R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(195mg，0.39mmol)的氯苯(5mL)溶液中，加入PCl5(162mg，0.78mmol)，氮气氛围，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱(PE/EA＝2/1)纯化得到(4S，5R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(110mg，0.21mmol，收率：54.4％)，LCMS m/z：515[M+H]+。To a solution of (4S,5R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (195 mg, 0.39 mmol) in chlorobenzene (5 mL) was added PCl5 (162 mg, 0.78 mmol) at room temperature and the mixture was heated at 100°C with stirring for 2 hours under nitrogen atmosphere. The mixed reaction liquid was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=2/1) to give (4S,5R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (110 mg, 0.21 mmol, yield: 54.4%), LCMS m/z: 515 [M+H] + .

5)、(R)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体三氟乙酸盐(MDR-001-1008-D)和(E)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体三氟乙酸盐(MDR-001-1008-Dde)的合成
5), (R)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomer trifluoroacetate (MDR-001-1008-D) and Synthesis of (E)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomer trifluoroacetate (MDR-001-1008-Dde)

在室温下，向溶有(4S，5R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰亚胺酰氯或异构体(110mg，0.21mmol)的DMF(3mL)溶液中，加入(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-铵(85mg，0.42mmol)和三乙胺(64mg，0.63mmol)，25℃搅拌16小时。将混合反应液通过制备级高效液相色谱(Waters 2767/Qda；柱：Sunfire C18 19*250*10μm；流动相A：0.1％FA/H2O，B：乙酸；流速：20ml/min；梯度：35-35％；保留时间：7.8-9.8min，共16分钟)纯化得到两个异构体：MDR-001-1008-D和MDR-001-1008-Dde：To a solution of (4S,5R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride or isomer (110 mg, 0.21 mmol) in DMF (3 mL) at room temperature were added (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-ammonium (85 mg, 0.42 mmol) and triethylamine (64 mg, 0.63 mmol), and the mixture was stirred at 25°C for 16 hours. The mixed reaction solution was purified by preparative HPLC (Waters 2767/Qda; column: Sunfire C18 19*250*10 μm; mobile phase A: 0.1% FA/H 2 O, B: acetic acid; flow rate: 20 ml/min; gradient: 35-35%; retention time: 7.8-9.8 min, 16 minutes in total) to obtain two isomers: MDR-001-1008-D and MDR-001-1008-Dde:

MDR-001-1008-D：(R)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体三氟乙酸盐(7.05mg，0.018mmol，收率：4.8％)，LCMS m/z：681[M]+。MDR-001-1008-D: (R)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer trifluoroacetate (7.05 mg, 0.018 mmol, yield: 4.8%), LCMS m/z: 681 [M] + .

1H NMR(400MHz，DMSO-d6)：δ10.74(s，1H)，δ7.46(d，J＝8.4Hz，2H)，7.39(d，J＝1.6Hz，2H)，7.37-7.24(m，3H)，7.12(s，2H)，5.73(d，J＝6.4Hz，1H)，5.18(d，J＝11.2Hz，1H)，4.84-4.76(m，1H)，4.52(s，1H)，3.40-3.38(m，2H)，3.27(t，J＝11.6Hz，2H)，3.14(s，9H)，3.10-3.00(m，2H)，2.71-2.57(m，2H)，2.01-1.74(m，2H)，1.72-1.68(m，2H)，1.00(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.74 (s, 1H), δ7.46 (d, J=8.4Hz, 2H), 7.39 (d, J=1.6Hz, 2H), 7.37-7.24 (m, 3H) , 7.12 (s, 2H), 5.73 (d, J = 6.4Hz, 1H), 5.18 (d, J = 11.2Hz, 1H), 4.84-4.76 (m, 1H), 4. 52(s, 1H), 3.40-3.38(m, 2H), 3.27(t, J=11.6Hz, 2H), 3.14(s, 9H), 3.10-3.00(m, 2 H), 2.71-2.57(m, 2H), 2.01-1.74(m, 2H), 1.72-1.68(m, 2H), 1.00(d, J=6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.50，-98.97. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.50, -98.97.

MDR-001-1008-Dde：(E)-4-((E)-2-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体三氟乙酸盐(1.62mg，0.002mmol，收率：1.1％)，LCMS m/z：663[M]+。MDR-001-1008-Dde: (E)-4-((E)-2-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer trifluoroacetate (1.62 mg, 0.002 mmol, yield: 1.1%), LCMS m/z: 663 [M] + .

1H NMR(400MHz，DMSO-d6)：δ11.06(s，1H)，δ7.45(d，J＝8.4Hz，2H)，7.38(d，J＝8.4Hz，2H)，7.34-7.26(m，3H)，7.12(s，2H)，7.02-6.94(m，1H)，6.64(d，J＝14.8Hz，1H)，5.2(d，J＝11.2Hz，1H)，4.86-4.78(m，1H)，4.19(d，J＝7.6Hz，2H)，3.27(t，J＝11.6Hz，2H)，3.13(s，9H)，3.06-3.01(m，2H)，2..01-1.92(m，2H)，1.73-1.72(m，2H)，1.00(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.06 (s, 1H), δ7.45 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4Hz, 2H), 7.34-7.26 (m, 3 H), 7.12 (s, 2H), 7.02-6.94 (m, 1H), 6.64 (d, J = 14.8Hz, 1H), 5.2 (d, J = 11.2Hz, 1H) , 4.86-4.78 (m, 1H), 4.19 (d, J=7.6Hz, 2H), 3.27 (t, J=11.6Hz, 2H), 3.13 (s, 9H), 3.06-3.01 (m, 2H), 2..01-1.92 (m, 2H), 1.73-1.72 (m, 2H), 1.00 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ-73.42，-98.98. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.42, -98.98.

实施例54、(R)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或异构体(MDR-001-1009-A和MDR-001-1009-B)和(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或异构体(MDR-001-1009-Ade和MDR-001-1009-Bde)的合成：Example 54, (R)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or isomers (MDR-001-1009-A and MDR-001-1009-B) and Synthesis of (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or isomers (MDR-001-1009-Ade and MDR-001-1009-Bde):

1)、3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
1) Synthesis of 3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑(700mg，2.72mmol)甲苯(10mL)溶液中，加入((4，4-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯(702mg，2.72mmol)，加热110℃搅拌3小时。将混合反应液减压浓缩并在异丙醇(30mL)中打浆，过滤，收集滤饼干燥得到3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(1.10g，2.28mmol，收率：83.8％)，LCMS m/z：483[M+H]+.At room temperature, methyl ((4,4-difluoropiperidin-1-yl)sulfonyl)carbamate (702 mg, 2.72 mmol) was added to a solution of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (700 mg, 2.72 mmol) in toluene (10 mL), and the mixture was heated to 110° C. and stirred for 3 hours. The mixed reaction solution was concentrated under reduced pressure and slurried in isopropanol (30 mL), filtered, and the filter cake was collected and dried to obtain 3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.10 g, 2.28 mmol, yield: 83.8%), LCMS m/z: 483 [M+H] + .

2)、(R)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体的合成
2) Synthesis of (R)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or its enantiomer

将3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(1.10g，2.28mmol)通过制备级超临界流体色谱(条件：系统：Waters SFC 150 Waters SFC 150；色谱柱名称：REGIS(S，S)WHELK-O1；色谱柱尺寸：250×25mm 10μm；流动相A；超临界CO2；流动相B：MEOH(+0.1％7.0mol/L Ammonia in MEOH)，A：B＝80：20；波长：214nm；流量：120mL/min；色谱柱温度：室温；背压：100bar：RT；背压：100bar；进样：2.0mL；循环时间：3.2min：)分离得到两种异构体：1009-3A和1009-3B：3-(4-Chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.10 g, 2.28 mmol) was purified by preparative supercritical fluid chromatography (conditions: system: Waters SFC 150 Waters SFC 150; column name: REGIS (S, S) WHELK-O1; column size: 250×25 mm 10 μm; mobile phase A: supercritical CO 2 ; mobile phase B: MEOH (+0.1% 7.0 mol/L Ammonia in MEOH), A: B = 80: 20; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; back pressure: 100bar: RT; back pressure: 100bar; injection: 2.0mL; cycle time: 3.2min:) Two isomers were separated: 1009-3A and 1009-3B:

1009-3A：峰1：Chiral-HPLC：2.990min；(R)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(546mg，1.13mmol，收率：49.6％)，LCMS：m/z：483[M+H]+。1009-3A: Peak 1: Chiral-HPLC: 2.990 min; (R)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (546 mg, 1.13 mmol, yield: 49.6%), LCMS: m/z: 483 [M+H] + .

1009-3B：峰2：Chiral-HPLC：4.083min；(S)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(512mg，1.06mmol，收率：46.5％)，LCMS：m/z：483[M+H]+。1009-3B: Peak 2: Chiral-HPLC: 4.083 min; (S)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (512 mg, 1.06 mmol, yield: 46.5%), LCMS: m/z: 483 [M+H] + .

3)、(R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体的合成
3) Synthesis of (R, E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer

在室温下，向溶有(R)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(546mg，1.13mmol)的氯苯(10mL)溶液中，加入PCl5(940mg，4.52mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩。残余物通过硅胶柱层析(PE：DCM＝1：2)纯化得到(R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(310mg，0.62mmol，收率：54.9％)，LCMS m/z：501[M+H]+.PCl 5 (940 mg, 4.52 mmol) was added to a solution of (R)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole- 1 -carboxamide or enantiomer (546 mg, 1.13 mmol) in chlorobenzene (10 mL) at room temperature, and the mixture was heated at 100° C. with stirring for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:DCM=1:2) to give (R,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (310 mg, 0.62 mmol, yield: 54.9%), LCMS m/z: 501 [M+H] + .

4)、(R)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体()的合成
4) Synthesis of (R)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its enantiomer ()

在室温下，向溶有(R)-4-胍-2-羟基-N，N，N-三甲基-4-氧代丁-1-胺(211mg，1.04mmol)的DMF(5mL)中，加入(R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(261mg，0.52mmol)，然后加入三乙胺(158mg，1.56mmol)，30℃搅拌16小时。将混合反应液通过prep-HPLC(Waters2767/Qda，色谱柱：Sunfire C18 19×250×10μm；流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：38-38％；保留时间：7.4-11.0min of16 min)纯化得到(R)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(62.73mg，0.09mmol，收率：17.3％)，LCMS m/z：667[M]+ To a solution of (R)-4-guanidine-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-amine (211 mg, 1.04 mmol) in DMF (5 mL) at room temperature was added (R,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (261 mg, 0.52 mmol) and then triethylamine (158 mg, 1.56 mmol), and the mixture was stirred at 30°C for 16 hours. The mixed reaction solution was purified by prep-HPLC (Waters 2767/Qda, column: Sunfire C18 19×250×10 μm; mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 38-38%; retention time: 7.4-11.0 min of 16 min) to obtain (R)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or enantiomer (62.73 mg, 0.09 mmol, yield: 17.3%), LCMS m/z: 667 [M] +

1H NMR(400MHz，DMSO-d6)δ10.78(s，1H)，7.56(d，J＝8.4Hz，2H)，7.40(d，J＝8.8Hz，2H)，7.35-7.25(m，5H)，5.75(s，1H)，5.04-5.01(m，1H)，4.54(s，1H)，4.45(t，J＝12.0Hz，1H)，3.86-3.75(m，1H)，3.40-3.38(m，2H)，3.19-3.15(m，2H)，3.10(s，9H)，2.67-2.58(m，4H)，2.09-2.02(m，4H). 1 H NMR (400MHz, DMSO-d 6 )δ10.78 (s, 1H), 7.56 (d, J=8.4Hz, 2H), 7.40 (d, J=8.8Hz, 2H), 7.35-7.25 (m, 5H), 5.75 (s, 1H), 5.04-5.01 (m, 1H), 4.54 (s, 1H), 4. 45(t, J=12.0Hz, 1H), 3.86-3.75(m, 1H), 3.40-3.38(m, 2H), 3.19-3.15(m, 2H), 3.10(s, 9H), 2.67-2.58(m, 4H), 2.09-2.02(m, 4H).

19F NMR(377MHz，DMSO-d6)δ-73.922，-96.371. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.922, -96.371.

5)、(S，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体的合成
5) Synthesis of (S, E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer

在室温下，向溶有(S)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(512mg，1.06mmol)的氯苯(10mL)溶液中，加入PCl5(882mg，4.24mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩。残余物通过硅胶柱层析(PE/DCM＝1/2)纯化得到(R，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(410mg，0.82mmol，收率：77.4％)，LCMS m/z：501[M+H]+.PCl 5 (882 mg, 4.24 mmol) was added to a solution of (S)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole- 1 -carboxamide or enantiomer (512 mg, 1.06 mmol) in chlorobenzene (10 mL) at room temperature, and the mixture was heated at 100° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/DCM=1/2) to give (R,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (410 mg, 0.82 mmol, yield: 77.4%), LCMS m/z: 501 [M+H] + .

6)、(R)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或异构体(MDR-001-1009-B)和(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或异构体(MDR-001-1009-Bde)的合成
6), (R)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or isomers (MDR-001-1009-B) and Synthesis of (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or isomer (MDR-001-1009-Bde)

在室温下，向溶有(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵(292mg，1.44mmol)的DMF(8mL)溶液中，加入(S，E)-3-(4-氯苯基)-N-((4，4-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(360mg，0.72mmol)，然后加入三乙胺(218mg，2.16mmol)，30℃搅拌16小时。将混合反应液通过prep-HPLC(Waters 2767/Qda，柱：Sunfire C18 19×250×10μm，流动相A：0.05％TFA/水；流动相B：ACN；流速：20mL/min；梯度：38-38％；保留时间：7.0-12.0min of 18min)纯化得到两 个异构体：MDR-001-1009-B和MDR-001-1009-Bde：To a solution of (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium (292 mg, 1.44 mmol) in DMF (8 mL) at room temperature was added (S,E)-3-(4-chlorophenyl)-N-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (360 mg, 0.72 mmol) and then triethylamine (218 mg, 2.16 mmol), and the mixture was stirred at 30°C for 16 hours. The mixed reaction solution was purified by prep-HPLC (Waters 2767/Qda, column: Sunfire C18 19×250×10 μm, mobile phase A: 0.05% TFA/water; mobile phase B: ACN; flow rate: 20 mL/min; gradient: 38-38%; retention time: 7.0-12.0 min of 18 min) to obtain two Isomers: MDR-001-1009-B and MDR-001-1009-Bde:

MDR-001-1009-B：(R)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(44.29mg，0.07mmol，收率：9.7％)，tR＝8.494min，LCMS m/z：667[M]+.MDR-001-1009-B: (R)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer (44.29 mg, 0.07 mmol, yield: 9.7%), t R =8.494 min, LCMS m/z: 667 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.78(s，1H)，7.56(d，J＝8.4Hz，2H)，7.39(d，J＝8.8Hz，2H)，7.35-7.29(m，4H)，7.27-7.23(m，1H)，5.75(s，1H)，5.06-5.01(m，1H)，4.54(s，1H)，4.46(t，J＝12.0Hz，1H)，3.83-3.79(m，1H)，3.41-3.35(m，2H)，3.19-3.17(m，4H)，3.15(s，9H)，2.70-2.62(m，2H)，2.10-2.03(m，4H). 1 H NMR (400 MHz, DMSO-d 6 )δ10.78 (s, 1H), 7.56 (d, J=8.4Hz, 2H), 7.39 (d, J=8.8Hz, 2H), 7.35-7.29 (m, 4H), 7.27-7.23 (m, 1H), 5.75 (s, 1H), 5.06-5.01 (m, 1H), 4.54 ( s, 1H), 4.46 (t, J=12.0Hz, 1H), 3.83-3.79 (m, 1H), 3.41-3.35 (m, 2H), 3.19-3.17(m, 4H), 3.15(s, 9H), 2.70-2.62(m, 2H), 2.10-2.03(m, 4H).

19F NMR(377MHz，DMSO-d6)δ-74.147，-96.456. 19 F NMR (377MHz, DMSO-d 6 ) δ -74.147, -96.456.

MDR-001-1009-Bde：(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4，4-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵(33.07mg，0.05mmol，收率：6.9％)，tR＝8.250min，LCMS m/z：649[M]+.MDR-001-1009-Bde: (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4,4-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium (33.07 mg, 0.05 mmol, yield: 6.9%), t R =8.250 min, LCMS m/z: 649 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.11(s，1H)，7.55(d，J＝8.0Hz，2H)，7.40(d，J＝8.8Hz，2H)，7.35-7.29(m，4H)，7.27-7.23(m，1H)，7.03-6.95(m，1H)，6.64(d，J＝15.2Hz，1H)，5.07-5.03(m，1H)，4.47(t，J＝12.0Hz，11.6Hz，1H)，4.19(d，J＝7.2Hz，2H)，3.84-3.80(m，1H)，3.20-3.18(m，4H)，3.15-3.14(m，1H)，3.10(s，9H)，2.09-2.03(m，4H). 1 H NMR (400MHz, DMSO-d 6 )δ11.11(s, 1H), 7.55(d, J=8.0Hz, 2H), 7.40(d, J=8.8Hz, 2H), 7.35-7.29(m, 4H), 7.27-7.23 (m, 1H), 7.03-6.95 (m, 1H), 6.64 (d, J=15.2Hz, 1H), 5.07-5.0 3(m, 1H), 4.47(t, J＝12.0Hz, 11.6Hz, 1H), 4.19(d, J＝7.2Hz, 2H), 3.84-3.80( m, 1H), 3.20-3.18 (m, 4H), 3.15-3.14 (m, 1H), 3.10 (s, 9H), 2.09-2.03 (m, 4H).

19F NMR(377MHz，DMSO-d6)δ-73.914，-96.555. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.914, -96.555.

实施例55、(R)-4-((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体(MDR-001-1010-A和MDR-001-1010-B)和(E)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体(MDR-001-1010-Ade和MDR-001-1010-Bde)的合成：Example 55, (R)-4-((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers (MDR-001-1010-A and MDR-001-1010-B) and Synthesis of (E)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers (MDR-001-1010-Ade and MDR-001-1010-Bde):

1)、3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
1) Synthesis of 3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有((3，3-二氟哌啶-1-基)磺酰基)氨基甲酸甲酯(1g，3.88mmol)的甲苯(20mL)溶液中，加入3-(4-氯苯基)-4，5-二氢-1H-吡唑(997mg，3.88mmol)，加热110℃，搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱(PE/EA＝3/1)纯化的得到3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(1.1g，2.28mmol，收率：58.82％)，LCMSm/z：483[M+H]+.At room temperature, 3-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (997 mg, 3.88 mmol) was added to a solution of methyl ((3,3-difluoropiperidin-1-yl)sulfonyl)carbamate (1 g, 3.88 mmol) in toluene (20 mL), heated to 110°C, and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1) to obtain 3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.1 g, 2.28 mmol, yield: 58.82%), LCMS m/z: 483 [M+H] + .

2)、(S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体的合成
2) Synthesis of (S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or its enantiomer

将化合物3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(1.1g，2.28mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：甲醇(+0.1％7.0mol/l氨甲醇)，A：B＝75：25；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：8.0mL；循环时间：6.0min)纯化得到两个异构体：MDR-001-1010-3A和MDR-001-1010-3BCompound 3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.1 g, 2.28 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: methanol (+0.1% 7.0mol/l ammonia methanol), A:B=75:25; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 8.0mL; cycle time: 6.0min) was purified to obtain two isomers: MDR-001-1010-3A and MDR-001-1010-3B

1010-3A：峰1 Chiral HPLC：2.336min；(S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(550mg，1.13mol，收率：50％)，LCMS m/z：483[M+H]+.1010-3A: Peak 1 Chiral HPLC: 2.336 min; (S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (550 mg, 1.13 mol, yield: 50%), LCMS m/z: 483 [M+H] + .

