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WO2018214980A1 - Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof - Google Patents

Aromatic amide as kv2.1 inhibitor and preparation method, pharmaceutical composition, and use thereof 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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Prior art keywords
substituted
nra
unsubstituted
group
straight
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Ceased
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PCT/CN2018/088561
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French (fr)
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/en
Publication of WO2018214980A1 publication Critical patent/WO2018214980A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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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

The present invention provides a novel aromatic amide as a Kv2.1 inhibitor and a preparation method, pharmaceutical composition, and use thereof. In particular, the present invention relates to an aromatic amide derivative shown in general formula I and a pharmaceutically acceptable salt thereof, a preparation method of the same, a composition comprising one or more such compounds, and a use of such compounds in preparing a drug for preventing and/or treating a disease related to Kv2.1.

Description

芳酰胺类Kv2.1抑制剂及其制备方法、药物组合物和用途Aromatic amide Kv2.1 inhibitor, preparation method thereof, pharmaceutical composition and use thereof 技术领域Technical field

本发明涉及式I所示的新结构的芳酰胺类Kv2.1抑制剂，其可药用盐，及其制备方法，含有一个或多个该类化合物的组合物，和该类化合物在抑制Kv2.1与治疗kv2.1有关的疾病，及在制备、预防和/或治疗精神神经系统疾病、代谢性疾病和心脑血管疾病药物中的用途。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.

背景技术Background technique

电压门控钾离子通道(Kv通道)广泛存在于许多可兴奋性细胞膜表面，能够参与细胞电生理活动和内分泌的调节。例如，在兴奋性细胞中，Kv通道能够调节动作电位的去极化，在非兴奋性细胞中，它能调控细胞膜的静息电位，因此Kv通道能参与很多电生理活动，是免疫、代谢、心血管和神经精神疾病甚至是癌症的重要治疗靶点[Molecular pharmacology,2011,80(6):959-964]。Kv通道按基因编码可分为12个亚族，如Kv1、Kv2、Kv3等，每个亚族根据不同功能又分为若干个亚型如Kv2.1、Kv2.2、Kv4.5等[Pharmacol Rev.2005,57：473-508]。其中Kv2.1是电压门控钾离子通道的一个亚型，分布于哺乳动物的多种组织中，包括大脑神经元、中枢神经系统神经元、心肌细胞、骨骼肌、心血管平滑肌、β胰岛细胞和某些癌细胞，对于调节神经元兴奋性，神经元细胞凋亡和胰岛素分泌等具有重要作用。对于该靶点的调控有助于老年痴呆、癫痫、糖尿病、脑卒中、抑郁症和肿瘤等多种常见疑难病的研究和治疗，所以Kv2.1的作用机制及其调控的研究具有非常重要的意义[Pharmacological Reports.2016,457–461；Brain research.2010,1359:67-74]。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. For example, in excitatory cells, Kv channels can regulate the depolarization of action potentials. In 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. Each subfamily is divided into several subtypes according to different functions such as Kv2.1, Kv2.2, Kv4.5, etc. [Pharmacol Rev. 2005, 57: 473-508]. 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].

早期发现的Kv2.1选择性阻断剂为一些多肽类化合物，它们来自于蜘蛛、蟾蜍等动物的毒液，如：敬钊缨毛蛛毒素-I，敬钊缨毛蛛毒素-III和GxTX-1E等，但是这些多肽来源有限，限制了它们在药理学中的应用。目前文献报道的Kv2.1小分子阻断剂多数是通过普筛的方法发现的，抑制活性弱，选择性差如：SC-791[Brain research,2010,1359:67-74]，普罗帕酮[Naunyn-Schmiedeberg's archives of pharmacology,2000,362(1):22-31]，三氟哌多[Brain research,1997,761(1):42-50]， 17β-雌二醇[Acta Pharm Sin(药学学报),2004,39(9):686-690]，布格呋喃(AF-5)[Acta Pharm Sin(药学学报),2013,48(1):38-44]等。2011年Merk公司研究人员报道了通过高通量筛选获得了苯并咪唑类RY785和取代的苯甲酰胺类RY796 Kv2.1小分子阻断剂，对Kv2.1具有较强的抑制活性和较好的选择性[Molecular pharmacology,2011,80(6):959-964]。因此，寻找新结构的高活性的Kv2.1小分子阻断剂具有重要意义，它们不仅是研究Kv2.1生物学功能的分子探针，还有可能发展成为以Kv2.1为靶点的药物。Early detection of 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], 17β-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. In 2011, Merk researchers reported that the high-throughput screening of benzimidazole RY785 and substituted benzamide RY796 Kv2.1 small molecule blockers has strong inhibitory activity against Kv2.1 and better Selectivity [Molecular pharmacology, 2011, 80(6): 959-964]. Therefore, it is important to look for new structures of highly active Kv2.1 small molecule blockers. They are not only molecular probes for studying the biological functions of Kv2.1, but also may be developed as drugs targeting Kv2.1. .

本专利设计合成了新结构的芳酰胺类Kv2.1抑制剂，旨在为治疗与Kv2.1相关的疾病提供全新的物质基础。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.

发明内容Summary of the invention

本发明解决的技术问题在于提供式I所示的含有芳酰胺类衍生物和生理上可接受的盐、其制备方法、药物组合物、及其在制备Kv2.1抑制剂及其潜在的药物中的用途、在制备治疗精神神经系统疾病药物、代谢性疾病药物和心脑血管疾病药物中的用途。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. Use, in the preparation of a medicament for treating psychotropic diseases, a metabolic disease drug, and a cardiovascular and cerebrovascular disease drug.

为解决本发明的技术问题，本发明提供了如下技术方案：In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

本发明技术方案的第一方面是提供了如通式I所示的芳酰胺类衍生物或生理上可接受的盐：A first aspect of the present invention provides an amidamide derivative or a physiologically acceptable salt as shown in Formula I:

Figure PCTCN2018088561-appb-000001
Figure PCTCN2018088561-appb-000001

在式I中，In formula I,

X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、 CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

R 1选自如下基团或结构片断： R 1 is selected from the group consisting of:

(1)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、 NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) 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 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, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基；3-8元环的氧杂环烷基和3-8元环的氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and The 3-8 membered ring nitrogen a heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10， 其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra '10 independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said benzene ring, nitrogen-containing six-membered aromatic heterocycle The five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of hetero atoms selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;

R 2选自如下基团或结构片断： R 2 is selected from the group consisting of:

(1)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6CONRf 4Rf 5、NRe 7SO 2Rf 6,其中所述的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独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 CONRf 4 Rf 5 , NRe 7 SO 2 Rf 6 , wherein 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 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkane a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein said 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, ring Propylmethylene, cyclobutyl, cyclopentyl;

所述的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也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , 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, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time;

所述的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也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , 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 , Ra' 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain One N atom may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms, and the hetero atom is selected from O, N, S; n is selected from 1, 2, 3 Wherein the halogen includes F, Cl, Br;

(2)CONRh 1Ri 1、COORh 2、SO 2Rh 3、SO 2NRh 4Ri 2，其中所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said 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 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C 1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Heterocycloalkyl, 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 , 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 a methylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring of an oxaheterocycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3； 其中所述的卤素包括F、Cl、Br； The 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight a chain or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted. It may also be a polysubstituted one; 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;

(3)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (3) a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, a substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 members) a cyclic lactam) 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments:

(1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of

(a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代 或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、 Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched Alkynyl, wherein said substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl;

(3)R 9、R 10可成环，环系大小为3-7元脂环； (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;

在通式I中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In Formula I, 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 .

根据本发明通式I，本发明优选的化合物和生理上可接受的盐，包括但不限于通式(IA)所示的化合物：According to the general formula I of the present invention, preferred compounds and physiologically acceptable salts of the present invention include, but are not limited to, the compounds of the formula (IA):

Figure PCTCN2018088561-appb-000002
Figure PCTCN2018088561-appb-000002

在式IA中，In formula IA,

X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

R 2选自如下基团或结构片断： R 2 is selected from the group consisting of:

(1)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6CONRf 4Rf 5、NRe 7SO 2Rf 6,其中所述的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独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、 Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 CONRf 4 Rf 5 , NRe 7 SO 2 Rf 6 , wherein 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 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkane a C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, 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, ring Propylmethylene, cyclobutyl, cyclopentyl;

所述的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也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , 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, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time;

所述的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也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , 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 , Ra' 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain One N atom may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms, and the hetero atom is selected from O, N, S; n is selected from 1, 2, 3 Wherein the halogen includes F, Cl, Br;

(2)CONRh 1Ri 1、COORh 2、SO 2Rh 3、SO 2NRh 4Ri 2，其中所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said 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 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C 1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Heterocycloalkyl, 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 , 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 a methylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring of an oxaheterocycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight a chain or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted. It may also be a polysubstituted one; 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;

(3)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (3) a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, a substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 members) a cyclic lactam) 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments:

(1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of

(a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳 杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

R 4选自如下基团或结构片断： R 4 is selected from the group consisting of the following groups or structural fragments:

(1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br;

R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl;

(3)R 9、R 10可成环，环系大小为3-7元脂环； (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;

在通式IA中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA, 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 .

根据本发明通式IA，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-1所示的化合物：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:

Figure PCTCN2018088561-appb-000003
Figure PCTCN2018088561-appb-000003

在式IA-1中，In formula IA-1,

X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 Chain 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, NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

R 3选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments:

(1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of

(a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

R 4选自如下基团或结构片断： R 4 is selected from the group consisting of the following groups or structural fragments:

(1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 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, Rb 5 is independently Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br;

R 7、R 8可独立地选自如下基团或结构片断： R 7 and R 8 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、 NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基；3-8元环的氧杂环烷基和3-8元环的氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and The 3-8 membered ring nitrogen a heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (3) CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 are independently selected From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkynyl 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, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子；所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, Cyclopropylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl may contain 1 hetero atom or may contain multiple heteroatoms; 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 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 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 , 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and 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、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl;

(3)R 9、R 10可成环，环系大小为3-7元脂环； (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;

在通式IA-1中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-1, 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 .

根据本发明通式IA-1，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-1a所示的化合物：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:

Figure PCTCN2018088561-appb-000004
Figure PCTCN2018088561-appb-000004

在式IA-1a中，In formula IA-1a,

X、Y、Z、R 4、R 7、R 8、R 9、R 10的定义同式IA-1一致； The definitions of X, Y, Z, R 4 , R 7 , R 8 , R 9 and R 10 are the same as those of the formula IA-1;

R 11选自如下基团或结构片段： R 11 is selected from the group consisting of:

(1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支 链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、 异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Containing multiple heteroatoms;

在通式IA-1a中，所述的X、Y、Z、A、B、C、D独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-1a, 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 .

根据本发明通式IA-1a，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-1a-1所示的化合物：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:

Figure PCTCN2018088561-appb-000005
Figure PCTCN2018088561-appb-000005

在式IA-1a-1中，In the formula IA-1a-1,

R 4、R 7、R 8、R 9、R 10和R 11的定义同通式IA-1a一致； R 4 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined for formula IA-1a;

A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N;

R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

(3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非 取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, cyclopropylene group; 3-6 membered ring oxacycloalkyl group and nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

在通式IA-1a-1中，所述的X'、Y'、Z'、A'、B'、C'、D'独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-1a-1, 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.

根据本发明通式IA-1a-1，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-1a-1a所示的化合物：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:

Figure PCTCN2018088561-appb-000006
Figure PCTCN2018088561-appb-000006

在式IA-1a-1a中，In the formula IA-1a-1a,

R 4、R 9、R 10、A'、B'、C'、D'、X'、Y'、Z'的定义同通式IA-1a-1一致； The definitions of R 4 , R 9 , R 10 , A′, B′, C′, D′, X′, Y′, Z′ are the same as those of the formula IA-1a-1;

A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N;

R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

(3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, cyclopropylene group; 3-6 membered ring oxacycloalkyl group and nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

R' 7、R' 8可独立地选自如下基团或结构片断： R '7, R' 8 may be independently selected from a group or structure fragments:

氢、甲基、乙基、丙基、CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-6直链或支链烷基、 取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； Hydrogen, methyl, ethyl, propyl, CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 is independently selected from H, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2- a straight or branched alkynyl group, wherein said 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 , R b 4 , Ra 8 , Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-3直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-3直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子；所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-3 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-3 straight or branched alkyl, cyclopropyl, Cyclopropylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl may contain 1 hetero atom or may contain multiple heteroatoms; 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 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 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 , 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and 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' 11选自如下基团或结构片段： R '11 group or a structural fragment selected from the following:

(1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支 链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

在通式IA-1a-1a中，所述的X'、Y'、Z'、A'、B'、C'、D'独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-1a-1a, 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 .

根据本发明通式IA-1a-1，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-1a-1b所示的化合物：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:

Figure PCTCN2018088561-appb-000007
Figure PCTCN2018088561-appb-000007

在式IA-1a-1b中，In formula IA-1a-1b,

R 4、R 9、R 10、A'、B'、C'、D'、X'、Y'、Z'的定义同通式IA-1a-1a一致； The definitions of R 4 , R 9 , R 10 , A′, B′, C′, D′, X′, Y′, Z′ are identical to those of the formula IA-1a-1a;

A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N;

R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

(3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, cyclopropylene group; 3-6 membered ring oxacycloalkyl group and nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

R' 7、R' 8可独立地选自如下基团或结构片断： R '7, R' 8 may be independently selected from a group or structure fragments:

氢、甲基、乙基、丙基、CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-6直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； Hydrogen, methyl, ethyl, propyl, CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 is independently selected from H, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2- a straight or branched alkynyl group, wherein said 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 , R b 4 , Ra 8 , Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-3直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-3直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子；所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-3 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-3 straight or branched alkyl, cyclopropyl, Cyclopropylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl may contain 1 hetero atom or may contain multiple heteroatoms; 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 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 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 , 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and 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;

Ar' 2可独立地选自如下基团或结构片断： Ar' 2 may be independently selected from the group consisting of:

(1)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、 CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (1) 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

在通式IA-1a-1b中，所述的X'、Y'、Z'、A'、B'、C'、D'独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-1a-1b, 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 .

根据本发明通式IA，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-2所示的化合物：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:

Figure PCTCN2018088561-appb-000008
Figure PCTCN2018088561-appb-000008

在式IA-2中，In formula IA-2,

X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二 个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁 基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

Ar 1选自如下基团或结构片断： Ar 1 is selected from the group consisting of the following groups or structural fragments:

取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 membered ring lactam) 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 the group consisting of H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments:

(1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of

(a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂 环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br;

R 4选自如下基团或结构片断： R 4 is selected from the group consisting of the following groups or structural fragments:

(1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br;

R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、 Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl;

(3)R 9、R 10可成环，环系大小为3-7元脂环； (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;

在通式IA-2中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-2, 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 .

根据本发明通式IA-2，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-2a所示的化合物：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:

Figure PCTCN2018088561-appb-000009
Figure PCTCN2018088561-appb-000009

在式IA-2a中，In formula IA-2a,

X、Y、Z、R 4、Ar 1、R 9、R 10的定义同通式IA-2一致； The definitions of X, Y, Z, R 4 , Ar 1 , R 9 and R 10 are the same as those of the formula IA-2;

R 11选自如下基团或结构片段： R 11 is selected from the group consisting of:

(1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、 NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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, Rb 5 is independently selected from H, C1-4 straight-chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Containing multiple heteroatoms;

在通式IA-2a中，所述的X、Y、Z、A、B、C、D独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-2a, 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 .

根据本发明通式IA-2a，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IA-2a-1所示的化合物：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:

Figure PCTCN2018088561-appb-000010
Figure PCTCN2018088561-appb-000010

在式IA-2a-1中，In formula IA-2a-1,

R 4、Ar 1、R 9、R 10的定义同通式IA-2a一致； The definitions of R 4 , Ar 1 , R 9 and R 10 are the same as those of the formula IA-2a;

R 11选自如下基团或结构片段： R 11 is selected from the group consisting of:

(1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、 CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N;

R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

(3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、 NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group, wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, cyclopropylene group; 3-6 membered ring oxacycloalkyl group and nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

在通式IA-2a-1中，所述的X'、Y'、Z'、A'、B'、C'、D'独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IA-2a-1, 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 .

根据本发明通式I，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB所示的化合物：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:

Figure PCTCN2018088561-appb-000011
Figure PCTCN2018088561-appb-000011

在式IB中，In the formula IB,

X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、 CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

R 2选自如下基团或结构片断： R 2 is selected from the group consisting of:

(1)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6CONRf 4Rf 5、NRe 7SO 2Rf 6,其中所述的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独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直 链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 CONRf 4 Rf 5 , NRe 7 SO 2 Rf 6 , wherein 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 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkane a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein said 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, ring Propylmethylene, cyclobutyl, cyclopentyl;

所述的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也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , 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, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time;

所述的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也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , 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 , Ra' 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain One N atom may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms, and the hetero atom is selected from O, N, S; n is selected from 1, 2, 3 Wherein the halogen includes F, Cl, Br;

(2)CONRh 1Ri 1、COORh 2、SO 2Rh 3、SO 2NRh 4Ri 2，其中所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、 环丙基、环丙亚甲基、环丁基、环戊基； (2) CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said 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 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C 1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Heterocycloalkyl, 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 , 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 a methylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring of an oxaheterocycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight a chain or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted. It may also be a polysubstituted one; 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;

(3)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (3) a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, a substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 members) a cyclic lactam) 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片段： R 3 is selected from the group consisting of the following groups or structural fragments:

(1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of

(a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

R 5、R 6可独立地选自如下基团或结构片段： R 5 and R 6 may be independently selected from the group consisting of:

(1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1 个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br;

R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl;

(3)R 9、R 10可成环，环系大小为3-7元脂环； (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;

在通式IB中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB, 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 .

根据本发明通式IB，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB-1所示的化合物：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:

Figure PCTCN2018088561-appb-000012
Figure PCTCN2018088561-appb-000012

在式IB-1中，In the formula IB-1,

X、Y、Z、R3、R5、R6、R9、R10的定义同通式IB；X, Y, Z, R3, R5, R6, R9, R10 are as defined in the formula IB;

R 7、R 8可独立地选自如下基团或结构片断： R 7 and R 8 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基；3-8元环的氧杂环烷基和3-8元环的氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and The 3-8 membered ring nitrogen a heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (3) CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 are independently selected From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkynyl 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, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基， 其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, a cypromethylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring oxacycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said benzene ring, nitrogen-containing six-membered aromatic heterocyclic ring, five-membered aromatic heterocyclic ring may be single The substitution may also be a multiple substitution; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms; Membered aromatic 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;

在通式IB-1中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB-1, 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 .

根据本发明通式IB-1，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB-1a所示的化合物：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:

Figure PCTCN2018088561-appb-000013
Figure PCTCN2018088561-appb-000013

在式IB-1a中，In the formula IB-1a,

X、Y、Z、R5、R6、R7、R8、R9、R10的定义同通式IB-1；X, Y, Z, R5, R6, R7, R8, R9, R10 are as defined for the formula IB-1;

R 11选自如下基团或结构片段： R 11 is selected from the group consisting of:

(1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、 NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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, Rb 5 is independently selected from H, C1-4 straight-chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时 含有多个杂原子； 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Containing multiple heteroatoms;

在通式IB-1a中，所述的X、Y、Z、A、B、C、D独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB-1a, 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 .

根据本发明通式IB-1a，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB-1a-1所示的化合物：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:

Figure PCTCN2018088561-appb-000014
Figure PCTCN2018088561-appb-000014

在式IB-1a-1中，In the formula IB-1a-1,

R5、R6、R7、R8、R9、R10、R11的定义同通式IB-1；R5, R6, R7, R8, R9, R10, R11 are as defined for the formula IB-1;

A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N;

R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

(3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂 原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, cyclopropylene group; 3-6 membered ring oxacycloalkyl group and nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

在通式IB-1a-1中，所述的X'、Y'、Z'、A'、B'、C'、D'独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB-1a-1, 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 .

根据本发明通式IB，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB-2所示的化合物：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:

Figure PCTCN2018088561-appb-000015
Figure PCTCN2018088561-appb-000015

在式IB-2中，In the formula IB-2,

X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2, 其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms;

Ar 1选自如下基团或结构片断： Ar 1 is selected from the group consisting of the following groups or structural fragments:

取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 membered ring lactam) 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 the group consisting of H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片段： R 3 is selected from the group consisting of the following groups or structural fragments:

(1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of

(a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代 或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

(2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br.

R 5、R 6可独立地选自如下基团或结构片段： R 5 and R 6 may be independently selected from the group consisting of:

(1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链 或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

(3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br;

R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of:

(1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl;

(2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、 异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 And Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , and Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, Cyclobutyl, cyclopentyl;

(3)R 9、R 10可成环，环系大小为3-7元脂环； (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 yuan alicyclic ring;

在通式IB-2中，所述的X、Y、Z独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB-2, 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 .

