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WO2018214980A1 - Amide aromatique en tant qu'inhibiteur de kv2.1 et son procédé de préparation, composition pharmaceutique et utilisation associée - Google Patents

Amide aromatique en tant qu'inhibiteur de kv2.1 et son procédé de préparation, composition pharmaceutique et utilisation associée Download PDF

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Publication number
WO2018214980A1
WO2018214980A1 PCT/CN2018/088561 CN2018088561W WO2018214980A1 WO 2018214980 A1 WO2018214980 A1 WO 2018214980A1 CN 2018088561 W CN2018088561 W CN 2018088561W WO 2018214980 A1 WO2018214980 A1 WO 2018214980A1
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nra
unsubstituted
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straight
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English (en)
Chinese (zh)
Inventor
徐柏玲
王晓良
周洁
王伟平
刘冬
郭婷婷
王雪
冯楠
王晓宇
徐少峰
李江
王玲
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Institute of Materia Medica of CAMS and PUMC
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Institute of Materia Medica of CAMS and PUMC
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Priority to CN201880033787.8A priority Critical patent/CN111108092A/zh
Publication of WO2018214980A1 publication Critical patent/WO2018214980A1/fr
Anticipated expiration legal-status Critical
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    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a novel structure of an aromatic Kv2.1 inhibitor of the formula I, a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a composition comprising one or more of such compounds, and a compound which inhibits Kv2 .1 Diseases associated with the treatment of kv2.1, and in the preparation, prevention and/or treatment of psychotropic diseases, metabolic diseases and cardiovascular and cerebrovascular diseases.
  • Kv channels Voltage-gated potassium channels
  • Kv channels are widely found on many excitable cell membranes and are involved in the regulation of cell electrophysiological activity and endocrine.
  • Kv channels can regulate the depolarization of action potentials.
  • non-excitable cells it can regulate the resting potential of cell membranes. Therefore, Kv channels can participate in many electrophysiological activities, which are immune, metabolic, and Cardiovascular and neuropsychiatric diseases are even important therapeutic targets for cancer [Molecular pharmacology, 2011, 80(6): 959-964].
  • Kv channels can be divided into 12 subfamilies according to gene coding, such as Kv1, Kv2, Kv3, etc.
  • Kv2.1 is a subtype of voltage-gated potassium channels that are distributed in various tissues of mammals, including brain neurons, central nervous system neurons, cardiomyocytes, skeletal muscle, cardiovascular smooth muscle, and beta islet cells. And some cancer cells play an important role in regulating neuronal excitability, neuronal apoptosis and insulin secretion. The regulation of this target is helpful for the research and treatment of many common diseases such as senile dementia, epilepsy, diabetes, stroke, depression and tumor. Therefore, the mechanism of action and regulation of Kv2.1 is very important. Significance [Pharmacological Reports. 2016, 457–461; Brain research. 2010, 1359: 67-74].
  • Kv2.1 selective blockers are peptide compounds derived from the venoms of spiders, mites and other animals, such as: scorpion toxin-I, scorpion toxin-III and GxTX- 1E, etc., but these peptides have limited sources, limiting their use in pharmacology. At present, most of the Kv2.1 small molecule blockers reported in the literature are found by the method of general screening.
  • the inhibitory activity is weak, and the selectivity is poor: SC-791 [Brain research, 2010, 1359: 67-74], propafenone [ Naunyn-Schmiedeberg's archives of pharmacology, 2000, 362(1): 22-31], trifluoperidone [Brain research, 1997, 761(1): 42-50], 17 ⁇ -estradiol [Acta Pharm Sin (Pharmaceutical) Journal), 2004, 39(9): 686-690], Bogfuran (AF-5) [Acta Pharm Sin (Pharmaceuticals of Pharmaceutical Sciences), 2013, 48(1): 38-44] and the like.
  • This patent is designed to synthesize a new structure of aromatic Kv2.1 inhibitors designed to provide a new material basis for the treatment of Kv2.1-related diseases.
  • the technical problem solved by the present invention is to provide an amidamide-containing derivative and a physiologically acceptable salt represented by Formula I, a process for the preparation thereof, a pharmaceutical composition, and a preparation thereof for use in the preparation of a Kv2.1 inhibitor and a potential drug thereof.