1010-3B：峰2 Chiral HPLC：3.966min；(R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(550mg，1.13mmol，收率：50％)，LCMS：m/z：483.1[M+H]+.1010-3B: Peak 2 Chiral HPLC: 3.966 min; (R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (550 mg, 1.13 mmol, yield: 50%), LCMS: m/z: 483.1 [M+H] + .

3)、(S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体的合成
3) Synthesis of (S, E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer

在室温下，向溶有(S)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(550mg，1.14mmol)的氯苯(10mL)溶液中，加入五氯化磷(948mg，4.56mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩，并通过硅胶柱色谱硅胶(PE/DCM＝1/4)纯化得到(S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(400mg，0.79mmol，收率：70.17％)，LCMS m/z：501[M+H]+.Phosphorus pentachloride (948 mg, 4.56 mmol) was added to a solution of (S)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (550 mg, 1.14 mmol) in chlorobenzene (10 mL) at room temperature, and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/4) to obtain (S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (400 mg, 0.79 mmol, yield: 70.17%), LCMS m/z: 501 [M+H] + .

4)、(R)-4-((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或异构体(MDR-001-1010-A)和(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或异构体(MDR-001-1010-Ade)的合成
4), (R)-4-((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or isomers (MDR-001-1010-A) and Synthesis of (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or isomer (MDR-001-1010-Ade)

在室温下，向溶有(S，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(200mg，0.40mmol)的N，N二甲基甲酰胺(8mL)溶液中，加入(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-氨(196mg，0.80mmol)和三乙胺(121mg，1.20mmol)，25℃搅拌16小时。将混合反应液通过prep-HPLC(色谱柱：Waters 2767/Qda，色谱柱：Sunfire C18，21.2*250mm，10μm；流动相A：0.1％TFA/H2O，B：乙酸；流速：20mL/min；梯度：33％-33％；保留时间：7.8-10.6min，16min)纯化得到两个异构体：MDR-001-1010-A和MDR-001-1010-Ade：To a solution of (S,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (200 mg, 0.40 mmol) in N,N-dimethylformamide (8 mL) at room temperature were added (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-amine (196 mg, 0.80 mmol) and triethylamine (121 mg, 1.20 mmol), and the mixture was stirred at 25°C for 16 hours. The mixed reaction solution was purified by prep-HPLC (chromatographic column: Waters 2767/Qda, chromatographic column: Sunfire C18, 21.2*250 mm, 10 μm; mobile phase A: 0.1% TFA/H 2 O, B: acetic acid; flow rate: 20 mL/min; gradient: 33%-33%; retention time: 7.8-10.6 min, 16 min) to obtain two isomers: MDR-001-1010-A and MDR-001-1010-Ade:

MDR-001-1010-A：(R)-4-((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(20.31mg，0.03mmol，收率：7.63％)，LCMS m/z：667[M]+.MDR-001-1010-A: (R)-4-((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer (20.31 mg, 0.03 mmol, yield: 7.63%), LCMS m/z: 667 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.80(s，1H)，7.57-7.55(m，2H)，7.41-7.38(m，2H)，7.35-7.30(m，4H)，7.27-7.23(m，1H)，5.75(d，J＝6.0Hz，1H)，5.06-5.01(m，1H)，4.52-4.46(m，2H)，3.89-3.85(m，1H)，3.43-3.38(m，2H)，3.23(t，J＝12.0Hz，2H)，3.15(s，9H)，3.04-3.02(m，2H)，2.71-2.58(m，2H)，1.98-1.90(m，2H)，1.71-1.68(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.80(s, 1H), 7.57-7.55(m, 2H), 7.41-7.38(m, 2H), 7.35-7.30(m, 4H), 7. 27-7.23 (m, 1H), 5.75 (d, J=6.0Hz, 1H), 5.06-5.01 (m, 1H), 4.52-4.46 (m, 2H) , 3.89-3.85(m, 1H), 3.43-3.38(m, 2H), 3.23(t, J=12.0Hz, 2H), 3.15(s, 9H), 3.04-3.02(m, 2H), 2.71-2.58(m, 2H), 1.98-1.90(m, 2H), 1.71-1.68(m, 2H).

19F NMR(377MHz，DMSO-d6)δ-73.407，-98.813. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.407, -98.813.

MDR-001-1010-Ade：(E)-4-(((E)-2-((Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体(17.19mg，0.03mmol，收率：6.63％)，LCMS m/z：649[M]+.MDR-001-1010-Ade: (E)-4-(((E)-2-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer (17.19 mg, 0.03 mmol, yield: 6.63%), LCMS m/z: 649 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.13(s，1H)，7.56-7.54(m，2H)，7.41-7.39(m，2H)，7.35-7.30(m，4H)，7.27-7.23(m，1H)，6.99-6.94(m，1H)，6.66-6.62(m，1H)，5.06-5.02(m，1H)，4.50(t，J＝12.0Hz，1H)，4.20-4.18(m，2H)，3.90-3.85(m，1H)，3.24(t，J＝12.0Hz，3H)，3.10(s，9H)，3.04-3.03(m，2H)，1.98-1.89(m，2H)，1.72-1.68(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ11.13(s, 1H), 7.56-7.54(m, 2H), 7.41-7.39(m, 2H), 7.35-7.30(m, 4H), 7. 27-7.23(m, 1H), 6.99-6.94(m, 1H), 6.66-6.62(m, 1H), 5.06-5.02(m, 1H), 4. 50(t, J＝12.0Hz, 1H), 4.20-4.18(m, 2H), 3.90-3.85(m, 1H), 3.24(t, J＝12.0H z, 3H), 3.10 (s, 9H), 3.04-3.03 (m, 2H), 1.98-1.89 (m, 2H), 1.72-1.68 (m, 2H).

19F NMR(377MHz，DMSO-d6)δ-73.396，-98.821. 19 F NMR (377MHz, DMSO-d 6 ) δ -73.396, -98.821.

5)、(R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体的合成
5) Synthesis of (R, E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer

在室温下，向溶有(R)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺或对映体(550mg，1.14mmol)的氯苯(10mL)溶液中，加入五氯化磷(948mg，4.56mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱色谱(PE/DCM＝1/4)纯化得到(R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体(400mg，0.79mmol，收率：70.17％)，LCMS m/z：501[M+H]+.Phosphorus pentachloride (948 mg, 4.56 mmol) was added to a solution of (R)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide or enantiomer (550 mg, 1.14 mmol) in chlorobenzene (10 mL) at room temperature, and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/4) to obtain (R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (400 mg, 0.79 mmol, yield: 70.17%), LCMS m/z: 501 [M+H] + .

6)、(R)-4-((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或其异构体(MDR-001-1010-B)和(E)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或其异构体(MDR-001-1010-Bde)的合成
6), (R)-4-((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-ammonium or its isomers (MDR-001-1010-B) and Synthesis of (E)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-ammonium or its isomers (MDR-001-1010-Bde)

在室温下，向溶有(R，E)-3-(4-氯苯基)-N-((3，3-二氟哌啶-1-基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或对映体((200mg，0.40mmol)的N，N二甲基甲酰胺(8mL)溶液中，加入(R)-4-胍基-2-羟基-N，N，N-三甲基-4-氧代丁烷-1-氨(196mg，0.80mmol)和三乙胺(121mg，1.20mmol)，25℃搅拌16小时。将混合反应液通过prep-HPLC(色谱柱：Waters 2767/Qda，色谱柱：Sunfire C18，21.2*250mm，10μm；流动相A：0.1％TFA/H2O，B：乙酸；流速：20mL/min；梯度：33％-33％；保留时间：7.8-10.6min，16min)纯化得到两个异构体：MDR-001-1010-B和MDR-001-1010-Bde：At room temperature, (R)-4-guanidino-2-hydroxy-N,N,N-trimethyl-4-oxobutane-1-amine (196 mg, 0.80 mmol) and triethylamine (121 mg, 1.20 mmol) were added to a solution of (R,E)-3-(4-chlorophenyl)-N-((3,3-difluoropiperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or enantiomer (200 mg, 0.40 mmol) in N,N-dimethylformamide (8 mL), and stirred at 25°C for 16 hours. The mixed reaction solution was purified by prep-HPLC (chromatographic column: Waters 2767/Qda, chromatographic column: Sunfire C18, 21.2*250 mm, 10 μm; mobile phase A: 0.1% TFA/H 2 O, B: acetic acid; flow rate: 20 mL/min; gradient: 33%-33%; retention time: 7.8-10.6 min, 16 min) was purified to obtain two isomers: MDR-001-1010-B and MDR-001-1010-Bde:

MDR-001-1010-B：(R)-4-((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-2-羟基-N，N，N-三甲基-4-氧代丁-1-铵或对映体(24.22mg，0.04mmol，收率：9.10％)，LCMSm/z：667[M]+.MDR-001-1010-B: (R)-4-((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-2-hydroxy-N,N,N-trimethyl-4-oxobutan-1-aminium or enantiomer (24.22 mg, 0.04 mmol, yield: 9.10%), LCMS m/z: 667 [M] + .

1H NMR(400MHz，DMSO-d6)δ10.78(s，1H)，7.57-7.55(m，2H)，7.41-7.38(m，2H)，7.35-7.29(m，4H)，7.27-7.23(m，1H)，5.76-5.75(m，1H)，5.05-5.01(m，1H)，4.52-4.46(m，2H)，3.89-3.85(m，1H)，3.40-3.38(m，2H)，3.23(t，J＝12.0Hz，2H)，3.15(s，9H)，3.05-3.03(m，2H)，2.68-2.62(m，2H)，1.99-1.91(m，2H)，1.69-1.66(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.78(s, 1H), 7.57-7.55(m, 2H), 7.41-7.38(m, 2H), 7.35-7.29(m, 4H), 7 .27-7.23(m, 1H), 5.76-5.75(m, 1H), 5.05-5.01(m, 1H), 4.52-4.46(m, 2H), 3.89-3.85(m, 1H), 3.40-3.38(m, 2H), 3.23(t, J=12.0Hz, 2H), 3.15(s, 9H), 3.05-3.03(m, 2H), 2.68-2.62(m, 2H), 1.99-1.91(m, 2H), 1.69-1.66(m, 2H).

19F NMR(377MHz，DMSO-d6)δ-98.821. 19 F NMR (377MHz, DMSO-d 6 ) δ-98.821.

MDR-001-1010-Bde：(E)-4-(((E)-2-((Z)-((R)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)(((3，3-二氟哌啶-1-基)磺酰基)亚氨基)甲基)胍)-N，N，N-三甲基-4-氧代丁-2-烯-1-铵或对映体(17.47mg，0.03mmol，收率：6.74％)，LCMS m/z：649[M]+.MDR-001-1010-Bde: (E)-4-(((E)-2-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((3,3-difluoropiperidin-1-yl)sulfonyl)imino)methyl)guanidine)-N,N,N-trimethyl-4-oxobut-2-en-1-aminium or enantiomer (17.47 mg, 0.03 mmol, yield: 6.74%), LCMS m/z: 649 [M] + .

1H NMR(400MHz，DMSO-d6)δ11.12(s，1H)，7.56-7.54(m，2H)，7.41-7.39(m，2H)，7.35-7.30(m，4H)，7.27-7.23(m，1H)，7.00-6.95(m，1H)，6.66-6.62(m，1H)，5.07-5.02(m，1H)，4.50(t，J＝12.0Hz，1H)，4.53-4.47(m，2H)，3.90-3.85(m，1H)，3.24(t，J＝12.0Hz，3H)，3.13(s，9H)，3.04-3.03(m，2H)，1.98-1.90(m，2H)，1.71-1.68(m，2H). 1 H NMR (400MHz, DMSO-d 6 )δ11.12(s, 1H), 7.56-7.54(m, 2H), 7.41-7.39(m, 2H), 7.35-7.30(m, 4H), 7. 27-7.23(m, 1H), 7.00-6.95(m, 1H), 6.66-6.62(m, 1H), 5.07-5.02(m, 1H), 4. 50(t, J＝12.0Hz, 1H), 4.53-4.47(m, 2H), 3.90-3.85(m, 1H), 3.24(t, J＝12.0H z, 3H), 3.13 (s, 9H), 3.04-3.03 (m, 2H), 1.98-1.90 (m, 2H), 1.71-1.68 (m, 2H).

19F NMR(377MHz，DMSO-d6)δ-98.821. 19 F NMR (377MHz, DMSO-d 6 ) δ-98.821.

实施例56、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺及其异构体(MRANK-111-05-1、MRANK-111-05-2、MRANK-111-05-3和MRANK-111-05-4)的合成：Example 56. Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorobenzene)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide and its isomers (MRANK-111-05-1, MRANK-111-05-2, MRANK-111-05-3 and MRANK-111-05-4):

1)、3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑的制备
1) Preparation of 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole

在室温下，向荣有1-(4-氯苯基)-2-苯基丁-2-烯-1-酮(3g，11.67mmol)的乙醇(50mL)溶液中，加入水合肼(875mg，17.51mmol)，加热80℃搅拌2小时。反应液用EtOAc(100mL)稀释，并用盐饱和食水(50mL×3)洗涤，干燥，过滤、减压浓缩得到3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(3.16g，粗品)，LCMS m/z：271[M+H]+.At room temperature, hydrazine hydrate (875 mg, 17.51 mmol) was added to a solution of 1-(4-chlorophenyl)-2-phenylbut-2-ene-1-one (3 g, 11.67 mmol) in ethanol (50 mL), and the mixture was heated at 80°C and stirred for 2 hours. The reaction solution was diluted with EtOAc (100 mL), washed with brine-saturated water (50 mL×3), dried, filtered, and concentrated under reduced pressure to obtain 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (3.16 g, crude product), LCMS m/z: 271 [M+H] + .

2)、3-(4-氯苯基)-N-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
2) Synthesis of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

室温下，向溶有3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(3.16g，11.67mmol)的甲苯(50mL)溶液中，加入((4-氯苯)磺酰基)氨基甲酸甲酯(2.62g，10.5mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩，并用异丙醇(10mL)打浆，过滤得到3-(4-氯苯基)-N-((4-氯苯)磺酰基)-5-甲基-4- 苯基-4，5-二氢-1H-吡唑-1-甲酰胺(3.5g，7.16mmol，收率：68.3％)，LCMS m/z：488[M+H]+.At room temperature, methyl ((4-chlorobenzene)sulfonyl)carbamate (2.62 g, 10.5 mmol) was added to a solution of 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (3.16 g, 11.67 mmol) in toluene (50 mL), and the mixture was heated at 110° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure, slurried with isopropanol (10 mL), and filtered to obtain 3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole. Phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (3.5 g, 7.16 mmol, yield: 68.3%), LCMS m/z: 488 [M+H] + .

3)、(E)-3-(4-氯苯基)-N-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯的合成
3) Synthesis of (E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride

在室温下，向溶有3-(4-氯苯基)-N-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(2.00g，4.09mmol)的氯苯(40mL)溶液中，加入PCl5(1.7g，8.181mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩。残余物通过硅胶柱色谱法(DCM：PE＝4：1)纯化得到(E)-3-(4-氯苯基)-N-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(1.2g，2.37mmol，收率：57.9％)，LCMS m/z：506[M+H]+.At room temperature, PCl 5 (1.7 g, 8.181 mmol) was added to a solution of 3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole- 1 -carboxamide (2.00 g, 4.09 mmol) in chlorobenzene (40 mL), and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:PE=4:1) to give (E)-3-(4-chlorophenyl)-N-((4-chlorobenzene)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (1.2 g, 2.37 mmol, yield: 57.9%), LCMS m/z: 506 [M+H] + .

4)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰脒酰胺的合成
4) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidamide

在0℃下，向(E)-3-(4-氯苯基)-N-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺酰氯(300mg，0.593mmol)和N-氨基甲酰甲磺酰胺(244mg，1.78mmol)的DMF(10mL)溶液中，加入t-BuOK(1M在THF中，3.56mL，3.56mmol)，室温搅拌1小时。将混合反应液通过反相柱色谱(柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：40mL/min；梯度：10分钟内5％B-95％B；检测器：214nm)。在60％B下，收集含有产物的级分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰脒酰胺(150mg，0.25mmol，收率：41.6％).LCMS m/z：607[M+H]+.To a solution of (E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide chloride (300 mg, 0.593 mmol) and N-carbamoylmethanesulfonamide (244 mg, 1.78 mmol) in DMF (10 mL) at 0° C., t-BuOK (1M in THF, 3.56 mL, 3.56 mmol) was added and stirred at room temperature for 1 hour. The mixed reaction solution was subjected to reverse phase column chromatography (column: spherical C18, 20-40 um, 80 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-95% B in 10 minutes; detector: 214 nm). At 60% B, fractions containing the product were collected and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorobenzene)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidamide (150 mg, 0.25 mmol, yield: 41.6%). LCMS m/z: 607 [M+H] + .

5)、(4S，5S，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或其异构体(MRANK-111-05-3和MRANK-111-05-4)的合成
5) Synthesis of (4S,5S,Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or its isomers (MRANK-111-05-3 and MRANK-111-05-4)

化合物(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酰脒酰胺(150mg，0.25mmol)通过SFC(条件：体系：Waters SFC 150；柱名：柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/l氨甲醇)，A：B＝50：50；检测波长：214nm；流速：70mL/min；柱温：RT背压：100bar，进样量：4.0mL；循环时间：12.7min)制备分离得到单体MRANK-111-05-3和混合物MRANK-111-105-M1(100mg，0.165mmol).Compound (Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidamide (150 mg, 0.25 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Column size: 250*30mm 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0mol/l ammonia methanol), A: B = 50:50; detection wavelength: 214nm; flow rate: 70mL/min; column temperature: RT back pressure: 100bar, injection volume: 4.0mL; cycle time: 12.7min) was prepared and separated to obtain monomer MRANK-111-05-3 and mixture MRANK-111-105-M1 (100mg, 0.165mmol).

MRANK-111-05-3：峰2，chiral-HPLC：2.585min；(4S，5S，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或对映体(9.20mg，0.015mmol，收率：6.0％)，LCMSm/z：607[M+H]+.MRANK-111-05-3: Peak 2, chiral-HPLC: 2.585 min; (4S, 5S, Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (9.20 mg, 0.015 mmol, yield: 6.0%), LCMS m/z: 607 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.38(s，1H)，7.80(d，J＝8.8Hz，2H)，7.59(d，J＝8.0Hz，2H)，7.53(d，J＝8.0Hz，2H)，7.39(d，J＝8.8Hz，2H)，7.26-7.16(m，5H)，5.12(d，J＝11.2Hz，1H)，4.77-4.75(m，1H)，2.67(s，3H)，0.84(d，J＝5.6Hz，3H).
 1 H NMR (400MHz, DMSO-d 6 ) δ9.38 (s, 1H), 7.80 (d, J = 8.8Hz, 2H), 7.59 (d, J = 8.0Hz, 2H), 7.53 (d, J = 8.0Hz, 2H), 7.39 (d, J = 8.8Hz, 2H), 7.26-7.16 (m, 5H), 5.12 (d, J=11.2Hz, 1H), 4.77-4.75 (m, 1H), 2.67 (s, 3H), 0.84 (d, J=5.6Hz, 3H).

混合物MRANK-111-05-M1(100mg，0.165mmol)通过SFC(条件：体系：Waters SFC 80；柱名：柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：MeOH(在MeOH中+0.1％7.0mol/l氨)，A：B＝65：35波长：214nm；流速：50mL/min；柱温：RT背压：100bar，进样量：2.0mL；循环时间：4.7min)制备得到单体MRANK-111-05-4和混合物MRANK-111-105-M2(80mg，0.132mmol).The mixture MRANK-111-05-M1 (100 mg, 0.165 mmol) was purified by SFC (conditions: system: Waters SFC 80; column name: Column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: MeOH (+0.1% 7.0mol/l ammonia in MeOH), A:B=65:35 wavelength: 214nm; flow rate: 50mL/min; column temperature: RT back pressure: 100bar, injection volume: 2.0mL; cycle time: 4.7min) to prepare monomer MRANK-111-05-4 and mixture MRANK-111-105-M2 (80mg, 0.132mmol).