根据本发明通式IB-2，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB-2a所示的化合物：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:

Figure PCTCN2018088561-appb-000016
Figure PCTCN2018088561-appb-000016

在式IB-2a中，In the formula IB-2a,

X、Y、Z、R 5、R 6、Ar 1、R 9、R 10的定义同通式IB-2； X, Y, Z, R 5 , R 6 , Ar 1 , R 9 , R 10 are as defined for the formula IB-2;

R 11选自如下基团或结构片段： R 11 is selected from the group consisting of:

(1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time;

(2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl;

苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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;

A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl;

(3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、 F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Containing multiple heteroatoms;

在通式IB-2a中，所述的X、Y、Z、A、B、C、D独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB-2a, 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 .

根据本发明通式IB-2a，本发明优选的化合物及其生理上可接受的盐，包括但不限于通式IB-2a-1所示的化合物：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:

Figure PCTCN2018088561-appb-000017
Figure PCTCN2018088561-appb-000017

在式IB-2a-1中，In the formula IB-2a-1,

R 5、R 6、Ar 1、R 9、R 10、R 11的定义同通式IB-2a； R 5 , R 6 , Ar 1 , R 9 , R 10 , R 11 are as defined for the formula IB-2a;

A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N;

R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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

(1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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;

(2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

(3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time;

(4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;

所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、 Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, cyclopropylene group; 3-6 membered ring oxacycloalkyl group and nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time;

在通式IB-2a-1中，所述的X'、Y'、Z'、A'、B'、C'、D'独立地优选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 In the formula IB-2a-1, 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 .

为完成本发明的目的，优选的化合物包括但不限定于：For the purposes of the present invention, preferred compounds include, but are not limited to:

Figure PCTCN2018088561-appb-000018
Figure PCTCN2018088561-appb-000018

Figure PCTCN2018088561-appb-000019
Figure PCTCN2018088561-appb-000019

Figure PCTCN2018088561-appb-000020
Figure PCTCN2018088561-appb-000020

Figure PCTCN2018088561-appb-000021
Figure PCTCN2018088561-appb-000021

Figure PCTCN2018088561-appb-000022
Figure PCTCN2018088561-appb-000022

Figure PCTCN2018088561-appb-000023
Figure PCTCN2018088561-appb-000023

Figure PCTCN2018088561-appb-000024
Figure PCTCN2018088561-appb-000024

本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法，采用的技术方案包括以下步骤：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:

芳甲酰胺类目标化合物(通式I所示)的合成是通过由2位和5位不同取代的酸和取代的伯胺发生缩合反应制备；其中关键酸中间体是由2-羟基-5-硝基芳(杂)酸、2-羟基-5-溴代芳(杂)酸在氯化亚砜的作用下发生酯化反应，然后进行取代反应和水解反应制备，或者是由2-氯-5-硝基芳(杂)酸与胺发生亲核取代反应得到；另一类关键中间体胺10是由溴代芳(杂)基酰基化合物7a出发，依次通过偶联反应，与羟胺缩合反应，还原反应制备；或者是由不同取代的芳(杂)基酰胺化合物7b依次通过加成消除反应，与羟胺反应，还原反应制备；或者是由不同取代的氰基化合物7c出发，依次发生加成消除反应，与羟胺反应，和还原反应制备。α位双取代的胺11是由不同取代的氰基化合物发生加成反应制备；将得到的酸与胺进行缩合反应，得到化合物12，15，17，20，23和26，然后化合物12、17、23和26通过还原反应、酰化反应或是还原氨化反应制备目标化合物。化合物15和20通过偶联反应制备目标化合物。The synthesis of the arylformamide target compound (shown in Formula I) 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 α-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.

Figure PCTCN2018088561-appb-000025
Figure PCTCN2018088561-appb-000025

Figure PCTCN2018088561-appb-000026
Figure PCTCN2018088561-appb-000026

试剂及反应条件：(a)o-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)，1-羟基苯并三唑(HOBT),二异丙基乙胺(DIEA)，N,N-二甲基甲酰胺(DMF),室温；或者1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC),1-羟基苯并三唑,二异丙基乙胺，N,N-二甲基甲酰胺，室温；(b)氯化亚砜(SOCl 2)，无水甲醇(Anhydrous MeOH)，60℃；(c)R-I或者R-Br,碳酸钾(K 2CO 3)，无水N,N-二甲基甲酰胺(Anhydrous DMF)，60℃；(d)氢氧化钠(NaOH)，四氢呋喃/水(THF/H 2O)，室温；(e)四三苯基磷化钯(Pd(PPh 3) 4)，碳酸钠(Na 2CO 3)，R-Br，1,4-二氧六环(1,4-dioxane)，水，氩气，110℃；或者三(二亚苄基丙酮)二钯(Pd 2(dba) 3)，(±)-2,2'-双-(二苯膦基)-1,1'-联萘(BINAP)，叔丁醇钠，甲苯(Toluene)，氩气，100℃；(f)甲基溴化镁(CH 3MgBr)，无水四氢呋喃，氩气，0℃；(g)甲基锂(CH 3Li)，无水四氢呋喃，氩气，-66℃；(h)50％羟胺水溶液，乙醇(EtOH)，水，60℃；(i)锌粉(Zn)，盐酸，乙醇，水，室温；或者10％钯/碳(10％Pd/C)，甲酸铵，甲醇，回流；(j)三氯化铈(CeCl 3)，甲基锂，氩气，-66℃；(k)10％钯/碳，氢气(H 2)，乙醇，室温；或者铁粉(Fe)，氯化铵(NH 4Cl)，乙醇，水，回流；(l)R-COCl，三乙胺(Et 3N)，二氯甲烷(DCM)，0℃；或者RR’CO，三乙酰氧基硼氢化钠(NaBH(OAc) 3)，二氯甲烷，室温；(m)三(二亚苄基丙酮)二钯，(±)-2,2'-双-(二苯膦基)-1,1'-联萘，叔丁醇钠，甲苯，氩气，100℃；或者四三苯基磷化钯，碳酸钠，1,4-二氧六环，水，氩气，110℃或者1,10-邻菲啰啉，碳酸钾，碘化铜(CuI)，N,N-二甲基甲酰胺，氩气，120℃；或者乙酰丙酮铁(III)，碳酸铯(Cs 2CO 3)，氧化铜(CuO)，N,N-二甲基甲酰胺，120℃；(n)R 5R 6-NH，乙腈，二异丙基乙胺，65℃； 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 / H 2 O), room temperature; e) tetrakistriphenylphosphine palladium (Pd(PPh 3 ) 4 ), sodium carbonate (Na 2 CO 3 ), R-Br, 1,4-dioxane, water, argon Gas, 110 ° C; or tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (BINAP), sodium tert-butoxide, toluene, argon, 100 ° C; (f) methyl magnesium bromide (CH 3 MgBr), anhydrous tetrahydrofuran, argon, 0 ° C; (g) methyl lithium (CH 3 Li), anhydrous tetrahydrofuran, argon, -66 ° C; (h) 50% aqueous hydroxylamine solution, ethanol (EtOH), water, 60 ° C; (i) Zinc powder (Zn), hydrochloric acid, ethanol, water, room temperature; or 10% palladium/carbon (10% Pd/C), ammonium formate, methanol, reflux; (j) cesium trichloride (CeCl 3 ), methyl lithium , argon, -66 ° C; (k) 10% palladium / carbon, hydrogen (H 2 ), ethanol, room temperature; or iron powder (Fe), ammonium chloride (NH 4 Cl), ethanol, water, reflux; l) R-COCl, triethylamine (Et 3 N), dichloromethane (DCM), 0 ° C; or RR 'CO, sodium triacetoxyborohydride (NaBH (OAc) 3 ), dichloromethane, room temperature (m) tris(dibenzylideneacetone)dipalladium, (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, sodium tert-butoxide, toluene, argon , 100 ° C; or tetrakistriphenylphosphine palladium, sodium carbonate, 1,4-dioxane, water, argon, 110 ° C or 1,10-phenanthroline, potassium carbonate, copper iodide (CuI ), N,N-dimethylformamide, argon, 120 ° C; or iron (III) acetylacetonate, cesium carbonate (Cs 2 CO 3 ), copper oxide (CuO), N, N-dimethylformamide , 120 ° C; (n) R 5 R 6 -NH, acetonitrile, diisopropylethylamine, 65 ° C;

其中所述的X、Y、Z、A、B、C、D、Ar 1、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11的定义如本发明技术方案第一方面所述。 Wherein X, Y, Z, A, B, C, D, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 And the definition of R 11 is as described in the first aspect of the technical solution of the present invention.

另外，上述反应中的起始原料及中间体容易得到，各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸的盐，如下列无机酸或有机酸的盐：盐酸，氢溴酸，磷酸，硫酸，甲磺酸，对甲苯磺酸，三氟乙酸，枸杞酸，马来酸，酒石酸，富马酸，柠檬酸，乳酸。通式I所述药学上可接受的盐还包括不同碱金属盐(锂，钠，钾盐)，碱土金属盐(钙，镁盐)及铵盐，和能提供生理上可接受的阳离子的有机碱的盐，如甲胺，二甲胺，三甲胺，哌啶，吗啉及三(2-羟乙基)胺的盐。在本发明范围内的所有这些盐都可采用常规方法制备。Further, the starting materials and intermediates in the above reaction are easily obtained, and the respective steps can be easily synthesized according to the reported literature or by a person skilled in the art by a conventional method in organic synthesis. 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.

本发明技术方案的第三方面是提供了一种药物组合物，所述药物组合物包括作为本发明技术方案第一方面所述的化合物或其可药用盐和药学上的常用载体。A third aspect of the present invention provides 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.

该组合物包括本发明中至少一种化合物和在药学上可接受的载体。所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。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.

本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。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.

给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。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.

本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。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.

这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。These formulations are prepared according to methods well known to those skilled in the art. The 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. Other 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.

为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤 维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。In order to form the compound of the present invention into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrating agents, lubricants, and glidants, can be widely used. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the 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 Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinyl pyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfonate, etc.; lubricant and flow aid The agent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol or the like.

还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。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.

为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。In order to prepare the administration unit as a capsule, 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.

为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。In order to prepare the compound of the present invention as an injection, 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-β-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. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.

此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。In addition, coloring agents, preservatives, perfumes, flavoring agents or other additives may also be added to the pharmaceutical preparations as needed.

为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。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.

本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.1-1000mg/Kg体重，优选为1-500mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。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. In general, 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.

本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。The compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.

本发明技术方案的第四方面是提供了本发明第一方面所述的化合物及其药用盐在制备Kv2.1抑制剂中的应用、在制备预防和\或治疗与Kv2.1有关的疾病的药物中的应用、在制备与Kv2.1有关的疾病选自精神神经系统疾病、代谢性疾病和心脑血管疾病治疗药物中的应用、在制备与阿尔茨海默病、抑郁症、糖尿病、动脉粥样硬化症、脑卒中等疾病有关药物中的作用。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 In the application of the drug, in the preparation of 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.

有益技术效果：Beneficial technical effects:

该专利申请芳酰胺类Kv2.1抑制剂具有非常强的抑制活性；相对于其他离子通道，该类化合物对Kv2.1具有非常好的选择性；体内活性显示具有治疗脑卒中作用、抗抑郁活性和降血脂活性、改善学习记忆功能。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.

附图说明DRAWINGS

图1.跳台实验中，化合物61对大鼠跳台错误时间的影响Figure 1. Effect of Compound 61 on the error time of rat jumping in the platform test

n＝14-16.##p<0.01vs.对照组,*p<0.05,**p<0.01vs.模型组.n=14-16.##p<0.01vs. Control group, *p<0.05, **p<0.01 vs. model group.

图2.化合物61对大鼠悬尾实验中不动时间的影响，n＝15.*p<0.05vs模型组Figure 2. Effect of Compound 61 on immobility time in rat tail suspension experiment, n=15.*p<0.05vs model group

图3.化合物61对急性缺氧(断头法)的作用，**p<0.01vs.对照组.Figure 3. Effect of Compound 61 on acute hypoxia (decapitation), **p<0.01 vs. control group.

图4.化合物61对脑缺氧(闷罐法)的作用,**p<0.01vs.对照组.Figure 4. Effect of Compound 61 on cerebral hypoxia (squeeze method), **p<0.01 vs. control group.

具体实施方式detailed description

以下将结合实施例对发明做进一步说明，但并不限制本发明的范围。The invention will be further illustrated by the following examples, without limiting the scope of the invention.

化合物的结构是通过核磁共振(NMR)或高分辨质谱(HRMS)来确定的。NMR的测定是用Varian mercury 300或者Varian mercury 400，测定溶剂为CDCl 3、DMSO-d 6、acetone-d 6、CD 3OD，内标为TMS，化学位移是以ppm作为单位给出。m.p.是以℃给出的熔点，温度未加校正。硅胶柱层析一般使用200-300目硅胶为载体。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS). 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.

缩写列表：List of abbreviations:

TLC:薄层色谱；TLC: thin layer chromatography;

DIEA：二异丙基乙胺；TFA：三氟乙酸；TEA：三乙胺DIEA: diisopropylethylamine; TFA: trifluoroacetic acid; TEA: triethylamine

DMF：N,N-二甲基甲酰胺；THF：四氢呋喃；PE：石油醚；EA：乙酸乙酯DMF: N,N-dimethylformamide; THF: tetrahydrofuran; PE: petroleum ether; EA: ethyl acetate

DCM：二氯甲烷；min：分钟；r.t.室温；h：小时；DCM: dichloromethane; min: minute; r.t. room temperature; h: hour;

EDC或EDCI：1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐EDC or EDCI: 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride

HBTU：O-苯并三氮唑-四甲基脲六氟磷酸酯HBTU: O-benzotriazole-tetramethylurea hexafluorophosphate

HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

HOBt：1-羟基苯并三氮唑；TFA：三氟乙酸；HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid;

Pd 2(dba) 3：三(二亚苄基丙酮)二钯；Pd(PPh 3) 4：四三苯基膦钯 Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; Pd(PPh 3 ) 4 : tetrakistriphenylphosphine palladium

Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽Xantphos: 4,5-bis-diphenylphosphino-9,9-dimethyloxazepine

BINAP：(±)-2,2'-双-(二苯膦基)-1,1'-联萘BINAP: (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl

K 3PO 4：磷酸钾；CS 2CO 3：碳酸铯；PPh 3：三苯基膦 K 3 PO 4 : potassium phosphate; CS 2 CO 3 : cesium carbonate; PPh 3 : triphenylphosphine

DDQ：2,3-二氯-5,6-二氰基-1,4-苯醌；Zn：锌粉；NaH：氢化钠；DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Zn: zinc powder; NaH: sodium hydride;

CDCl 3：氘代氯仿；DMSO-d 6：氘代二甲基亚砜； CDCl 3 : deuterated chloroform; DMSO-d 6 : deuterated dimethyl sulfoxide;

中间体的制备Preparation of intermediates

(一)2-(二甲氨基)-5-硝基苯甲酸(a) 2-(dimethylamino)-5-nitrobenzoic acid

Figure PCTCN2018088561-appb-000027
Figure PCTCN2018088561-appb-000027

取2-氯-5-硝基苯甲酸(2.0g,10.00mmol)，加入二甲胺(40％水溶液)(20mL)，加热至65℃，8h后原料反应完全，逐滴加入稀乙酸溶液，调pH为酸性，EA萃取(30mL×5)，合并浓缩，干燥得黄色固体1.6g,76.7％。Take 2-chloro-5-nitrobenzoic acid (2.0 g, 10.00 mmol), add dimethylamine (40% aqueous solution) (20 mL), and heat to 65 ° C. After 8 h, the starting material is completely reacted, and dilute acetic acid solution is added dropwise. The pH was adjusted to be acidic, extracted with EA (30 mL×5), concentrated and concentrated to give a yellow solid, 1.6 g, 76.7%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.92(d,J＝2.8Hz,1H),8.33(dd,J＝9.2,2.8Hz,1H),7.36(d,J＝9.2Hz,1H),2.96(s,6H)；ESI-MS m/z:209.06[M-H] -。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.92 (d, J = 2.8Hz, 1H), 8.33 (dd, J = 9.2,2.8Hz, 1H), 7.36 (d, J = 9.2Hz, 1H), 2.96 (s, 6H); ESI-MS m/z: 209.06 [MH] - .

(二)2-乙氧基-5-苯甲酸的制备(2) Preparation of 2-ethoxy-5-benzoic acid

Figure PCTCN2018088561-appb-000028
Figure PCTCN2018088561-appb-000028

a)2-羟基-5-硝基苯甲酸甲酯a) Methyl 2-hydroxy-5-nitrobenzoate

Figure PCTCN2018088561-appb-000029
Figure PCTCN2018088561-appb-000029

将2-羟基-5-硝基苯甲酸(6g，32.7mmol)溶于无水甲醇(50mL)，搅拌下缓慢加入SOCl 2溶液，60℃反应10h，冷却，过滤，冰甲醇洗涤滤饼，得类白色固体 5.585g，收率86％。 2-Hydroxy-5-nitrobenzoic acid (6 g, 32.7 mmol) was dissolved in anhydrous methanol (50 mL), and the SOCl 2 solution was slowly added with stirring, and reacted at 60 ° C for 10 h, cooled, filtered, and washed with ice methanol. The white solid was 5.585 g, yield 86%.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.44(s,1H),8.79(d,J＝2.8Hz,1H),8.34(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),7.09(d,J＝9.2Hz,1H),4.04(s,3H).m.p.115-117. 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.44 (s, 1H), 8.79 (d, J = 2.8 Hz, 1H), 8.34 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H ), 7.09 (d, J = 9.2 Hz, 1H), 4.04 (s, 3H). mp115-117.

b)2-乙氧基-5-硝基苯甲酸甲酯b) Methyl 2-ethoxy-5-nitrobenzoate

Figure PCTCN2018088561-appb-000030
Figure PCTCN2018088561-appb-000030

将2-羟基-5-硝基苯基酸甲酯(5g，25.3mmol)溶于无水DMF(40mL)，加入K 2CO 3(6.982g，50.6mmol)，加入C 2H 5I(11.84g，75.9mmol)，加热至70℃反应。原料消失后，冷却，加水析出类白色固体，过滤，水洗涤滤饼，得类白色固体5.5g，收率96％。m.p.121-123℃ 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%. Mp121-123°C

1H NMR(400MHZ,CDCl 3)δ(ppm):8.69(d,J＝2.8Hz,1H),8.34(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),7.04(d,J＝9.2Hz,1H),4.24(q,J＝6.8Hz,2H).3.93(s,3H),1.52(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.69 (d, J = 2.8 Hz, 1H), 8.34 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 7.04 (d, J) =9.2 Hz, 1H), 4.24 (q, J = 6.8 Hz, 2H). 3.93 (s, 3H), 1.52 (t, J = 6.8 Hz, 3H).

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000031
Figure PCTCN2018088561-appb-000031

Figure PCTCN2018088561-appb-000032
Figure PCTCN2018088561-appb-000032

c)2-乙氧基-5-硝基苯甲酸c) 2-ethoxy-5-nitrobenzoic acid

Figure PCTCN2018088561-appb-000033
Figure PCTCN2018088561-appb-000033

将2-乙氧基-5-硝基苯甲酸甲酯(4.1g，18.2mmol)溶于THF(60mL)/(30mL)，搅拌下加入NaOH(3.64g，91mmol)，室温下反应过夜，浓缩，加入乙醚洗涤水层，浓盐酸调节至pH＝2，析出白色固体3.75g，收率97％。Methyl 2-ethoxy-5-nitrobenzoate (4.1 g, 18.2 mmol) was dissolved in THF (60 mL) / (30 mL). The aqueous layer was washed with diethyl ether, and concentrated hydrochloric acid was adjusted to pH = 2 to yield white solid 3.75 g, yield 97%.

1H NMR(500MHZ，CDCl 3)δ(ppm):9.03(d,J＝2.5Hz,1H),8.43(dd,J 1＝2.5Hz, J 2＝9.0Hz,1H),7.16(d,J＝9.0Hz,1H),4.44(q,J＝7.0Hz,2H),1.63(t,J＝7.0Hz,3H).m.p.80-82℃. 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 9.03 (d, J = 2.5 Hz, 1H), 8.43 (dd, J 1 = 2.5 Hz, J 2 = 9.0 Hz, 1H), 7.16 (d, J) = 9.0 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 1.63 (t, J = 7.0 Hz, 3H). mp 80-82 ° C.