  • the present invention provides the following technical solutions:
  • a first aspect of the present invention provides an amidamide derivative or a physiologically acceptable salt as shown in Formula I:
  • X is selected from CR x , N; Y is selected from CR y , N; Z is selected from CR z , N; X, Y, Z may be N alone, two N and/or three simultaneously N;
  • R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl And a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • R 1 is selected from the group consisting of:
  • a substituted or unsubstituted C1-8 straight or branched alkyl group a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group
  • the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H , C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene,
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted.
  • a nitrogen-containing six-membered aromatic heterocyclic ring a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1-4 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , wherein Ra' 1 , Ra' 2 , Ra' 3 Rb' 1 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 ,
  • R 2 is selected from the group consisting of:
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 , Re 7 , Rf 5 , Rf 6 may also be independently selected from the substitution or the non- Substituted C3-7 cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected From C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 And NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 , Re 7 , Rf 5 , Rf 6 may also be independently selected from the substitution or the non- a substituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1- 4 linear or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 ,
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from H, a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein The substituents are selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , Wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 may also be independently selected from substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 3-8 membered ring oxygen.
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 may also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or non-substituted.
  • a substituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1-4 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, sub Methanedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1 , Ra' 4 , Ra' 5 Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8
  • the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • Heterocyclic ring may contain a hetero atom, may contain a plurality of hetero atoms, hetero atoms selected from O, N, S;
  • n is selected from 2, 3; wherein the halogens include F, Cl, Br;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 3 is selected from the group consisting of the following groups or structural fragments:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 9 and R 10 may be independently selected from the group consisting of:
  • R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;
  • the X, Y, and Z are independently selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , and CNHC 2 H 5 .
  • preferred compounds and physiologically acceptable salts of the present invention include, but are not limited to, the compounds of the formula (IA):
  • X is selected from CR x , N; Y is selected from CR y , N; Z is selected from CR z , N; X, Y, Z may be N alone, two N and/or three simultaneously N;
  • R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl And a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • R 2 is selected from the group consisting of:
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 , Re 7 , Rf 5 , Rf 6 may also be independently selected from the substitution or the non- Substituted C3-7 cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected From C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 And NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 , Re 7 , Rf 5 , Rf 6 may also be independently selected from the substitution or the non- a substituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1- 4 linear or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 ,
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from H, a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein The substituents are selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , Wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 may also be independently selected from substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 3-8 membered ring oxygen.
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 may also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or non-substituted.
  • a substituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1-4 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, sub Methanedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1 , Ra' 4 , Ra' 5 Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8
  • the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • Heterocyclic ring may contain a hetero atom, may contain a plurality of hetero atoms, hetero atoms selected from O, N, S;
  • n is selected from 2, 3; wherein the halogens include F, Cl, Br;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 3 is selected from the group consisting of the following groups or structural fragments:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 4 is selected from the group consisting of the following groups or structural fragments:
  • an azacycloalkyl group which may be selected from a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring, a substituted or unsubstituted 3-8 membered ring azacycloalkane a substituent wherein the substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , and NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl
  • (3) may be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branch Alkenyl, halogen-substituted C1-4 straight or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa '10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1
  • R 9 and R 10 may be independently selected from the group consisting of:
  • R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;
  • the X, Y, and Z are independently selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , and CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA of the present invention include, but are not limited to, the compounds of the formula IA-1:
  • X is selected from CR x , N; Y is selected from CR y , N; Z is selected from CR z , N; X, Y, Z may be N alone, two N and/or three simultaneously N;
  • R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl And a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • R 3 is selected from the group consisting of the following groups or structural fragments:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 4 is selected from the group consisting of the following groups or structural fragments:
  • an azacycloalkyl group which may be selected from a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring, a substituted or unsubstituted 3-8 membered ring azacycloalkane a substituent wherein the substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , and NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl
  • (3) may be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branch Alkenyl, halogen-substituted C1-4 straight or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa '10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1
  • R 7 and R 8 may be independently selected from the group consisting of:
  • Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 may also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted 3-8 membered rings.