MRANK-111-05-4：峰3，chiral HPLC：2.985min；(4R，5R，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或对映体(4.20mg，0.007mmol，收率：4.2％)，LCMS m/z：607[M+H]+.MRANK-111-05-4: Peak 3, chiral HPLC: 2.985 min; (4R, 5R, Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (4.20 mg, 0.007 mmol, yield: 4.2%), LCMS m/z: 607 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.35(s，1H)，7.81-7.78(m，2H)，7.62-7.55(m，4H)，7.41(d，J＝8.4Hz，2H)，7.24-7.12(m，5H)，5.18(d，J＝10.4Hz，1H)，4.83-4.75(m，1H)，2.68(s，3H)，0.79(d，J＝4.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.35 (s, 1H), 7.81-7.78 (m, 2H), 7.62-7.55 (m, 4H), 7.41 (d, J=8.4Hz, 2H), 7.24-7.12 (m, 5H), 5.18 (d, J = 10.4Hz, 1H), 4.83-4.75 (m, 1H), 2.68 (s, 3H), 0.79 (d, J = 4.4Hz, 3H).

6)、(4S，5R，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或其异构体(MRANK-111-05-1和MRANK-111-05-2)的合成
6) Synthesis of (4S, 5R, Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or its isomers (MRANK-111-05-1 and MRANK-111-05-2)

混合物MRANK-111-05-M2(80mg，0.132mmol)通过SFC(条件：体系：Waters SFC 150；柱名：柱尺寸：250*25mm 10μm；流动相A；超临界CO2；流动相B：IPA(+0.2％DEA)，A：B＝60：40；检测波长：214nm；流速：120mL/min柱温：RT；柱压：100bar，进样量：6.0mL；循环时间：16.0min)制备分离得到单体MRANK-111-05-1和单体MRAN K-111-05-2.The mixture MRANK-111-05-M2 (80 mg, 0.132 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Column size: 250*25mm 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.2% DEA), A: B = 60:40; detection wavelength: 214nm; flow rate: 120mL/min column temperature: RT; column pressure: 100bar, injection volume: 6.0mL; cycle time: 16.0min) prepared and separated to obtain monomer MRAN K-111-05-1 and monomer MRAN K-111-05-2.

MRANK-111-05-1：峰1，chiral HPLC：2.287min；(4S，5R，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或对映体(28.13mg，0.046mmol，收率35.2％)，LCMS m/z：607[M+H]+.MRANK-111-05-1: Peak 1, chiral HPLC: 2.287 min; (4S, 5R, Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (28.13 mg, 0.046 mmol, yield 35.2%), LCMS m/z: 607 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ9.41(s，1H)，7.84-7.81(m，2H)，7.71-7.70(m，2H)，7.58(d，J＝8.4Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.31-7.23(m，5H)，4.70(s，1H)，4.28-4.26(m，1H)，2.58(s，3H)，1.37(d，J＝5.2Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.41 (s, 1H), 7.84-7.81 (m, 2H), 7.71-7.70 (m, 2H), 7.58 (d, J=8.4Hz, 2H), 7.45 (d, J=8.8Hz , 2H), 7.31-7.23(m, 5H), 4.70(s, 1H), 4.28-4.26(m, 1H), 2.58(s, 3H), 1.37(d, J=5.2Hz, 3H).

MRANK-111-05-2：峰4，chiral HPLC：4.367min；(4R，5S，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-3-(4-氯苯基)-N′-((4-氯苯)磺酰基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或对映体(31.39mg，0.052mmol，收率：39％)，LCMSm/z：607[M+H]+.MRANK-111-05-2: Peak 4, chiral HPLC: 4.367 min; (4R, 5S, Z)-N-((E)-amino(methylsulfonamido)methylene)-3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (31.39 mg, 0.052 mmol, yield: 39%), LCMS m/z: 607 [M+H] + .

1H NMR(400MHz，DMSO-d6)7.83-7.81(m，2H)，7.67-7.65(m，2H)，7.55(d，J＝8.4Hz，2H)，7.42(d，J＝8.4Hz，2H)，7.33-7.21(m，5H)，4.61(s，1H)，4.27-4.25(m，1H)，2.61(s，3H)，1.38(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )7.83-7.81(m, 2H), 7.67-7.65(m, 2H), 7.55(d, J＝8.4Hz, 2H), 7.42(d, J＝8.4Hz, 2H), 7 .33-7.21(m, 5H), 4.61(s, 1H), 4.27-4.25(m, 1H), 2.61(s, 3H), 1.38(d, J=6.4Hz, 3H).

实施例57、(S，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或其异构体(MRANK-111-08-1和MRANK-111-08-2)的合成：Example 57. Synthesis of (S,Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or its isomers (MRANK-111-08-1 and MRANK-111-08-2):

1)、1-(4-溴苯基)-2-苯基乙烷-1-酮的合成
1) Synthesis of 1-(4-bromophenyl)-2-phenylethane-1-one

在0℃下，向溶有4-溴苯甲酸甲酯(4.00g，18.60mmol)和2-苯基乙酸(2.53g，18.6mmol)的DMF(40mL)溶液中，加入LiHMDS(1M的THF中，55.80mmol，55.8mL)，室温搅拌1小时。混合反应液用饱和氯化铵水溶液(10mL)淬灭，并用(100mL)萃取。合并的有机相用饱和食盐水(20mL×5)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余无通过硅胶柱色谱法(PE/EA＝20/1)纯化得到1-(4-溴苯基)-2-苯基乙烷-1-酮(3.7g，13.45mmol，收率：72.54％)，LCMS m/z：275[M+H]+。 At 0°C, LiHMDS (1M in THF, 55.80 mmol, 55.8 mL) was added to a DMF (40 mL) solution of methyl 4-bromobenzoate (4.00 g, 18.60 mmol) and 2-phenylacetic acid (2.53 g, 18.6 mmol) and stirred at room temperature for 1 hour. The mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with (100 mL). The combined organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=20/1) to give 1-(4-bromophenyl)-2-phenylethane-1-one (3.7 g, 13.45 mmol, yield: 72.54%), LCMS m/z: 275[M+H] + .

2)、1-(4-溴苯基)-3-羟基-2-苯基丙-1-酮的合成
2) Synthesis of 1-(4-bromophenyl)-3-hydroxy-2-phenylpropan-1-one

向溶有1-(4-溴苯基)-2-苯基乙烷-1-酮(3.7g，13.45mmol)的THF(40mL)溶液中，加入多聚甲醛(12.11g，134.50mmol)和K2CO3(5.57g，40.35mmol)，加热40℃搅拌2小时，将混合反应液过滤，减压浓缩得到1-(4-溴苯基)-3-羟基-2-苯基丙-1-酮(4.1g，13.44mmol，收率，98.08％)，LCMS m/z：305[M+H]+。To a solution of 1-(4-bromophenyl)-2-phenylethane-1-one (3.7 g, 13.45 mmol) in THF (40 mL) were added paraformaldehyde (12.11 g, 134.50 mmol) and K 2 CO 3 (5.57 g, 40.35 mmol), heated at 40°C with stirring for 2 hours, the mixed reaction liquid was filtered and concentrated under reduced pressure to give 1-(4-bromophenyl)-3-hydroxy-2-phenylpropan-1-one (4.1 g, 13.44 mmol, yield, 98.08%), LCMS m/z: 305 [M+H] + .

3)、1-(4-溴苯基)-2-苯基丙-2-烯-1-酮的合成
3) Synthesis of 1-(4-bromophenyl)-2-phenylprop-2-en-1-one

在室温下，向溶有1-(4-溴苯基)-3-羟基-2-苯基丙-1-酮(4.1g，13.44mmol)的甲苯(40mmol)溶液中，加入一水合对甲苯磺酸(2.55g，13.4mmol)，加热100℃搅拌2小时。将混合反应液过滤，减压浓缩。残余物通过硅胶柱色谱法(PE/EA＝10/1)纯化得到1-(4-溴苯基)-2-苯基丙-2-烯-1-酮(2.6g，9.05mmol，收率：67.53％)，LCMS/z：289[M+H+2]+。At room temperature, p-toluenesulfonic acid monohydrate (2.55 g, 13.4 mmol) was added to a solution of 1-(4-bromophenyl)-3-hydroxy-2-phenylpropan-1-one (4.1 g, 13.44 mmol) in toluene (40 mmol), and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction liquid was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=10/1) to give 1-(4-bromophenyl)-2-phenylprop-2-en-1-one (2.6 g, 9.05 mmol, yield: 67.53%), LCMS/z: 289 [M+H+2] + .

4)、3-(4-溴苯基)-4-苯基-4，5-二氢-1H-吡唑的合成
4) Synthesis of 3-(4-bromophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole

在室温下，向溶有1-(4-溴苯基)-2-苯基丙-2-烯-1-酮(2.6g，9.06mmol)的EtOH(30mmol)溶液中，加入H2NNH2·H2O(960mg，18.12mmol)，加热80℃搅拌2小时。将混合反应液过滤，并用乙醇洗涤滤饼，收集滤饼真空干燥得到3-(4-溴苯基)-4-苯基-4，5-二氢-1H-吡唑(1.7g，5.64mmol，收率：62.96％)，LCMS m/z：303[M+H+2]+。At room temperature, H2NNH2 · H2O ( 960 mg, 18.12 mmol) was added to a solution of 1-(4-bromophenyl)-2-phenylprop-2-en-1-one (2.6 g, 9.06 mmol) in EtOH (30 mmol), and the mixture was heated at 80°C with stirring for 2 hours. The mixed reaction liquid was filtered, and the filter cake was washed with ethanol, and the filter cake was collected and dried in vacuo to give 3-(4-bromophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (1.7 g, 5.64 mmol, yield: 62.96%), LCMS m/z: 303 [M+H+2] + .

5)、4-(4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈的合成
5) Synthesis of 4-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile

在室温下，向溶有3-(4-溴苯基)-4-苯基-4，5-二氢-1H-吡唑(1.4g，4.65mmol)的DMF(20mL)溶液中，加入Zn(CN)2(817mg，6.98mmol)和Pd(PPh3)4(543mg，0.47mmol)，加热氮气保护下，加热100℃搅拌16小时。将混合反应液过滤，滤液用EA(50mL)稀释，并用饱和食盐水(10mL×3)洗涤，无水Na2SO4干燥，过滤，减压浓缩。残余我通过硅胶柱色谱法(PE/EA＝3/1)纯化得到4-(4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈(1.13g，4.57mmol，收率：99.12％)，LCMS m/z：248[M+H]+。 At room temperature, Zn(CN) 2 (817 mg, 6.98 mmol) and Pd(PPh 3 ) 4 (543 mg, 0.47 mmol) were added to a DMF (20 mL) solution of 3-(4-bromophenyl)-4-phenyl- 4,5- dihydro-1H-pyrazole (1.4 g, 4.65 mmol), and the mixture was heated at 100°C with stirring for 16 hours under nitrogen protection. The mixed reaction liquid was filtered, and the filtrate was diluted with EA (50 mL), washed with saturated brine (10 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give 4-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (1.13 g, 4.57 mmol, yield: 99.12%), LCMS m/z: 248 [M+H] + .

6)、N-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
6) Synthesis of N-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

在室温下，向溶有4-(4-苯基-4，5-二氢-1H-吡唑-3-基)苄腈(600mg，2.43mmol)的甲苯(20mL)溶液中，加入((4-氯苯基)磺酰基)氨基甲酸甲酯(608mg，2.43mmol)，加热110℃搅拌2小时。将混合反应液浓缩并用EA(40mL)稀释，饱和食盐水(10mL)洗涤，无水Na2SO4干燥，过滤、减压浓缩。残余物通过硅胶柱色谱法(PE/EA＝3/1)纯化得到N-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(560mg，1.20mmol，收率：50.00％)，LCMS m/z：465[M+H]+。To a solution of 4-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzonitrile (600 mg, 2.43 mmol) in toluene (20 mL) was added methyl ((4-chlorophenyl)sulfonyl)carbamate (608 mg, 2.43 mmol) at room temperature, and the mixture was heated at 110°C and stirred for 2 hours. The mixed reaction solution was concentrated and diluted with EA (40 mL), washed with saturated brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give N-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (560 mg, 1.20 mmol, yield: 50.00%), LCMS m/z: 465 [M+H] + .

7)、(Z)-1-((((4-氯苯基)磺酰基)亚氨基)(3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
7) Synthesis of (Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-4-(dimethylamino)pyridin-1-ium

在室温下，向溶有N-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(560mg，1.20mmol)的DCM(20mL)溶液中，加入DMAP(732mg，6.00mmol)和POCl3(551mg，3.60mmol)，加热50℃搅拌2小时。将混合反应液减压浓缩并用反相柱色谱(条件如下：柱：球形C18，20-40um，330g；流动相A：水；流动相B：乙腈；流速：100mL/min；梯度：5％B-60％B，12分钟；检测器：214nm)纯化，在55％B下，收集产物的物的级分，减压浓缩得到(Z)-1-((((4-氯苯基)磺酰基)亚氨基)(3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)-4-(二甲基氨基)吡啶-1-鎓(700mg，1.22mmol，收率：＞99％)，LCMS m/z：569[M]+。To a solution of N-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (560 mg, 1.20 mmol) in DCM (20 mL) were added DMAP (732 mg, 6.00 mmol) and POCl 3 (551 mg, 3.60 mmol) at room temperature, and the mixture was heated at 50° C. with stirring for 2 hours. The mixed reaction liquid was concentrated under reduced pressure and purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40um, 330g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 100mL/min; gradient: 5%B-60%B, 12 minutes; detector: 214nm). At 55%B, the fractions of the product were collected and concentrated under reduced pressure to give (Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-4-(dimethylamino)pyridin-1-ium (700mg, 1.22mmol, yield: >99%), LCMS m/z: 569[M] + .

8)、(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺的合成
8) Synthesis of (Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide

在0℃下，向溶有(Z)-1-((((4-氯苯基)磺酰基)亚氨基)(3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)甲基)-4-(二甲基氨基)吡啶-1-鎓(200mg，0.35mmol)的DMF(10mL)溶液中，的加入N-氨基甲酰甲磺酰胺2，2，2-三氟乙酸盐(165mg，0.70mmol)和t-BuOK(1M的THF溶液，1.4mL， 1.1mmol)，0℃搅拌10分钟。混合反应液用EA(30mL)稀释。有机相用饱和食盐水洗涤。(5mL)，无水Na2SO4干燥，过滤、减压浓缩。残余物通过反相柱色谱(条件如下：柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：10分钟内5％B-60％B；检测器：214nm)纯化，在59％B下，收集含有产物的级分，减压浓缩得到(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺(70mg，0.11mmol，收率：34.31％)，LCMS m/z：584[M+H]+。To a solution of (Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-4-(dimethylamino)pyridin-1-ium (200 mg, 0.35 mmol) in DMF (10 mL) at 0°C were added N-carbamoylmethanesulfonamide 2,2,2-trifluoroacetate (165 mg, 0.70 mmol) and t-BuOK (1 M in THF, 1.4 mL, 1.1 mmol), stirred at 0°C for 10 minutes. The mixed reaction solution was diluted with EA (30 mL). The organic phase was washed with saturated brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40 um, 80 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-60% B in 10 minutes; detector: 214 nm), and the fractions containing the product were collected at 59% B and concentrated under reduced pressure to give (Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide (70 mg, 0.11 mmol, yield: 34.31%), LCMS m/z: 584 [M+H] + .

9)、(S，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或其异构体(MRANK-111-08-1和MRANK-111-08-2)的制备：
9) Preparation of (S, Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or its isomers (MRANK-111-08-1 and MRANK-111-08-2):

将化合物(Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酰亚胺(70mg，0.11mmol)通过SFC纯化(条件：体系：Waters SFC 150；柱名：柱尺寸：250*40mm 10μm；流动相A；超临界CO2；流动相B：IPA(+0.1％7.0mol/l氨在MeOH中)，A：B＝45：55；波长：214nm流量：140mL/min；柱温：RT背压：100bar，进样量：8.0mL；循环时间：20.0min)，纯化得到两个异构体：MRANK-111-08-1和MRANK-111-08-2：Compound (Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximide (70 mg, 0.11 mmol) was purified by SFC (conditions: system: Waters SFC 150; column name: Column size: 250*40mm 10μm; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0mol/l ammonia in MeOH), A:B=45:55; wavelength: 214nm flow rate: 140mL/min; column temperature: RT back pressure: 100bar, injection volume: 8.0mL; cycle time: 20.0min), purification to obtain two isomers: MRANK-111-08-1 and MRANK-111-08-2:

MRANK-111-08-1：峰1：ChiralHPLC：1.601min；(S，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或对映体(18.54mg，0.03mmol，收率：26.48％)，LCMS m/z：584[M+H]+.MRANK-111-08-1: Peak 1: ChiralHPLC: 1.601 min; (S, Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (18.54 mg, 0.03 mmol, yield: 26.48%), LCMS m/z: 584 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ7.87-7.77(m，6H)，7.59-7.57(m，2H)，7.35-7.28(m，4H)，7.25-7.22(m，1H)，5.09-5.08(m，1H)，4.52(t，J＝11.6Hz，3H)，3.88-3.84(m，1H)，2.76(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.87-7.77(m, 6H), 7.59-7.57(m, 2H), 7.35-7.28(m, 4H), 7.25-7.22(m, 1H ), 5.09-5.08 (m, 1H), 4.52 (t, J=11.6Hz, 3H), 3.88-3.84 (m, 1H), 2.76 (s, 3H).

MRANK-111-08-2：峰2：ChiralHPLC：3.917min；(R，Z)-N-((E)-氨基(甲基磺酰胺基)亚甲基)-N′-((4-氯苯基)磺酰基)-3-(4-氰基苯基)-4-苯基-4，5-二氢-1H-吡唑-1-羧酸脒酰胺或对映体(12.22mg，0.02mmol，收率：17.45％)，LCMS m/z：584[M+H]+.MRANK-111-08-2: Peak 2: ChiralHPLC: 3.917 min; (R, Z)-N-((E)-amino(methylsulfonamido)methylene)-N′-((4-chlorophenyl)sulfonyl)-3-(4-cyanophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (12.22 mg, 0.02 mmol, yield: 17.45%), LCMS m/z: 584 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ7.87-7.79(m，6H)，7.59-7.56(m，2H)，7.35-7.28(m，4H)，7.26-7.22(m，1H)，5.09-5.07(m，1H)，4.52(t，J＝11.6Hz，3H)，3.88-3.84(m，1H)，2.74(s，3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.87-7.79(m, 6H), 7.59-7.56(m, 2H), 7.35-7.28(m, 4H), 7.26-7.22(m, 1H ), 5.09-5.07 (m, 1H), 4.52 (t, J=11.6Hz, 3H), 3.88-3.84 (m, 1H), 2.74 (s, 3H).