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000034
Figure PCTCN2018088561-appb-000034

Figure PCTCN2018088561-appb-000035
Figure PCTCN2018088561-appb-000035

2-乙氧基-5-异丁酰氨基苯甲酸2-ethoxy-5-isobutyrylaminobenzoic acid

Figure PCTCN2018088561-appb-000036
Figure PCTCN2018088561-appb-000036

(a)5-氨基-2-乙氧基苯甲酸甲酯(a) Methyl 5-amino-2-ethoxybenzoate

将2-乙氧基-5-硝基苯甲酸甲酯(1g,4.44mmol)溶于THF(15mL)中，加入Pd/C100mg，在室温下通入氢气，反应过夜，过滤，滤液浓缩，得黄绿色油状物859mg，收率为99.2％。Methyl 2-ethoxy-5-nitrobenzoate (1 g, 4.44 mmol) was dissolved in THF (15 mL), Pd / C 100 mg was added, and hydrogen was passed at room temperature overnight, filtered, and the filtrate was concentrated. Yellow green oil 859mg, the yield was 99.2%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.19-7.08(m,1H),6.84-6.80(m,2H),4.02(q,J＝7.2Hz,2H),3.87(s,3H),3.09(s,2H),1.40(t,J＝7.2Hz,3H)；ESI-MS m/z:196.10[M+H] +。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.19-7.08 (m, 1H), 6.84-6.80 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H) ), 3.09 (s, 2H), 1.40 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 196.10 [M+H] + .

(b)2-乙氧基-5-异丁酰氨基苯甲酸甲酯(b) Methyl 2-ethoxy-5-isobutyrylaminobenzoate

将5-氨基-2-乙氧基苯甲酸甲酯(294mg,1.5mmol)，加入DMF(20mL)，EDC(576mg,3mmol)，HOBt(405mg,3mmol)，DIEA(0.52mL,3mmol)以及异丁酸(0.14mL,1.5mmol)，室温搅拌反应，次日停止反应，加水，用乙酸乙酯50mL×2，合并有机层用饱和NaCl溶液30mL×2洗，无水硫酸镁干燥，柱层析(E:P＝1:5,E:P＝1:3)得到白色固体306mg，产率77％.Methyl 5-amino-2-ethoxybenzoate (294 mg, 1.5 mmol) was added to DMF (20 mL), EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) Butyric acid (0.14 mL, 1.5 mmol), the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, ethyl acetate 50 mL × 2, and the combined organic layer was washed with saturated NaCl solution 30 mL × 2, dried over anhydrous magnesium sulfate, column chromatography (E: P = 1: 5, E: P = 1: 3) gave 306 mg of white solid, yield 77%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.75-7.80(m,2H),7.44(brs,0.5H),7.27(brs,0.5H),6.89-6.93(m,1H),4.05-4.10(m,2H),3.86(d,J＝5.2Hz,3H),2.46-2.54(m,1H),1.40-1.45(m,3H),1.22-1.25(m,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.75-7.80 (m, 2H), 7.44 (brs, 0.5H), 7.27 (brs, 0.5H), 6.89-6.93 (m, 1H), 4.05 -4.10 (m, 2H), 3.86 (d, J = 5.2 Hz, 3H), 2.46-2.54 (m, 1H), 1.40-1.45 (m, 3H), 1.22-1.25 (m, 6H).

(c)2-乙氧基-5-异丁酰氨基苯甲酸(c) 2-ethoxy-5-isobutyrylaminobenzoic acid

将甲基2-乙氧基-5-异丁酰氨基苯酸酯(271mg,1.02mmol)置于反应瓶中，加入THF(3mL)，MeOH(3mL)，将氢氧化锂(32mg,1.33mmol)溶于水(2mL)中，滴加入反应瓶中，滴毕，室温搅拌反应，次日，停止反应，浓缩，加水，用乙醚10mL萃取，水层用稀盐酸溶液调PH值至3左右，有固体析出，抽滤，滤饼水洗，得到白色固体250mg，产率97.6％。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%.

1H-NMR(400MHz,CDCl 3)δ(ppm):12.51(s,1H),9.76(s,1H),7.87(s,1H),7.67(d,J＝8.8Hz,1H),7.03(d,J＝8.8Hz,1H),4.03(q,J＝6.8Hz,2H),2.50-2.55(m,1H),1.29(t,J＝6.4Hz,3H),1.07(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 12.51 (s, 1H), 9.76 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8Hz, 1H), 7.03 ( d, J = 8.8 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 2.50 - 2.55 (m, 1H), 1.29 (t, J = 6.4 Hz, 3H), 1.07 (d, J = 6.8) Hz, 6H).

3-(噻唑-2-基)苯甲醛3-(thiazol-2-yl)benzaldehyde

Figure PCTCN2018088561-appb-000037
Figure PCTCN2018088561-appb-000037

将Pd(AcO) 2(1.5g,6.67mmol)，PPh 3(7.0g,26.68mmol)加入到二氧六环(50mL)中，氩气保护下室温反应30min，依次加入2-溴噻唑(10.9g,66.67mmol)，Na 2CO 3(21.2g,200mmol)，3-甲酰基苯硼酸(10g,66.67mmol)和10mL蒸馏水，氩气保护下，110℃反应8h，原料消失。过滤，滤液浓缩，加入EA(50mL)稀释，水洗(20mL×2)，饱和食盐水洗(20mL)，柱层析(PE/EA＝13:1)，得白色固体10.7g，产率为84.9％，m.p.61-62℃。 Pd(AcO) 2 (1.5 g, 6.67 mmol), PPh 3 (7.0 g, 26.68 mmol) was added to dioxane (50 mL), and reacted at room temperature for 30 min under argon atmosphere, followed by 2-bromothiazole (10.9). g, 66.67 mmol), Na 2 CO 3 (21.2 g, 200 mmol), 3-formylbenzeneboronic acid (10 g, 66.67 mmol), and 10 mL of distilled water, argon gas, and reacted at 110 ° C for 8 h, the starting material disappeared. Filtration, the filtrate was concentrated, diluted with EA (50 mL), washed with water (20 mL×2), washed with brine (20 mL) and purified by column chromatography (PE/EA=13:1) to give white solid 10.7 g, yield 84.9% , mp61-62 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.09(s,1H),8.45(s,1H),8.25(d,J＝7.6Hz,1H),7.93(dd,J＝10.4,5.6Hz,2H),7.63(t,J＝7.8Hz,1H),7.41(d,J＝3.2Hz,1H)；ESI-MS m/z:190.03[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.09 (s, 1H), 8.45 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.93 (dd, J = 10.4, 5.6 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H); ESI-MS m/z: 190.03 [M+H] + .

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000038
Figure PCTCN2018088561-appb-000038

Figure PCTCN2018088561-appb-000039
Figure PCTCN2018088561-appb-000039

Figure PCTCN2018088561-appb-000040
Figure PCTCN2018088561-appb-000040

3-(2-羰基哌啶-1-基)苯甲醛3-(2-carbonylpiperidin-1-yl)benzaldehyde

Figure PCTCN2018088561-appb-000041
Figure PCTCN2018088561-appb-000041

将间溴苯甲醛(0.29mL,2.5mmol)置于反应瓶中，加入dioxane(20mL)，氩气保护下加入Pd 2(dba) 3(229mg,0.25mmol)，xantphos(434mg,0.75mmol)，K 3PO 4(1.32g,6.25mmol)以及2-哌啶酮(248mg,2.5mmol)，升温至100℃反应，8h后停止反应，过滤，浓缩，柱层析(D:M＝200:1,D:M＝150:1)，得到淡黄色油状物350mg，产率69％。 M-bromobenzaldehyde (0.29 mL, 2.5 mmol) was placed in a reaction flask, dioxane (20 mL) was added, and Pd 2 (dba) 3 (229 mg, 0.25 mmol), xantphos (434 mg, 0.75 mmol) was added under argon. K 3 PO 4 (1.32 g, 6.25 mmol) and 2-piperidone (248 mg, 2.5 mmol), warmed to 100 ° C, the reaction was stopped after 8 h, filtered, concentrated, column chromatography (D:M=200:1) , D: M = 150: 1) to give a pale yellow oil, 350 mg, yield 69%.

1H-NMR(500MHz,CDCl 3)δ(ppm):10.00(s,1H),7.79(s,1H),7.76(d,J＝7.0Hz,1H),7.53-7.59(m,2H),3.70(t,J＝5.5Hz,2H),2.59(t,J＝6.0Hz,2H),1.92-2.00(m,4H). 1 H-NMR (500MHz, CDCl 3) δ (ppm): 10.00 (s, 1H), 7.79 (s, 1H), 7.76 (d, J = 7.0Hz, 1H), 7.53-7.59 (m, 2H), 3.70 (t, J = 5.5 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 1.92-2.00 (m, 4H).

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000042
Figure PCTCN2018088561-appb-000042

Figure PCTCN2018088561-appb-000043
Figure PCTCN2018088561-appb-000043

3-(噻唑-2-基)苯甲醛肟3-(thiazol-2-yl)benzaldehyde oxime

Figure PCTCN2018088561-appb-000044
Figure PCTCN2018088561-appb-000044

将3-(噻唑-2-基)苯甲醛(3.5g,18.50mmol)溶于乙醇(20mL)/水(5mL)中，依次加入盐酸羟胺(2.57g,37.00mmol)、乙酸钠(4.55g,55.50mmol)，回流反应4h，原料消失。停止反应，浓缩，加入EA(40mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱层析(PE/EA＝8:1)得白色固体2.68g，收率为71.1％，m.p.111-112℃。 3-(thiazol-2-yl)benzaldehyde (3.5 g, 18.50 mmol) was dissolved in ethanol (20 mL) / water (5 mL), and then hydroxyamine hydrochloride (2.57 g, 37.00 mmol), sodium acetate (4.55 g, 55.50 mmol), refluxing for 4 h, the starting material disappeared. The reaction was stopped, concentrated, EA (40mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (PE / EA = 8: 1 ) to give 2.68 g of a white solid, yield 71.1%, Mp111-112 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.21(s,2H),7.98(d,J＝7.8Hz,1H),7.90(d,J＝3.2Hz,1H),7.65(d,J＝7.8Hz,1H),7.47(t,J＝7.8Hz,1H),7.37(d,J＝3.2Hz,1H)；ESI-MS m/z:205.04[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.21 (s, 2H), 7.98 (d, J = 7.8Hz, 1H), 7.90 (d, J = 3.2Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H); ESI-MS m/z: 205.04 [M+H] + .

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000045
Figure PCTCN2018088561-appb-000045

Figure PCTCN2018088561-appb-000046
Figure PCTCN2018088561-appb-000046

Figure PCTCN2018088561-appb-000047
Figure PCTCN2018088561-appb-000047

Figure PCTCN2018088561-appb-000048
Figure PCTCN2018088561-appb-000048

Figure PCTCN2018088561-appb-000049
Figure PCTCN2018088561-appb-000049

Figure PCTCN2018088561-appb-000050
Figure PCTCN2018088561-appb-000050

Figure PCTCN2018088561-appb-000051
Figure PCTCN2018088561-appb-000051

(3-(噻唑-2-基)苯基)甲胺(3-(thiazol-2-yl)phenyl)methylamine

Figure PCTCN2018088561-appb-000052
Figure PCTCN2018088561-appb-000052

将3-(噻唑-2-基)苯甲醛肟(1.0g,4.90mmol)溶于乙醇(20mL)/水(10mL)中，依次加入Zn(637mg,9.80mmol)、HCl(5N)(5mL,24.5mmol)，室温反应4h，原料消失。停止反应，加入饱和碳酸氢钠溶液调pH>7，过滤，加入EA(30mL×3)萃取，合并有机相，无水硫酸钠干燥，浓缩得浅黄色油状物813mg，收率为87.3％。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).

1H-NMR(400MHz,CD 3OD)δ(ppm):8.15(s,2H),8.06(d,J＝7.2Hz,1H),7.96(s,1H),7.71(m,2H),4.26(s,2H)；ESI-MS m/z:191.06[M+H] +。 1 H-NMR (400MHz, CD 3 OD) δ (ppm): 8.15 (s, 2H), 8.06 (d, J = 7.2Hz, 1H), 7.96 (s, 1H), 7.71 (m, 2H), 4.26 (s, 2H); ESI-MS m/z: 191.06 [M+H] + .

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000053
Figure PCTCN2018088561-appb-000053

Figure PCTCN2018088561-appb-000054
Figure PCTCN2018088561-appb-000054

Figure PCTCN2018088561-appb-000055
Figure PCTCN2018088561-appb-000055

Figure PCTCN2018088561-appb-000056
Figure PCTCN2018088561-appb-000056

Figure PCTCN2018088561-appb-000057
Figure PCTCN2018088561-appb-000057

(3-(四氢呋喃-2-基)苯基)甲胺(3-(tetrahydrofuran-2-yl)phenyl)methanamine

Figure PCTCN2018088561-appb-000058
Figure PCTCN2018088561-appb-000058

将3-(呋喃-2-基)苯甲醛肟(400mg,2.14mmol)溶于甲醇(10mL)中，加入Pd/C(240mg)升温至回流，加入甲酸铵(1.35g,21.4mmol)，回流反应10min，原料消失。停止反应，过滤，加入水(10mL)，乙醚(15mL×3)萃取，合并乙醚层，浓缩得棕色油状物211mg，收率为55.8％。3-(Furan-2-yl)benzaldehyde oxime (400 mg, 2.14 mmol) was dissolved in MeOH (10 mL). EtOAc (EtOAc) (EtOAc) The reaction disappeared for 10 min. The reaction was quenched, filtered, EtOAc EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.71(s,3H),7.37(s,1H),7.28-7.22(m,2H),4.80(t,J＝7.2Hz,1H),4.02(dd,J＝14.4,7.2Hz,1H),3.90(s,2H),3.83(dd,J＝14.4,7.6Hz,1H),2.30-2.24(m,1H),2.00-1.92(m,2H),1.78-1.71(m,1H)；ESI-MS m/z:178.12[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.71 (s, 3H), 7.37 (s, 1H), 7.28-7.22 (m, 2H), 4.80 (t, J = 7.2Hz, 1H), 4.02 (dd, J = 14.4, 7.2 Hz, 1H), 3.90 (s, 2H), 3.83 (dd, J = 14.4, 7.6 Hz, 1H), 2.30-2.24 (m, 1H), 2.00-1.92 (m, 2H), 1.78-1.71 (m, 1H); ESI-MS m/z: 178.12 [M+H] + .

按照上述一般方法制备下列中间体Prepare the following intermediates according to the above general method

Figure PCTCN2018088561-appb-000059
Figure PCTCN2018088561-appb-000059

Figure PCTCN2018088561-appb-000060
Figure PCTCN2018088561-appb-000060

实施例(化合物)1Example (compound) 1

2-(二甲氨基)-5-异丁酰氨基-N-(吡啶-2-基甲基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-2-ylmethyl)benzamide

Figure PCTCN2018088561-appb-000061
Figure PCTCN2018088561-appb-000061

a)2-(二甲氨基)-5-硝基-N-(吡啶-2-基甲基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(pyridin-2-ylmethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(200mg,0.95mmol)溶于DMF(15mL)中，依次加入DIEA(185mg,1.43mmol)、HATU(542mg,1.43mmol)，20min后加入2-胺甲基吡啶(93mg,0.86mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水 Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得黄色固体248mg，收率95.0％，熔点：140-142℃。 2-(Dimethylamino)-5-nitrobenzoic acid (200 mg, 0.95 mmol) was dissolved in DMF (15 mL), then DIEA (185 mg, 1.43 mmol), HATU (542 mg, 1.43 mmol). 2-Aminomethylpyridine (93 mg, 0.86 mmol) was stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume 2:3) gave 248 mg of a yellow solid, yield 95.0%, m.p.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.58-8.55(m,2H),8.27(s,1H),8.17(dd,J＝9.2,1.6Hz,1H),7.71(t,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),7.23(d,J＝6.0Hz,1H),6.96(d,J＝9.2Hz,1H),4.78(d,J＝4.8Hz,2H),2.95(s,6H)；HR-MS(ESI):m/z,calcd.For C 15H 16O 3N 4 301.1295[M+H] +,Found:301.1280。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.58-8.55 (m, 2H), 8.27 (s, 1H), 8.17 (dd, J = 9.2,1.6Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 4.78 (d, J = 4.8) Hz, 2H), 2.95 (s, 6H); HR-MS (ESI): m/z, calcd. For C 15 H 16 O 3 N 4 301.1295 [M+H] + , Found: 301.1280.

b)2-(二甲氨基)-5-异丁酰氨基-N-(吡啶-2-基甲基)苯甲酰胺b) 2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-2-ylmethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(吡啶-2-基甲基)苯甲酰胺(200mg,0.67mmol)溶于甲醇(20mL)中，加入pd/C(20mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得褐色油状物175mg；将异丁酸(86mg,0.97mmol)溶于DMF(12mL)中，依次加入DIEA(188mg,1.46mmol)、HATU(553mg,1.46mmol)，20min后加入上述褐色油状物(175mg,0.65mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体88mg，收率40.0％，熔点：169-170℃。 2-(Dimethylamino)-5-nitro-N-(pyridin-2-ylmethyl)benzamide (200 mg, 0.67 mmol) was dissolved in MeOH (20 mL). The mixture was stirred with EtOAc EtOAc EtOAc (EtOAc:EtOAc.sssssssssssssssssssssssssssssssss 1.46 mmol), after 20 min, EtOAc (EtOAc) Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 88 mg of white solid, yield 40.0%, m.p.: 169-170.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.99(s,1H),8.57(d,J＝4.4Hz,1H),8.24(d,J＝8.8Hz,1H),7.91(d,J＝2.4Hz,1H),7.77(s,1H),7.66(t,J＝7.6Hz,1H),7.34(d,J＝8.0Hz,1H),7.26(d,J＝8.8Hz,1H),7.21-7.18(m,1H),4.80(d,J＝5.2Hz,2H),2.71(s,6H),2.59-2.52(m,1H),1.23(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 19H 24O 2N 4 341.1972[M+H] +,Found:341.1965。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.99 (s, 1H), 8.57 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H) , 7.21-7.18 (m, 1H), 4.80 (d, J = 5.2 Hz, 2H), 2.71 (s, 6H), 2.59-2.52 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 19 H 24 O 2 N 4 341.1972 [M+H] + , Found: 341.1965.

实施例(化合物)2Example (compound) 2

2-(二甲氨基)-5-异丁酰氨基-N-(1-(吡啶-2-基)乙基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(1-(pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000062
Figure PCTCN2018088561-appb-000062

a)2-(二甲氨基)-5-硝基-N-(1-(吡啶-2-基)乙基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(1-(pyridin-2-yl)ethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(356mg,1.69mmol)溶于DMF(10mL)中，依次加入DIEA(696mg,5.40mmol)、HATU(965mg,2.54mmol)，搅拌反应20min后加入1-(吡啶-2-基)乙胺·盐酸盐(300mg,1.54mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗， 水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体247mg，收率51.1％，熔点：158-160℃。 2-(Dimethylamino)-5-nitrobenzoic acid (356 mg, 1.69 mmol) was dissolved in DMF (10 mL). EtOAc (EtOAc, EtOAc (EtOAc) After the addition of 1-(pyridin-2-yl)ethylamine hydrochloride (300 mg, 1.54 mmol), Concentrated, diluted with addition of EA (20mL), saturated ammonium chloride solution (10 mL) washed saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 247 mg of a yellow solid, yield 51.1%, melting point: 158-160 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.56(d,J＝4.8Hz,1H),8.49(d,J＝2.8Hz,1H),8.35(d,J＝6.8Hz,1H),8.14(dd,J＝9.2,2.8Hz,1H),7.73(t,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.26-7.21(m,1H),6.91(d,J＝9.2Hz,1H),5.34(p,J＝6.8Hz,1H),2.91(s,6H),1.59(d,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 16H 19O 3N 4315.1452[M+H] +,Found:315.1439。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.56 (d, J = 4.8Hz, 1H), 8.49 (d, J = 2.8Hz, 1H), 8.35 (d, J = 6.8Hz, 1H) , 8.14 (dd, J = 9.2, 2.8 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.26 - 7.21 (m, 1H), 6.91 ( d, J = 9.2 Hz, 1H), 5.34 (p, J = 6.8 Hz, 1H), 2.91 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H); HR-MS (ESI): m/ z,calcd.For C 16 H 19 O 3 N 4 315.1452 [M+H] + , Found: 315.1439.

b)5-氨基-2-(二甲氨基)-N-(1-(吡啶-2-基)乙基)苯甲酰胺b) 5-amino-2-(dimethylamino)-N-(1-(pyridin-2-yl)ethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(1-(吡啶-2-基)乙基)苯甲酰胺(200mg,0.64mmol)溶于THF(20mL)中，加入pd/C(20mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物168mg，收率92.8％。2-(Dimethylamino)-5-nitro-N-(1-(pyridin-2-yl)ethyl)benzamide (200 mg, 0.64 mmol) was dissolved in THF (20 mL). (20 mg), hydrogen was added, stirred at room temperature overnight, filtered, and concentrated to give 168 mg of pale yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.31(s,1H),8.57(d,J＝4.4Hz,1H),7.64(t,J＝7.6Hz,1H),7.54(d,J＝2.8Hz,1H),7.32(d,J＝7.6Hz,1H),7.20-7.13(m,1H),7.09(d,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.8Hz,1H),5.45-5.30(m,1H),3.55(s,2H),2.65(s,6H),1.59(d,J＝6.8Hz,3H)；ESI-MS m/z:285.17[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.31 (s, 1H), 8.57 (d, J = 4.4Hz, 1H), 7.64 (t, J = 7.6Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.20-7.13 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 8.4, 2.8 Hz, 1H), 5.45-5.30 (m, 1H), 3.55 (s, 2H), 2.65 (s, 6H), 1.59 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 285.17 [M +H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(1-(吡啶-2-基)乙基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(1-(pyridin-2-yl)ethyl)benzamide

将异丁酸(279mg,3.17mmol)溶于DMF(10mL)中，依次加入DIEA(409mg,3.17mmol)、HATU(1.2g,3.17mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(1-(吡啶-2-基)乙基)苯甲酰胺(300mg,1.06mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得白色固体109mg，收率29.1％，熔点：161-162℃。 Isobutyric acid (279 mg, 3.17 mmol) was dissolved in DMF (10 mL), DIEA (409 mg, 3.17 mmol), HATU (1.2 g, 3.17 mmol) was added, and the reaction was stirred for 20 min. Methylamino)-N-(1-(pyridin-2-yl)ethyl)benzamide (300 mg, 1.06 mmol). Concentrated, diluted with addition of EA (20mL), saturated ammonium chloride solution (10 mL) washed saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purified by volume ratio of 2:3) to give a white solid (109 mg, yield 29.1%, m.p.: 161 - 162.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.00(d,J＝7.2Hz,1H),8.58(d,J＝4.4Hz,1H),8.21(d,J＝8.4Hz,1H),7.85(d,J＝2.4Hz,1H),7.78(s,1H),7.65(t,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,1H),7.22(d,J＝8.8Hz,1H),7.19-7.16(m,1H),5.38(p,J＝6.8Hz,1H),2.69(s,6H),2.58-2.52(m,1H),1.58(d,J＝6.8Hz,3H),1.22(dd,J＝6.8,1.6Hz,6H)；HR-MS(ESI):m/z,calcd.For C 20H 26O 2N 4 355.2129[M+H] +,Found:355.2113。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 11.00 (d, J = 7.2 Hz, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H) , 7.85 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.19-7.16 (m, 1H), 5.38 (p, J = 6.8 Hz, 1H), 2.69 (s, 6H), 2.58-2.52 (m, 1H), 1.58 (d, J = 6.8) Hz, 3H), 1.22 (dd, J = 6.8, 1.6 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 20 H 26 O 2 N 4 355.2129 [M+H] + ,Found :355.2113.