  • R 9 and R 10 may be independently selected from the group consisting of:
  • R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;
  • the X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA-1 of the present invention include, but are not limited to, the compounds of the formula IA-1a:
  • R 11 is selected from the group consisting of:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • A is selected from CR a , N; B is selected from CR b , N; C is selected from CR c , N; D is selected from CR d , N; A, B, C, D can be N alone, and both N and / or three at the same time N;
  • R a , R b , R c and R d are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and nitrogen
  • the heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched chain An alkyl group, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6
  • the X, Y, Z, A, B, C, D are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA-1a of the present invention include, but are not limited to, the compounds of the formula IA-1a-1:
  • R 4 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined for formula IA-1a;
  • R' a , R' b , R' c , R' d , R' x , R' y , R' z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from the group consisting of methyl, ethyl, propyl , isopropyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein The Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra
  • the X', Y', Z', A', B', C', D' are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5, COCH 3, COC 2 H 5, CNHCH 3, CNHC 2 H 5.
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA-1a-1 of the present invention include, but are not limited to, the compounds of the formula IA-1a-1a:
  • R 4 , R 9 , R 10 , A′, B′, C′, D′, X′, Y′, Z′ are the same as those of the formula IA-1a-1;
  • R' a , R' b , R' c , R' d , R' x , R' y , R' z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from the group consisting of methyl, ethyl, propyl , isopropyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein The Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra
  • R '7, R' 8 may be independently selected from a group or structure fragments:
  • Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 may also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-6 membered rings.
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the X', Y', Z', A', B', C', D' are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA-1a-1 of the present invention include, but are not limited to, the compounds of the formula IA-1a-1b:
  • R 4 , R 9 , R 10 , A′, B′, C′, D′, X′, Y′, Z′ are identical to those of the formula IA-1a-1a;
  • R' a , R' b , R' c , R' d , R' x , R' y , R' z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from the group consisting of methyl, ethyl, propyl , isopropyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein The Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra
  • R '7, R' 8 may be independently selected from a group or structure fragments:
  • Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 may also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-6 membered rings.
  • Ar' 2 may be independently selected from the group consisting of:
  • a substituted or unsubstituted phenyl group a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopenty
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • the X', Y', Z', A', B', C', D' are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA of the present invention include, but are not limited to, the compounds of the formula IA-2:
  • X is selected from CR x , N; Y is selected from CR y , N; Z is selected from CR z , N; X, Y, Z may be N alone, two N and/or three simultaneously N;
  • R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl And a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • Ar 1 is selected from the group consisting of the following groups or structural fragments:
  • the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from the group consisting of H, C1-4 straight or branched
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 3 is selected from the group consisting of the following groups or structural fragments:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 4 is selected from the group consisting of the following groups or structural fragments:
  • an azacycloalkyl group which may be selected from a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring, a substituted or unsubstituted 3-8 membered ring azacycloalkane a substituent wherein the substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , and NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl
  • (3) may be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branch Alkenyl, halogen-substituted C1-4 straight or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa '10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1
  • R 9 and R 10 may be independently selected from the group consisting of:
  • R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;
  • the X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA-2 of the present invention include, but are not limited to, the compounds of the formula IA-2a:
  • R 11 is selected from the group consisting of:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • A is selected from CR a , N; B is selected from CR b , N; C is selected from CR c , N; D is selected from CR d , N; A, B, C, D can be N alone, and both N and / or three at the same time N;
  • R a , R b , R c and R d are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and nitrogen
  • the heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched chain An alkyl group, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6
  • the X, Y, Z, A, B, C, D are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IA-2a of the present invention include, but are not limited to, the compounds of the formula IA-2a-1:
  • R 4 , Ar 1 , R 9 and R 10 are the same as those of the formula IA-2a;
  • R 11 is selected from the group consisting of:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R' a , R' b , R' c , R' d , R' x , R' y , R' z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from the group consisting of methyl, ethyl, propyl , isopropyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein The Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra
  • the X', Y', Z', A', B', C', D' are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula I of the present invention include, but are not limited to, the compounds of the formula IB:
  • X is selected from CR x , N; Y is selected from CR y , N; Z is selected from CR z , N; X, Y, Z may be N alone, two N and/or three simultaneously N;
  • R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl And a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • R 2 is selected from the group consisting of:
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 , Re 7 , Rf 5 , Rf 6 may also be independently selected from the substitution or the non- Substituted C3-7 cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected From C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 And NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 , Re 7 , Rf 5 , Rf 6 may also be independently selected from the substitution or the non- a substituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1- 4 linear or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 ,
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 are independently selected from H, a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein The substituents are selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , Wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 may also be independently selected from substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted 3-8 membered ring oxygen.