实施例58、N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-氨基磺酰基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MRANK-111-09-1、MRANK-111-09-2、MRANK-111-09-3和MRANK-111-09-4)的合成：Example 58. Synthesis of N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -aminosulfonyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (MRANK-111-09-1, MRANK-111-09-2, MRANK-111-09-3 and MRANK-111-09-4):

1)、3-(4-氯苯基)-5-甲基-N-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺的合成
1) Synthesis of 3-(4-chlorophenyl)-5-methyl-N-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide

室温下，向溶有((4-(五氟-λ6-硫基)苯基)磺酰基)氨基甲酸甲酸(500mg，1.47mmol)的甲苯(20mL)溶液中，加入3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑(398mg，1.47mmol)，加热110℃搅拌2小时。将混合反应液减压浓缩。残余物用乙酸乙酯(30mL)稀释，并用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。产业通过硅胶柱层析(PE/EA＝3/1)纯化得到3-(4-氯苯基)-5-甲基-N-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(490mg，0.77mmol，收率：57.64％)，LCMS m/z：580[M+H]+.At room temperature, 3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazole (398 mg, 1.47 mmol) was added to a solution of ((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)carbamic acid (500 mg, 1.47 mmol) in toluene (20 mL), and the mixture was heated at 110°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE/EA=3/1) to give 3-(4-chlorophenyl)-5-methyl-N-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (490 mg, 0.77 mmol, yield: 57.64%), LCMS m/z: 580 [M+H] + .

2)、(Z)-1-((3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((((4-(五氟-λ6-硫基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓的合成
2) Synthesis of (Z)-1-((3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((((4-(pentafluoro-λ 6 -sulfenyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium

室温下，向溶有3-(4-氯苯基)-5-甲基-N-((4-(五氟-λ6-硫烷基)苯基)磺酰基)-4-苯基-4，5-二氢-1H-吡唑-1-甲酰胺(490mg，0.84mmol)的二氯甲烷(20mL)溶液中，加入4-二甲氨基吡啶(512mg，4.20mmol)和三氯氧磷(386mg，2.52mmol)，室温搅拌2小时。将混合反应液减压浓缩并通过反相柱快速柱色谱(条件如下：柱：球形C18，20-40um，330g；流动相A：水；流动相B：乙腈；流速：100mL/min；梯度：12分钟内5％B-60％B；探测器：214nm)纯化。在55％B下，收集含有产物的馏分，减压浓缩得到(Z)-1-((3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((((4-(五氟-λ6-硫基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(600mg，0.87mmol，收率：＞99％)，LCMS m/z：684[M]+.At room temperature, 4-dimethylaminopyridine (512 mg, 4.20 mmol) and phosphorus oxychloride (386 mg, 2.52 mmol) were added to a solution of 3-(4-chlorophenyl)-5-methyl-N-((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (490 mg, 0.84 mmol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by reverse phase flash column chromatography (conditions are as follows: column: spherical C18, 20-40 um, 330 g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 5% B-60% B in 12 minutes; detector: 214 nm). At 55% B, fractions containing the product were collected and concentrated under reduced pressure to give (Z)-1-((3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)imino)methyl)-4-(dimethylamino)pyridin-1-ium (600 mg, 0.87 mmol, yield: >99%), LCMS m/z: 684 [M] + .

3)、N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((((4-(五氟-λ6-硫基)苯基)磺酰基)亚氨基)甲基)氨基甲酰胺基)乙酰胺的合成
3) Synthesis of N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((((4-(pentafluoro-λ 6 -sulfenyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide

室温下，向溶有(Z)-1-((3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((((4-(五氟 -λ6-硫基)苯基)磺酰基)亚氨基)甲基)-4-(二甲基氨基)吡啶-1-鎓(600mg，0.88mmol)的N，N-二甲基甲酰胺(20mL)溶液中，加入N-氨基甲酰胺基乙酰胺(444mg，4.40mmol)和三乙胺(444mg，4.40mmol)，室温搅拌2小时。将混合反应液用乙酸乙酯(40mL)稀释，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(条件如下：柱：球形C18，20-40um，330g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：100mL/min；梯度：10分钟内5％B-75％B；探测器：214nm)纯化，在70％B下，收集含有产物的馏分，减压浓缩的得到N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((((4-(五氟-λ6-硫基)苯基)磺酰基)亚氨基)甲基)氨基甲酰胺基)乙酰胺(290mg，0.43mmol，收率：50.00％)，LCMS m/z：663[M+H]+.At room temperature, a solution of (Z)-1-((3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((((4-(pentafluorophenyl)- To a solution of 4-( 6 -thio)-1-(4-( ... The residue was purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40 um, 330 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 100 mL/min; gradient: 5% B-75% B in 10 minutes; detector: 214 nm). At 70% B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (290 mg, 0.43 mmol, yield: 50.00%), LCMS m/z: 663 [M+H] + .

4)、N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-氨基磺酰基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺及其异构体(MRANK-111-09-1、MRANK-111-09-2、MRANK-111-09-3和MRANK-111-09-4)的合成
4) Synthesis of N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -aminosulfonyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide and its isomers (MRANK-111-09-1, MRANK-111-09-2, MRANK-111-09-3 and MRANK-111-09-4)

将化合物N-((E)-N′-((Z)-(3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)((((4-(五氟-λ6-硫基)苯基)磺酰基)亚氨基)甲基)氨基甲酰胺基)乙酰胺(150mg，0.22mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝65：35；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：2.0mL；循环时间：8.1min)纯化得到单一异构体：MRANK-111-09-1和混合物MRANK-111-09-M(60mg，0.09mmol)。Compound N-((E)-N′-((Z)-(3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((((4-(pentafluoro-λ 6 -sulfanyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (150 mg, 0.22 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*30mm 10μm; mobile phase A; supercritical CO2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=65:35; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 2.0mL; cycle time: 8.1min) was purified to obtain a single isomer: MRANK-111-09-1 and a mixture MRANK-111-09-M (60mg, 0.09mmol).

MRANK-111-09-1：峰1Chiral HPLC：0.753min；N-((E)-N′-(Z)-((4S，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-氨基磺酰基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(37.26mg，0.05mmol，收率：24.84％)，LCMS m/z：663[M+H]+ MRANK-111-09-1: Peak 1 Chiral HPLC: 0.753 min; N-((E)-N′-(Z)-((4S,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ6-aminosulfonyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (37.26 mg, 0.05 mmol, yield: 24.84%), LCMS m/z: 663 [M+H] +

1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，8.06-7.95(m，5H)，7.56-7.54(m，2H)，7.42-7.40(m，2H)，7.32-7.22(m，6H)，4.64(s，1H)，4.35-4.32(m，1H)，2.09(s，3H)，1.49-1.47(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.63(s, 1H), 8.06-7.95(m, 5H), 7.56-7.54(m, 2H), 7.42-7.40(m, 2H), 7.32 -7.22(m, 6H), 4.64(s, 1H), 4.35-4.32(m, 1H), 2.09(s, 3H), 1.49-1.47(m, 3H).

19F NMR(377MHz，DMSO-d6)δ87.010，86.616，86.207，85.809，85.419，64.068，63.666. 19 F NMR (377MHz, DMSO-d 6 ) δ 87.010, 86.616, 86.207, 85.809, 85.419, 64.068, 63.666.

将化合物MRANK-111-09-M(60mg，0.09mmol)通过超临界流体色谱(色谱条件：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A；超临界CO2；流动相B：异丙醇(+0.1％7.0mol/l氨甲醇)，A：B＝75：25；波长：214nm；流速：120mL/min；柱温：室温；柱压：100bar，进样量：3.0mL；循环时间：17.0min)纯化得到三个单一异构体：MRANK-111-09-2，MRANK-111-09-3和MRANK-111-09-4。Compound MRANK-111-09-M (60 mg, 0.09 mmol) was purified by supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column name: Chromatographic column size: 250*30mm 10μm; mobile phase A; supercritical CO2 ; mobile phase B: isopropanol (+0.1% 7.0mol/l ammonia methanol), A:B=75:25; wavelength: 214nm; flow rate: 120mL/min; column temperature: room temperature; column pressure: 100bar, injection volume: 3.0mL; cycle time: 17.0min) was purified to obtain three single isomers: MRANK-111-09-2, MRANK-111-09-3 and MRANK-111-09-4.

MRANK-111-09-2：峰3：chiral-HPLC：1.628min；N-((E)-N′-(Z)-((4R，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-氨基磺酰基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(29.72mg，0.04mmol，收率：49.53％)，LCMS m/z：663[M+H]+.MRANK-111-09-2: Peak 3: chiral-HPLC: 1.628 min; N-((E)-N′-(Z)-((4R,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -aminosulfonyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (29.72 mg, 0.04 mmol, yield: 49.53%), LCMS m/z: 663 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.63(s，1H)，8.15-7.82(m，5H)，7.56-7.40(m，4H)，7.32-7.22(m，6H)，4.64(s，1H)，4.35-4.32(m，1H)，2.09(s，3H)，1.49-1.47(m，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.63 (s, 1H), 8.15-7.82 (m, 5H), 7.56-7.40 (m, 4H), 7.32-7.22 (m, 6H), 4.64 (s, 1H), 4.35-4.32 (m, 1H), 2.09 (s, 3H), 1.49-1.47 (m, 3H).

19F NMR(377MHz，DMSO-d6)δ87.014，86.605，86.203，85.802，85.400，64.068，63.666. 19 F NMR (377MHz, DMSO-d 6 ) δ 87.014, 86.605, 86.203, 85.802, 85.400, 64.068, 63.666.

MRANK-111-09-3：峰2：chiral-HPLC：1.410min；N-((E)-N′-(Z)-((4S，5S)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-氨基磺酰基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(9.78mg，0.01mmol，收率：16.30％)，LCMS m/z：663[M+H]+.MRANK-111-09-3: Peak 2: chiral-HPLC: 1.410 min; N-((E)-N′-(Z)-((4S,5S)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -aminosulfonyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (9.78 mg, 0.01 mmol, yield: 16.30%), LCMS m/z: 663 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.52(s，1H)，8.02-7.97(m，4H)，7.41-7.35(m，4H)，7.32-7.23(m，3H)，7.09(s，2H)，5.19-5.16(m，1H)，4.82-4.77(m，1H)，2.07(s，3H)，0.99(d，J＝6.8Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.52(s, 1H), 8.02-7.97(m, 4H), 7.41-7.35(m, 4H), 7.32-7.23(m, 3H), 7.09( s, 2H), 5.19-5.16 (m, 1H), 4.82-4.77 (m, 1H), 2.07 (s, 3H), 0.99 (d, J=6.8Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ87.021，86.612，86.211，85.806，85.408，64.068，63.666. 19 F NMR (377MHz, DMSO-d 6 ) δ 87.021, 86.612, 86.211, 85.806, 85.408, 64.068, 63.666.

MRANK-111-09-4：峰4：Chiral-HPLC：1.871min；N-((E)-N′-(Z)-((4R，5R)-3-(4-氯苯基)-5-甲基-4-苯基-4，5-二氢-1H-吡唑-1-基)(((4-(五氟-λ6-氨基磺酰基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或对映体(9.87mg，0.01mmol，收率：16.45％)，LCMS：m/z：663.2[M+H]+.MRANK-111-09-4: Peak 4: Chiral-HPLC: 1.871 min; N-((E)-N′-(Z)-((4R,5R)-3-(4-chlorophenyl)-5-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(pentafluoro-λ 6 -aminosulfonyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or enantiomer (9.87 mg, 0.01 mmol, yield: 16.45%), LCMS: m/z: 663.2 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ10.51(s，1H)，8.02-7.97(m，4H)，7.41-7.35(m，4H)，7.32-7.23(m，3H)，7.09(s，2H)，5.19-5.16(m，1H)，4.82-4.77(m，1H)，2.07(s，3H)，0.99(d，J＝6.4Hz，3H). 1 H NMR (400MHz, DMSO-d 6 )δ10.51(s, 1H), 8.02-7.97(m, 4H), 7.41-7.35(m, 4H), 7.32-7.23(m, 3H), 7.09( s, 2H), 5.19-5.16 (m, 1H), 4.82-4.77 (m, 1H), 2.07 (s, 3H), 0.99 (d, J=6.4Hz, 3H).

19F NMR(377MHz，DMSO-d6)δ87.017，86.612，86.203，85.802，85.393，64.068，63.666. 19 F NMR (377MHz, DMSO-d 6 ) δ 87.017, 86.612, 86.203, 85.802, 85.393, 64.068, 63.666.

实施例59、N-((E)-N′-(Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-2，2，2-三氟乙酰胺或对映体(MRANK-111-14-1)的合成：Example 59. Synthesis of N-((E)-N′-(Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-2,2,2-trifluoroacetamide or enantiomer (MRANK-111-14-1):

1)、N-((E)-N′-(Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体的合成
1) Synthesis of N-((E)-N′-(Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide or isomers

在室温下，向溶有(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(150mg，0.29mmol)的DMF(10mL)溶液中，加入N-氨基甲酰乙酰胺(146mg，1.45mmol)和TEA(146mg，1.45mmol)，室温搅拌1小时。将混合反应液用EA(20mL)稀释。有机相用饱和食盐水(5mL)洗涤，无水Na2SO4干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(条件如下(柱：球形C18，20-40um，80g；流动相A：水(0.03％TFA)；流动相B：乙腈；流速：50mL/min；梯度：10分钟内5％B-75％B；检测器：214nm)纯化，在70％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺(150mg，0.25mmol，收率：89.28％)，LCMS m/z：591[M+H]+。To a solution of (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (150 mg, 0.29 mmol) in DMF (10 mL) was added N-carbamoylacetamide (146 mg, 1.45 mmol) and TEA (146 mg, 1.45 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixed reaction liquid was diluted with EA (20 mL). The organic phase was washed with saturated brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions as follows (column: spherical C18, 20-40 um, 80 g; mobile phase A: water (0.03% TFA); mobile phase B: acetonitrile; flow rate: 50 mL/min; gradient: 5% B-75% B in 10 minutes; detector: 214 nm), and the fractions containing the product were collected at 70% B and concentrated under reduced pressure to give N-((E)-N′-(Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)acetamide (150 mg, 0.25 mmol, yield: 89.28%), LCMS m/z: 591 [M+H] + .

2)、(S，Z)-3-(4-氯苯基)-N-(二氨基乙烯)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体的合成
2) Synthesis of (S, Z)-3-(4-chlorophenyl)-N-(diaminoethylene)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomers

在室温下，向溶有N-((E)-N′-(Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)乙酰胺或异构体(150mg，0.25mmol)的甲醇(20mL)和H2O(5mL)溶液中，加入K2CO3(57mg，0.63mmol)，室温搅拌1小时。将混合反应液过滤，并用甲醇洗涤，收集滤饼真空干燥得到(S，Z)-3-(4-氯苯基)-N-(二氨基乙烯)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(90mg，0.16mmol，收率：64.74％)，LCMS m/z：549[M+H]+。To a solution of N-((E)-N′-(Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoimido)acetamide or isomer (150 mg, 0.25 mmol) in methanol (20 mL) and H2O (5 mL) was added K2CO3 ( 57 mg, 0.63 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixed reaction liquid was filtered and washed with methanol. The filter cake was collected and dried in vacuo to give (S,Z)-3-(4-chlorophenyl)-N-(diaminoethylene)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (90 mg, 0.16 mmol, yield: 64.74%), LCMS m/z: 549 [M+H] + .

3)、N-((E)-N′-(Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-2，2，2-三氟乙酰胺或对映体的合成
3) Synthesis of N-((E)-N′-(Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-2,2,2-trifluoroacetamide or its enantiomer

在室温下，向(S，Z)-3-(4-氯苯基)-N-(二氨基乙烯)-4-苯基-N′-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰亚胺或异构体(90mg，0.16mmol)的DMF(5mL)溶液中，加入TEA(81mg，0.80mmol)和TFAA(50mg，0.24mmol)，室温搅拌2小时。将用EA(20mL)稀释，并用冰水(0.03％TFA)洗涤有机层，直到pH为5-6，再用无水硫酸钠干燥，过滤、减压浓缩。残余物通过反相快速柱色谱(条件如下：柱：球形C18，20-40um，80g；流动相A：水；流动相B：乙腈；流速：50mL/min；梯度：5％B-80％B，12分钟；检测器：214nm)。在75％B下，收集含有产物的馏分，减压浓缩得到N-((E)-N′-(Z)-((S)-3-(4-氯苯基)-4-苯基-4，5-二氢-1H-吡唑-1-基)((4-(三氟甲基)苯基)磺酰基)亚氨基)甲基)氨基甲酰亚胺基)-2，2，2-三氟乙酰胺或对映体(29.97mg，0.04mmol，收率：28.54％)。LCMS m/z：645[M+H]+。To a solution of (S,Z)-3-(4-chlorophenyl)-N-(diaminoethylene)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide or isomer (90 mg, 0.16 mmol) in DMF (5 mL) at room temperature, TEA (81 mg, 0.80 mmol) and TFAA (50 mg, 0.24 mmol) were added and stirred at room temperature for 2 hours. The mixture was diluted with EA (20 mL) and the organic layer was washed with ice water (0.03% TFA) until the pH was 5-6, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography (conditions as follows: column: spherical C18, 20-40um, 80g; mobile phase A: water; mobile phase B: acetonitrile; flow rate: 50mL/min; gradient: 5%B-80%B, 12 minutes; detector: 214nm). At 75%B, the fractions containing the product were collected and concentrated under reduced pressure to give N-((E)-N′-(Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamoyl)-2,2,2-trifluoroacetamide or enantiomer (29.97mg, 0.04mmol, yield: 28.54%). LCMS m/z: 645[M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.03-8.01(m，2H)，7.83-7.81(m，2H)，7.57-7.55(m，2H)，7.42-7.40(m，2H)，7.32-7.22(m，5H)，5.11-5.08(m，1H)，4.59-4.46(m，1H)，3.91-3.87(m，1H). 1 H NMR (400MHz, DMSO-d 6 )δ8.03-8.01(m, 2H), 7.83-7.81(m, 2H), 7.57-7.55(m, 2H), 7.42-7.40(m, 2H) , 7.32-7.22(m, 5H), 5.11-5.08(m, 1H), 4.59-4.46(m, 1H), 3.91-3.87(m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.496，-74.191，-75.282. 19 F NMR (377MHz, DMSO-d 6 ) δ -61.496, -74.191, -75.282.

实施例60、(R，Z)-3-(4-氰基苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或其异构体(MRANK-111-21-1和MRANK-111-21-2)的合成：Example 60, Synthesis of (R, Z)-3-(4-cyanophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or its isomers (MRANK-111-21-1 and MRANK-111-21-2):

1)、(S)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或其异构体的制备：
1) Preparation of (S)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or its isomers:

将3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺(600mg，1.20mmol)溶液通过SFC纯化(条件如下：系统：Waters SFC 150；色谱柱名称：色谱柱尺寸：250*30mm 10μm；流动相A：超临界CO2；流动相B：MeOH(+0.1％7.0mol/l氨水/MeOH)，A：B＝70：30；波长：214nm；流速：140mL/min；色谱柱温度：RT；背压：100bar；流速：140mL/min；色谱柱压力：1.0mL/min：RT；背压：100bar；进样：2.5mL；循环时间：4.0min)纯化的得到：单体异构体21-2-1和单体异构体21-2-2： A solution of 3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (600 mg, 1.20 mmol) was purified by SFC (conditions as follows: system: Waters SFC 150; column name: Column size: 250*30mm 10μm; mobile phase A: supercritical CO 2 ; mobile phase B: MeOH (+0.1% 7.0mol/l ammonia/MeOH), A:B=70:30; wavelength: 214nm; flow rate: 140mL/min; column temperature: RT; back pressure: 100bar; flow rate: 140mL/min; column pressure: 1.0mL/min: RT; back pressure: 100bar; injection: 2.5mL; cycle time: 4.0min) was purified to obtain: monomer isomer 21-2-1 and monomer isomer 21-2-2:

21-2-1：峰1 chiral HPLC：1.509min；(S)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(300mg，0.60mmol，收率：50.0％)，LCMSm/z：499[M+H]+。21-2-1: Peak 1 chiral HPLC: 1.509 min; (S)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (300 mg, 0.60 mmol, yield: 50.0%), LCMS m/z: 499 [M+H] + .

21-2-2：峰2：chiralHPLC：3.112min；(R)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(300mg，0.60mmol，收率：50.0％)，LCMS m/z：499[M+H]+.21-2-2: Peak 2: chiralHPLC: 3.112 min; (R)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (300 mg, 0.60 mmol, yield: 50.0%), LCMS m/z: 499 [M+H] + .