实施例(化合物)3Example (compound) 3

2-(二甲氨基)-5-异丁酰氨基-N-(吡啶-3-基甲基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-3-ylmethyl)benzamide

Figure PCTCN2018088561-appb-000063
Figure PCTCN2018088561-appb-000063

a)2-(二甲氨基)-5-硝基-N-(吡啶-3-基甲基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(pyridin-3-ylmethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(777mg,3.70mmol)溶于DCM(30mL)中，依次加入DIEA(525mg,4.07mmol)、HATU(1.55g,4.07mmol)，搅拌反应20min后加入3-氨甲基吡啶(400mg,3.70mmol)，室温搅拌过夜。加入DCM(20mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体591mg，收率53.2％，熔点：144-145℃。 2-(Dimethylamino)-5-nitrobenzoic acid (777 mg, 3.70 mmol) was dissolved in DCM (30 mL), then DIEA (525 mg, 4.07 mmol), HATU (1.55 g, 4.07 mmol) After 20 min, 3-aminomethylpyridine (400 mg, 3.70 mmol) was added and stirred at room temperature overnight. DCM was added (20mL) diluted with saturated ammonium chloride solution (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume Purification of 1:2) gave 591 mg of a yellow solid, yield 53.2%, melting: 144-145.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.61(s,1H),8.53(d,J＝4.8Hz,1H),8.51(d,J＝2.8Hz,1H),8.13(dd,J＝9.2,2.8Hz,1H),7.80(s,1H),7.76(d,J＝7.6Hz,1H),7.30(dd,J＝7.6,4.8Hz,1H),6.96(d,J＝9.2Hz,1H),4.65(d,J＝6.0Hz,2H),2.87(s,6H)；ESI-MS m/z:301.13[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.61 (s, 1H), 8.53 (d, J = 4.8Hz, 1H), 8.51 (d, J = 2.8Hz, 1H), 8.13 (dd, J = 9.2, 2.8 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.30 (dd, J = 7.6, 4.8 Hz, 1H), 6.96 (d, J = 9.2) Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 2.87 (s, 6H); ESI-MS m/z: 301.13 [M+H] + .

b)5-氨基-2-(二甲氨基)-N-(吡啶-3-基甲基)苯甲酰胺b) 5-amino-2-(dimethylamino)-N-(pyridin-3-ylmethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(吡啶-3-基甲基)苯甲酰胺(600mg,2.00mmol)溶于THF(20mL)中，加入pd/C(120mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物501mg，收率92.8％。2-(Dimethylamino)-5-nitro-N-(pyridin-3-ylmethyl)benzamide (600 mg, 2.00 mmol) was dissolved in THF (20 mL). Hydrogen was introduced, and the mixture was stirred at room temperature overnight, filtered and concentrated to give 501 g of pale yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.05(s,1H),8.61(s,1H),8.51(d,J＝4.4Hz,1H),7.70(d,J＝7.6Hz,1H),7.57(d,J＝2.8Hz,1H),7.26(dd,J＝8.4,4.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.75(dd,J＝8.4,2.8Hz,1H),4.66(d,J＝5.6Hz,2H),3.71(s,2H),2.58(s,6H)；ESI-MS m/z:271.16[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.05 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 4.4Hz, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.26 (dd, J = 8.4, 4.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.4, 2.8 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.71 (s, 2H), 2.58 (s, 6H); ESI-MS m/z: 271.16 [M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(吡啶-3-基甲基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-3-ylmethyl)benzamide

将异丁酸(352mg,4.00mmol)溶于DMF(15mL)中，依次加入DIEA(516mg,4.00mmol)、HATU(1.52g,4.00mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(吡啶-3-基甲基)苯甲酰胺(360mg,1.33mmol)，室温搅拌过夜。浓缩，加入DCM(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-甲醇，体积比50:1)纯化，得白色固体201mg，收率44.4％，熔点：180-181℃。 Isobutyric acid (352 mg, 4.00 mmol) was dissolved in DMF (15 mL), then DIEA (516 mg, 4.00 mmol), HATU (1.52 g, 4.00 mmol) was added, and the reaction was stirred for 20 min. Methylamino)-N-(pyridin-3-ylmethyl)benzamide (360 mg, 1.33 mmol) was stirred at room temperature overnight. Concentrated, diluted were added DCM (30mL), saturated ammonium chloride solution (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - methanol, Purification by volume ratio of 50:1) gave a white solid, 201 mg, yield 44.4%, melting point: 180-181 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.65(s,1H),8.62(s,1H),8.54(d,J＝4.4Hz,1H),8.24(d,J＝8.8Hz,1H),7.89(d,J＝2.4Hz,1H),7.76-7.61(m,2H),7.32-7.26(m, 2H),4.68(d,J＝5.6Hz,2H),2.64(s,6H),2.60-2.45(m,1H),1.23(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 19H 24O 2N 4 341.1972[M+H] +,Found:341.1966。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.65 (s, 1H), 8.62 (s, 1H), 8.54 (d, J = 4.4Hz, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.76-7.61 (m, 2H), 7.32-7.26 (m, 2H), 4.68 (d, J = 5.6 Hz, 2H), 2.64 (s, 6H) ), 2.60-2.45 (m, 1H), 1.23 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, cald. For C 19 H 24 O 2 N 4 341.1972 [M+H ] + , Found: 341.1966.

实施例(化合物)4Example (compound) 4

2-(二甲氨基)-5-异丁酰氨基-N-(吡啶-4-基甲基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-4-ylmethyl)benzamide

Figure PCTCN2018088561-appb-000064
Figure PCTCN2018088561-appb-000064

a)2-(二甲氨基)-5-硝基-N-(吡啶-4-基甲基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(pyridin-4-ylmethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(777mg,3.70mmol)溶于DCM(30mL)中，依次加入DIEA(525mg,4.07mmol)、HATU(1.55g,4.07mmol)，搅拌反应20min后加入4-氨甲基吡啶(400mg,3.70mmol)，室温搅拌过夜。加入DCM(20mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体683mg，收率61.5％，熔点：213-214℃。 2-(Dimethylamino)-5-nitrobenzoic acid (777 mg, 3.70 mmol) was dissolved in DCM (30 mL), then DIEA (525 mg, 4.07 mmol), HATU (1.55 g, 4.07 mmol) After 20 min, 4-aminomethylpyridine (400 mg, 3.70 mmol) was added and stirred at room temperature overnight. DCM was added (20mL) diluted with saturated ammonium chloride solution (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume Purification of 1:2) gave 683 mg of a yellow solid. Yield: 61.5%.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.19(t,J＝5.6Hz,1H),8.54(d,J＝4.8Hz,2H),8.10(dd,J＝12.4,2.8Hz,2H),7.35(d,J＝4.8Hz,2H),6.95(d,J＝9.2Hz,1H),4.47(d,J＝6.0Hz,2H),2.95(s,6H)；ESI-MS m/z:301.13[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 9.19 (t, J = 5.6 Hz, 1H), 8.54 (d, J = 4.8 Hz, 2H), 8.10 (dd, J = 12.4, 2.8 Hz, 2H), 7.35 (d, J = 4.8 Hz, 2H), 6.95 (d, J = 9.2 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 2.95 (s, 6H); ESI-MS m /z:301.13[M+H] + .

b)5-氨基-2-(二甲氨基)-N-(吡啶-4-基甲基)苯甲酰胺b) 5-amino-2-(dimethylamino)-N-(pyridin-4-ylmethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(吡啶-4-基甲基)苯甲酰胺(700mg,2.33mmol)溶于THF(20mL)中，加入pd/C(140mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物577mg，收率91.6％。2-(Dimethylamino)-5-nitro-N-(pyridin-4-ylmethyl)benzamide (700 mg, 2.33 mmol) was dissolved in THF (20 mL). Hydrogen was introduced, and the mixture was stirred at room temperature overnight, filtered and concentrated to yield 577 g of pale yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.75(s,1H),8.51(d,J＝5.2Hz,2H),7.31(d,J＝5.2Hz,2H),7.17(d,J＝2.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.68(dd,J＝8.8,2.6Hz,1H),5.12(s,2H),4.53(d,J＝6.0Hz,2H),2.56(s,6H)；ESI-MS m/z:271.16[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.75 (s, 1H), 8.51 (d, J = 5.2Hz, 2H), 7.31 (d, J = 5.2Hz, 2H), 7.17 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 8.8, 2.6 Hz, 1H), 5.12 (s, 2H), 4.53 (d, J = 6.0 Hz, 2H), 2.56 (s, 6H); ESI-MS m/z: 271.16 [M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(吡啶-4-基甲基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(pyridin-4-ylmethyl)benzamide

将异丁酸(489mg,5.56mmol)溶于DMF(20mL)中，依次加入DIEA(717mg,5.56mmol)、HATU(2.11g,5.56mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(吡啶-4-基甲基)苯甲酰胺(500mg,1.85mmol)，室温搅拌过夜。浓缩，加 入DCM(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-甲醇，体积比50:1)纯化，得白色固体254mg，收率40.4％，熔点：134-135℃。 Isobutyric acid (489 mg, 5.56 mmol) was dissolved in DMF (20 mL), DIEA (717 mg, 5.56 mmol), HATU (2.11 g, 5.56 mmol) was added, and the reaction was stirred for 20 min. Methylamino)-N-(pyridin-4-ylmethyl)benzamide (500 mg, 1.85 mmol) was stirred at room temperature overnight. Concentrated, diluted were added DCM (30mL), saturated ammonium chloride solution (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - methanol, Purification by volume ratio of 50:1) gave 254 mg of white solid, yield 40.4%, mp.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.78(s,1H),8.56(d,J＝6.0Hz,2H),8.25(d,J＝8.4Hz,1H),7.90(d,J＝2.4Hz,1H),7.74(s,1H),7.29(d,J＝9.6Hz,2H),4.68(d,J＝6.0Hz,2H),2.68(s,6H),2.57-2.50(m,1H),1.22(d,J＝7.2Hz,6H)；HR-MS(ESI):m/z,calcd.For C 19H 24O 2N 4 341.1972[M+H] +,Found:341.1966。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.78 (s, 1H), 8.56 (d, J = 6.0Hz, 2H), 8.25 (d, J = 8.4Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.29 (d, J = 9.6 Hz, 2H), 4.68 (d, J = 6.0 Hz, 2H), 2.68 (s, 6H), 2.57-2.50 ( m,1H), 1.22 (d, J = 7.2 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 19 H 24 O 2 N 4 341.1972 [M+H] + , Found: 341.1966 .

实施例(化合物)5Example (compound) 5

2-(二甲氨基)-5-异丁酰氨基-N-(萘-1-基甲基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(naphthalen-1-ylmethyl)benzamide

Figure PCTCN2018088561-appb-000065
Figure PCTCN2018088561-appb-000065

a)2-(二甲氨基)-N-(萘-1-基甲基)-5-硝基苯甲酰胺a) 2-(Dimethylamino)-N-(naphthalen-1-ylmethyl)-5-nitrobenzamide

将2-(二甲氨基)-5-硝基苯甲酸(294mg,1.40mmol)溶于DMF(10mL)中，依次加入DIEA(271mg,2.10mmol)、HATU(796mg,2.10mmol)，搅拌反应20min后加入1-萘甲胺(200mg,1.27mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体313mg，收率70.5％，熔点：179-180℃。 2-(Dimethylamino)-5-nitrobenzoic acid (294 mg, 1.40 mmol) was dissolved in DMF (10 mL), then DIEA (271 mg, 2.10 mmol), HATU (796 mg, 2.10 mmol) Thereafter, 1-naphthylmethylamine (200 mg, 1.27 mmol) was added, and stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 313 mg of a yellow solid, yield 70.5%, melting point: 179-180 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.56(s,1H),8.12(d,J＝8.4Hz,2H),7.90(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.61-7.37(m,5H),6.92(d,J＝9.2Hz,1H),5.10(d,J＝5.2Hz,2H),2.74(s,6H)；ESI-MS m/z:350.15[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.56 (s, 1H), 8.12 (d, J = 8.4Hz, 2H), 7.90 (d, J = 8.0Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.61-7.37 (m, 5H), 6.92 (d, J = 9.2 Hz, 1H), 5.10 (d, J = 5.2 Hz, 2H), 2.74 (s, 6H); MS m/z: 350.15 [M + H] + .

b)5-氨基-2-(二甲氨基)-N-(萘-1-基甲基)苯甲酰胺b) 5-amino-2-(dimethylamino)-N-(naphthalen-1-ylmethyl)benzamide

将2-(二甲氨基)-N-(萘-1-基甲基)-5-硝基苯甲酰胺(280mg,0.80mmol)溶于THF(20mL)中，加入pd/C(28mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物233mg，收率91.0％。2-(Dimethylamino)-N-(naphthalen-1-ylmethyl)-5-nitrobenzamide (280 mg, 0.80 mmol) was dissolved in THF (20 mL). Hydrogen was added thereto, and the mixture was stirred at room temperature overnight, filtered and concentrated to yield 233 g of pale yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.03(s,1H),8.14(d,J＝8.4Hz,1H),7.88(d,J＝8.0Hz,1H),7.80(d,J＝8.4Hz,1H),7.63(d,J＝2.4Hz,1H),7.52(p,J＝6.8Hz,3H),7.43(t,J＝7.6Hz,1H),7.02(d,J＝8.4Hz,1H),6.72(dd,J＝8.4,2.8Hz,1H),5.10(d,J＝5.2Hz,2H),3.86(s,2H),2.34(s,6H)；ESI-MS m/z:320.18[M+H] +。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 11.03 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.52 (p, J = 6.8 Hz, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 8.4, 2.8 Hz, 1H), 5.10 (d, J = 5.2 Hz, 2H), 3.86 (s, 2H), 2.34 (s, 6H); ESI-MS m /z: 320.18[M + H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(萘-1-基甲基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(naphthalen-1-ylmethyl)benzamide

将异丁酸(166mg,1.88mmol)溶于DMF(10mL)中，依次加入DIEA(243mg,1.88mmol)、HATU(714mg,1.88mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(萘-1-基甲基)苯甲酰胺(200mg,0.63mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得白色固体101mg，收率40.4％，熔点：185-186℃。 Isobutyric acid (166 mg, 1.88 mmol) was dissolved in DMF (10 mL), DIEA (243 mg, 1.88 mmol), HATU (714 mg, 1.88 mmol) was added, and the reaction was stirred for 20 min. Amino)-N-(naphthalen-1-ylmethyl)benzamide (200 mg, 0.63 mmol) was stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 101 mg of white solid, yield 40.4%, m.p.: 185-186.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.71(s,1H),8.23(d,J＝8.4Hz,1H),8.11(d,J＝8.0Hz,1H),7.95(s,1H),7.89(d,J＝8.0Hz,1H),7.85(s,1H),7.82(d,J＝8.0Hz,1H),7.53(m,3H),7.44(t,J＝7.6Hz,1H),7.17(d,J＝8.8Hz,1H),5.12(d,J＝5.6Hz,2H),2.60-2.53(m,1H),2.38(s,6H),1.21(d,J＝7.2Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 2N 3 390.2176[M+H] +,Found:390.2166。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.71 (s, 1H), 8.23 (d, J = 8.4Hz, 1H), 8.11 (d, J = 8.0Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.12 (d, J = 5.6 Hz, 2H), 2.60-2.53 (m, 1H), 2.38 (s, 6H), 1.21 (d, J = 7.2) Hz, 6H); HR-MS (ESI): m/z, calcd. For C 24 H 27 O 2 N 3 390.2176 [M+H] + , Found: 390.2166.

实施例(化合物)6Example (compound) 6

2-(二甲氨基)-5-异丁酰氨基-N-(1-(萘-1-基)乙基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(1-(naphthalen-1-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000066
Figure PCTCN2018088561-appb-000066

a)2-(二甲氨基)-N-(1-(萘-1-基)乙基)-5-硝基苯甲酰胺a) 2-(Dimethylamino)-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzamide

将2-(二甲氨基)-5-硝基苯甲酸(200mg,0.95mmol)溶于DMF(15mL)中，依次加入DIEA(185mg,1.43mmol)、HATU(542mg,1.43mmol)，20min后加入1-萘乙胺(148mg,0.87mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得黄色固体261mg，收率83.1％，熔点：193-194℃。 2-(Dimethylamino)-5-nitrobenzoic acid (200 mg, 0.95 mmol) was dissolved in DMF (15 mL), then DIEA (185 mg, 1.43 mmol), HATU (542 mg, 1.43 mmol). 1-Naphthylethylamine (148 mg, 0.87 mmol) was stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio of 2:3) gave 261 mg of a yellow solid, yield: 83.1%, melting point: 193-194 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.52(s,1H),8.23(d,J＝8.4Hz,1H),8.12(d,J＝9.2Hz,1H),7.88(d,J＝7.6Hz,1H),7.83(d,J＝8.0Hz,1H),7.52(m,4H),7.38(d,J＝7.2Hz,1H),6.92(d,J＝9.2Hz,1H),6.28-6.08(m,1H),2.79(s,6H),1.80(d,J＝6.8Hz,3H)；ESI-MS m/z:364.17[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.52 (s, 1H), 8.23 (d, J = 8.4Hz, 1H), 8.12 (d, J = 9.2Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.52 (m, 4H), 7.38 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H) , 6.28-6.08 (m, 1H), 2.79 (s, 6H), 1.80 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 364.17 [M+H] + .

b)5-氨基-2-(二甲氨基)-N-(1-(萘-1-基)乙基)苯甲酰胺b) 5-amino-2-(dimethylamino)-N-(1-(naphthalen-1-yl)ethyl)benzamide

将2-(二甲氨基)-N-(1-(萘-1-基)乙基)-5-硝基苯甲酰胺(200mg,0.55mmol)溶于甲醇(20mL)中，加入pd/C(20mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得褐色油状物178mg，收率97.1％。2-(Dimethylamino)-N-(1-(naphthalen-1-yl)ethyl)-5-nitrobenzamide (200 mg, 0.55 mmol) was dissolved in methanol (20 mL). (20 mg), EtOAc (m.).