  • Rh 1 , Ri 1 , Rh 2 , Rh 3 , Rh 4 , Ri 2 may also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or non-substituted.
  • a substituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1-4 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, sub Methanedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1 , Ra' 4 , Ra' 5 Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8
  • the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • Heterocyclic ring may contain a hetero atom, may contain a plurality of hetero atoms, hetero atoms selected from O, N, S;
  • n is selected from 2, 3; wherein the halogens include F, Cl, Br;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 3 is selected from the group consisting of the following groups or structural fragments:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 5 and R 6 may be independently selected from the group consisting of:
  • an azacycloalkyl group which may be selected from a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring, a substituted or unsubstituted 3-8 membered ring azacycloalkane a substituent wherein the substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , and NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl
  • (3) may be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branch Alkenyl, halogen-substituted C1-4 straight or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa '10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1
  • R 9 and R 10 may be independently selected from the group consisting of:
  • R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;
  • the X, Y and Z are independently selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IB of the present invention include, but are not limited to, the compounds of the formula IB-1:
  • X, Y, Z, R3, R5, R6, R9, R10 are as defined in the formula IB;
  • R 7 and R 8 may be independently selected from the group consisting of:
  • Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 may also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted 3-8 membered rings.
  • Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 may also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted Or an unsubstituted five-membered aromatic heterocyclic ring wherein the substituent is selected from a C1-4 straight or branched alkyl group, a halogen-substituted C1-4 straight or branched alkyl group, F, Cl, Br, NO 2 , CN Methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa ' 8 CORb' 5 , (CH 2 )nNRa' 9 Rb' 6 , (CH
  • the X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IB-1 of the present invention include, but are not limited to, the compounds of the formula IB-1a:
  • X, Y, Z, R5, R6, R7, R8, R9, R10 are as defined for the formula IB-1;
  • R 11 is selected from the group consisting of:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • A is selected from CR a , N; B is selected from CR b , N; C is selected from CR c , N; D is selected from CR d , N; A, B, C, D can be N alone, and both N and / or three at the same time N;
  • R a , R b , R c and R d are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and nitrogen
  • the heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched chain An alkyl group, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6
  • the X, Y, Z, A, B, C, and D are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IB-1a of the present invention include, but are not limited to, the compounds of the formula IB-1a-1:
  • R5, R6, R7, R8, R9, R10, R11 are as defined for the formula IB-1;
  • R' a , R' b , R' c , R' d , R' x , R' y , R' z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from the group consisting of methyl, ethyl, propyl , isopropyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein The Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra
  • the X', Y', Z', A', B', C', D' are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IB of the present invention include, but are not limited to, the compounds of the formula IB-2:
  • X is selected from CR x , N; Y is selected from CR y , N; Z is selected from CR z , N; X, Y, Z may be N alone, two N and/or three simultaneously N;
  • R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl And a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • Ar 1 is selected from the group consisting of the following groups or structural fragments:
  • the substituent is selected from the group consisting of F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from the group consisting of H, C1-4 straight or branched
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 3 is selected from the group consisting of the following groups or structural fragments:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • R 5 and R 6 may be independently selected from the group consisting of:
  • an azacycloalkyl group which may be selected from a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring, a substituted or unsubstituted 3-8 membered ring azacycloalkane a substituent wherein the substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , and NRa 8 CORb 5 , wherein the Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl
  • (3) may be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branch Alkenyl, halogen-substituted C1-4 straight or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa' 1 , SRa' 2 , NRa' 3 Rb' 1 , COORa' 4 , CONRa' 5 Rb' 2 , NRa' 6 COORb' 3 , SO 2 NRa' 7 Rb' 4 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa '10 , wherein said Ra' 1 , Ra' 2 , Ra' 3 , Rb' 1
  • R 9 and R 10 may be independently selected from the group consisting of:
  • R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;
  • the X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IB-2 of the present invention include, but are not limited to, the compounds of the formula IB-2a:
  • X, Y, Z, R 5 , R 6 , Ar 1 , R 9 , R 10 are as defined for the formula IB-2;
  • R 11 is selected from the group consisting of:
  • Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl Or a nitrogen heterocycloalkyl group may contain one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring or the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms;
  • the aromatic heterocyclic ring may contain a hetero atom or a plurality of hetero atoms, the hetero atom is selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;
  • A is selected from CR a , N; B is selected from CR b , N; C is selected from CR c , N; D is selected from CR d , N; A, B, C, D can be N alone, and both N and / or three at the same time N;
  • R a , R b , R c and R d are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
  • Rb 5 is independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and nitrogen
  • the heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched chain An alkyl group, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra 5 , Rb 2 , Ra 6
  • the X, Y, Z, A, B, C, and D are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • Preferred compounds of the invention and physiologically acceptable salts thereof according to the general formula IB-2a of the present invention include, but are not limited to, the compounds of the formula IB-2a-1:
  • R 5 , R 6 , Ar 1 , R 9 , R 10 , R 11 are as defined for the formula IB-2a;
  • R' a , R' b , R' c , R' d , R' x , R' y , R' z are independently selected from the group consisting of the following atoms or groups or structural fragments, including
  • Rc 1 , Rc 2 , Rc 3 , Rc 4 , Rd 1 , Rd 2 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
  • the Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 may also be independently selected from substituted or unsubstituted C 3-6 cycloalkyl groups, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from the group consisting of methyl, ethyl, propyl , isopropyl, F, Cl, Br, CN, ORa 1 , SRa 2 , NRa 3 Rb 1 , COORa 4 , CONRa 5 Rb 2 , NRa 6 COORb 3 , SO 2 NRa 7 Rb 4 , NRa 8 CORb 5 , wherein The Ra 1 , Ra 2 , Ra 3 , Rb 1 , Ra 4 , Ra
  • the X', Y', Z', A', B', C', D' are independently preferably selected from CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 .
  • preferred compounds include, but are not limited to:
  • a second aspect of the present invention provides a method for preparing the compound of the first aspect, and the technical solution adopted includes the following steps:
  • the synthesis of the arylformamide target compound is carried out by condensation of an acid substituted with a different position at the 2 and 5 positions and a substituted primary amine; wherein the key acid intermediate is 2-hydroxy-5-
  • the nitroaromatic acid, 2-hydroxy-5-bromoaryl(hetero) acid is esterified by the action of thionyl chloride, and then subjected to a substitution reaction and a hydrolysis reaction, or 2-chloro-
  • the 5-nitroaryl(hetero) acid is obtained by nucleophilic substitution reaction with an amine;
  • the other key intermediate, amine 10 is derived from the bromoaryl(hetero)yl acyl compound 7a, which is then subjected to a coupling reaction to condense with hydroxylamine.
  • the reduction reaction is prepared; or the different substituted aryl (hetero) amide compound 7b is sequentially subjected to an addition elimination reaction, reacted with hydroxylamine to prepare a reduction reaction, or is started by a differently substituted cyano compound 7c, and sequentially added.
  • the reaction is eliminated, reacted with hydroxylamine, and reduced.
  • the ⁇ -disubstituted amine 11 is prepared by addition reaction of different substituted cyano compounds; the obtained acid is subjected to condensation reaction with an amine to obtain compounds 12, 15, 17, 20, 23 and 26, and then compounds 12 and 17 , 23 and 26, the target compound is prepared by a reduction reaction, an acylation reaction or a reductive amination reaction.
  • Compounds 15 and 20 were prepared by a coupling reaction to prepare a target compound.
  • Reagents and reaction conditions (a) o-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIEA), N , N-dimethylformamide (DMF), room temperature; or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1-hydroxybenzotriazole, diisopropyl Ethylamine, N,N-dimethylformamide, room temperature; (b) thionyl chloride (SOCl 2 ), anhydrous methanol (Anhydrous MeOH), 60 ° C; (c) RI or R-Br, potassium carbonate (K 2 CO 3 ), anhydrous N,N-dimethylformamide (Anhydrous DMF), 60 ° C; (d) sodium hydroxide (NaOH), tetrahydrofuran / water (THF /
  • the compounds of formula I may exist in solvated or unsolvated forms, and crystallization from different solvents may result in different solvates.
  • the pharmaceutically acceptable salts of the formula I include salts of different acids, such as the salts of the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, Tannin, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.
  • the pharmaceutically acceptable salts of formula I also include various alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and organics which provide physiologically acceptable cations. Salts of bases such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the invention can be prepared by conventional methods.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition includes at least one compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, an injection, a sustained release preparation, a controlled release preparation, or various microparticle delivery systems.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • auxiliary materials used for the manufacture of tablets, capsules and coating agents are conventional auxiliaries such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils. Such as corn oil, peanut oil, olive oil and so on.