2)、(S，E)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体的合成
2) Synthesis of (S, E)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomers

室温下，向溶有(S)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(300mg，0.60mmol)的PhCl(5mL)溶液中，加入PCl5(499mg，2.40mmol)，加热100℃搅拌2小时。将混合反应液浓缩。残余物通过IPA打浆，过滤。收集固体干燥得到化合物(S，E)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(300mg，0.58mmol，收率：96.7％)。LCMS m/z：517[M+H]+。At room temperature, PCl 5 (499 mg, 2.40 mmol) was added to a solution of (S)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1 -carboxamide or isomer (300 mg, 0.60 mmol) in PhCl (5 mL), and the mixture was heated at 100° C. and stirred for 2 hours. The mixed reaction solution was concentrated. The residue was slurried with IPA and filtered. The solid was collected and dried to give compound (S, E)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (300 mg, 0.58 mmol, yield: 96.7%). LCMS m/z: 517 [M+H] + .

3)、(S，Z)-3-(4-氰基苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体的合成
3) Synthesis of (S, Z)-3-(4-cyanophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer

在室温下，向溶有(S，E)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(100mg，0.19mmol)的DMF(2mL)溶液中，加入2-氨基-3，5-二氢-4H-咪唑-4-酮盐酸盐(78mg，0.57mmol)和TEA(96mg，0.95mmol)，室温搅拌3小时。将混合反应液通过制备级高效液相色谱(条件如下：Waters 2767/Qda：色谱柱：Sunfire C18，19×250×10um；流动相A：0.05％TFA/水；流动相B：乙腈；流速：20mL/min；梯度：45％B-50％B；保留时间：9.4-10.8min of16min)纯化得到化合物(S，Z)-3-(4-氰基苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体(26.40mg，0.05mmol，收率：26.3％)，LCMS m/z：580[M+H]+ To a solution of (S,E)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (100 mg, 0.19 mmol) in DMF (2 mL) at room temperature were added 2-amino-3,5-dihydro-4H-imidazole-4-one hydrochloride (78 mg, 0.57 mmol) and TEA (96 mg, 0.95 mmol), and the mixture was stirred at room temperature for 3 hours. The mixed reaction solution was purified by preparative HPLC (conditions as follows: Waters 2767/Qda: chromatographic column: Sunfire C18, 19×250×10 um; mobile phase A: 0.05% TFA/water; mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient: 45% B-50% B; retention time: 9.4-10.8 min of 16 min) to obtain compound (S, Z)-3-(4-cyanophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (26.40 mg, 0.05 mmol, yield: 26.3%), LCMS m/z: 580 [M+H] +

1H NMR(400MHz，DMSO-d6)δ8.11(d，J＝8.4Hz，2H)，7.95(d，J＝8.4Hz，2H)，7.86(d，J＝8.4Hz，2H)，7.78(d，J＝8.8Hz，2H)，7.35-7.29(m，4H)，7.28-7.25(m，1H)，5.29-5.25(m，1H)，4.61(t，J＝12.4Hz，11.6Hz，1H)，4.46-3.36(m，2H)，2.51-2.50(m，1H). 1 H NMR (400MHz, DMSO-d 6 )δ8.11(d, J=8.4Hz, 2H), 7.95 (d, J=8.4Hz, 2H), 7.86 (d, J=8.4Hz, 2H), 7.78 (d, J=8.8Hz, 2H), 7.35-7.29 (m, 4H ), 7.28-7.25(m, 1H), 5.29-5.25(m, 1H), 4.61(t, J=12.4Hz, 11.6Hz, 1H), 4.46-3.36(m, 2H), 2.51-2.50(m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.543. 19 F NMR (377MHz, DMSO-d 6 ) δ-61.543.

4)、(R，E)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或其异构体的合成
4) Synthesis of (R, E)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or its isomers

室温下，向溶有化合物(R)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-羧酰胺或异构体(300mg，0.60mmol)的PhCl(5mL)溶液中，加入PCl5(499mg，2.40mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩。残余物通过IPA打浆，过滤，收集固体干燥得到化合物(R，E)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(290mg，0.56mmol，收率：93.3％)，LCMS m/z：517[M+H]+。At room temperature, PCl 5 (499 mg, 2.40 mmol) was added to a solution of compound (R)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (300 mg, 0.60 mmol) in PhCl ( 5 mL), and the mixture was heated at 100° C. and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was slurried with IPA, filtered, and the solid was collected and dried to give compound (R, E)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (290 mg, 0.56 mmol, yield: 93.3%), LCMS m/z: 517 [M+H] + .

5)、(R，Z)-3-(4-氰基苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或其异构体(MRANK-111-21-1和MRANK-111-21-2)的合成
5) Synthesis of (R, Z)-3-(4-cyanophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or its isomers (MRANK-111-21-1 and MRANK-111-21-2)

在室温下，向溶有(R，E)-3-(4-氰基苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(100mg，0.19mmol，1.0eq.)的DMF(2mL)溶液中，加入2-氨基-3，5-二氢-4H-咪唑-4-酮盐酸盐(78mg，0.57mmol，3.0eq)和TEA(96mg，0.95mmol，5.0eq)，然后混合物在室温下搅拌3小时。反应混合物用反相柱纯化，条件如下(色谱柱：球形C18，20-40um，40g；流动相A：水(含有0.1％TFA)；流动相B：乙腈；流速：40mL/min；梯度：30分钟内5％B-95％B；检测器：214nm)。在64％B下收集含有所需产物的馏分，并在减压下浓缩，得到(R，Z)-3-(4-氰基苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体(40.17mg，0.07mmol，收率：36.8％)。LCMS：m/z：580.4[M+H]+.To a solution of (R,E)-3-(4-cyanophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (100 mg, 0.19 mmol, 1.0 eq.) in DMF (2 mL) at room temperature, 2-amino-3,5-dihydro-4H-imidazol-4-one hydrochloride (78 mg, 0.57 mmol, 3.0 eq) and TEA (96 mg, 0.95 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by reverse phase column under the following conditions (chromatographic column: spherical C18, 20-40 um, 40 g; mobile phase A: water (containing 0.1% TFA); mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5% B-95% B in 30 minutes; detector: 214 nm). The fractions containing the desired product were collected at 64% B and concentrated under reduced pressure to give (R,Z)-3-(4-cyanophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer (40.17 mg, 0.07 mmol, yield: 36.8%). LCMS: m/z: 580.4 [M+H] + .

1H NMR(400MHz，DMSO-d6)δ8.11(d，J＝8.0Hz，2H)，7.95(d，J＝8.4Hz，2H)，7.87-7.85(m，2H)，7.79-7.77(m，2H)，7.35-7.29(m，4H)，7.28-7.25(m，1H)，5.29-5.24(m，1H)，4.61(t，J＝12.4Hz，11.6Hz，1H)，4.44-4.35(m，2H)，3.95-3.91(m，1H). 1 H NMR (400MHz, DMSO-d 6 )δ8.11 (d, J=8.0Hz, 2H), 7.95 (d, J=8.4Hz, 2H), 7.87-7.85 (m, 2H), 7.79-7.77 (m, 2H), 7.35-7.29 (m, 4H), 7 .28-7.25(m, 1H), 5.29-5.24(m, 1H), 4.61(t, J=12.4Hz, 11.6Hz, 1H), 4.44-4.35(m, 2H), 3.95-3.91(m, 1H).

19F NMR(377MHz，DMSO-d6)δ-61.540，-74.486. 19 F NMR (377MHz, DMSO-d 6 ) δ -61.540, -74.486.

实施例61、(R，Z)-3-(4-氯苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺和其对映体三氟乙酸盐(MRANK-111-26-1和MRANK-111-26-2)的合成：Example 61. Synthesis of (R, Z)-3-(4-chlorophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide and its enantiomer trifluoroacetate salt (MRANK-111-26-1 and MRANK-111-26-2):

1)、(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体的合成
1) Synthesis of (R, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomers

在室温下，向溶有(R)-3-(4-氯苯基)-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(900mg，1.77mmol)的氯苯(20mL)溶液中，加入PCl5(737mg，3.54mmol)，加热100℃搅拌2小时。将混合反应液反减压浓缩并通过硅胶柱色谱法(PE/DCM＝1/5)纯化的得到(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(450mg，0.854mmol，收率：48.3％)，LCMS m/z：526[M+H]+。PCl5 (737 mg, 3.54 mmol) was added to a solution of (R)-3-(4-chlorophenyl)-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide or isomer (900 mg, 1.77 mmol) in chlorobenzene (20 mL) at room temperature, and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/5) to obtain (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (450 mg, 0.854 mmol, yield: 48.3%), LCMS m/z: 526 [M+H] + .

2)、(R，Z)-3-(4-氯苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体三氟乙酸盐的合成
2) Synthesis of (R, Z)-3-(4-chlorophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer trifluoroacetate

在室温下，向溶有(R，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体((60mg，0.114mmol)和2-氨基-3，5-二氢-4H-咪唑-4-酮盐酸盐(78mg，0.57mmol)的DMF(5mL)溶液中，加入TEA(81mg，0.8mmol)，25℃搅拌1小时。将混合反应液通过反相柱色谱(条件如下：柱：球形C18，20-40um，40g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：40mL/min；梯度：5％-100％B 40分钟，检测器：214nm)。在55％B下收集含有所需产物的馏分，减压浓缩得到(R，Z)-3-(4-氯苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体三氟乙酸盐(27.37mg，0.046mmol，收率：34％)，LCMS m/z：589[M+H]+ At room temperature, TEA (81 mg, 0.8 mmol) was added to a DMF (5 mL) solution of (R, E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (60 mg, 0.114 mmol) and 2-amino-3,5-dihydro-4H-imidazole-4-one hydrochloride (78 mg, 0.57 mmol), and the mixture was stirred at 25° C. for 1 hour. The mixed reaction solution was subjected to reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40 um, 40 g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 5%-100% B The fractions containing the desired product were collected at 55% B and concentrated under reduced pressure to give (R, Z)-3-(4-chlorophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer trifluoroacetate (27.37 mg, 0.046 mmol, yield: 34%), LCMS m/z: 589 [M+H] +

1H NMR(400MHz，DMSO-d6)：δ8.85(s，1H)，8.40(s，1H)，8.10(d，J＝8.0Hz，2H)，7.94(d，J＝8.4Hz，2H)，7.64(d，J＝8.4Hz，2H)，7.46(d，J＝8.4Hz，2H)，7.36-7.24(m，5H)，5.24-5.20(m，1H)，4.58(t，J＝12.0Hz，1H)，4.43-4.34(m，2H)，3.92-3.88(m，1H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.85 (s, 1H), 8.40 (s, 1H), 8.10 (d, J = 8.0Hz, 2H), 7.94 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 7.46 (d, J = 8 .4Hz, 2H), 7.36-7.24(m, 5H), 5.24-5.20(m, 1H), 4.58(t, J=12.0Hz, 1H), 4.43-4.34(m, 2H), 3.92-3.88(m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.52 19 F NMR (377MHz, DMSO-d 6 ): δ-61.52

3)、(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体的合成
3) Synthesis of (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomers

在室温下，向溶有(S)-3-(4-氯苯基)-4-苯基-N-(4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺或异构体(900mg，1.77mmol)的氯苯(20mL)溶液中，加入PCl5(737mg，3.54mmol)，加热100℃搅拌2小时。将混合反应液减压浓缩并通过硅胶柱层析(PE/DCM＝1/5)纯化得到(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(420mg，0.8mmol，收率：45％)，LCMS m/z：526[M+H]+ At room temperature, PCl 5 (737 mg, 3.54 mmol) was added to a solution of (S)-3-(4-chlorophenyl)-4-phenyl-N-(4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1- carboxamide or isomer (900 mg, 1.77 mmol) in chlorobenzene (20 mL), and the mixture was heated at 100°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE/DCM=1/5) to obtain (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (420 mg, 0.8 mmol, yield: 45%), LCMS m/z: 526 [M+H]+

4)(S，Z)-3-(4-氯苯基)-N-(5-氧代-4，5-二二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体三氟乙酸盐的合成
4) Synthesis of (S, Z)-3-(4-chlorophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer trifluoroacetate

在室温下，向溶有(S，E)-3-(4-氯苯基)-4-苯基-N-((4-(三氟甲基)苯基)磺酰基)-4，5-二氢-1H-吡唑-1-甲酰胺酰氯或异构体(60mg，0.114mmol)和2-氨基-3，5-二氢-4H-咪唑-4-酮盐酸盐(78mg，0.57mmol)的DMF(5mL)溶液中，加入TEA(81mg，0.8mmol)，25℃搅拌1小时。混合反应液通过反相柱色谱(条件如下：柱：球形C18，20-40um，40g；流动相A：水(含0.03％TFA)；流动相B：乙腈；流速：40mL/min；梯度：5％-100％B 40分钟，检测器：214nm)纯化，在55％B下，收集含有所需产物的级分减压浓缩得到(S，Z)-3-(4-氯苯基)-N-(5-氧代-4，5-二氢-1H-咪唑-2-基)-4-苯基-N’-((4-(三氟甲基)苯基)磺酰基)-4，5-双氢-1H-吡唑-1-羧酸脒酰胺或对映体三氟乙酸盐(24.48mg，0.042mmol，收率：31％)，LCMS m/z：589[M+H]+ To a solution of (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide chloride or isomer (60 mg, 0.114 mmol) and 2-amino-3,5-dihydro-4H-imidazol-4-one hydrochloride (78 mg, 0.57 mmol) in DMF (5 mL) was added TEA (81 mg, 0.8 mmol) at room temperature, and the mixture was stirred at 25°C for 1 hour. The mixed reaction solution was purified by reverse phase column chromatography (conditions as follows: column: spherical C18, 20-40um, 40g; mobile phase A: water (containing 0.03% TFA); mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 5%-100% B 40 minutes, detector: 214nm), and the fractions containing the desired product were collected and concentrated under reduced pressure at 55% B to give (S,Z)-3-(4-chlorophenyl)-N-(5-oxo-4,5-dihydro-1H-imidazol-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxylic acid amidamide or enantiomer trifluoroacetate (24.48mg, 0.042mmol, yield: 31%), LCMS m/z: 589[M+H] +

1H NMR(400MHz，DMSO-d6)：δ8.91(s，1H)，8.51(s，1H)，8.10(d，J＝8.0Hz，2H)，7.94(d，J＝8.4Hz，2H)，7.64(d，J＝8.4Hz，2H)，7.46(d，J＝8.4Hz，2H)，7.34-7.24(m，5H)，5.25-5.20(m，1H)，4.58(t，J＝12.0Hz，1H)，4.46-4.37(m，2H)，3.93-3.88(m，1H). 1 H NMR (400MHz, DMSO-d 6 ): δ8.91 (s, 1H), 8.51 (s, 1H), 8.10 (d, J = 8.0Hz, 2H), 7.94 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 7.46 (d, J = 8 .4Hz, 2H), 7.34-7.24(m, 5H), 5.25-5.20(m, 1H), 4.58(t, J=12.0Hz, 1H), 4.46-4.37(m, 2H), 3.93-3.88(m, 1H).

19F NMR(377MHz，DMSO-d6)：δ-61.53. 19 F NMR (377MHz, DMSO-d 6 ): δ-61.53.

实施例62、如下化合物的合成：Example 62, Synthesis of the following compound:

与实施例1-61中化合物类似的合成步骤，可以得到如下化合物：






















































































































































































































Figure PCTCN2024113428-ftappb-I100772

Figure PCTCN2024113428-ftappb-I100773
The following compounds can be obtained by similar synthetic steps to those in Example 1-61:






















































































































































































































Figure PCTCN2024113428-ftappb-I100772

Figure PCTCN2024113428-ftappb-I100773

本发明采用如下试验来评价代表性化合物的成药性，且为了体现代表性化合物的创造性优势，选择INV-202作为参照化合物。The present invention uses the following test to evaluate the drugability of representative compounds, and in order to reflect the creative advantages of representative compounds, INV-202 is selected as a reference compound.

测试例1、hCB1受体拮抗生化分析Test Example 1: hCB1 receptor antagonist biochemical analysis

1)、实验材料1) Experimental materials

细胞：hCB1-CHO细胞，来自北京爱思益普生物科技股份有限公司。Cells: hCB1-CHO cells were obtained from Beijing Aisiyipu Biotechnology Co., Ltd.

试剂：试剂信息详见表1。Reagents: See Table 1 for reagent information.

仪器：二氧化碳细胞培养箱(CLM-240B-8-TC)购自ESCO科技公司，HTS高通量药筛多功能酶标仪(PHERAstar FSX)购自BMG LABTECH公司，微孔板低速离心机(TD5B)购自长沙湘智离心机仪器有限公司。 Instruments: The carbon dioxide cell culture incubator (CLM-240B-8-TC) was purchased from ESCO Technology Company, the HTS high-throughput drug screening multifunctional microplate reader (PHERAstar FSX) was purchased from BMG LABTECH Company, and the microplate low-speed centrifuge (TD5B) was purchased from Changsha Xiangzhi Centrifuge Instrument Co., Ltd.

表1-1试剂信息

Figure PCTCN2024113428-ftappb-I100774
Table 1-1 Reagent information
Figure PCTCN2024113428-ftappb-I100774

2)、实验方法2) Experimental methods

化合物配制Compound formulation

称取合适质量的受试物，根据公式：DMSO体积＝实际量×纯度/(分子量×理论浓度)，计算出所需的DMSO的体积，并溶解于相应体积的DMSO。Weigh an appropriate amount of the test substance, calculate the required volume of DMSO according to the formula: DMSO volume = actual amount × purity/(molecular weight × theoretical concentration), and dissolve it in the corresponding volume of DMSO.

检测方法Detection Methods

收集对数生长期的hCB1-CHO细胞，胰酶消化后用含有10％胎牛血清及0.2mg/mL Hygromycin B的F-12培养基重悬，计数后将细胞接种于384-well微孔板中。hCB1-CHO cells in the logarithmic growth phase were collected, digested with trypsin, and resuspended in F-12 medium containing 10% fetal bovine serum and 0.2 mg/mL Hygromycin B. After counting, the cells were inoculated into a 384-well microplate.

按照

Figure PCTCN2024113428-ftappb-I100775
Ultra cAMP Kit说明书配制1×Stimulation Buffer待用。according to
Figure PCTCN2024113428-ftappb-I100775
Prepare 1×Stimulation Buffer according to the Ultra cAMP Kit instructions and set aside.

将阳性化合物和待测化合物分别进行梯度稀释10个浓度，然后用1×Stimulation Buffer稀释至10×。The positive compound and the test compound were serially diluted to 10 concentrations respectively, and then diluted to 10× with 1×Stimulation Buffer.

取1μL稀释好的10×化合物加入至相应实验孔中，放置于37℃孵育20分钟。Take 1 μL of the diluted 10× compound and add it to the corresponding experimental wells, and incubate at 37°C for 20 minutes.

用1×Stimulation Buffer配制Forskolin&CP55940激动剂溶液，然后取4μL/well分别加入至相应实验孔中孵育30min，诱导cAMP产生。Use 1×Stimulation Buffer to prepare Forskolin&CP55940 agonist solution, then take 4μL/well and add it to the corresponding experimental wells and incubate for 30 minutes to induce cAMP production.

将Eu-cAMP用Detection buffer稀释至4×工作浓度，取5μL/well加入相应实验孔中。Dilute Eu-cAMP to 4× working concentration with detection buffer and add 5 μL/well into the corresponding experimental wells.

将ULightTM-anti-cAMP抗体用Detection buffer稀释至4×工作浓度，取5μL/well加入相应实验孔中；离心后室温孵育1小时。Dilute the ULight TM -anti-cAMP antibody to 4× working concentration with detection buffer, take 5 μL/well and add it to the corresponding experimental wells; incubate at room temperature for 1 hour after centrifugation.