1H-NMR(400MHz,CDCl 3)δ(ppm):10.65(s,1H),8.22(d,J＝7.6Hz,2H),7.87(d,J＝7.2Hz,2H),7.79(d,J＝8.0Hz,1H),7.65(s,1H),7.59-7.40(m,3H),7.18(d,J＝8.4Hz,1H),6.25-6.02(m,1H),2.63-2.37(s,6H),1.75(d,J＝6.8Hz,3H)；ESI-MS m/z:334.19[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.65 (s, 1H), 8.22 (d, J = 7.6Hz, 2H), 7.87 (d, J = 7.2Hz, 2H), 7.79 (d, J=8.0Hz, 1H), 7.65(s,1H), 7.59-7.40(m,3H), 7.18(d,J=8.4Hz,1H), 6.25-6.02(m,1H),2.63-2.37(s , 6H), 1.75 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 334.19 [M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(1-(萘-1-基)乙基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(1-(naphthalen-1-yl)ethyl)benzamide

将异丁酸(86mg,0.97mmol)溶于DMF(12mL)中，依次加入DIEA(188mg,1.46mmol)、HATU(553mg,1.46mmol)，20min后加入5-氨基-2-(二甲氨基)-N-(1-(萘-1-基)乙基)苯甲酰胺(175mg,0.65mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体79mg，收率36.7％，熔点：171-172℃。 Isobutyric acid (86 mg, 0.97 mmol) was dissolved in DMF (12 mL), then DIEA (188 mg, 1.46 mmol), HATU (553 mg, 1.46 mmol) was added, and after 5 min, 5-amino-2-(dimethylamino) was added. -N-(1-(Naphthalen-1-yl)ethyl)benzamide (175 mg, 0.65 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purified by volume ratio 1:3) to give a white solid, 79 mg, yield 36.7%, melting point: 171-172 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.65(s,1H),8.22(d,J＝7.6Hz,2H),7.87(d,J＝7.2Hz,2H),7.79(d,J＝8.0Hz,1H),7.65(s,1H),7.56-7.45(m,4H),7.18(d,J＝8.4Hz,1H),6.17-6.10(m,1H),2.57-2.52(m,1H),2.47(s,6H),1.75(d,J＝6.8Hz,3H),1.21(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 25H 29O 2N 3 404.2333[M+H] +,Found:404.2326。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.65 (s, 1H), 8.22 (d, J = 7.6Hz, 2H), 7.87 (d, J = 7.2Hz, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.56-7.45 (m, 4H), 7.18 (d, J=8.4 Hz, 1H), 6.17-6.10 (m, 1H), 2.57-2.52 (m) , 1H), 2.47 (s, 6H), 1.75 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 25 H 29 O 2 N 3 404.2333 [M+H] + , Found: 404.2326.

实施例(化合物)7Example (compound) 7

3-((2-(二甲氨基)-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸甲酯Methyl 3-((2-(dimethylamino)-5-isobutyrylaminobenzoylamino)methyl)benzoate

Figure PCTCN2018088561-appb-000067
Figure PCTCN2018088561-appb-000067

a)3-(氨基甲基)苯甲酸甲酯·盐酸盐a) 3-(Aminomethyl)benzoic acid methyl ester hydrochloride

将3-氰基苯甲酸甲酯(500mg,3.1mmol)溶于甲醇(20mL)中，依次加入HCl(4N)(3.9mL,15.5mmol)，Pd/C(50mg)，室温，60psi/H 2反应24h，原料消失。停止反应，过滤，滤液浓缩，加入乙醚(30mL)，过滤得白色固体597mg，收率为95.7％，熔点：182-183℃。 3-cyano-benzoic acid methyl ester (500mg, 3.1mmol) was dissolved in methanol (20mL) were sequentially added HCl (4N) (3.9mL, 15.5mmol ), Pd / C (50mg), at room temperature, 60psi / H 2 After 24 hours of reaction, the starting materials disappeared. The reaction was quenched, filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

1H-NMR(400MHz,CD 3OD)δ(ppm):8.15(s,1H),8.07(d,J＝7.6Hz,1H),7.71(d,J ＝7.6Hz,1H),7.58(t,J＝7.6Hz,1H),4.20(s,2H),3.92(s,3H)；ESI-MS m/z:166.09[M+H] +。 1 H-NMR (400 MHz, CD 3 OD) δ (ppm): 8.15 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.58 (t , J = 7.6 Hz, 1H), 4.20 (s, 2H), 3.92 (s, 3H); ESI-MS m/z: 166.09 [M+H] + .

b)3-((2-(二甲氨基)-5-硝基苯甲酰氨基)甲基)苯甲酸甲酯b) Methyl 3-((2-(dimethylamino)-5-nitrobenzoylamino)methyl)benzoate

将2-(二甲氨基)-5-硝基苯甲酸(345mg,1.64mmol)溶于DMF(10mL)中，依次加入DIEA(606mg,4.70mmol)、HATU(935mg,2.46mmol)，20min后加入3-(氨基甲基)苯甲酸甲酯·盐酸盐(300mg,1.49mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得黄色固体440mg，收率82.6％，熔点：180-181℃。 2-(Dimethylamino)-5-nitrobenzoic acid (345 mg, 1.64 mmol) was dissolved in DMF (10 mL), then DIEA (606 mg, 4.70 mmol), HATU (935 mg, 2.46 mmol). Methyl 3-(aminomethyl)benzoate hydrochloride (300 mg, 1.49 mmol) was stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio of 2:3) gave 440 mg of a yellow solid, yield 82.6%, melting point: 180-181 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.58(d,J＝2.8Hz,1H),8.17(dd,J＝9.2,2.8Hz,1H),8.04(s,1H),7.98(d,J＝7.6Hz,1H),7.59(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,1H),7.00(d,J＝9.2Hz,1H),4.70(d,J＝6.0Hz,2H),3.92(s,3H),2.90(s,6H)；ESI-MS m/z:357.13[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.2, 2.8 Hz, 1H), 8.04 (s, 1H), 7.78 ( d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 2.90 (s, 6H); ESI-MS m/z: 357.13 [M+H] + .

c)3-((5-氨基-2-(二甲氨基)苯甲酰氨基)甲基)苯甲酸甲酯c) methyl 3-((5-amino-2-(dimethylamino)benzoylamino)methyl)benzoate

将甲基3-((2-(二甲氨基)-5-硝基苯甲酰氨基)甲基)苯甲酸酯(370mg,1.04mmol)溶于甲醇(20mL)中，加入pd/C(37mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得褐色油状物319mg，收率94.4％。Methyl 3-((2-(dimethylamino)-5-nitrobenzoylamino)methyl)benzoate (370 mg, 1.04 mmol) was dissolved in methanol (20 mL). The mixture was stirred at rt.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.12(s,1H),8.04(s,1H),7.95(d,J＝7.6Hz,1H),7.58(d,J＝6.8Hz,2H),7.42(t,J＝7.6Hz,1H),7.13(d,J＝8.0Hz,1H),6.77(dd,J＝8.4,2.8Hz,1H),4.70(d,J＝5.6Hz,2H),3.91(s,3H),2.61(s,6H)；ESI-MS m/z:327.16[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.12 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 7.6Hz, 1H), 7.58 (d, J = 6.8Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.77 (dd, J = 8.4, 2.8 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.61 (s, 6H); ESI-MS m/z: 327.16 [M+H] + .

d)3-((2-(二甲氨基)-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸甲酯d) methyl 3-((2-(dimethylamino)-5-isobutyrylaminobenzoylamino)methyl)benzoate

将异丁酸(218mg,2.48mmol)溶于DMF(10mL)中，依次加入DIEA(320mg,2.48mmol)、HATU(942mg,2.48mmol)，20min后加入甲基3-((5-氨基-2-(二甲氨基)苯甲酰氨基)甲基)苯甲酸酯(270mg,0.83mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体147mg，收率45.0％，熔点：150-151℃。 Isobutyric acid (218 mg, 2.48 mmol) was dissolved in DMF (10 mL), DIEA (320 mg, 2.48 mmol), HATU (942 mg, 2.48 mmol) was added, and methyl 3-((5-amino-2) was added after 20 min. -(Dimethylamino)benzoylamino)methyl)benzoate (270 mg, 0.83 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 147 mg of white solid, yield 45.0%, m.p.: 150-151.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.69(s,1H),8.26(d,J＝6.8Hz,1H),8.04(s,1H),7.96(d,J＝7.6Hz,1H),7.91(s,1H),7.71(s,1H),7.56(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),7.26(d,J＝8.8Hz,1H),4.72(d,J＝5.6Hz,2H),3.91(s,3H),2.65(s, 6H),2.58-2.51(m,1H),1.22(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 22H 27O 4N 3 398.2074[M+H] +,Found:398.2069。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.69 (s, 1H), 8.26 (d, J = 6.8Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 7.6Hz, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 4.72 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.65 (s, 6H), 2.58-2.51 (m, 1H), 1.22 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, Cald. For C 22 H 27 O 4 N 3 398.2074 [M+H] + , Found: 398.2069.

实施例(化合物)8Example (compound) 8

3-(1-(2-(二甲氨基)-5-异丁酰氨基苯甲酰氨基)乙基)苯甲酸甲酯Methyl 3-(1-(2-(dimethylamino)-5-isobutyrylaminobenzoylamino)ethyl)benzoate

Figure PCTCN2018088561-appb-000068
Figure PCTCN2018088561-appb-000068

a)3-(1-(2-(二甲氨基)-5-硝基苯甲酰氨基)乙基)苯甲酸甲酯a) methyl 3-(1-(2-(dimethylamino)-5-nitrobenzoylamino)ethyl)benzoate

将2-(二甲氨基)-5-硝基苯甲酸(200mg,0.95mmol)溶于DCM(15mL)中，依次加入DIEA(245mg,1.90mmol)、HATU(543mg,1.43mmol)，搅拌反应20min后加入3-(1-氨基乙基)苯甲酸甲酯(170mg,0.95mmol)，室温搅拌过夜。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(二氯甲烷-甲醇，体积比150:1)纯化，得黄色固体302mg，收率85.6％，熔点：144-145℃。 2-(Dimethylamino)-5-nitrobenzoic acid (200 mg, 0.95 mmol) was dissolved in DCM (15 mL), then DIEA (245 mg, 1.90 mmol), HATU (543 mg, 1.43 mmol). Methyl 3-(1-aminoethyl)benzoate (170 mg, 0.95 mmol) was then added and stirred at room temperature overnight. DCM was added (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash with saturated brine (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography ( Purification by dichloromethane-methanol in a volume ratio of 150:1) afforded ayel.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.54(d,J＝2.8Hz,1H),8.16(dd,J＝9.2,2.8Hz,1H),8.06(s,1H),7.97(d,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,1H),7.57(d,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),6.99(d,J＝9.2Hz,1H),5.38(p,J＝7.2Hz,1H),3.93(s,3H),2.86(s,6H),1.63(d,J＝6.8Hz,3H)；ESI-MS m/z:372.16[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.54 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 9.2, 2.8 Hz, 1H), 8.06 (s, 1H), 7.97 ( d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H), 5.38 (p, J = 7.2 Hz, 1H), 3.93 (s, 3H), 2.86 (s, 6H), 1.63 (d, J = 6.8 Hz, 3H); ESI-MS m /z:372.16[M+H] + .

b)3-(1-(5-氨基-2-(二甲氨基)苯甲酰氨基)乙基)苯甲酸甲酯b) methyl 3-(1-(5-amino-2-(dimethylamino)benzoylamino)ethyl)benzoate

将甲基3-(1-(2-(二甲氨基)-5-硝基苯甲酰氨基)乙基)苯甲酸酯(220mg,0.59mmol)溶于THF(15mL)中，加入pd/C(44mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物179mg，收率88.6％。Methyl 3-(1-(2-(dimethylamino)-5-nitrobenzoylamino)ethyl)benzoate (220 mg, 0.59 mmol) was dissolved in THF (15 mL). C (44 mg) was added with EtOAc EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.32(s,1H),8.07(s,1H),7.92(d,J＝7.6Hz,1H),7.58(d,J＝7.2Hz,1H),7.47(s,1H),7.40(t,J＝7.6Hz,1H),7.13(d,J＝8.4Hz,1H),6.66(d,J＝8.6Hz,1H),5.37-5.32(m,1H),3.91(s,3H),2.65(s,6H),1.57(d,J＝6.8Hz,3H)；ESI-MS m/z:342.18[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.32 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 7.6Hz, 1H), 7.58 (d, J = 7.2Hz, 1H), 7.47 (s, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 5.37-5.32 ( m, 1H), 3.91 (s, 3H), 2.65 (s, 6H), 1.57 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 342.18 [M+H] + .

c)3-(1-(2-(二甲氨基)-5-异丁酰氨基苯甲酰氨基)乙基)苯甲酸甲酯c) methyl 3-(1-(2-(dimethylamino)-5-isobutyrylaminobenzoylamino)ethyl)benzoate

将甲基3-(1-(5-氨基-2-(二甲氨基)苯甲酰氨基)乙基)苯甲酸酯(179mg,0.52mmol)溶于无水THF(15mL)中，冰浴下依次加入TEA(79mg,0.78mmol)，异丁酰氯(56mg,0.52mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯30mL稀释， 饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得白色固体153mg，收率为71.2％，熔点：158-159℃。 Methyl 3-(1-(5-amino-2-(dimethylamino)benzoylamino)ethyl)benzoate (179 mg, 0.52 mmol) was dissolved in anhydrous THF (15 mL) Next, TEA (79 mg, 0.78 mmol), isobutyryl chloride (56 mg, 0.52 mmol) was added, and the reaction was continued for 1 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate 30 mL, and washed with saturated ammonium chloride (10 mL), saturated NaHCO 3 (10 mL) wash, water (10mL) wash, brine water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 2) to give 153 mg of a white solid, The yield was 71.2%, and the melting point was 158-159 °C.

1H-NMR(500MHz,CDCl 3)δ(ppm):10.82(d,J＝7.0Hz,1H),8.28(d,J＝7.5Hz,1H),8.11(s,1H),7.99(d,J＝7.5Hz,1H),7.87(d,J＝1.5Hz,1H),7.67(s,1H),7.61(d,J＝7.5Hz,1H),7.46(t,J＝7.5Hz,1H),7.30(s,1H),5.42(p,J＝7.0Hz,1H),3.96(s,3H),2.73(s,6H),2.59-2.54(m,1H),1.63(d,J＝7.0Hz,3H),1.26(d,J＝7.0Hz,6H)；HR-MS(ESI):m/z,calcd.For C 23H 29O 4N 3 412.2231[M+H] +,Found:412.2215。 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 10.82 (d, J = 7.0 Hz, 1H), 8.28 (d, J = 7.5 Hz, 1H), 8.11 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H) , 7.30 (s, 1H), 5.42 (p, J = 7.0 Hz, 1H), 3.96 (s, 3H), 2.73 (s, 6H), 2.59-2.54 (m, 1H), 1.63 (d, J = 7.0) Hz, 3H), 1.26 (d, J = 7.0 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 23 H 29 O 4 N 3 412.2231 [M+H] + , Found: 412.2215 .

实施例(化合物)9Example (compound) 9

N-([1,1'-联苯基]-3-基甲基)-2-(二甲氨基)-5-异丁酰氨基苯甲酰胺N-([1,1'-biphenyl]-3-ylmethyl)-2-(dimethylamino)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000069
Figure PCTCN2018088561-appb-000069

a)[1,1'-联苯基]-3-甲腈a) [1,1'-biphenyl]-3-carbonitrile

将溴苯(500mg,3.18mmol)溶于二氧六环(20mL)中，依次加入Pd(PPh 3) 4(368mg,0.318mmol)，Na 2CO 3(1.69g,15.9mmol)，3-氰基苯硼酸(514mg,3.5mmol)和蒸馏水(5mL)，氩气保护下，110℃反应5h，原料消失。过滤，滤液浓缩，加入EA(20mL)稀释，水洗(20mL×2)，饱和食盐水洗(20mL)，柱层析(PE/EA＝40:1)，得白色固体420mg，收率为73.3％，熔点：29-30℃。 The bromobenzene (500mg, 3.18mmol) was dissolved in dioxane (20mL) were sequentially added Pd (PPh 3) 4 (368mg , 0.318mmol), Na 2 CO 3 (1.69g, 15.9mmol), 3- cyano The phenyl boronic acid (514 mg, 3.5 mmol) and distilled water (5 mL) were reacted under an argon atmosphere at 110 ° C for 5 h, and the starting material disappeared. Filtration, the filtrate was concentrated, diluted with EA (20 mL), washed with water (20 mL×2), washed with brine (20 mL) and purified by column chromatography (PE/EA=40:1) to give 420 mg of white solid. Melting point: 29-30 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.87(s,1H),7.84-7.78(m,1H),7.63(dt,J＝7.6,1.2Hz,1H),7.59-7.56(m,1H),7.55(d,J＝3.2Hz,2H),7.51-7.45(m,2H),7.42(ddd,J＝7.2,3.6,1.2Hz,1H)；ESI-MS m/z:180.08[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.87 (s, 1H), 7.84-7.78 (m, 1H), 7.63 (dt, J = 7.6, 1.2 Hz, 1H), 7.59-7.56 (m) , 1H), 7.55 (d, J = 3.2 Hz, 2H), 7.51 - 7.45 (m, 2H), 7.42 (ddd, J = 7.2, 3.6, 1.2 Hz, 1H); ESI-MS m/z: 180.08 [ M+H] + .

b)[1,1'-联苯基]-3-基甲胺·盐酸盐b) [1,1'-biphenyl]-3-ylmethylamine hydrochloride

将[1,1'-联苯基]-3-甲腈(300mg,1.68mmol)溶于甲醇(20mL)中，依次加入HCl(4N)(2.1mL,8.38mmol)，Pd/C(30mg)，室温，60psi/H 2反应24h，原料少量剩余。停止反应，过滤，滤液浓缩，加入乙醚(30mL)，过滤得白色固体311mg，收率为78.0％，熔点：157-159℃。 [1,1'-Biphenyl]-3-carbonitrile (300 mg, 1.68 mmol) was dissolved in MeOH (20 mL). EtOAc (4N) At room temperature, 60 psi / H 2 reaction for 24 h, a small amount of raw materials remained. The reaction was quenched, filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

1H-NMR(400MHz,CD 3OD)δ(ppm):7.75(s,1H),7.68(dd,J＝13.6,7.6Hz,3H),7.54(t,J＝7.6Hz,1H),7.47(t,J＝7.2Hz,3H),7.37(t,J＝7.2Hz,1H),4.20(s,2H)；ESI-MS m/z:184.11[M+H] +。 1 H-NMR (400 MHz, CD 3 OD) δ (ppm): 7.75 (s, 1H), 7.68 (dd, J = 13.6, 7.6 Hz, 3H), 7.54 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.2 Hz, 3H), 7.37 (t, J = 7.2 Hz, 1H), 4.20 (s, 2H); ESI-MS m/z: 184.11 [M+H] + .

c)N-([1,1'-联苯基]-3-基甲基)-2-(二甲氨基)-5-硝基苯甲酰胺c) N-([1,1'-biphenyl]-3-ylmethyl)-2-(dimethylamino)-5-nitrobenzamide

将2-(二甲氨基)-5-硝基苯甲酸(285mg,1.36mmol)溶于DMF(10mL)中，依次加入DIEA(434mg,3.37mmol)、HATU(948mg,2.50mmol)，20min后加入[1,1'-联苯基]-3-基甲胺·盐酸盐(270mg,1.23mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得黄色固体386mg，收率83.5％，熔点：138-139℃。 2-(Dimethylamino)-5-nitrobenzoic acid (285 mg, 1.36 mmol) was dissolved in DMF (10 mL), then DIEA (434 mg, 3.37 mmol), HATU (948 mg, 2.50 mmol). [1,1'-Biphenyl]-3-ylmethylamine hydrochloride (270 mg, 1.23 mmol) was stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 386 mg of a yellow solid, yield: 83.5%, m.p.: 138-139.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.57(d,J＝2.8Hz,1H),8.15(dd,J＝9.2,2.8Hz,1H),7.60-7.50(m,4H),7.48-7.39(m,4H),7.35(t,J＝7.6Hz,2H),6.96(d,J＝9.2Hz,1H),4.71(d,J＝5.6Hz,2H),2.88(s,6H)；ESI-MS m/z:375.16[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.57 (d, J = 2.8Hz, 1H), 8.15 (dd, J = 9.2,2.8Hz, 1H), 7.60-7.50 (m, 4H), 7.48-7.39 (m, 4H), 7.35 (t, J = 7.6 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H), 2.88 (s, 6H) ESI-MS m/z: 375.16 [M+H] + .

d)N-([1,1'-联苯基]-3-基甲基)-2-(二甲氨基)-5-异丁酰氨基苯甲酰胺d) N-([1,1'-biphenyl]-3-ylmethyl)-2-(dimethylamino)-5-isobutyrylaminobenzamide

将N-([1,1'-联苯基]-3-基甲基)-2-(二甲氨基)-5-硝基苯甲酰胺(310mg,0.83mmol)溶于甲醇(20mL)中，加入pd/C(31mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得褐色油状物245mg；将异丁酸(187mg,2.13mmol)溶于DMF(10mL)中，依次加入DIEA(275mg,2.13mmol)、HATU(809mg,2.13mmol)，20min后加入上述褐色油状物(245mg,0.71mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体121mg，收率41.2％，熔点：180-181℃。 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). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purified by volume ratio 1:3) to give a white solid, 121 mg, yield 41.2%, melting point: 180-181 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.63(s,1H),8.27(d,J＝8.8Hz,1H),7.93(brs,2H),7.59-7.51(m,4H),7.45-7.41(m,3H),7.37-7.33(m,2H),7.24(brs,1H),4.75(d,J＝5.6Hz,2H),2.63(s,6H),2.57-2.52(m,1H),1.21(s,6H)；HR-MS(ESI):m/z,calcd.For C 26H 29O 2N 3 416.2333[M+H] +,Found:416.2325。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.63 (s, 1H), 8.27 (d, J = 8.8Hz, 1H), 7.93 (brs, 2H), 7.59-7.51 (m, 4H), 7.45-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.24 (brs, 1H), 4.75 (d, J = 5.6 Hz, 2H), 2.63 (s, 6H), 2.57-2.52 (m, 1H), 1.21 (s, 6H); HR-MS (ESI): m/z, calcd. For C 26 H 29 O 2 N 3 416.2333 [M+H] + , Found: 416.2325.