  • auxiliaries such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like may also be present in the formulations containing the compounds of the invention.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low-
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulating agent may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.1 to 1000 mg/kg body weight, preferably from 1 to 500 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • a fourth aspect of the present invention provides the use of the compound of the first aspect of the present invention and a pharmaceutically acceptable salt thereof for the preparation of a Kv2.1 inhibitor, for the preparation of a prophylactic and/or treatment of a disease associated with Kv2.1
  • a disease associated with Kv2.1 selected from the treatment of psychotropic diseases, metabolic diseases and cardiovascular and cerebrovascular diseases, in the preparation of Alzheimer's disease, depression, diabetes, The role of drugs in atherosclerosis and stroke-related diseases.
  • the patent application of the aromatic Kv2.1 inhibitor has a very strong inhibitory activity; compared with other ion channels, the compound has very good selectivity for Kv2.1; the in vivo activity shows that it has therapeutic effect on stroke and antidepressant activity. And hypolipidemic activity, improve learning and memory.
  • n 14-16.##p ⁇ 0.01vs. Control group, *p ⁇ 0.05, **p ⁇ 0.01 vs. model group.
  • Figure 4 Effect of Compound 61 on cerebral hypoxia (squeeze method), **p ⁇ 0.01 vs. control group.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS).
  • NMR nuclear magnetic resonance
  • HRMS high resolution mass spectrometry
  • the NMR was measured using Varian mercury 300 or Varian mercury 400, and the solvents were determined to be CDCl 3 , DMSO-d 6 , acetate-d 6 , CD 3 OD, internal standard TMS, and chemical shifts are given in ppm.
  • Mp is the melting point given in ° C and the temperature is not corrected.
  • Silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • DIEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • HBTU O-benzotriazole-tetramethylurea hexafluorophosphate
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • TFA trifluoroacetic acid
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphine palladium
  • K 3 PO 4 potassium phosphate
  • CS 2 CO 3 cesium carbonate
  • PPh 3 triphenylphosphine
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • Zn zinc powder
  • NaH sodium hydride
  • Methyl 2-hydroxy-5-nitrophenylate (5 g, 25.3 mmol) was dissolved in anhydrous DMF (40 mL), K 2 CO 3 (6.982 g, 50.6 mmol) was added and C 2 H 5 I (11. g, 75.9 mmol), heated to 70 ° C for reaction. After the disappearance of the starting material, the mixture was cooled, water was added to precipitate a white solid, and filtered, and the filter cake was washed with water to obtain 5.5 g of a white solid, yield 96%.
  • Methyl 2-ethoxy-5-isobutyrylamino benzoate (271 mg, 1.02 mmol) was placed in a reaction flask, THF (3 mL), MeOH (3 mL), and lithium hydroxide (32 mg, 1.33 mmol) Soluble in water (2mL), drip into the reaction flask, drip, stir the reaction at room temperature, the next day, stop the reaction, concentrate, add water, extract with 10mL of ether, the water layer with dilute hydrochloric acid solution to adjust the pH to about 3, A solid precipitated, suction filtered, and the filter cake was washed with water to give a white solid, 250 mg, yield 97.6%.
  • 3-(thiazol-2-yl)benzaldehyde oxime (1.0 g, 4.90 mmol) was dissolved in ethanol (20 mL) / water (10 mL), EtOAc (EtOAc, EtOAc, EtOAc 24.5 mmol), reacted at room temperature for 4 h, and the starting material disappeared. The reaction was stopped, and the mixture was added with a saturated aqueous solution of sodium bicarbonate, and the mixture was filtered. EtOAc (30 mL, 3).
  • N-([1,1'-Biphenyl]-3-ylmethyl)-2-(dimethylamino)-5-nitrobenzamide (310 mg, 0.83 mmol) was dissolved in methanol (20 mL) Add pd/C (31 mg), EtOAc (3 mL), EtOAc EtOAc (EtOAc) , 2.13 mmol), HATU (809 mg, 2.13 mmol).
  • N-Boc-DL-alanine (284 mg, 1.50 mmol) was dissolved in DCM (20 mL), then DIEA (258 mg, 2.00 mmol), HATU (608 mg, 1.60 mmol) was added, and reacted at room temperature for 30 min, then added 5- Amino-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide (353 mg, 1.00 mmol) was reacted at room temperature for 8 h.