孵育完成后，利用酶标仪检测波长330nm激发下，665nm和620nm读值。After the incubation is completed, the ELISA reader is used to detect the readings at 665 nm and 620 nm under the excitation wavelength of 330 nm.

3)、数据分析3) Data analysis

计算公式Calculation formula

Z’factor＝1-3*(SD High+SD Low)/(Ave High-Ave Low)Z’factor＝1-3*(SD High+SD Low)/(Ave High-Ave Low)

CV High＝(SD High/Ave High)*100％CV High＝(SD High/Ave High)*100%

CV Low＝(SD Low/Ave Low)*100％CV Low＝(SD Low/Ave Low)*100%

S/B＝AveHigh/AveLowS/B＝AveHigh/AveLow

利用GraphPad非线性拟合公式计算化合物EC50：The EC50 of the compound was calculated using the GraphPad nonlinear fitting formula:

Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))

％激动率公式：

Figure PCTCN2024113428-ftappb-I100776
% Arousal formula:
Figure PCTCN2024113428-ftappb-I100776

Figure PCTCN2024113428-ftappb-I100777
阳性对照的平均值
Figure PCTCN2024113428-ftappb-I100777
The average value of positive control

Figure PCTCN2024113428-ftappb-I100778
阴性对照的平均值(DMSO)
Figure PCTCN2024113428-ftappb-I100778
Average value of negative control (DMSO)

4)、结果与分析4) Results and analysis

表1-2 hCB1受体拮抗生化分析结果

Figure PCTCN2024113428-ftappb-I100779

Figure PCTCN2024113428-ftappb-I100780
Table 1-2 Results of biochemical analysis of hCB1 receptor antagonism
Figure PCTCN2024113428-ftappb-I100779

Figure PCTCN2024113428-ftappb-I100780

测试例2、代表性化合物小鼠PK评价Test Example 2: PK evaluation of representative compounds in mice

采用CD1小鼠来评价代表性化合物MDR-001-305-3和参照化合物INV-202在小鼠体内的药代动力学特征。CD1 mice were used to evaluate the pharmacokinetic characteristics of the representative compound MDR-001-305-3 and the reference compound INV-202 in mice.

将待测化合物和参照化合物用给药溶媒(IV：5％DMSO+5％Solutol+90％生理盐水；PO：5％DMSO+5％Solutol+90％水)溶解做成储备液。 The test compound and the reference compound were dissolved in the administration vehicle (IV: 5% DMSO + 5% Solutol + 90% saline; PO: 5% DMSO + 5% Solutol + 90% water) to prepare a stock solution.

给药和采血：Medication and blood collection:

本试验采用的为CD1雄性小鼠，每组6只，按照IV 1mg/kg、PO 10mg/kg剂量给药。This study used CD1 male mice, with 6 mice in each group, and the mice were given IV 1 mg/kg and PO 10 mg/kg doses.

给药后，采集全血样品，采样时间点为：IV给药后0.0333、0.0833、0.25、0.5、1、2、4、6、8和24小时；PO给药后0.0833、0.25、0.5、4、8和24小时。(采集静脉血，采血体积每次约0.025mL)。采血管含K2EDTA抗凝剂，采血后将样品管放置于湿冰上。血样采集后1小时内分离得到血浆(离心条件：3200g，2-8℃离心10分钟)。血浆样品将被储存于-60℃或更低温度的冰箱中直至分析。After administration, whole blood samples were collected at 0.0333, 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after IV administration; 0.0833, 0.25, 0.5, 4, 8, and 24 hours after PO administration. (Venous blood was collected, and the blood volume was approximately 0.025 mL each time). The blood collection tube contained K2EDTA anticoagulant, and the sample tube was placed on wet ice after blood collection. Plasma was separated within 1 hour after blood sample collection (centrifugation conditions: 3200g, 2-8℃ centrifugation for 10 minutes). Plasma samples will be stored in a refrigerator at -60℃ or lower until analysis.

生物样品分析Biological sample analysis

采用LC-MS/MS方法检测血浆中的药物浓度。方法的定量下限为1.00ng/mL，线性范围为1.00-3000ng/mL。The drug concentration in plasma was detected by LC-MS/MS method. The lower limit of quantification of the method was 1.00 ng/mL and the linear range was 1.00-3000 ng/mL.

结果汇总和分析Results summary and analysis

代表性化合物在小鼠中的平均药代动力学参数如下表：The average pharmacokinetic parameters of representative compounds in mice are shown in the following table:

表2-1小鼠中的平均药代动力学参数

Figure PCTCN2024113428-ftappb-I100781
Table 2-1 Average pharmacokinetic parameters in mice
Figure PCTCN2024113428-ftappb-I100781

备注：表中数据为均值，Tmax除外，为中位数；MPK：mg/kg；IV：静脉注射；PO：经口给药。Note: The data in the table are means, except T max , which is the median; MPK: mg/kg; IV: intravenous injection; PO: oral administration.

上述结果表明，相较于参照化合物INV-202，代表性化合物MDR-001-305-3具有更低地清除率和更长的半衰期。且口服给药后，具有更高的系统暴露量AUC。The above results show that compared with the reference compound INV-202, the representative compound MDR-001-305-3 has a lower clearance rate and a longer half-life, and has a higher systemic exposure AUC after oral administration.

测试例3、代表性化合物在C57BL/6J小鼠DIO模型上的降体重药效Test Example 3: Weight-reducing efficacy of representative compounds in the C57BL/6J mouse DIO model

实验方法：Experimental methods:

4-6周龄的C57BL/6J小鼠用高脂饲料喂养12周，体重达到40g左右。按照体重和基础摄食量将动物随机分为4组，每组7只，分别为Vehicle组、3mg/kg INV-202组、1mg/kg和3mg/kg的MDR-001-305-3组。所有给药组动物均灌胃给予相应药物，每天一次，连续11天。给药期间每天测定一次小鼠体重并临床观察。具体给药方案见表3-1。C57BL/6J mice aged 4-6 weeks were fed with a high-fat diet for 12 weeks, and their body weight reached about 40g. According to body weight and basal food intake, the animals were randomly divided into 4 groups, with 7 mice in each group, namely the Vehicle group, the 3mg/kg INV-202 group, and the 1mg/kg and 3mg/kg MDR-001-305-3 groups. All animals in the drug-treated groups were given the corresponding drugs by gavage once a day for 11 consecutive days. The body weight of the mice was measured once a day during the drug-treated period and clinical observation was performed. The specific dosing regimen is shown in Table 3-1.

表3-1.C57BL/6J小鼠DIO模型给药方案

Figure PCTCN2024113428-ftappb-I100782

注：QD指每天给药1次，po为口服给药。Table 3-1. Dosing regimen for C57BL/6J mouse DIO model
Figure PCTCN2024113428-ftappb-I100782

Note: QD means administration once a day, po means oral administration.

数据分析：Data Analysis:

体重变化百分比(％)为与给药前Day0相比动物体重的变化百分比。The body weight change percentage (%) is the change percentage of the animal body weight compared with Day 0 before administration.

结果分析用平均数和标准误表示(Mean±SEM)。组间比较采用双尾t-检验，与vehicle组*p＜0.05，认为有显著性差异。**P＜0.01为极显著差异，结果分析时同时考虑统计学意义和生物学意义。The results were analyzed using mean ± SEM. Two-tailed t-test was used for comparison between groups. *P < 0.05 was considered to be significantly different from the vehicle group. **P < 0.01 was considered to be extremely significantly different. Both statistical significance and biological significance were considered when analyzing the results.

实验结果：Experimental results:

待测化合物对DIO小鼠的体重影响详见表3-2。The effects of the test compounds on the body weight of DIO mice are detailed in Table 3-2.

表3-2.待测化合物对DIO小鼠体重的影响

Figure PCTCN2024113428-ftappb-I100783

Figure PCTCN2024113428-ftappb-I100784
Table 3-2. Effects of the test compounds on the body weight of DIO mice
Figure PCTCN2024113428-ftappb-I100783

Figure PCTCN2024113428-ftappb-I100784

同等剂量下，代表性化合物MDR-001-305-3具有与参照化合物INV-202类似的减重效果。给药11天后动物体重最大降幅为15.0％左右。At the same dose, the representative compound MDR-001-305-3 had a similar weight loss effect as the reference compound INV-202. The maximum weight loss of the animals after 11 days of administration was about 15.0%.

测试例4、代表性化合物和参照化合物在有效剂量下小鼠PK和血脑屏障透过率(BBB)对比试验Test Example 4: Comparative test of PK and blood-brain barrier permeability (BBB) in mice of representative compounds and reference compounds at effective doses

考虑到CB1反向激动剂开发最大的风险是透脑以及潜在的中枢神经毒性风险如抑郁等，我们进一步评价了代表性化合物MDR-001-305-3和参照化合物INV-202在最大药效剂量(3mg/kg)下，给予小鼠后的药代动力学特征和脑中的药物浓度和脑脊液中的游离药物浓度。Considering that the biggest risk in the development of CB1 inverse agonists is brain penetration and potential central nervous system toxicity risks such as depression, we further evaluated the pharmacokinetic characteristics and drug concentrations in the brain and free drug concentrations in the cerebrospinal fluid of the representative compound MDR-001-305-3 and the reference compound INV-202 after administration to mice at the maximum effective dose (3 mg/kg).

给药溶媒为5％DMSO+5％Solutol+90％水。将MDR-001-305-3和INV-202用给药溶媒溶解。采用ICR雄性小鼠，每组6只(3只PK采全血+24小时点脑组织和脑脊液；3只在Tmax附近采脑组织和脑脊液)。按照3mg/kg剂量给药。The dosing solvent was 5% DMSO + 5% Solutol + 90% water. MDR-001-305-3 and INV-202 were dissolved in the dosing solvent. ICR male mice were used, 6 mice per group (3 PK whole blood + 24-hour brain tissue and cerebrospinal fluid; 3 brain tissue and cerebrospinal fluid were collected near Tmax). The dose was 3 mg/kg.

给药和采血：Medication and blood collection:

采集全血样品，采样时间点为给药后0.05、0.25、0.5、1、2、4、6、8、和24小时；Whole blood samples were collected at 0.05, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration;

采集脑组织和脑脊液样品，采样时间点为给药后Tmax附近和24小时。Brain tissue and cerebrospinal fluid samples were collected near Tmax and 24 hours after administration.

生物样品处理Biological sample processing

采集静脉血，采血体积每次约0.050mL。采血管含K2EDTA抗凝剂，采血后将样品管放置于湿冰上。血样采集后1小时内分离得到血浆(离心条件：6000rpm，2-8℃离心3分钟)。血浆样品将被储存于-80℃冰箱中直至分析。Venous blood was collected, and the blood collection volume was about 0.050mL each time. The blood collection tube contained K 2 EDTA anticoagulant, and the sample tube was placed on wet ice after blood collection. Plasma was separated within 1 hour after blood sample collection (centrifugation conditions: 6000rpm, 2-8℃ centrifugation for 3 minutes). Plasma samples will be stored in a -80℃ refrigerator until analysis.

采集脑组织和脑脊液，根据脑组织重量，加入4倍体积的匀浆液(50％甲醇-水溶液)进行匀浆处理。将脑匀浆液样品储存于-80℃冰箱中直至分析。Brain tissue and cerebrospinal fluid were collected, and 4 volumes of homogenate (50% methanol-water solution) were added according to the weight of brain tissue for homogenization. Brain homogenate samples were stored in a -80°C refrigerator until analysis.

采用LC-MS/MS方法检测血浆、脑组织匀浆液和脑脊液中的药物浓度。方法的定量下限为1.00ng/mL，线性范围为1.00-2000ng/mL。The drug concentration in plasma, brain tissue homogenate and cerebrospinal fluid was determined by LC-MS/MS method. The lower limit of quantification of the method was 1.00 ng/mL and the linear range was 1.00-2000 ng/mL.

结果汇总Results Summary

MDR-001-305-3和INV-202在小鼠中的平均药代动力学参数和血脑屏障透过率见表4-1。The average pharmacokinetic parameters and blood-brain barrier permeability of MDR-001-305-3 and INV-202 in mice are shown in Table 4-1.

表4-1 MDR-001-305-3和INV-202在小鼠中的平均药代动力学参数和血脑屏障透过率比较

Figure PCTCN2024113428-ftappb-I100785
Table 4-1 Comparison of average pharmacokinetic parameters and blood-brain barrier permeability of MDR-001-305-3 and INV-202 in mice
Figure PCTCN2024113428-ftappb-I100785

备注：表中数据为均值，Tmax除外，为中位数；B/P为脑组织和血浆浓度比；CSF为脑脊液中药物浓度；NC：因CSF浓度低于检测定量下限，未计算；*因部分个体血浆浓度未检测到，此B/P为根据血浆浓度均值计算得到；MPK：mg/kg；PO：经口给药。Notes: The data in the table are means, except Tmax , which is the median; B/P is the ratio of brain tissue and plasma concentration; CSF is the drug concentration in cerebrospinal fluid; NC: not calculated because the CSF concentration was lower than the lower limit of detection; *Because the plasma concentration of some individuals was not detected, this B/P was calculated based on the mean plasma concentration; MPK: mg/kg; PO: oral administration.

从上表结果可以看出：血脑屏障透过率方面，小鼠经口给药后，无论是在Tmax附近还是给药后24h点，代表性化合物MDR-001-305-3的透脑率均显著低于INV-202(脑血比约为参照化合物INV-202的1/3～1/15)，且脑脊液中没有检测到游离药物存在(参照化合物INV-202给药后24h内脑脊液中可以持续检测到游离药物存在)。From the results in the above table, it can be seen that in terms of blood-brain barrier permeability, after oral administration to mice, the brain permeability of the representative compound MDR-001-305-3 was significantly lower than that of INV-202, both near Tmax and 24 hours after administration (the brain-blood ratio was approximately 1/3 to 1/15 of that of the reference compound INV-202), and no free drug was detected in the cerebrospinal fluid (the free drug could be continuously detected in the cerebrospinal fluid within 24 hours after administration of the reference compound INV-202).

以上研究结果表明，相较于参照分子INV-202，代表性化合物MDR-001-305-3具有更低的血脑屏障透过率，且脑脊液中没有游离药物存在，预期没有中枢神经相关毒副作用如抑郁等，或与INV-202比较，中枢神经毒副作用潜在风险更小。The above research results show that compared with the reference molecule INV-202, the representative compound MDR-001-305-3 has a lower blood-brain barrier permeability and no free drug is present in the cerebrospinal fluid. It is expected that there will be no central nervous system-related toxic side effects such as depression, or compared with INV-202, the potential risk of central nervous system toxic side effects is smaller.

测试例5、代表性化合物大鼠PK和血脑屏障透过率(BBB)试验Test Example 5: Rat PK and blood-brain barrier permeability (BBB) tests of representative compounds

1.试验目的1. Purpose of the experiment

评价代表性化合物MDR-001-305-3和参照化合物INV-202在大鼠中药代动力学特征、生物利用度以及血脑屏障透过率。The pharmacokinetic characteristics, bioavailability and blood-brain barrier permeability of the representative compound MDR-001-305-3 and the reference compound INV-202 in rats were evaluated.

2.试验流程2. Test process

3.供试品3. Test products

4.给药溶媒4. Drug administration solvent

给药溶媒：IV：5％DMSO+5％Solutol+90％生理盐水；PO：5％DMSO+5％Solutol+90％水。Dosing vehicle: IV: 5% DMSO + 5% Solutol + 90% saline; PO: 5% DMSO + 5% Solutol + 90% water.

5.试验系统5. Test system

试验系统为SD大鼠。 The experimental system was SD rats.

6.试验设计6. Experimental Design

受试化合物按照IV 1mg/kg，PO 1mg/kg和3mg/kg给药。The test compounds were administered IV 1 mg/kg, PO 1 mg/kg and 3 mg/kg.

7.生物样品采集7. Biological Sample Collection

第1组(IV组)：采集全血样品，采样时间点为给药后0.05、0.25、0.5、1、2、4、6、8、和24小时。Group 1 (Group IV): Whole blood samples were collected at 0.05, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.

第2和3组(PO组)：采集全血样品，采样时间点为给药后0.05、0.25、0.5、1、2、4、6、8、和24小时；采集脑组织和脑脊液样品，采样时间点为给药后24小时。Groups 2 and 3 (PO group): whole blood samples were collected at 0.05, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration; brain tissue and cerebrospinal fluid samples were collected at 24 hours after administration.

1.7生物样品处理1.7 Biological sample processing

1.7.1血浆样品1.7.1 Plasma samples

采集静脉血，采血体积每次约0.200mL。采血管含K2EDTA抗凝剂，采血后将样品管放置于湿冰上。血样采集后1小时内分离得到血浆(离心条件：6000rpm，2-8℃离心3分钟)。血浆样品将被储存于-80℃冰箱中直至分析。Collect venous blood, the blood collection volume is about 0.200mL each time. The blood collection tube contains K2EDTA anticoagulant, and the sample tube is placed on wet ice after blood collection. Plasma is separated within 1 hour after blood sample collection (centrifugation conditions: 6000rpm, 2-8℃ centrifugation for 3 minutes). Plasma samples will be stored in a -80℃ refrigerator until analysis.

1.7.2脑组织样品1.7.2 Brain tissue samples

根据脑组织重量，加入4倍体积的匀浆液(50％甲醇-水溶液)进行匀浆处理。将脑匀浆液样品储存于-80℃冰箱中直至分析。According to the weight of brain tissue, 4 volumes of homogenate (50% methanol-water solution) were added for homogenization. The brain homogenate samples were stored in a -80°C refrigerator until analysis.

1.8生物样品分析1.8 Biological sample analysis

采用LC-MS/MS方法检测血浆、脑组织匀浆液和脑脊液中的药物浓度。方法的定量下限为1.00ng/mL，线性范围为1.00-2000ng/mL。The drug concentration in plasma, brain tissue homogenate and cerebrospinal fluid was determined by LC-MS/MS method. The lower limit of quantification of the method was 1.00 ng/mL and the linear range was 1.00-2000 ng/mL.

8.结果汇总8. Results Summary

代表性化合物MDR-001-305-3和参照化合物INV-202在大鼠中的平均药代动力学参数和血脑屏障透过率比较见表5-1。The average pharmacokinetic parameters and blood-brain barrier permeability of the representative compound MDR-001-305-3 and the reference compound INV-202 in rats are compared in Table 5-1.

表5-1 INV-202和MDR-001-305-3在大鼠中的平均药代动力学参数和血脑屏障透过率比较

Figure PCTCN2024113428-ftappb-I100786
Table 5-1 Comparison of average pharmacokinetic parameters and blood-brain barrier permeability of INV-202 and MDR-001-305-3 in rats
Figure PCTCN2024113428-ftappb-I100786

备注：表中数据为均值，Tmax除外，为中位数；B/P为脑组织和血浆浓度比；CSF/P为脑脊液和血浆浓度比；NC：因CSF浓度低于检测定量下限，未计算；*因部分个体血浆浓度未检测到，此B/P为根据血浆浓度均值计算得到；MPK：mg/kg；IV：静脉注射；PO：经口给药。Note: The data in the table are means, except T max , which is the median; B/P is the ratio of brain tissue and plasma concentration; CSF/P is the ratio of cerebrospinal fluid and plasma concentration; NC: not calculated because the CSF concentration was below the lower limit of detection; *Because the plasma concentration of some individuals was not detected, this B/P was calculated based on the mean plasma concentration; MPK: mg/kg; IV: intravenous injection; PO: oral administration.