实施例(化合物)10Example (compound) 10

N-(1-([1,1'-联苯基]-3-基)乙基)-2-(二甲氨基)-5-异丁酰氨基苯甲酰胺0N-(1-([1,1'-biphenyl]-3-yl)ethyl)-2-(dimethylamino)-5-isobutyrylaminobenzamide 0

Figure PCTCN2018088561-appb-000070
Figure PCTCN2018088561-appb-000070

a)N-(1-([1,1'-联苯基]-3-基)乙基)-2-(二甲氨基)-5-硝基苯甲酰胺a) N-(1-([1,1'-biphenyl]-3-yl)ethyl)-2-(dimethylamino)-5-nitrobenzamide

将2-(二甲氨基)-5-硝基苯甲酸(317mg,1.51mmol)溶于DMF(10mL)中，依次加入DIEA(483mg,3.74mmol)、HATU(859mg,2.26mmol)，搅拌反应20min后加入1-([1,1'-联苯基]-3-基)乙胺(320mg,1.37mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得黄色固体227mg，收率51.9％，熔点：138-141℃。 2-(Dimethylamino)-5-nitrobenzoic acid (317 mg, 1.51 mmol) was dissolved in DMF (10 mL), then DIEA (483 mg, 3.74 mmol), HATU (859 mg, 2.26 mmol). After the addition of 1-([1,1'-biphenyl]-3-yl)ethylamine (320 mg, 1.37 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 227 mg of a yellow solid, yield 51.9%, m.p.: 138-141.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.56-8.48(m,1H),8.15(dd,J＝9.2,6.0Hz,1H),7.59(d,J＝8.0Hz,3H),7.53(d,J＝7.6Hz,1H),7.49-7.32(m,6H),6.95(dd,J＝8.8,5.2Hz,1H),5.47-5.34(m,1H),2.86(s,6H),1.67(d,J＝6.8Hz,3H)；ESI-MS m/z:390.18[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.56-8.48 (m, 1H), 8.15 (dd, J = 9.2,6.0Hz, 1H), 7.59 (d, J = 8.0Hz, 3H), 7.53 (d, J = 7.6 Hz, 1H), 7.49-7.32 (m, 6H), 6.95 (dd, J = 8.8, 5.2 Hz, 1H), 5.47-5.34 (m, 1H), 2.86 (s, 6H) , 1.67 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 390.18 [M+H] + .

b)N-(1-([1,1'-联苯基]-3-基)乙基)-5-氨基-2-(二甲氨基)苯甲酰胺b) N-(1-([1,1'-biphenyl]-3-yl)ethyl)-5-amino-2-(dimethylamino)benzamide

将N-(1-([1,1'-联苯基]-3-基)乙基)-2-(二甲氨基)-5-硝基苯甲酰胺(221mg,0.57mmol)溶于THF(20mL)中，加入pd/C(22mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物200mg，收率98.5％。Dissolving N-(1-([1,1'-biphenyl]-3-yl)ethyl)-2-(dimethylamino)-5-nitrobenzamide (221 mg, 0.57 mmol) in THF (20 mL), pd/C (22 mg) was added, and hydrogen was added, and the mixture was stirred at room temperature overnight, filtered, and concentrated to give a pale yellow oil (200 mg, yield: 98.5%).

1H-NMR(400MHz,CDCl 3)δ(ppm):11.03(s,1H),7.41-7.37(m,10H),7.10(s,1H),6.74(s,1H),5.38(s,1H),3.78(s,2H),2.62(s,6H),1.62(s,3H)；ESI-MS m/z:360.21[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.03 (s, 1H), 7.41-7.37 (m, 10H), 7.10 (s, 1H), 6.74 (s, 1H), 5.38 (s, 1H ), 3.78 (s, 2H), 2.62 (s, 6H), 1.62 (s, 3H); ESI-MS m/z: 360.21.[M+H] + .

c)N-(1-([1,1'-联苯基]-3-基)乙基)-2-(二甲氨基)-5-异丁酰氨基苯甲酰胺c) N-(1-([1,1'-biphenyl]-3-yl)ethyl)-2-(dimethylamino)-5-isobutyrylaminobenzamide

将异丁酸(147mg,1.67mmol)溶于DMF(10mL)中，依次加入DIEA(215mg,1.67mmol)、HATU(635mg,1.67mmol)，搅拌反应20min后加入N-(1-([1,1'-联苯基]-3-基)乙基)-5-氨基-2-(二甲氨基)苯甲酰胺(200mg,0.56mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体142mg，收率59.4％，熔点：116-118℃。 Isobutyric acid (147 mg, 1.67 mmol) was dissolved in DMF (10 mL), then DIEA (215 mg, 1.67 mmol), HATU (635 mg, 1.67 mmol) was added, and the reaction was stirred for 20 min, then N-(1-([1, 1'-Biphenyl]-3-yl)ethyl)-5-amino-2-(dimethylamino)benzamide (200 mg, 0.56 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 142 mg of white solid, yield 59.4%, m.p.: 116-118.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.61(s,1H),8.23(d,J＝8.4Hz,1H),7.83(s,1H),7.57(m,4H),7.49(d,J＝7.6Hz,1H),7.47-7.39(m,3H),7.35(d,J＝6.0Hz,2H),7.23(d,J＝8.8Hz,1H),5.40(p,J＝7.2Hz,1H),2.64(s,6H),2.58-2.46(m,1H),1.62(d,J＝6.8Hz,3H),1.22(d,J＝6.4Hz,6H)；HR-MS(ESI):m/z,calcd.For C 27H 31O 2N 3430.2489[M+H] +,Found:430.2482。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.61 (s, 1H), 8.23 (d, J = 8.4Hz, 1H), 7.83 (s, 1H), 7.57 (m, 4H), 7.49 ( d, J = 7.6 Hz, 1H), 7.47-7.39 (m, 3H), 7.35 (d, J = 6.0 Hz, 2H), 7.23 (d, J = 8.8 Hz, 1H), 5.40 (p, J = 7.2) Hz, 1H), 2.64 (s, 6H), 2.58-2.46 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.4 Hz, 6H); HR-MS (ESI) ): m/z, calcd. For C 27 H 31 O 2 N 3 430.2489 [M+H] + , Found: 430.2482.

实施例(化合物)11Example (compound) 11

2-(二甲氨基)-N-(3-(呋喃-2-基)苯甲基)-5-异丁酰氨基苯甲酰胺2-(Dimethylamino)-N-(3-(furan-2-yl)benzyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000071
Figure PCTCN2018088561-appb-000071

a)2-(二甲氨基)-N-(3-(呋喃-2-基)苯甲基)-5-硝基苯甲酰胺a) 2-(Dimethylamino)-N-(3-(furan-2-yl)benzyl)-5-nitrobenzamide

将2-(二甲氨基)-5-硝基苯甲酸(267mg,1.27mmol)溶于DMF(10mL)中，依次加入DIEA(246mg,1.91mmol)、HATU(727mg,1.91mmol)，搅拌反应20min后加入(3-(呋喃-2-基)苯基)甲胺(200mg,1.16mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体344mg，收率81.5％，熔点：150-151℃。 2-(Dimethylamino)-5-nitrobenzoic acid (267 mg, 1.27 mmol) was dissolved in DMF (10 mL), EtOAc (EtOAc, EtOAc. (3-(Furan-2-yl)phenyl)methanamine (200 mg, 1.16 mmol) was added, and stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 344 mg of a yellow solid, yield 81.5%, melting point: 150-151 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.58(d,J＝2.8Hz,1H),8.17(dd,J＝9.2,2.8Hz,1H),7.68(s,1H),7.60(d,J＝7.6Hz,1H),7.47(brs,2H),7.38(t,J＝7.6Hz,1H),7.26(s,1H),7.06(d,J＝9.2Hz,1H),6.67(d,J＝3.2Hz,1H),6.48(dd,J＝3.2,2.0Hz,1H),4.68(s,2H),2.92(s,6H)；ESI-MS m/z:366.15[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.2, 2.8 Hz, 1H), 7.68 (s, 1H), 7.60 ( d, J = 7.6 Hz, 1H), 7.47 (brs, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.67 ( d, J = 3.2 Hz, 1H), 6.48 (dd, J = 3.2, 2.0 Hz, 1H), 4.68 (s, 2H), 2.92 (s, 6H); ESI-MS m/z: 366.15 [M+H ] + .

b)5-氨基-2-(二甲氨基)-N-(3-(呋喃-2-基)苯甲基)苯甲酰胺b) 5-Amino-2-(dimethylamino)-N-(3-(furan-2-yl)benzyl)benzamide

将2-(二甲氨基)-N-(3-(呋喃-2-基)苯甲基)-5-硝基苯甲酰胺(300mg,0.82mmol)溶于THF(20mL)中，加入pd/C(30mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物254mg，收率92.4％。2-(Dimethylamino)-N-(3-(furan-2-yl)benzyl)-5-nitrobenzamide (300 mg, 0.82 mmol) was dissolved in THF (20 mL). C (30 mg), EtOAc (m.)

1H-NMR(400MHz,CDCl 3)δ(ppm):10.95(s,1H),7.68(s,1H),7.64(s,1H),7.57(d,J＝7.6Hz,1H),7.45(s,1H),7.35(t,J＝7.6Hz,1H),7.27(d,J＝3.6Hz,1H),7.11(d,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.8Hz,1H),6.65(d,J＝3.2Hz,1H),6.46(s,1H),4.69(d,J＝5.6Hz,2H),3.92(s,2H),2.61(s,6H)；ESI-MS m/z:336.17[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.95 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.45 ( s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.8 Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 6.46 (s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 3.92 (s, 2H), 2.61 (s, 6H); ESI-MS m/z: 336.17 [M+H] + .

c)2-(二甲氨基)-N-(3-(呋喃-2-基)苯甲基)-5-异丁酰氨基苯甲酰胺c) 2-(Dimethylamino)-N-(3-(furan-2-yl)benzyl)-5-isobutyrylaminobenzamide

将异丁酸(189mg,2.15mmol)溶于DMF(10mL)中，依次加入DIEA(307mg,2.38mmol)、HATU(903mg,2.38mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(3-(呋喃-2-基)苯甲基)苯甲酰胺(240mg,0.72mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得白色固体113mg，收率39.0％，熔点：138-139℃。 Isobutyric acid (189 mg, 2.15 mmol) was dissolved in DMF (10 mL), DIEA (307 mg, 2.38 mmol), HATU (903 mg, 2.38 mmol) was added, and the reaction was stirred for 20 min. Amino)-N-(3-(furan-2-yl)benzyl)benzamide (240 mg, 0.72 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio of 2:3) gave 113 mg of white solid, yield: 39.0%, m.p.: 138-139.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.64(s,1H),8.27(d,J＝8.0Hz,1H),7.96(s,2H),7.67(s,1H),7.58(d,J＝8.0Hz,1H),7.45(s,1H),7.36(t,J＝7.6Hz,1H),7.25(brs,2H),6.65(d,J＝3.2Hz,1H),6.50-6.41(m,1H),4.70(d,J＝5.2Hz,2H),2.64(s,6H),2.62-2.48(m,1H),1.21(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 3N 4 406.2125[M+H] +,Found:406.2110。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.64 (s, 1H), 8.27 (d, J = 8.0Hz, 1H), 7.96 (s, 2H), 7.67 (s, 1H), 7.58 ( d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (brs, 2H), 6.65 (d, J = 3.2 Hz, 1H), 6.50- 6.41 (m, 1H), 4.70 (d, J = 5.2 Hz, 2H), 2.64 (s, 6H), 2.62-2.48 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 24 H 27 O 3 N 4 406.2125 [M+H] + , Found: 406.2110.

实施例(化合物)12Example (compound) 12

2-(二甲氨基)-N-(1-(3-(呋喃-2-基)苯基)乙基)-5-异丁酰氨基苯甲酰胺2-(Dimethylamino)-N-(1-(3-(furan-2-yl)phenyl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000072
Figure PCTCN2018088561-appb-000072

a)2-(二甲氨基)-N-(1-(3-(呋喃-2-基)苯基)乙基)-5-硝基苯甲酰胺a) 2-(Dimethylamino)-N-(1-(3-(furan-2-yl)phenyl)ethyl)-5-nitrobenzamide

将2-(二甲氨基)-5-硝基苯甲酸(199mg,0.95mmol)溶于DCM(15mL)中，依次加入DIEA(168mg,1.30mmol)、HATU(490mg,1.30mmol)，搅拌反应20min后加入1-(3-(呋喃-2-基)苯基)乙胺(160mg,0.86mmol)，室温搅拌过夜。加入DCM(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体244mg，收率75.3％，熔点：154-155℃。 2-(Dimethylamino)-5-nitrobenzoic acid (199 mg, 0.95 mmol) was dissolved in DCM (15 mL), then DIEA (168 mg, 1.30 mmol), HATU (490 mg, 1.30 mmol) After the addition of 1-(3-(furan-2-yl)phenyl)ethylamine (160 mg, 0.86 mmol). Was added DCM (20mL) diluted with saturated ammonium chloride solution (10 mL) washed saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume Purification over 1:2) gave 244 mg of a yellow solid. Yield: 75.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.53(d,J＝2.8Hz,1H),8.15(dd,J＝9.2,2.8Hz,1H),7.70(s,1H),7.59(d,J＝7.6Hz,1H),7.46(d,J＝10.8Hz,2H),7.38(t,J＝7.6Hz,1H),7.27(d,J＝9.6Hz,1H),6.95(d,J＝9.2Hz,1H),6.68(d,J＝3.2Hz,1H),6.52-6.45(m,1H),5.44-5.30(m,1H),2.85(s,6H),1.64(d,J＝6.8Hz,3H)；ESI-MS m/z:380.16[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.53 (d, J = 2.8Hz, 1H), 8.15 (dd, J = 9.2,2.8Hz, 1H), 7.70 (s, 1H), 7.59 ( d, J = 7.6 Hz, 1H), 7.46 (d, J = 10.8 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 6.95 (d, J=9.2 Hz, 1H), 6.68 (d, J=3.2 Hz, 1H), 6.52-6.45 (m, 1H), 5.44-5.30 (m, 1H), 2.85 (s, 6H), 1.64 (d, J) = 6.8 Hz, 3H); ESI-MS m/z: 380.16 [M+H] + .

b)5-氨基-2-(二甲氨基)-N-(1-(3-(呋喃-2-基)苯基)乙基)苯甲酰胺b) 5-Amino-2-(dimethylamino)-N-(1-(3-(furan-2-yl)phenyl)ethyl)benzamide

将2-(二甲氨基)-N-(1-(3-(呋喃-2-基)苯基)乙基)-5-硝基苯甲酰胺(230mg,0.61mmol)溶于THF(20mL)中，加入pd/C(23mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物210mg，收率99.0％。2-(Dimethylamino)-N-(1-(3-(furan-2-yl)phenyl)ethyl)-5-nitrobenzamide (230 mg, 0.61 mmol) was dissolved in THF (20 mL) The pd/C (23 mg) was added, and the mixture was stirred and evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.09(s,1H),7.70(s,1H),7.56(d,J＝11.2Hz,2H),7.45(s,1H),7.35(t,J＝7.6Hz,1H),7.28(s,1H),7.10(d,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.8Hz,1H),6.65(d,J＝3.2Hz,1H),6.50-6.43(m,1H),5.34(m,1H),3.85(s,2H),2.63(s,6H),1.59(d,J＝6.8Hz,2H)；ESI-MS m/z:350.19[M+H] +。 c)2-(二甲氨基)-N-(1-(3-(呋喃-2-基)苯基)乙基)-5-异丁酰氨基苯甲酰胺 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.09 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 11.2Hz, 2H), 7.45 (s, 1H), 7.35 ( t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.74 (dd, J = 8.4, 2.8 Hz, 1H), 6.65 (d, J = 3.2) Hz, 1H), 6.50-6.43 (m, 1H), 5.34 (m, 1H), 3.85 (s, 2H), 2.63 (s, 6H), 1.59 (d, J = 6.8 Hz, 2H); ESI-MS m/z: 350.19 [M+H] + . c) 2-(Dimethylamino)-N-(1-(3-(furan-2-yl)phenyl)ethyl)-5-isobutyrylaminobenzamide

将异丁酸(151mg,1.72mmol)溶于DMF(15mL)中，依次加入DIEA(222mg,1.72mmol)、HATU(654mg,1.72mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(1-(3-(呋喃-2-基)苯基)乙基)苯甲酰胺(200mg,0.57mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体101mg，收率42.1％，熔点：130-131℃。 Isobutyric acid (151 mg, 1.72 mmol) was dissolved in DMF (15 mL), then DIEA (222 mg, 1.72 mmol), HATU (654 mg, 1.72 mmol) was added, and the reaction was stirred for 20 min. Amino)-N-(1-(3-(furan-2-yl)phenyl)ethyl)benzamide (200 mg, 0.57 mmol). Concentrated, diluted with addition of EA (20mL), saturated ammonium chloride solution (10 mL) washed saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purified by volume ratio 1:3) to give a white solid, 101 mg, yield 42.1%, melting point: 130-131 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.72(d,J＝7.6Hz,1H),8.25(d,J＝8.4Hz,1H),7.88(s,2H),7.69(s,1H),7.56(d,J＝7.6Hz,1H),7.46(s,1H),7.36(t,J＝7.6Hz,1H),7.24(d,J＝8.4Hz,2H),6.65(d,J＝3.2Hz,1H),6.47(dd,J＝3.2,1.6Hz,1H),5.39-5.32(m,1H),2.66(s,6H),2.58-2.51(m,1H),1.60(d,J＝6.8Hz,3H),1.21(dd,J＝6.8,3.2Hz,6H)；HR-MS(ESI):m/z,calcd.For C 25H 29O 3N 3 420.2282[M+H] +,Found:420.2275。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.72 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.88 (s, 2H), 7.69 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.65 (d, J=3.2 Hz, 1H), 6.47 (dd, J=3.2, 1.6 Hz, 1H), 5.39-5.32 (m, 1H), 2.66 (s, 6H), 2.58-2.51 (m, 1H), 1.60 (d) , J = 6.8 Hz, 3H), 1.21 (dd, J = 6.8, 3.2 Hz, 6H); HR-MS (ESI): m/z, cald. For C 25 H 29 O 3 N 3 420.2282 [M+H ] + , Found: 420.2275.