  • N-Boc-4-oxopiperidine (199 mg, 1 mmol) was added to the reaction mixture, DCM (10 mL) was added, and a solution of DAST (0.26 mL, 2 mmol) in DCM (2 mL) After the completion of the reaction, the reaction was stirred for 30 min in an ice bath, and then the mixture was warmed to room temperature. The reaction was stopped after 1.5 h. The reaction mixture was poured into ice water and extracted with DCM (20 mL ⁇ 2), and the organic layer was combined with saturated NaCl (20 mL ⁇ 2) The extract was dried over anhydrous magnesium sulfate (MgSO4).
  • MgSO4 magnesium sulfate
  • tert-Butyl 4,4-difluoropiperidine-1-carboxylate (380 mg, 1.727 mmol) was placed in a reaction flask, DCM (15 mL) was added, then TFA (1.28 mL, 17.27 mmol) After 2 h, the reaction was stopped, concentrated, diethyl ether was added, and the solid was washed, filtered, and filtered, and then washed with diethyl ether to give 325 mg of white solid.
  • N-Boc-3-oxopiperidine (598 mg, 3 mmol) was placed in the reaction mixture, DCM (20 mL) was added, and a solution of DAST (0.78 mL, 6 mmol) in DCM (5 mL) After being added to the reaction flask, the reaction mixture was stirred for 1 hour, and the reaction was stopped. The reaction solution was poured into ice water and extracted with DCM (30 mL ⁇ 2), and the organic layer was washed with saturated NaCl (20 mL ⁇ 2). The residue was dried over MgSO.sub.sub.sub.
  • tert-Butyl 3,3-difluoropiperidine-1-carboxylate 250 mg, 1.13 mmol was placed in a reaction flask, DCM (10 mL) was added, then TFA (0.84 mL, 11.3 mmol) After 2 h, the reaction was stopped, concentrated, diethyl ether was added, and the solid was washed, filtered, and filtered.
  • the tert-butyl 3,3-difluoropyrrolidine-l-carboxylate (830 mg, 4 mmol) was placed in a reaction flask, DCM (20 mL) was added, and then TFA (2.96 mL, 40 mmol) After the reaction was stopped, the mixture was concentrated, and diethyl ether was added, and the solid was washed out, and the mixture was allowed to stand on the freezer layer of the refrigerator, and solid was precipitated, and filtered, and the filter cake was washed with diethyl ether to obtain a white solid (600 mg, yield: 67.8%).
  • N-Boc-DL-alanine (219 mg, 1.02 mmol) was dissolved in DCM (15 mL), then DIEA (175 mg, 1.36 mmol), HATU (414 mg, 1.09 mmol) was added, and reacted at room temperature for 30 min, then added 5 -Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (240 mg, 0.68 mmol).
  • the cyclopentylcarboxylic acid 72 mg, 0.63 mmol was dissolved in DCM (15 mL), then DIEA (163 mg, 1.26 mmol), HATU (319 mg, 0.84 mmol) was added, and reacted at room temperature for 30 min, then 5-amino-2- Ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (150 mg, 0.42 mmol) was reacted at room temperature for 10 h and the material disappeared.
  • Methyl 5-amino-2-ethoxybenzoate (600 mg, 3.08 mmol) was dissolved in anhydrous THF (10 mL). EtOAc (EtOAc, EtOAc. 778mg, 7.70mmol), the reaction was continued 2h, filtered and the filtrate was concentrated, diluted with addition of ethyl acetate (20 mL), a 0.5N aqueous HCl (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10 mL), saturated brine (10 mL), dried over anhydrous Na 2 SO 4, concentrated, PE / EA to give a pale brown solid was recrystallized from 899 mg, yield 97.4%, mp: 95-96 °C.
  • Methyl 5-(4-chlorobutyrylamino)-2-ethoxybenzoate 400 mg, 1.33 mmol was dissolved in THF (15 mL) / water (2 mL). The reaction was carried out for 6 h at room temperature, and the combined reactions 1 and 2 were concentrated, diluted with water (10 mL), and the aqueous layer was washed with diethyl ether (10 mL ⁇ 2). The aqueous layer was adjusted to pH 3 with hydrochloric acid, and 377 mg of solid was precipitated. : 132-133 ° C.