从上表结果可以看出，相较于参照化合物INV-202，同等剂量下代表性化合物MDR-001-305-3在大鼠中经口给药后的暴漏量更大(约增加1倍)，生物利用度更高，清除更慢，半衰期更长(约增加1倍)。From the results in the above table, it can be seen that compared with the reference compound INV-202, the representative compound MDR-001-305-3 at the same dose has a larger exposure amount after oral administration in rats (approximately 1 times increased), higher bioavailability, slower clearance, and longer half-life (approximately 1 times increased).

血脑屏障透过率方面，与小鼠模型上类似，相较于参照化合物INV-202，同等剂量下本发明代表性化合物MDR-001-305-3的透脑率更低。大鼠经口给药后24h，不同剂量下参照化合物INV-202的透脑率均显著高于代表性化合物MDR-001-305-3：1mg/kg剂量下INV-202的B/P约为MDR-001-305-3的4.4倍；3mg/kg剂量下INV-202的B/P约为MDR-001-305-3的13倍。In terms of blood-brain barrier permeability, similar to the mouse model, the representative compound MDR-001-305-3 of the present invention has a lower brain permeability than the reference compound INV-202 at the same dose. 24 hours after oral administration to rats, the brain permeability of the reference compound INV-202 at different doses was significantly higher than that of the representative compound MDR-001-305-3: the B/P of INV-202 at a dose of 1 mg/kg was about 4.4 times that of MDR-001-305-3; the B/P of INV-202 at a dose of 3 mg/kg was about 13 times that of MDR-001-305-3.

因此与INV-202比较，本发明代表性化合物MDR-001-305-3透脑率更低，中枢神经毒副作用潜在风险更小，更适合作为药物开发用于预防或治疗与CB1靶点及其信号通路相关的疾病。Therefore, compared with INV-202, the representative compound MDR-001-305-3 of the present invention has a lower brain penetration rate and a smaller potential risk of central nervous system toxicity and side effects, and is more suitable for drug development for the prevention or treatment of diseases related to the CB1 target and its signaling pathway.

以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the protection scope of the claims of this application.

Claims (11)