实施例(化合物)13Example (compound) 13

2-(二甲氨基)-5-异丁酰氨基-N-(3-(四氢呋喃-2-基)苯甲基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(3-(tetrahydrofuran-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000073
Figure PCTCN2018088561-appb-000073

a)2-(二甲氨基)-5-硝基-N-(3-(四氢呋喃-2-基)苯甲基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(3-(tetrahydrofuran-2-yl)benzyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(400mg,1.90mmol)溶于DCM(30mL)中，依次加入DIEA(490mg,3.80mmol)、HATU(1.09g,2.86mmol)，搅拌反应20min后加入(3-(四氢呋喃-2-基)苯基)甲胺(336mg,1.90mmol)，室温搅拌过夜。加入DCM(20mL)稀释，饱和氯化铵溶液(20mL×2)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得黄色固体417mg，收率59.4％，熔点：137-138℃。 2-(Dimethylamino)-5-nitrobenzoic acid (400 mg, 1.90 mmol) was dissolved in DCM (30 mL), then DIEA (490 mg, 3.80 mmol), HATU (1.09 g, 2.86 mmol) After 20 min, (3-(tetrahydrofuran-2-yl)phenyl)methanamine (336 mg, 1.90 mmol). Dilute with DCM (20 mL), wash with saturated aqueous ammonium chloride solution (20 mL×2), wash with saturated brine (20 mL), dry over anhydrous Na 2 SO 4 and elute with ethyl acetate- petroleum ether, volume ratio 2:3 Purification gave 417 mg of a yellow solid, yield 59.4%, mp.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.55(d,J＝2.4Hz,1H),8.15(dd,J＝9.2,2.4Hz,1H),7.34-7.31(m,3H),7.25(d,J＝7.2Hz,2H),6.96(d,J＝9.2Hz,1H),4.87(t,J＝7.2Hz,1H),4.64(d,J＝5.2Hz,2H),4.09(dd,J＝14.8,7.2Hz,1H),3.93(dd,J＝14.8,7.2Hz,1H),2.89(s,6H),2.37-2.30(m,1H),2.04-2.00(m,2H),1.81-1.74(m,1H)；ESI-MS m/z:370.18[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.55 (d, J = 2.4Hz, 1H), 8.15 (dd, J = 9.2,2.4Hz, 1H), 7.34-7.31 (m, 3H), 7.25 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 4.87 (t, J = 7.2 Hz, 1H), 4.64 (d, J = 5.2 Hz, 2H), 4.09 ( Dd, J=14.8, 7.2 Hz, 1H), 3.93 (dd, J=14.8, 7.2 Hz, 1H), 2.89 (s, 6H), 2.37-2.30 (m, 1H), 2.04-2.00 (m, 2H) , 1.81-1.74 (m, 1H); ESI-MS m/z: 370.18 [M+H] + .

b)5-氨基-2-(二甲氨基)-N-(3-(四氢呋喃-2-基)苯甲基)苯甲酰胺b) 5-Amino-2-(dimethylamino)-N-(3-(tetrahydrofuran-2-yl)benzyl)benzamide

将2-(二甲氨基)-5-硝基-N-(3-(四氢呋喃-2-基)苯甲基)苯甲酰胺(200mg,0.54mmol)溶于THF(15mL)中，加入pd/C(40mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物182mg，收率98.9％。2-(Dimethylamino)-5-nitro-N-(3-(tetrahydrofuran-2-yl)benzyl)benzamide (200 mg, 0.54 mmol) was dissolved in THF (15 mL). C (40 mg) was added with EtOAc EtOAc EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.88(s,1H),7.60(d,J＝2.8Hz,1H),7.33(s,1H),7.29(d,J＝7.2Hz,1H),7.25-7.22(m,2H),7.09(d,J＝8.4Hz,1H),6.75(dd,J＝8.4,2.8Hz,1H),4.87(t,J＝7.2Hz,1H),4.66(dd,J＝5.6,2.4Hz,2H),4.08(dd,J＝14.8,7.2Hz,1H),3.92(dd,J＝14.8,7.6Hz,1H),3.71(s,2H),2.57(s,6H),2.35-2.27(m,1H),2.05-1.96(m,2H),1.83-1.74(m,1H)；ESI-MS m/z:340.20[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.88 (s, 1H), 7.60 (d, J = 2.8Hz, 1H), 7.33 (s, 1H), 7.29 (d, J = 7.2Hz, 1H), 7.25-7.22 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.4, 2.8 Hz, 1H), 4.87 (t, J = 7.2 Hz, 1H), 4.66 (dd, J=5.6, 2.4 Hz, 2H), 4.08 (dd, J=14.8, 7.2 Hz, 1H), 3.92 (dd, J=14.8, 7.6 Hz, 1H), 3.71 (s, 2H), 2.57 (s, 6H), 2.35-2.27 (m, 1H), 2.05-1.96 (m, 2H), 1.83-1.74 (m, 1H); ESI-MS m/z: 340.20 [M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(3-(四氢呋喃-2-基)苯甲基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(3-(tetrahydrofuran-2-yl)benzyl)benzamide

将5-氨基-2-(二甲氨基)-N-(3-(四氢呋喃-2-基)苯甲基)苯甲酰胺(165mg,0.49mmol)溶于无水THF(15mL)中，冰浴下依次加入TEA(75mg,0.74mmol)，异丁酰氯(52mg,0.49mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯30mL稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化，得白色固体143mg，收率为71.9％，熔点：147-148℃。 5-Amino-2-(dimethylamino)-N-(3-(tetrahydrofuran-2-yl)benzyl)benzamide (165 mg, 0.49 mmol) was dissolved in anhydrous THF (15 mL) Next, TEA (75 mg, 0.74 mmol), isobutyryl chloride (52 mg, 0.49 mmol) was added, and the reaction was continued for 1 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate 30 mL, and washed with saturated aqueous ammonium chloride (10 mL), saturated NaHCO 3 (10 mL) wash, water (10mL) wash, brine water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 1) to give 143 mg as a white solid, The yield was 71.9%, and the melting point was 147-148 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.54(s,1H),8.25(dd,J＝8.4,2.8Hz,1H),7.92(d,J＝2.4Hz,1H),7.88(s,1H),7.32(s,1H),7.29(d,J＝7.6Hz,1H),7.24-7.21(m,3H),4.86(t,J＝7.2Hz,1H),4.66(dd,J＝5.6,1.6Hz,2H),4.10-4.04(m,1H),3.94-3.86(m,1H),2.61(s,6H),2.58-2.51(m,1H),2.35-2.27(m,1H),2.03-1.95(m,2H),1.81-1.72(m,1H),1.20(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 31O 3N 3 410.2438[M+H] +,Found:410.2424。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.54 (s, 1H), 8.25 (dd, J = 8.4,2.8Hz, 1H), 7.92 (d, J = 2.4Hz, 1H), 7.88 ( s, 1H), 7.32 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.24 - 7.21 (m, 3H), 4.86 (t, J = 7.2 Hz, 1H), 4.66 (dd, J = 5.6, 1.6 Hz, 2H), 4.10-4.04 (m, 1H), 3.94-3.86 (m, 1H), 2.61 (s, 6H), 2.58-2.51 (m, 1H), 2.35-2.27 (m, 1H) ), 2.03-1.95 (m, 2H), 1.81-1.72 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 24 H 31 O 3 N 3 410.2438 [M+H] + , Found: 410.2424.

实施例(化合物)14Example (compound) 14

2-(二甲氨基)-5-异丁酰氨基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000074
Figure PCTCN2018088561-appb-000074

a)2-(二甲氨基)-5-硝基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(242mg,1.15mmol)溶于DMF(10mL)中，依次加入DIEA(223mg,1.73mmol)、HATU(657mg,1.73mmol)，搅拌反应20min 后加入1-(3-(四氢呋喃-2-基)苯基)乙胺(200mg,1.05mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体210mg，收率52.4％，熔点：136-138℃。 2-(Dimethylamino)-5-nitrobenzoic acid (242 mg, 1.15 mmol) was dissolved in DMF (10 mL). EtOAc (EtOAc, EtOAc, EtOAc After the addition of 1-(3-(tetrahydrofuran-2-yl)phenyl)ethylamine (200 mg, 1.05 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 210 mg of a yellow solid, yield 52.4%, melting point: 136-138 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.50(d,J＝2.8Hz,1H),8.14(dd,J＝9.2,2.8Hz,1H),7.34(m,3H),7.29-.20(m,2H),6.98(d,J＝9.2Hz,1H),5.41-5.26(m,1H),4.87(t,J＝7.2Hz,1H),4.17-4.01(m,1H),4.00-3.84(m,1H),2.86(d,J＝6.4Hz,6H),2.34(td,J＝12.8,6.8Hz,1H),2.08-1.94(m,2H),1.78(m,1H),1.61(d,J＝6.8Hz,3H)；ESI-MS m/z:384.19[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.50 (d, J = 2.8Hz, 1H), 8.14 (dd, J = 9.2,2.8Hz, 1H), 7.34 (m, 3H), 7.29- .20(m, 2H), 6.98 (d, J = 9.2 Hz, 1H), 5.41-5.26 (m, 1H), 4.87 (t, J = 7.2 Hz, 1H), 4.17-4.01 (m, 1H), 4.00-3.84 (m, 1H), 2.86 (d, J = 6.4 Hz, 6H), 2.34 (td, J = 12.8, 6.8 Hz, 1H), 2.08-1.94 (m, 2H), 1.78 (m, 1H) , 1.61 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 384.19 [M+H] + .

b)5-氨基-2-(二甲氨基)-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺b) 5-Amino-2-(dimethylamino)-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺(170mg,0.44mmol)溶于THF(20mL)中，加入pd/C(20mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物144mg，收率91.9％。2-(Dimethylamino)-5-nitro-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide (170 mg, 0.44 mmol) was dissolved in THF (20 mL) Pd/C (20 mg) was added, and hydrogen was added, and the mixture was stirred at room temperature overnight, filtered, and concentrated to give 144 mg of yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.01(s,1H),7.55(d,J＝2.8Hz,1H),7.35(s,1H),7.33-7.27(m,1H),7.25-7.17(m,2H),7.08(d,J＝8.4Hz,1H),6.73(dd,J＝8.4,2.9Hz,1H),5.36-5.23(m,1H),4.88(t,J＝7.2Hz,1H),4.08(ddd,J＝15.2,10.4,7.2Hz,1H),3.92(ddd,J＝15.2,7.6,3.2Hz,1H),3.68(s,2H),2.60(s,6H),2.38-2.25(m,1H),1.99-1.94(m,2H),1.79-1.75(m,1H),1.56(d,J＝6.8Hz,3H)；ESI-MS m/z:354.22[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.01 (s, 1H), 7.55 (d, J = 2.8Hz, 1H), 7.35 (s, 1H), 7.33-7.27 (m, 1H), 7.25-7.17(m,2H),7.08(d,J=8.4Hz,1H),6.73(dd,J=8.4,2.9Hz,1H),5.36-5.23(m,1H),4.88(t,J= 7.2 Hz, 1H), 4.08 (ddd, J = 15.2, 10.4, 7.2 Hz, 1H), 3.92 (ddd, J = 15.2, 7.6, 3.2 Hz, 1H), 3.68 (s, 2H), 2.60 (s, 6H) ), 2.38-2.25 (m, 1H), 1.99-1.94 (m, 2H), 1.79-1.75 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 354.22 [ M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

将异丁酸(103mg,1.17mmol)溶于DMF(10mL)中，依次加入DIEA(166mg,1.29mmol)、HATU(489mg,1.29mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺(138mg,0.39mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得白色固体68mg，收率41.2％，熔点：134-136℃。 Isobutyric acid (103 mg, 1.17 mmol) was dissolved in DMF (10 mL), then DIEA (166 mg, 1.29 mmol), HATU (489 mg, 1.29 mmol), and the mixture was stirred for 20 min. Amino)-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide (138 mg, 0.39 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 2:3) gave 68 mg of white solid, yield 41.2%, m.p.: 134-136.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.50(d,J＝2.8Hz,1H),8.14(dd,J＝9.2,2.8Hz,1H),7.34(m,3H),7.29-.20(m,2H),6.98(d,J＝9.2Hz,1H),5.41-5.26(m,1H),4.87(t,J＝7.2Hz,1H),4.17-4.01(m,1H),4.00-3.84(m,1H),2.86(d,J＝6.4Hz,6H),2.34(td,J＝12.8,6.8Hz,1H),2.08-1.94(m,2H),1.78(m,1H),1.61(d,J＝6.8Hz,3H)；ESI-MS m/z:384.19[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.50 (d, J = 2.8Hz, 1H), 8.14 (dd, J = 9.2,2.8Hz, 1H), 7.34 (m, 3H), 7.29- .20(m, 2H), 6.98 (d, J = 9.2 Hz, 1H), 5.41-5.26 (m, 1H), 4.87 (t, J = 7.2 Hz, 1H), 4.17-4.01 (m, 1H), 4.00-3.84 (m, 1H), 2.86 (d, J = 6.4 Hz, 6H), 2.34 (td, J = 12.8, 6.8 Hz, 1H), 2.08-1.94 (m, 2H), 1.78 (m, 1H) , 1.61 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 384.19 [M+H] + .

d)5-氨基-2-(二甲氨基)-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺d) 5-Amino-2-(dimethylamino)-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺(170mg,0.44mmol)溶于THF(20mL)中，加入pd/C(20mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物144mg，收率91.9％。2-(Dimethylamino)-5-nitro-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide (170 mg, 0.44 mmol) was dissolved in THF (20 mL) Pd/C (20 mg) was added, and hydrogen was added, and the mixture was stirred at room temperature overnight, filtered, and concentrated to give 144 mg of yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.01(s,1H),7.55(d,J＝2.8Hz,1H),7.35(s,1H),7.33-7.27(m,1H),7.25-7.17(m,2H),7.08(d,J＝8.4Hz,1H),6.73(dd,J＝8.4,2.9Hz,1H),5.36-5.23(m,1H),4.88(t,J＝7.2Hz,1H),4.08(ddd,J＝15.2,10.4,7.2Hz,1H),3.92(ddd,J＝15.2,7.6,3.2Hz,1H),3.68(s,2H),2.60(s,6H),2.38-2.25(m,1H),1.99-1.94(m,2H),1.79-1.75(m,1H),1.56(d,J＝6.8Hz,3H)；ESI-MS m/z:354.22[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.01 (s, 1H), 7.55 (d, J = 2.8Hz, 1H), 7.35 (s, 1H), 7.33-7.27 (m, 1H), 7.25-7.17(m,2H),7.08(d,J=8.4Hz,1H),6.73(dd,J=8.4,2.9Hz,1H),5.36-5.23(m,1H),4.88(t,J= 7.2 Hz, 1H), 4.08 (ddd, J = 15.2, 10.4, 7.2 Hz, 1H), 3.92 (ddd, J = 15.2, 7.6, 3.2 Hz, 1H), 3.68 (s, 2H), 2.60 (s, 6H) ), 2.38-2.25 (m, 1H), 1.99-1.94 (m, 2H), 1.79-1.75 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 354.22 [ M+H] + .

e)2-(二甲氨基)-5-异丁酰氨基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺e) 2-(Dimethylamino)-5-isobutyrylamino-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

将异丁酸(103mg,1.17mmol)溶于DMF(10mL)中，依次加入DIEA(166mg,1.29mmol)、HATU(489mg,1.29mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺(138mg,0.39mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化，得白色固体68mg，收率41.2％，熔点：134-136℃。 Isobutyric acid (103 mg, 1.17 mmol) was dissolved in DMF (10 mL), then DIEA (166 mg, 1.29 mmol), HATU (489 mg, 1.29 mmol), and the mixture was stirred for 20 min. Amino)-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide (138 mg, 0.39 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 2:3) gave 68 mg of white solid, yield 41.2%, m.p.: 134-136.

1H-NMR(500MHz,CDCl 3)δ(ppm):10.60(dd,J＝13.5,8.0Hz,1H),8.23(d,J＝8.5Hz,1H),7.84(s,1H),7.70(s,1H),7.35(s,1H),7.31(td,J＝7.5,1.5Hz,1H),7.25-7.22(m,3H),5.33(p,J＝7.5Hz,1H),4.88(t,J＝7.0Hz,1H),4.12-4.05(m,1H),3.95-3.90(m,1H),2.64(d,J＝1.5Hz,6H),2.57-2.51(m,1H),2.35-2.29(m,1H),2.04-1.97(m,2H),1.82-1.74(m,1H),1.57(d,J＝6.5Hz,4H),1.22(dd,J＝7.0,2.0Hz,7H)；HR-MS(ESI):m/z,calcd.For C 25H 33O 3N 3 424.2595[M+H] +,Found:424.2578。 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 10.60 (dd, J = 13.5, 8.0 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.70 ( s, 1H), 7.35 (s, 1H), 7.31 (td, J = 7.5, 1.5 Hz, 1H), 7.25-7.22 (m, 3H), 5.33 (p, J = 7.5 Hz, 1H), 4.88 (t , J=7.0 Hz, 1H), 4.12-4.05 (m, 1H), 3.95-3.90 (m, 1H), 2.64 (d, J = 1.5 Hz, 6H), 2.57-2.51 (m, 1H), 2.35- 2.29 (m, 1H), 2.04-1.97 (m, 2H), 1.82-1.74 (m, 1H), 1.57 (d, J = 6.5 Hz, 4H), 1.22 (dd, J = 7.0, 2.0 Hz, 7H) ;HR-MS (ESI): m/z, calcd. For C 25 H 33 O 3 N 3 424.2595 [M+H] + , Found: 424.2578.

实施例(化合物)15Example (compound) 15

2-(二甲氨基)-5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000075
Figure PCTCN2018088561-appb-000075

a)2-(二甲氨基)-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(307mg,1.46mmol)溶于DMF(10mL)中，依次 加入DIEA(468mg,3.63mmol)、HATU(862mg,2.19mmol)，搅拌反应20min后加入(3-(噻唑-2-基)苯基)甲胺(300mg,1.33mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体247mg，收率48.7％，熔点：169-170℃。 2-(Dimethylamino)-5-nitrobenzoic acid (307 mg, 1.46 mmol) was dissolved in DMF (10 mL), then DIEA (468 mg, 3.63 mmol), HATU (862 mg, 2.19 mmol). (3-(thiazol-2-yl)phenyl)methanamine (300 mg, 1.33 mmol) was added, and stirred at room temperature overnight. Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 247 mg of a yellow solid, yield 48.7%, melting point: 169-170 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.56(d,J＝2.8Hz,1H),8.15(dd,J＝8.8,2.8Hz,1H),7.99(s,1H),7.87(d,J＝3.2Hz,2H),7.59(s,1H),7.45(s,1H),7.44(s,1H),7.35(d,J＝3.2Hz,1H),6.96(d,J＝9.2Hz,1H),4.71(d,J＝6.0Hz,2H),2.90(s,6H)；HR-MS(ESI):m/z,calcd.For C 19H 18O 3N 4S 383.1172[M+H] +,Found:383.1159。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.56 (d, J = 2.8Hz, 1H), 8.15 (dd, J = 8.8,2.8Hz, 1H), 7.99 (s, 1H), 7.87 ( d, J = 3.2 Hz, 2H), 7.59 (s, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 7.35 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 9.2) Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.90 (s, 6H); HR-MS (ESI): m/z, cald. For C 19 H 18 O 3 N 4 S 383.1172 [M +H] + , Found: 383.1159.

b)5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺b) 5-amino-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-(二甲氨基)-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(200mg,0.52mmol)溶于THF(20mL)中，加入pd/C(100mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物161mg，收率87.5％。2-(Dimethylamino)-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide (200 mg, 0.52 mmol) was dissolved in THF (20 mL). C (100 mg), EtOAc (m.)

1H-NMR(400MHz,CDCl 3)δ(ppm):11.01(s,1H),7.98(s,1H),7.89-7.82(m,2H),7.60(d,J＝2.8Hz,1H),7.47-7.37(m,2H),7.33(d,J＝3.2Hz,1H),7.11(d,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.8Hz,1H),4.73(d,J＝5.6Hz,2H),2.61(s,6H)；ESI-MS m/z:353.14[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 11.01 (s, 1H), 7.78 (s, 1H), 7.89-7.82 (m, 2H), 7.60 (d, J = 2.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.8 Hz, 1H), 4.73 (d) , J = 5.6 Hz, 2H), 2.61 (s, 6H); ESI-MS m/z: 353.14 [M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)benzamide

将异丁酸(121mg,1.37mmol)溶于DMF(10mL)中，依次加入DIEA(177mg,1.37mmol)、HATU(521mg,1.37mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(161mg,0.46mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体73mg，收率37.8％，熔点：149-150℃。 Isobutyric acid (121 mg, 1.37 mmol) was dissolved in DMF (10 mL), DIEA (177 mg, 1.37 mmol), HATU (521 mg, 1.37 mmol) was added, and the reaction was stirred for 20 min. Amino)-N-(3-(thiazol-2-yl)benzyl)benzamide (161 mg, 0.46 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 73 mg of a white solid, yield 37.8%, melting point: 149-150 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.72(s,1H),8.27(s,1H),7.99(s,1H),7.91(s,1H),7.87(d,J＝3.2Hz,2H),7.70(brs,1H),7.43(d,J＝4.8Hz,2H),7.34(d,J＝3.2Hz,1H),7.25(s,1H),4.75(d,J＝5.6Hz,2H),2.65(s,6H),2.55(s,1H),1.22(d,J＝6.0Hz,6H)；HR-MS(ESI):m/z,calcd.For C 23H 26O 2N 4S 423.1849[M+H] +,Found:423.1841。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 10.72 (s, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 3.2) Hz, 2H), 7.70 (brs, 1H), 7.43 (d, J = 4.8 Hz, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.25 (s, 1H), 4.75 (d, J = 5.6) Hz, 2H), 2.65 (s, 6H), 2.55 (s, 1H), 1.22 (d, J = 6.0 Hz, 6H); HR-MS (ESI): m/z, cald. For C 23 H 26 O 2 N 4 S 423.1849 [M+H] + , Found: 423.1841.