  • Reaction 1 Methyl 5-amino-2-ethoxybenzoate (200 mg, 1.03 mmol), isobutyraldehyde (81 mg, 1.03 mmol) was dissolved in isopropyl alcohol (10 mL) / water (1 mL). Ammonium formate (649 mg, 10.3 mmol), Pd/C (200 mg) was reacted at room temperature for 4 h, and the starting material disappeared.
  • Reaction 2 Methyl 5-amino-2-ethoxybenzoate (400 mg, 2.06 mmol), isobutyraldehyde (162 mg, 2.06 mmol) was dissolved in isopropyl alcohol (10 mL) / water (1 mL).
  • Reaction 3 The same as Reaction 2, the combined reactions 1, 2 and 3, concentrated, diluted with EA (50 mL), washed with water (20 mL ⁇ 2), washed with brine (20 mL), dried Na 2 SO 4 Purified with ethyl acetate-petroleum ether (1:7) to give a pale green oil (yield: 7).
  • Reaction 1 Methyl 2-ethoxy-5-(isobutylamino)benzoate (160 mg, 0.64 mmol) was dissolved in THF (10 mL) / water (1 mL). ), reacted at room temperature for 6 h.
  • Reaction 2 Methyl 2-ethoxy-5-(isobutylamino)benzoate (500 mg, 2.00 mmol) was dissolved in THF (15 mL) / water (2 mL). The reaction was carried out for 6 h at room temperature, and the combined reactions 1 and 2 were combined, concentrated, diluted with water (10 mL), and the aqueous layer was washed with diethyl ether (10 mL ⁇ 2). The aqueous layer was adjusted to pH 3 with hydrochloric acid, and 531 mg of solid was precipitated. The yield was 85.2%. Melting point: 80-81 ° C.
  • Methyl 5-(dimethylcarbamoyl)-2-ethoxybenzoate (300 mg, 1.20 mmol) was dissolved in THF (20 mL) / water (10 mL). The mixture was reacted at room temperature for 6 hours, concentrated, and the aqueous layer was washed with diethyl ether (20 mL). The aqueous layer was adjusted to pH 3 with hydrochloric acid, and 244 mg of solid was precipitated, yield 86.2%, melting point: 102-103 °C.
  • Methyl 2-ethoxy-5-formylbenzoate (500 mg, 2.40 mmol) was dissolved in trifluoroethanol (20 mL), isopropylamine (1.42 g, 24 mmol) was added and reacted at room temperature for 2 h, then NaBH was added. 4 (180 mg, 4.80 mmol), the reaction was continued for 2 h, and the reaction of the starting material was completed.
  • Methyl 2-ethoxy-5-((isopropylamino)methyl)benzoate (450 mg, 0.08 mmol) was dissolved in anhydrous THF (10 mL), then CbzCl (612 mg, 3.60 mmol), TEA (545 mg, 5.40 mmol), reacted at room temperature for 3 h, and the reaction of the starting material was completed.

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Abstract

La présente invention concerne un nouvel amide aromatique en tant qu'inhibiteur de Kv2.1, un procédé de préparation, une composition pharmaceutique et l'utilisation de celui-ci. En particulier, la présente invention concerne un dérivé d'amide aromatique représenté par la formule générale I et un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation de celui-ci, une composition comprenant un ou plusieurs de ces composés, et l'utilisation de tels composés dans la préparation d'un médicament pour la prévention et/ou le traitement d'une maladie liée à Kv2.1.
PCT/CN2018/088561 2017-05-26 2018-05-26 Amide aromatique en tant qu'inhibiteur de kv2.1 et son procédé de préparation, composition pharmaceutique et utilisation associée Ceased WO2018214980A1 (fr)

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US11603355B2 (en) 2019-03-11 2023-03-14 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
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US12018015B2 (en) 2021-06-18 2024-06-25 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
WO2023064493A1 (fr) * 2021-10-13 2023-04-20 Clear Creek Bio, Inc. Composés et méthodes de traitement des coronavirus
US12428427B2 (en) 2021-12-16 2025-09-30 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
WO2024130691A1 (fr) * 2022-12-23 2024-06-27 中国医学科学院基础医学研究所 Nouveau composé cx-1 et son utilisation thérapeutique dans des maladies inflammatoires et des tumeurs
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US12534450B2 (en) 2024-05-08 2026-01-27 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

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