式(I)所示化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，
The compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer or isotope substitution,
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; X1独立地选自N或CR1；X 1 is independently selected from N or CR 1 ; R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2- 10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl , C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from L选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；L is selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2)C(Rd1 ) ( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy ; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基 的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group. or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 are substituted with each other or/and R 1 or R 2 and the atoms to which they are attached to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted with a substituent selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2. 根据权利要求1所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(IA)结构，
The compound according to claim 1, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product, characterized in that it has a structure of formula (IA),
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2- 10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl , C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、 C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R 1 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy ; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、 C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C2-50 alkenyl acyl, C10-50 alkenylalkyl acyl or C10-50 alkylalkenylalkyl acyl, C1-10 alkyl acyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl or M group; further Rd1, Rd2, Rd3, Rd4 , Rd5 , Rd6, Rd7 , Rd8, Rd9, Rd10 , Rd11, Rd12, Rd13, Rd14, Rd15 , Rd16 , Rd9 , Rd17 , Rd18, Rd19, Rd110 , Rd111 , Rd12 The hydrogen on d7 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , and R d7 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl , saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 3-10 saturated or partially substituted cycloalkyl, or heterocyclic group. The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 2 groups selected from hydrogen, deuterium, halogen , oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups ; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数n is an integer randomly selected from 0, 1, 2, 3, 4 and 5 r任意地选自0、1和2中的整数；r is an integer arbitrarily selected from 0, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(IB)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (IB),
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2- 10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基 取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R 0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy ; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰 基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkyl sulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkyl acyl, C 1-10 alkyl sulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl substituted by R6 and R7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R6 , R7 and R8 can be optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl and saturated or partially saturated C3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4, Rd5 , Rd6 , and Rd7 are substituted with each other or/ and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数n is an integer randomly selected from 0, 1, 2, 3, 4 and 5 r任意的选自1、1和2中的整数；r is an integer arbitrarily selected from 1, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(IC)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (IC):
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、- C(Rd1)＝C(Rd1)-、-C(Rd1）(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1）(Rd2)C(＝O)-、-C(Rd1）(Rd2)C(＝S)-、-C(Rd1）(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1）(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1）(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, - C(R d1 )＝C(R d1 )-, -C(R d1 )(R d2 )C(R d1 )＝C(R d1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C(＝ O)C(R d1 )(R d2 )-, -C (＝S)C(R d1 )(R d2 )-, -S(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝ O ) 2 -, or C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 5-12 membered aryl, C 4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C 1-3 alkyl, C 1-3 alkyl, C 1-12 ... 1-3 alkoxy, alkenyl, alkynyl; R0独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2- 10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl , C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy ; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、 -NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group The C 1-10 alkyl substituted by a C 3-10 cycloalkyl or a C 3-10 heterocyclyl substituted by 1 to 20 cycloalkyl or C 3-10 heterocyclyl is optionally substituted by 1 to 20 substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and a C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to 20 heteroatoms or unsaturated bonds; further, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to 20 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to 20 cycloalkyl or C 3-10 heterocyclyl is optionally substituted by 1 to 20 substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, halogenated alkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4, Rd5 , Rd6 , and Rd7 are substituted with each other or/ and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; r任意地选自0、1和2中的整数；r is an integer arbitrarily selected from 0, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(ID)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product, is characterized in that it has a structure of formula (ID):
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; R0独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3- 10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is independently selected from hydrogen, deuterium, halogen, pentafluoride sulfur, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl , C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on O is optionally substituted with one to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy ; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 alkyl substituted by C 3-10 R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 are optionally substituted with one or more substituents selected from hydrogen, deuterium , halogen, oxo , CN, OH, acetyl, dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino or -COOH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 , R d7 are substituted with each other or/ and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; r任意选自0、1和2中的整数；r is an integer selected from 0, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(IE)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (IE):
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; R0优先选自M基团；且R0上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；R 0 is preferably selected from the M group; and the hydrogen on R 0 is optionally substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱 和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally replaced by 1 to more selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl , C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated and heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, or a substituent of a C 3-10 heterocyclyl ; or any two adjacent R 1s together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C R1-6 alkoxy is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl. And the hydrogen on R1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , saturated or partially saturated C3-6 cycloalkyl ; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；优先为芳基、杂芳基、杂环基；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; preferably aryl, heteroaryl, heterocyclic group; and the hydrogen on R is further optionally substituted by 1 to more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4, Rd5 , Rd6 , and Rd7 are substituted with each other or/ and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; r任意地选自0、1和2中的整数；r is an integer arbitrarily selected from 0, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(IF)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (IF):
其中，in, 环A任意独立地为不存在或代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；如果环A不存在的话，则R2直接连接在X上；Ring A is arbitrarily and independently absent or represents a 3-20-membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; if Ring A does not exist, R 2 is directly connected to X; X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代 物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo The hydrogen on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen , oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；优选为芳基、杂芳基、杂环基；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute or M group; preferably aryl, heteroaryl, heterocyclic group; and the hydrogen on R is further optionally substituted by 1 to more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选 地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4, Rd5 , Rd6 , and Rd7 are substituted with each other or/ and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by is substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; r任意选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2. 根据权利要求1或2所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(1-IE)结构：
The compound according to claim 1 or 2, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product, characterized in that it has the structure of formula (1-IE):
其中，in, 环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基 团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. The hydrogen on R 1 is optionally replaced by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. Group replacement; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷 基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1- 6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3, R d4 , R d5 , and R d6 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkane, The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by 1 to 2 groups selected from hydrogen, deuterium, halogen, oxo , CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(1-IF)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (1-IF):
环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N- 二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl , C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N- di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 heterocycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl , C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl , -YQ or M group; or optionally two R R 2 can form, together with the atoms to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl ; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1- 6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or any of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5. 根据权利要求1-3任一项所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(2-I)结构，
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that it has a structure of formula (2-I),
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1独立地选自N或CR1 X 1 is independently selected from N or CR 1 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙 酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyethyl acyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl ) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素； The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-IA)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-IA),
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子 一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 atoms to which they can be attached together to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic group are optionally substituted by one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1, R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1, R d2, R d3 , R d4, R d5, and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素； The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-IB)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-IB),
其中，in, 环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1任意独立地选自CR1或N；X 1 is arbitrarily and independently selected from CR 1 or N; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、 C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 heterocycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl are optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl ; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-IC)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-IC):
其中，in, 环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C (Rd1)( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1)＝C(Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; X1任意独立地选自CR1或N；X 1 is arbitrarily and independently selected from CR 1 or N; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-10 alkyl, C 2-10 alkenyl, C 2- 1-10 alkynyl, C 1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfonamide, N,N-di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy , C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 heterocycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl , -YQ or M group; or optionally two R R 2 can form, together with the atoms to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl ; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至 多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1 to 2 substituted with multiple groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-ID)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-ID):
其中，in, 环A和B任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A and Ring B arbitrarily and independently represent a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C (Rd1)( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1)＝C(Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6 烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =0, and saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-IE)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-IE):
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、 C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 heterocycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl are optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl ; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代； Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 且R和A不同时为苯环，或者当R和A同时为苯环时，任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基；and R and A are not benzene rings at the same time, or when R and A are benzene rings at the same time, any two adjacent R1s together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-IF)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-IF):
环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙 酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyethyl acyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl ) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , R d4 , R d5 , R d6 are each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素； The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5. 前提是当任意两相邻的R1不与其附着的原子一起形成4-30元杂芳基，4-30元饱和或部分饱和环烷基、4-30元饱和或部分饱和杂环基时，或者Rd4不为氢，或者Rd4为氢，但Rd1为烷基、卤代烷基、氘代烷基、环烷基、烷硫基或环烷基硫基；Provided that when any two adjacent R 1's do not form together with the atoms to which they are attached a 4-30 membered heteroaryl, a 4-30 membered saturated or partially saturated cycloalkyl, or a 4-30 membered saturated or partially saturated heterocyclyl, or R d4 is not hydrogen, or R d4 is hydrogen, but R d1 is alkyl, haloalkyl, deuterated alkyl, cycloalkyl, alkylthio, or cycloalkylthio; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(2-IG)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (2-IG):
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N- 二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl , C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N- di(C 1-10 alkyl)amino, C 1-10 alkyloxy, C 1-10 alkylacyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C 3-10 heterocycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 heterocycloalkyloxy, C 3-10 cycloalkylacyl, C 3-10 cycloalkyloxyacetyl , C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl , -YQ or M group; or optionally two R R 2 can form, together with the atoms to which it is attached, a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, or a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted by one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl ; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; R3独立地选自氘、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C2-10杂烷基、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基、-COOH、C3-10饱和/部分饱和的环烷基、C3-10饱和或部分饱和的杂环基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基； R3 is independently selected from deuterium, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C2-10 heteroalkyl , haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino, -COOH, C3-10 saturated/partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocyclyl, aryl, heteroaryl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl , C1-10 alkyl substituted with carboxyl or carboxyl surrogate; and R The hydrogen on 3 is further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、 烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl ; The hydrogen on d6 is optionally replaced by 1 to 2 selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, or any of R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 together with each other or/and R 1 or R 2 and the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by hydrogen, deuterium , halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and a saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl is substituted by a saturated or partially saturated cycloalkyl or heterocyclyl; C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数。n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5. 根据权利要求1-4任一项所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(3-I)结构，
The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that it has a structure of formula (3-I),
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; L和X各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L和X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；L and X are each independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L and X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; L0、L1、L2、L3、L4各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基； 且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L0 , L1 , L2 , L3 , and L4 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 ) -, -C(Rd1)(Rd2)S(＝O)2-, or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L 1 , L 2 and L 3 is further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、 C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl; C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl, or C3-10 heterocyclyl substituted by C3-10 cycloalkyl, C3-10 heterocyclyl is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl ; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium , halogen, -CN, -OH, CF3 , C1-6 alkyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocyclyl, or C3-10 heterocyclyl. The group may be substituted with -1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, halogenated alkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(3-IA)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (3-IA),
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代 物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo The hydrogen on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen , oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl ; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10 环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C 1-10 alkyl substituted by cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3中的整数；t is an integer arbitrarily selected from 0, 1, 2, and 3; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(3-IB)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (3-IB),
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、 以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10 环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C 1-10 alkyl substituted by cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(3-IC)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (3-IC):
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、 以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10 环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C 1-10 alkyl substituted by cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3中的整数；t is an integer arbitrarily selected from 0, 1, 2, and 3; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(3-ID)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (3-ID):
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; L1、L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L1 , L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、 以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted by 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10 环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C 1-10 alkyl substituted by cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl , saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl . , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其具有式(3-IE)结构：
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product has the structure of formula (3-IE):
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2)C(Rd1 ) ＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选 地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on R 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl; or any two adjacent R 1 together with the atoms to which they are attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl , saturated or partially saturated cycloalkyl, heterocyclyl is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH 3 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 3-10 alkyl substituted with C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 heterocyclyl; R 1 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and saturated or partially saturated C 3-6 cycloalkyl, and C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、五氟化硫基、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino , C3-10 heterocycloalkylamino , C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10 环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C 1-10 alkyl substituted by cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(3-IF)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product, is characterized in that it has a structure of formula (3-IF),
其中，in, 环A任意独立地代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；Ring A arbitrarily and independently represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, and the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring, or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; X独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1- 3烷氧基、烯基、炔基；X is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1)(Rd2 ) -, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1- 3. Alkoxy, alkenyl, alkynyl; L2和L3各自独立地选自不存在、单键、-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L2和L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； L2 and L3 are each independently selected from the group consisting of absence, a single bond, -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 )( Rd2)C(Rd1 ) ＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L2 and L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; X1和X2独立地选自N或CR1； X1 and X2 are independently selected from N or CR1 ; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或 部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or The R 1 is substituted with a partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl group and the C 1-6 alkoxy group are optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups. The hydrogen group on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-10烷基、C2-10烯基、C2- 10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1- 6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C3-10 cycloalkylsulfonyl and C3-10 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form a 5-6 membered aryl or heteroaryl group together with the atoms to which they are attached, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with 1 to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen on Z is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每个R可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Each R may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl , C3-10 saturated, partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted by C3-10 cycloalkyl , C3-10 heterocyclyl , C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Ra和Rb任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Ra和Rb或Ra和R2或Ra和R1也可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Ra and Rb are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl ; wherein the C1-10 alkyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted by C3-10 cycloalkyl or C3-10 heterocyclyl C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo , CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or Ra and Rb or Ra and R2 or Ra and R1 can also be connected to form a 3-30 membered ring structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; further, the hydrogen on Ra is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C 1-6 alkyl, C 1-6 alkoxy, -NH2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2- 10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10 环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或更进一步地Rd1、Rd2、Rd3、Rd4上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , and R d4 may be the same or different and are independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 3-10 C 1-10 alkyl substituted by cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; Further, the hydrogen on R d1 , R d2 , R d3 , and R d4 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially saturated cycloalkyl or heterocyclic group; or any R d1 , R d2 , R d3 , and R d4 are substituted with each other or/and R 1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 每一个Rd5、Rd6、Rd7可以相同或不同，且彼此任意独立地选自C1-10烷基、C2-10炔基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、烷基、烷氧基、烷硫基、环烷基、杂环烷基、环烷基硫基、杂环烷基硫基、杂环烷氧基、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分饱和环烷基或杂环基的取代基取代；或者任意的Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each Rd5 , Rd6 , and Rd7 may be the same or different and are arbitrarily and independently selected from C1-10 alkyl, C2-10 alkynyl, C2-10 heteroalkyl, C3-10 cycloalkyl , C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl; further, the hydrogen on Rd5 , Rd6 , and Rd7 is optionally replaced by one or more selected from hydrogen, deuterium, halogen, oxo, CN, OH, alkyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkylthio, heterocycloalkylthio, heterocycloalkyloxy, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and C or any of R d5 , R d6 , and R d7 are each other or/and R 1 or R 2 and the atoms to which they are attached together to form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclic group is optionally substituted by a saturated or partially saturated C 3-6 cycloalkyl group, and the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more saturated or partially saturated C 3-6 cycloalkyl groups ... , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3中的整数。t is an integer arbitrarily selected from 0, 1, 2, and 3. 根据权利要求1-5任一项所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(7-ID)结构，
The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that it has a structure of formula (7-ID),
其中，in, X任意独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且X上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；X is arbitrarily and independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C(Rd1)＝C (Rd1 ) -, -C( Rd1 )( Rd2 )C( Rd1 )＝C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on X is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C1-3 alkoxy, alkenyl, alkynyl; 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基， 其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, -YQ or M group; or optionally two R 2 can form together with the atoms to which they are attached a 5-6 membered aryl or heteroaryl group, a 3-8 membered saturated or partially saturated cycloalkyl group, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl are optionally substituted by one or more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基； 且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d 6)-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2 -, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 ) -, -C(Rd1)(Rd2)S(＝O)2-, or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl , C5-12 membered aryl, C4-12 saturated or partially saturated heterocyclic aryl; and the hydrogen on L 1 , L 2 or L 3 is further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 are substituted with each other or/and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; r任意地选自0、1和2中的整数；r is an integer arbitrarily selected from 0, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(7-IE)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product, is characterized in that it has a structure of formula (7-IE),
其中，in, 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基；Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、- C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, - C(R d1 )(R d2 )C(R d1 )=C(R d1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 are substituted with each other or/and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; r任意地选自0、1和2中的整数；r is an integer arbitrarily selected from 0, 1 and 2; 优选地，所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(7-IF)结构，
Preferably, the compound, its pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product, is characterized in that it has a structure of formula (7-IF),
其中，in, 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、-CN、-OH、-SH和-NH2、-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl , dialkylphosphonyl , alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q或M基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代； Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 may be taken together with the atoms to which they are attached to form a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; M任意独立地选自 M is arbitrarily and independently selected from 每一个L1、L2或L3可以相同或不同，且各自独立地选自-C(Rd1)(Rd2)-、-C(＝Rd1)-、-(Rd1)P(＝O)-、＝C(Rd1)-、NH、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(Rd1)(Rd2)C(＝O)-、-C(Rd1)(Rd2)C(＝S)-、-C(Rd1)(Rd2)S(＝O)-、-C(Rd1)(Rd2)S(＝O)2-、-C(＝O)C(Rd1)(Rd2)-、-C(＝S)C(Rd1)(Rd2)-、-S(＝O)C(Rd1)(Rd2)-、-C(Rd1)(Rd2)S(＝O)2-或C3- 10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C5-12元芳基、C4-12饱和或部分饱和的杂环芳基；且L1、L2或L3上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基、烯基、炔基； Each L1 , L2 or L3 may be the same or different and is independently selected from -C( Rd1 )( Rd2 )-, -C(＝ Rd1 )-, -( Rd1 )P(＝O)-, ＝C( Rd1 )-, NH, -C( Rd1 )(Rd2)C( Rd1 )( Rd2 )-, -C( Rd1 )＝C( Rd1 )-, -C( Rd1 ) (Rd2)C(Rd1 ) ＝ C( Rd1 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -NHC(R d1 )(R d2 )-, -C(R d1 )(R d2 )NH-, -C(＝O)N(R d3 )-, -N(R d4 )-, -C(＝NR d5 )-, -S(＝O) 2 N(R d6 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)-, -S(＝O) 2 -, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -C(R d1 )(R d2 )S(＝O)-, -C( Rd1 )( Rd2 )S(＝O) 2- , -C(＝O)C( Rd1 )( Rd2 )-, -C(＝S)C( Rd1 )( Rd2 )-, -S(＝O)C( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )S(＝O) 2- , or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C5-12 membered aryl, C4-12 saturated or partially saturated heterocycloaryl; and the hydrogen on L1 , L2 or L3 is further optionally substituted with one or more substituents, and the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O＝, OH, C1-3 alkyl, C 1-3 alkoxy, alkenyl, alkynyl; Z独立地选自不存在、C(Rd1)(Rd2)、O、NRd1、-C(Rd1)(Rd2)C(Rd1)(Rd2)-、-C(Rd1)＝C(Rd1)-、-C(Rd1)(Rd2)C(Rd1)＝C(Rd1)-、-OC(Rd1)(Rd2)-、-C(Rd1)(Rd2)O-、-NHC(Rd1)(Rd2)-、-C(Rd1)(Rd2)NH-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-N(Rd7)-、-O-、-S-、-C(＝O)O-、-OC(＝O)-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、C4-10饱和或部分饱和的芳基、C4-10饱和或部分饱和的杂芳基；且Z1、Z2上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；Z is independently selected from absent, C( Rd1 )( Rd2 ), O, NRd1 , -C( Rd1 )( Rd2 )C( Rd1 )( Rd2 )-, -C( Rd1 )=C( Rd1 )-, -C( Rd1 )( Rd2 )C( Rd1 )=C( Rd1 )-, -OC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )O-, -NHC( Rd1 )( Rd2 )-, -C( Rd1 )( Rd2 )NH-, -C(═O)N( Rd3 )-, -N( Rd4 )-, -C( ═NRd5 )-, -S(═O) 2N ( Rd6 )-, -N(Rd7)-, -O-, -S-, -C( ═O )O-, -OC(═O)-, -C(═O)-, -C(═S)-, -S(═O)-, -S(═O) 2- or C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C4-10 saturated or partially saturated aryl, C 4-10 saturated or partially saturated heteroaryl groups; and the hydrogen groups on Z 1 and Z 2 are further optionally substituted with one or more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个Ra相同或不同，且任意独立地选自氢、氘、卤素、氰基、羧基、酰胺基、氨酰基、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地，Ra上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；更进一步地Ra上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each Ra is the same or different and is arbitrarily and independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, amide, aminoacyl, NH2 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C1-10 alkylacyl, C1-10 alkylsulfonyl, C2-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl substituted with C3-10 cycloalkyl or C3-10 heterocyclyl ; further, the hydrogen on Ra is optionally substituted with 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C3-10 saturated or partially substituted cycloalkyl or heterocyclyl; further R The hydrogen on a is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; R6、R7和R8任意独立地选自氢、氘、NH2、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；其中，所述的C1-10烷基、C2-10炔基或C1-10烷氧基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基任选地被1至多个选自氢、氘、卤素、氧代、CN、OH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者R6和R7可以连接起来一起形成3-30元环状结构，所述的环状结构可以为单环、双环、桥环或螺环结构，且可任意含有0至多个杂原子或不饱和键；更进一步地R6、R7和R8上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；R 6 , R 7 and R 8 are arbitrarily and independently selected from hydrogen, deuterium, NH 2 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; wherein the C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 1-10 alkylacyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl, or M group C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH and C 3-10 saturated or partially substituted cycloalkyl or heterocyclyl; or R 6 and R 7 can be linked together to form a 3-30 membered cyclic structure, which can be a monocyclic, bicyclic, bridged or spirocyclic structure, and can arbitrarily contain 0 to more heteroatoms or unsaturated bonds; furthermore, the hydrogen on R 6 , R 7 and R 8 is optionally substituted by 1 to more substituents selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxy, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl; 每一个Rd1、Rd2、Rd3、Rd4、Rd5、Rd6或Rd7可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3- 10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7上的氢任选地被1至多个选自选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者任意的Rd1、Rd2、Rd3、Rd4、Rd5、Rd6、Rd7彼此之间或/和R1或R2及其附着的原子一起形成5-30元杂芳基，5-30元饱和或部分饱和环烷基、5-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d1 , R d2 , R d3 , R d4 , R d5 , R d6 or R d7 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, or M group; further, R d1 , R The hydrogen on Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methylsulfonylamino, or -COOH and a C3-10 saturated or partially substituted cycloalkyl or heterocyclic group; or any of Rd1 , Rd2 , Rd3 , Rd4 , Rd5 , Rd6 , and Rd7 are substituted with each other or/and R1 or R 2 and the atoms to which it is attached together form a 5-30 membered heteroaryl, a 5-30 membered saturated or partially saturated cycloalkyl, or a 5-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1、2、3、4中的整数；t is an integer arbitrarily selected from 0, 1, 2, 3, and 4; r任意地选自0、1和2中的整数。r is an integer arbitrarily selected from 0, 1 and 2. 根据权利要求1-6任一项所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(8-I)结构，
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that it has a structure of formula (8-I),
其中，in, 每一个R1可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R1上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1-10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R1与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 1 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; and R The hydrogen on 1 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, C3-10 heterocyclyl; or any two adjacent R 1 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF3 , C1-6 alkyl, C1-6 alkoxy, -NH2 , -NHC1-6 alkyl, -N( C1-6 alkyl) 2 , =O, and a saturated or partially saturated C3-6 cycloalkyl, and the C1-6 alkyl and C1-6 alkoxy are optionally substituted by one to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF3 , OH, OCH3 , OCH2CH3 , a saturated or partially saturated C3-6 cycloalkyl. and the hydrogen on R 1 is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; 每一个R2可以相同或不同，彼此独立地选自氢、氘、卤素、氨基、羟基、巯基、五氟化硫基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷基氨基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、N，N-二(C1-10烷基)氨基、C1-10烷基氧基、C1-10烷基酰基、C1-10烷基氧基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、C3-10环烷基胺基、C3-10杂环烷基氨基、C3-10环烷氧基、C3-10杂环烷氧基、C3-10环烷基酰基、C3-10环烷氧基乙酰基、C3-10环烷基磺酰基和C3-10环烷基亚磺酰基、-Y-Q基团；或者任选地两个R2可以与其附着的原子一起形成5-6元芳基或杂芳基，3-8元饱和或部分饱和环烷基、3-8元饱和或部分饱和杂环基，其中，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、杂环基任选地被1至多个选自氢、氘、烷基、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3的基团取代；且R2上的氢任选地被1至多个选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、氧基、卤代烷基、氘代烷基以及饱和或部分饱和的C3-6环烷基或杂环烷基取代；Each R2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, pentafluorosulfur, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkylamino, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, N,N-di( C1-10 alkyl)amino, C1-10 alkyloxy, C1-10 alkylacyl, C1-10 alkyloxy, C1-10 alkylsulfonyl, C1-10 alkylsulfinyl, C3-10 cycloalkylamino, C3-10 heterocycloalkylamino, C3-10 cycloalkyloxy, C3-10 heterocycloalkyloxy, C3-10 cycloalkylacyl, C3-10 cycloalkyloxyacetyl, C or optionally two R 2 can form together with the atoms to which they are attached a 5-6 membered aryl or heteroaryl, a 3-8 membered saturated or partially saturated cycloalkyl, a 3-8 membered saturated or partially saturated heterocyclic group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally substituted with one to more groups selected from hydrogen, deuterium, alkyl, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ; and the hydrogen on R 2 is optionally substituted with one to more groups selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxo, haloalkyl, deuterated alkyl, and saturated or partially saturated C 3-6 cycloalkyl or heterocycloalkyl substituted; 每一个R3可以相同或不同，且彼此独立地选自氢、氘、卤素、五氟化硫基、-CN、-OH、-SH和-NH2、-COOH或选自C1-10烷基、C2-10烯基、C2-10炔基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物或M基团；且R3上的氢任选最佳被1至多个选自H、氘、卤素、OCH3、C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱和或部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基的取代基取代；或者任意两相邻的R3与其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的芳基、杂芳基、饱和或部分饱和的环烷基、杂环基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代。且R1上的氢任选地最佳被 1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each R 3 may be the same or different and is independently selected from hydrogen, deuterium, halogen, sulfur pentafluoride, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute or M group ; and R The hydrogen on R3 is optionally substituted with one or more substituents selected from H, deuterium, halogen, OCH3 , C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl or C1-10 alkoxy, C2-10 heteroalkyl, C3-10 saturated or partially saturated cycloalkyl, C3-10 saturated or partially saturated heterocycloalkyl, C1-10 alkyl substituted with C3-10 cycloalkyl or C3-10 heterocycloalkyl, C2-10 heteroalkyl substituted with C3-10 cycloalkyl, or C3-10 heterocyclyl; or any two adjacent R R 3 and the atoms to which it is attached form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclyl, and the hydrogen on the aryl, heteroaryl, saturated or partially saturated cycloalkyl, or heterocyclyl is optionally substituted by a group selected from hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , =O, and a saturated or partially saturated C 3-6 cycloalkyl, and the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. And the hydrogen on R 1 is optionally substituted by a group selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , a saturated or partially saturated C 3-6 cycloalkyl. substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; Y任意独立地选自O、S或NR；Y is arbitrarily and independently selected from O, S or NR; Q任意代表着3-20元环状结构，其可以是单环、双环或三环结构，所述的环状结构可以为芳环、杂芳环、脂肪环、杂环、桥环或螺环或由芳环、杂芳环、脂肪环、杂环、桥环组合而成的并环结构；且环Q上的氢任选地最佳被1至多个选自氢、氘、卤素、氧代物、烷基、烯基、炔基、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Q arbitrarily represents a 3-20 membered cyclic structure, which may be a monocyclic, bicyclic or tricyclic structure, wherein the cyclic structure may be an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a bridged ring or a spirocyclic ring or a cyclic structure composed of an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring and a bridged ring; and the hydrogen on the ring Q is optionally substituted with one or more groups selected from hydrogen, deuterium, halogen, oxo, alkyl, alkenyl, alkynyl, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl; R9独立地选自氢、氘、卤素、-CN、卤代烷基、卤代烷氧基、氘代烷基、氘代烷氧基、-OH、-SH和-NH2、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH或选自C1- 10烷基、C2-10烯基、C2-10炔基或C1-10烷氧基、C2-10杂烷基、C3-10饱、部分饱和的环烷基、C3-10饱和或部分饱和的杂环烷基、芳基、杂芳基、被C3-10环烷基或C3-10杂环烷基取代的C1-10烷基、被C3-10环烷基取代的C2-10杂烷基、C3-10杂环基、C1-10烷基取代的羧基或羧基替代物；且R上的氢进一步任选地最佳被1至多个取代基取代，所述的取代基任意选自氢、氘、卤素、烷基、卤代烷基、氰基、氰乙基、O＝、OH、C1-3烷基、C1-3烷氧基；R 9 is independently selected from hydrogen, deuterium, halogen, -CN, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, -OH, -SH and -NH 2 , dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated, partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl , C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; and the hydrogen on R is further optionally substituted with 1 to more substituents, wherein the substituents are arbitrarily selected from hydrogen, deuterium, halogen, alkyl, haloalkyl, cyano, cyanoethyl, O=, OH, C 1-3 alkyl, C 1-3 alkoxy; Rd1和Rd2任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1-10烷氧基、C2-50烯基酰基、C10- 50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3- 10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基或M基团；更进一步地Rd1或Rd2上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3-10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Rd1和Rd2及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；R d1 and R d2 are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl or M group; further R d1 or R The hydrogen on d2 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or R d1 and R d2 and the atoms to which they are attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted with hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups; 每一个Rd3和Rd4可以相同或不同，且彼此任意独立地选自氢、氘、卤素、NH2、C1-10烷基、C2-10炔基或C1- 10烷氧基、C2-50烯基酰基、C10-50烯基烷基酰基或C10-50烷基烯基烷基酰基、C1-10烷基酰基、C1-10烷基磺酰基、C2-10杂烷基、C3-10环烷基、C3-10杂环烷基、经C3-10环烃基取代的C1-10烷基或由C3-10环烷基、C3-10杂环烷基取代的C3-10杂环基；更进一步地Rd3和Rd4上的氢任选地被1至多个选自氢、氘、卤素、氧代、CN、OH、乙酰基、二烷基膦酰基、烷基磺酰基、磺酰基、烷基亚磺酰基、氨磺酰基、胺磺酰胺基、甲磺酰氨基或-COOH和C3- 10饱和或部分取代的基团饱和环烷基或杂环基的取代基取代；或者Rd3和Rd及其附着的原子一起形成5-30元杂芳基，3-30元饱和或部分饱和环烷基、3-30元饱和或部分饱和杂环基，且所述的杂芳基、饱和或部分饱和的环烷基、杂环烷基上的氢任选地被选自氢、氘、卤素、-CN、-OH、CF3、C1-6烷基、C1-6烷氧基、-NH2、-NHC1- 6烷基、-N(C1-6烷基)2、＝O、以及饱和或部分饱和的C3-6环烷基取代，且C1-6烷基和C1-6烷氧基任选地被1至多个选自氢、氘、卤素、氧代物、CN、CF3、OH、OCH3、OCH2CH3、饱和或部分饱和的C3-6环烷基的基团取代；Each of R d3 and R d4 may be the same or different and are arbitrarily and independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl; further, R d3 and R d4 are each independently selected from hydrogen, deuterium, halogen, NH 2 , C 1-10 alkyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-50 alkenyl acyl, C 10-50 alkenylalkyl acyl or C 10-50 alkylalkenylalkyl acyl, C 1-10 alkyl acyl, C 1-10 alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocyclyl; further, R d3 and R The hydrogen on d4 is optionally substituted with one to more substituents selected from hydrogen, deuterium, halogen, oxo, CN, OH, acetyl, dialkylphosphonyl, alkylsulfonyl, sulfonyl, alkylsulfinyl, sulfamoyl, sulfamoyl, methanesulfonylamino or -COOH and C 3-10 saturated or partially substituted saturated cycloalkyl or heterocyclic group; or R d3 and R d and the atoms to which they are attached together form a 5-30 membered heteroaryl, a 3-30 membered saturated or partially saturated cycloalkyl, or a 3-30 membered saturated or partially saturated heterocyclic group, and the hydrogen on the heteroaryl, saturated or partially saturated cycloalkyl, or heterocycloalkyl is optionally substituted with hydrogen, deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , ＝O, and saturated or partially saturated C The C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted by one or more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 , saturated or partially saturated C 3-6 cycloalkyl groups; 所述的杂代表着任意独立地选自O、N、S、P、-P＝O、S＝O或SO2的杂原子或基团及其同位素；The hetero represents any heteroatom or group independently selected from O, N, S, P, -P=O, S=O or SO2 and isotopes thereof; 所述的卤素任意独立地选自F、Cl、Br、I及其同位素；The halogen is arbitrarily and independently selected from F, Cl, Br, I and isotopes thereof; m任意地选自0、1、2、3、4中的整数；m is an integer arbitrarily selected from 0, 1, 2, 3, and 4; n任意地选自0、1、2、3、4和5中的整数；n is an integer arbitrarily selected from 0, 1, 2, 3, 4 and 5; t任意地选自0、1和2中的整数。t is arbitrarily selected from an integer among 0, 1 and 2. 前提是当R9为烷基时，R1或R3至少有一个为氰基或五氟化硫基，或者Rd4、Rd1和Rd2不同时为氢。Provided that when R 9 is an alkyl group, at least one of R 1 or R 3 is a cyano group or a sulfur pentafluoride group, or R d4 , R d1 and R d2 are not hydrogen atoms at the same time. 根据权利要求1-7任一项所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，其具有式(II)结构，
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that it has a structure of formula (II):
(II)其中，(II) Among them, A选自C6-10芳基、5-10元杂环基； A is selected from C 6-10 aryl, 5-10 membered heterocyclic group; E选自N或CH2；当E为N时，为双键；当E为CH2时，为单键；E is selected from N or CH 2 ; when E is N, is a double bond; when E is CH 2 , is a single bond; R选自C1-6烷基、C6-10芳基、5-10元杂芳基；R is selected from C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl; R0选自R9选自无取代或任选被一个、两个或更多个R91取代的下列基团：C1- 6烷基、C2-6烯基；每个R91相同或不同，彼此独立地选自H、OH、-N+(C1-6烷基)；R10选自-C1-6烷基-S(O)2NH2；R 0 is selected from R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 91 : C 1-6 alkyl, C 2-6 alkenyl; each R 91 is the same or different and is independently selected from H, OH, -N + (C 1-6 alkyl); R 10 is selected from -C 1-6 alkyl-S(O) 2 NH 2 ; R1选自H、CN、卤素、C1-6烷基、C1-6烷氧基；或者两个R1与其各自连接的原子形成3-8元杂环基；R 1 is selected from H, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy; or two R 1 and the atoms to which they are attached form a 3-8 membered heterocyclic group; R2选自H、卤素、五氟化硫基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基；R 2 is selected from H, halogen, pentafluorosulfur, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy; Rd1、Rd2相同或不同，彼此独立地选自H、C1-6烷基、C1-6烷氧基；R d1 and R d2 are the same or different and are independently selected from H, C 1-6 alkyl, and C 1-6 alkoxy; m选自0、1、2、3、4、5；m is selected from 0, 1, 2, 3, 4, 5; n选自0、1、2、3、4、5；n is selected from 0, 1, 2, 3, 4, 5; w选自0或1；w is selected from 0 or 1; 优选地，A选自苯基、5-6元杂环基；Preferably, A is selected from phenyl, 5-6 membered heterocyclic group; 优选地，A选自苯基、哌啶基(例如)；Preferably, A is selected from phenyl, piperidinyl (e.g. ); 优选地，选自 Preferably, Selected from 优选地，选自 Preferably, Selected from 优选地，R选自C1-3烷基、苯基、5-6元杂芳基；Preferably, R is selected from C 1-3 alkyl, phenyl, 5-6 membered heteroaryl; 优选地，R选自甲基、苯基、噻吩基(例如)；Preferably, R is selected from methyl, phenyl, thienyl (e.g. ); 优选地，R9选自无取代或任选被一个、两个或更多个R91取代的下列基团：甲基、丙基、丙烯基；每个R91相同或不同，彼此独立地选自H、OH、 Preferably, R 9 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R 91 : methyl, propyl, propenyl; each R 91 is the same or different and is independently selected from H, OH, 优选地，R9选自甲基、 Preferably, R 9 is selected from methyl, 优选地，R10选自 Preferably, R 10 is selected from 优选地，R1选自H、CN、卤素；或者两个R1与其各自连接的原子形成4元杂环基；Preferably, R 1 is selected from H, CN, halogen; or two R 1 and the atoms to which they are attached form a 4-membered heterocyclic group; 优选地，R1选自H、Cl、CN；或者两个R1与其各自连接的原子形成 Preferably, R 1 is selected from H, Cl, CN; or two R 1 and the atoms to which they are attached form 优选地，选自 Preferably, Selected from 优选地，选自 Preferably, Selected from 优选地，R2选自H、卤素、五氟化硫基、卤代C1-3烷基；Preferably, R 2 is selected from H, halogen, pentafluorinated sulfur, halogenated C 1-3 alkyl; 优选地，R2选自H、F、三氟甲基、五氟化硫基；Preferably, R 2 is selected from H, F, trifluoromethyl, pentafluorosulfur; 优选地，Rd1、Rd2相同或不同，彼此独立地选自H、C1-3烷基；Preferably, R d1 and R d2 are the same or different and are independently selected from H, C 1-3 alkyl; 优选地，Rd1、Rd2相同或不同，彼此独立地选自H、甲基。Preferably, R d1 and R d2 are the same or different, and are independently selected from H and methyl. 根据权利要求1-7任一项所述的化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物，其特征在于，所述化合物选自本发明说明书中所公开结构的新化合物。The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof, characterized in that the compound is selected from the novel compounds with structures disclosed in the specification of the present invention. 一种药物组合物，其包含治疗有效量的权利要求1-8任一项所述化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物中的至少一种。A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope thereof. 权利要求1-8任一项所述化合物、其药学上可接受的盐、溶剂合物、对映异构体或同位素取代物在制备用于预防和/或治疗CB1信号通路异常导致的相关疾病的药物中的应用。 Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, enantiomer or isotope substituted product thereof, in the preparation of a medicament for preventing and/or treating related diseases caused by abnormal CB1 signaling pathway.
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