实施例(化合物)16Example (compound) 16

2-(二甲氨基)-5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-(Dimethylamino)-5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000076
Figure PCTCN2018088561-appb-000076

a)2-(二甲氨基)-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-(Dimethylamino)-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(226mg,1.08mmol)溶于DMF(10mL)中，依次加入DIEA(209mg,1.62mmol)、HATU(616mg,1.62mmol)，搅拌反应20min后加入1-(3-(噻唑-2-基)苯基)乙胺(200mg,0.98mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化，得黄色固体221mg，收率57.1％，熔点：139-141℃。 2-(Dimethylamino)-5-nitrobenzoic acid (226 mg, 1.08 mmol) was dissolved in DMF (10 mL), EtOAc (EtOAc, EtOAc (EtOAc) After the addition of 1-(3-(thiazol-2-yl)phenyl)ethylamine (200 mg, 0.98 mmol), Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 221 mg of a yellow solid, yield 57.1%, m.p.: 139-141.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.52(d,J＝2.8Hz,1H),8.14(dd,J＝8.8,2.8Hz,1H),8.03(s,1H),7.87-7.84(m,2H),7.58(d,J＝7.6Hz,1H),7.47-7.42(m,2H),7.35(d,J＝3.2Hz,1H),6.96(d,J＝8.8Hz,1H),5.47-5.32(m,1H),2.87(s,6H),1.65(d,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 20H 20O 3N 4S 397.1329[M+H] +,Found:397.1308。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.52 (d, J = 2.8Hz, 1H), 8.14 (dd, J = 8.8,2.8Hz, 1H), 8.03 (s, 1H), 7.87- 7.84 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.47-7.42 (m, 2H), 7.35 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H) ), 5.47-5.32 (m, 1H), 2.87 (s, 6H), 1.65 (d, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 20 H 20 O 3 N 4 S 397.1329 [M+H] + , Found: 397.1308.

b)5-氨基-2-(二甲氨基)-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 5-Amino-2-(dimethylamino)-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(180mg,0.45mmol)溶于THF(20mL)中，加入pd/C(90mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得微黄色油状物151mg，收率91.0％。2-(Dimethylamino)-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (180 mg, 0.45 mmol) was dissolved in THF (20 mL) The pd/C (90 mg) was added, and the mixture was stirred and evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):11.18(s,1H),8.03(s,1H),7.90-7.81(m,2H),7.56(d,J＝2.8Hz,1H),7.44(m,2H),7.34(d,J＝3.2Hz,1H),7.12(d,J＝8.4Hz,1H),6.76(dd,J＝8.4,2.8Hz,1H),5.47-5.29(m,1H),3.70(s,2H),2.66(s,6H),1.62(d,J＝6.8Hz,3H)；ESI-MS m/z:367.16[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 11.18 (s, 1H), 8.03 (s, 1H), 7.90-7.81 (m, 2H), 7.56 (d, J = 2.8Hz, 1H), 7.44 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.8 Hz, 1H), 5.47-5.29 (m , 1H), 3.70 (s, 2H), 2.66 (s, 6H), 1.62 (d, J = 6.8 Hz, 3H); ESI-MS m/z: 367.16 [M+H] + .

c)2-(二甲氨基)-5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-(Dimethylamino)-5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将异丁酸(180mg,2.05mmol)溶于DMF(10mL)中，依次加入DIEA(265mg,2.05mmol)、HATU(780mg,2.05mmol)，搅拌反应20min后加入5-氨基-2-(二甲氨基)-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(250mg,0.68mmol)，室温搅拌过夜。浓缩，加入EA(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚， 体积比1:2)纯化，得白色固体159mg，收率53.4％，熔点：143-144℃。 Isobutyric acid (180 mg, 2.05 mmol) was dissolved in DMF (10 mL), DIEA (265 mg, 2.05 mmol), HATU (780 mg, 2.05 mmol) was added, and the reaction was stirred for 20 min. Amino)-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (250 mg, 0.68 mmol). Concentrated, diluted with addition of EA (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:2) gave 159 mg of white solid, yield 53.4%, m.p.: 143-144.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.76(d,J＝7.6Hz,1H),8.26(d,J＝8.4Hz,1H),8.04(s,1H),7.88-7.86(m,3H),7.69(s,1H),7.44(d,J＝5.6Hz,2H),7.35(d,J＝3.2Hz,1H),7.25(s,1H),5.44-5.37(m,1H),2.70(s,6H),2.58-2.51(m,1H),1.63(d,J＝6.8Hz,3H),1.23(dd,J＝6.8,2.0Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 28O 2N 4S 437.2006[M+H] +,Found:437.1990。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.76 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.88-7.86 ( m, 3H), 7.69 (s, 1H), 7.44 (d, J = 5.6 Hz, 2H), 7.35 (d, J = 3.2 Hz, 1H), 7.25 (s, 1H), 5.44 - 5.37 (m, 1H) ), 2.70 (s, 6H), 2.58-2.51 (m, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.23 (dd, J = 6.8, 2.0 Hz, 6H); HR-MS (ESI) : m/z,calcd.For C 24 H 28 O 2 N 4 S 437.2006 [M+H] + , Found: 437.1990.

实施例(化合物)17Example (compound) 17

3-((4-(二甲氨基)-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)氨基甲酰)吡咯烷-1-羧酸叔丁酯3-((4-(Dimethylamino)-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Figure PCTCN2018088561-appb-000077
Figure PCTCN2018088561-appb-000077

将(dl)-N-Boc-β-脯氨酸(331mg,1.54mmol)溶于DCM(20mL)中，依次加入DIEA(298mg,2.31mmol)，HATU(733mg,1.93mmol)，室温反应30min后，加入5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(270mg,0.77mmol)，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体288mg，收率为68.4％，熔点：86-88℃。 (dl)-N-Boc-β-proline (331 mg, 1.54 mmol) was dissolved in DCM (20 mL), then DIEA (298 mg, 2.31 mmol), HATU (733 mg, 1.93 mmol) 5-Amino-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide (270 mg, 0.77 mmol) was added. DCM was added (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash with saturated brine (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography ( Ethyl acetate-petroleum ether (1:1 by volume) was purified to yield 288 mg of white solid, yield: 68.4%, m.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.66(s,1H),8.65(brs,1H),8.20(s,1H),8.00(s,1H),7.97(s,1H),7.85(d,J＝3.2Hz,2H),7.40(d,J＝4.4Hz,2H),7.32(d,J＝3.2Hz,1H),7.25(brs,1H),4.71(d,J＝4.8Hz,2H),3.56(brs,3H),3.31(s,1H),3.13(s,1H),2.67(s,6H),2.14(brs,2H),1.44(s,9H)；HR-MS(ESI):m/z,calcd.For C 29H 35O 4N 5S 550.2483[M+H] +,Found:550.2477。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.66 (s, 1H), 8.65 (brs, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.85 (d, J = 3.2 Hz, 2H), 7.40 (d, J = 4.4 Hz, 2H), 7.32 (d, J = 3.2 Hz, 1H), 7.25 (brs, 1H), 4.71 (d, J = 4.8) Hz, 2H), 3.56 (brs, 3H), 3.31 (s, 1H), 3.13 (s, 1H), 2.67 (s, 6H), 2.14 (brs, 2H), 1.44 (s, 9H); HR-MS (ESI): m/z, Calcd. For C 29 H 35 O 4 N 5 S 550.2483 [M+H] + , Found: 550.2477.

实施例(化合物)18Example (compound) 18

N-(4-(二甲氨基)-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)吡咯烷-3-甲酰胺·盐酸盐N-(4-(Dimethylamino)-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)pyrrolidine-3-carboxamide hydrochloride

Figure PCTCN2018088561-appb-000078
Figure PCTCN2018088561-appb-000078

将3-((4-(二甲氨基)-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)氨基甲酰)吡咯烷-1-羧酸叔丁酯(80mg,0.15mmol)溶于无水DCM(10mL)中，加入HCl的EA溶液(1mL)，室温下反应5h，浓缩，加入乙醚(20mL)析出白色固体，过滤得59mg，收率为83.1％，熔点：151-153℃。3-((4-(Dimethylamino)-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl The ester (80 mg, 0.15 mmol) was dissolved in EtOAc EtOAc (EtOAc) (EtOAc) %, melting point: 151-153 ° C.

1H-NMR(500MHz,DMSO)δ(ppm):10.94(s,1H),9.98(s,1H),9.56(s,1H),9.35(s,1H),8.19(s,1H),7.98(s,1H),7.93(s,1H),7.91(s,1H),7.87(s,1H),7.81(d,J＝3.0Hz,1H),7.50(brs,2H),4.61(d,J＝5.5Hz,2H),3.45(brs,1H),3.38-3.30(m,2H),3.21(brs,2H),3.11(s,6H),2.29-2.25(m,1H),2.05-2.01(m,1H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 2N 5S 450.1958[M+H] +,Found:450.1950。 1 H-NMR (500MHz, DMSO ) δ (ppm): 10.94 (s, 1H), 9.98 (s, 1H), 9.56 (s, 1H), 9.35 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.81 (d, J = 3.0 Hz, 1H), 7.50 (brs, 2H), 4.61 (d, J=5.5 Hz, 2H), 3.45 (brs, 1H), 3.38-3.30 (m, 2H), 3.21 (brs, 2H), 3.11 (s, 6H), 2.29-2.25 (m, 1H), 2.05-2.01 (m, 1H); HR-MS (ESI): m/z, calcd. For C 24 H 27 O 2 N 5 S 450.1958 [M+H] + , Found: 450.1950.

实施例(化合物)19Example (compound) 19

(1-((4-二甲氨基-3-((3-(噻唑-2-基)苯甲基)氨甲酰基)苯基)氨基)-1-羰基丙烷-2-基)氨基甲酸叔丁酯(1-((4-Dimethylamino-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)amino)-1-carbonylpropan-2-yl)carbamic acid Butyl ester

Figure PCTCN2018088561-appb-000079
Figure PCTCN2018088561-appb-000079

将N-Boc-DL-丙氨酸(284mg,1.50mmol)溶于DCM(20mL)中，依次加入DIEA(258mg,2.00mmol)、HATU(608mg,1.60mmol)，室温反应30min后，加入5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(353mg,1.00mmol)，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体422mg，收率为80.5％，熔点：98-99℃。 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. DCM was added (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash with saturated brine (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography ( Ethyl acetate-petroleum ether (1:1 by volume) was purified to yield 422 mg of white solid,yield: 80.5%, m.p.: 98-99.

1H-NMR(500MHz,CDCl 3)δ(ppm):10.51(s,1H),8.48(s,1H),8.12(d,J＝6.5Hz,1H),7.99(s,1H),7.92(s,1H),7.86(brs,2H),7.43-7.40(m,2H),7.33(d,J＝3.0Hz,1H),7.24(d,J＝9.0Hz,1H),5.04(s,1H),4.74(d,J＝5.5Hz,2H),4.34(s,1H),2.65(s,6H),1.46(s,9H),1.44(d,J＝7.0Hz,3H)；HR-MS(ESI):m/z,calcd.For C 27H 33O 4N 5S 524.2326[M+H] +,Found:524.2318。 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 10.51 (s, 1H), 8.48 (s, 1H), 8.12 (d, J = 6.5 Hz, 1H), 7.99 (s, 1H), 7.92 ( s, 1H), 7.86 (brs, 2H), 7.43-7.40 (m, 2H), 7.33 (d, J = 3.0 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 5.04 (s, 1H) ), 4.74 (d, J = 5.5 Hz, 2H), 4.34 (s, 1H), 2.65 (s, 6H), 1.46 (s, 9H), 1.44 (d, J = 7.0 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 27 H 33 O 4 N 5 S 524.2326 [M+H] + , Found: 524.2318.

实施例(化合物)20Example (compound) 20

5-(2-氨基丙酰氨基)-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺·盐酸盐5-(2-Aminopropionylamino)-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide hydrochloride

Figure PCTCN2018088561-appb-000080
Figure PCTCN2018088561-appb-000080

将(1-((4-二甲氨基-3-((3-(噻唑-2-基)苯甲基)氨甲酰基)苯基)氨基)-1-羰基丙烷-2-基)氨基甲酸叔丁酯(80mg,0.15mmol)溶于无水DCM(10mL)中，加入HCl的EA溶液(1mL)，室温下反应5h，浓缩，加入乙醚(20mL)析出白色固体，过滤白色固体69mg，收率为98.6％，熔点：177-178℃。(1-((4-Dimethylamino-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)amino)-1-carbonylpropan-2-yl)carbamic acid The tert-butyl ester (80 mg, 0.15 mmol) was dissolved in anhydrous EtOAc (EtOAc) (EtOAc) The rate was 98.6%, and the melting point was 177-178 °C.

1H-NMR(500MHz,DMSO)δ(ppm):11.53(s,1H),10.03(s,1H),8.51(s,3H),8.19(s,1H),7.99(s,3H),7.94(d,J＝3.0Hz,1H),7.87(s,1H),7.82(d,J＝3.0Hz,1H),7.51(d,J＝4.5Hz,2H),5.76(s,1H),4.62(d,J＝5.5Hz,2H),4.17-4.14(m,1H),3.16(s,6H),1.49(d,J＝7.0Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 25O 2N 5S 424.1802[M+H] +,Found:424.1792。 1 H-NMR (500 MHz, DMSO) δ (ppm): 11.53 (s, 1H), 10.03 (s, 1H), 8.51 (s, 3H), 8.19 (s, 1H), 7.99 (s, 3H), 7.94 (d, J = 3.0 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 3.0 Hz, 1H), 7.51 (d, J = 4.5 Hz, 2H), 5.76 (s, 1H), 4.62 (d, J = 5.5 Hz, 2H), 4.17 - 4.14 (m, 1H), 3.16 (s, 6H), 1.49 (d, J = 7.0 Hz, 3H); HR-MS (ESI): m/z, calcd.For C 22 H 25 O 2 N 5 S 424.1802 [M+H] + , Found: 424.1792.

实施例(化合物)21Example (compound) 21

2-(二甲氨基)-5-(4-甲氧基苯甲酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-(Dimethylamino)-5-(4-methoxybenzoylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000081
Figure PCTCN2018088561-appb-000081

将5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(200mg,0.57mmol)溶于无水THF(15mL)中，冰浴下，依次加入TEA(173mg,1.71mmol)，4-甲氧基苯甲酰氯(147mg,0.86mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，HCl(0.5N)水溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体139mg，收率为50.4％，熔点：173-174℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):10.64(s,1H),8.36(d,J＝7.6Hz,1H),8.28(s,1H),8.04(s,1H),7.95(s,1H),7.87(brs,4H),7.43-7.37(m,2H),7.33(d,J＝3.2Hz,1H),7.30(d,J＝8.8Hz,1H),6.95(d,J＝8.8Hz,2H),4.65(d,J＝5.6Hz,2H),3.84(s, 3H),2.66(s,6H)；HR-MS(ESI):m/z,calcd.For C 27H 26O 3N 4S 487.1798[M+H] +,Found:487.1784。 5-Amino-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide (200 mg, 0.57 mmol) was dissolved in anhydrous THF (15 mL) Next, TEA (173 mg, 1.71 mmol), 4-methoxybenzoyl chloride (147 mg, 0.86 mmol) was added sequentially, and the reaction was continued for 1 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (20 mL), HCl (0.5N) aqueous solution (10 mL) washed saturated NaHCO 3 (10mL) wash, water (10mL) wash, brine water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 1) 139 mg of a white solid was obtained, the yield was 50.4%, m.p.: 173-174. 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.64 (s, 1H), 8.36 (d, J = 7.6Hz, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.95 ( s, 1H), 7.87 (brs, 4H), 7.43-7.37 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.95 (d, J) = 8.8 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 3.84 (s, 3H), 2.66 (s, 6H); HR-MS (ESI): m/z, calcd. For C 27 H 26 O 3 N 4 S 487.1798 [M+H] + , Found: 487.1784.

实施例(化合物)22Example (compound) 22

5-(环戊基甲酰氨基)-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-(cyclopentylformylamino)-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000082
Figure PCTCN2018088561-appb-000082

将环戊基甲酸(146mg,1.28mmol)溶于DCM(20mL)中，依次加入DIEA(248mg,1.92mmol)，HATU(536mg,1.41mmol)，室温反应30min后，加入底物5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(224mg,0.64mmol)，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体125mg，收率为43.9％，熔点：165-166℃。 The cyclopentylcarboxylic acid (146 mg, 1.28 mmol) was dissolved in DCM (20 mL), then DIEA (248 mg, 1.92 mmol), HATU (536 mg, 1.41 mmol) was added, and reacted at room temperature for 30 min, then the substrate 5-amino-2 was added. -(Dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide (224 mg, 0.64 mmol). DCM was added (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash with saturated brine (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography ( Ethyl acetate-petroleum ether (1:1 by volume) was purified to give a white solid (yield: 125 mg, yield: 43.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.67(s,1H),8.25(d,J＝6.8Hz,1H),7.98(s,1H),7.90(s,1H),7.86(brs,2H),7.73(s,1H),7.42(d,J＝4.8Hz,2H),7.33(d,J＝3.2Hz,1H),7.23(s,1H),4.74(d,J＝5.6Hz,2H),2.76-2.68(m,1H),2.64(s,6H),1.94-1.82(m,4H),1.81-1.71(m,2H),1.62-1.56(m,2H)；HR-MS(ESI):m/z,calcd.For C 25H 28O 2N 4S 449.2006[M+H] +,Found:449.1999。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.67 (s, 1H), 8.25 (d, J = 6.8Hz, 1H), 7.98 (s, 1H), 7.90 (s, 1H), 7.86 ( Brs, 2H), 7.73 (s, 1H), 7.42 (d, J = 4.8 Hz, 2H), 7.33 (d, J = 3.2 Hz, 1H), 7.23 (s, 1H), 4.74 (d, J = 5.6 Hz, 2H), 2.76-2.68 (m, 1H), 2.64 (s, 6H), 1.94-1.82 (m, 4H), 1.81-1.71 (m, 2H), 1.62-1.56 (m, 2H); HR- MS (ESI): m/z, Cald. For C 25 H 28 O 2 N 4 S 449.2006 [M+H] + , Found: 449.1999.

实施例(化合物)23Example (compound) 23

2-(二甲氨基)-5-(1-异丙基磺酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-(Dimethylamino)-5-(1-isopropylsulfonylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000083
Figure PCTCN2018088561-appb-000083

将5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(180mg,0.51mmol)溶于无水THF(20mL)中，冰浴下依次加入异丙基磺酰氯(145mg,1.02mmol)，吡啶(201mg,2.55mmol)，搅拌反应8h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水洗(10mL)， 饱和食盐水洗(10mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体57mg，收率为24.4％，熔点：130-131℃。 5-Amino-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide (180 mg, 0.51 mmol) was dissolved in anhydrous THF (20 mL) Next, isopropylsulfonyl chloride (145 mg, 1.02 mmol), pyridine (201 mg, 2.55 mmol) was added, and the mixture was stirred for 8h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (20mL), and washed with saturated ammonium chloride (10mL) , saturated NaHCO 3 (10mL) wash, water (10 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 1) to give a white solid 57mg The yield was 24.4%, and the melting point was 130-131 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.83(s,1H),8.29(s,1H),8.24(s,1H),8.03(s,1H),7.91-7.88(m,2H),7.71(dd,J＝8.4,2.8Hz,1H),7.71(dd,J＝8.4,2.8Hz,1H),7.52-7.44(m,2H),7.36(d,J＝3.2Hz,1H),7.27(brs,1H),4.85(d,J＝5.6Hz,2H),3.30-3.24(m,1H),2.68(s,6H),1.40(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 22H 26O 3N 4S 2 459.1519[M+H] +,Found:459.1503。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.83 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.91-7.88 (m, 2H ), 7.71 (dd, J = 8.4, 2.8 Hz, 1H), 7.71 (dd, J = 8.4, 2.8 Hz, 1H), 7.52-7.44 (m, 2H), 7.36 (d, J = 3.2 Hz, 1H) , 7.27 (brs, 1H), 4.85 (d, J = 5.6 Hz, 2H), 3.30-3.24 (m, 1H), 2.68 (s, 6H), 1.40 (d, J = 6.8 Hz, 6H); HR- MS (ESI): m/z, Cald. For C 22 H 26 O 3 N 4 S 2 459.1519 [M+H] + , Found:459.

实施例(化合物)24Example (compound) 24

2-(二甲氨基)-5-(1-甲基磺酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-(Dimethylamino)-5-(1-methylsulfonylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000084
Figure PCTCN2018088561-appb-000084

将5-氨基-2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(200mg,0.57mmol)溶于无水THF(15mL)中，冰浴下，依次加入甲磺酰氯(78mg,0.68mmol)，吡啶(90mg,1.14mmol)，继续反应8h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水洗(10mL)，饱和食盐水洗(10mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体127mg，收率为52.0％，熔点：165-166℃。 5-Amino-2-(dimethylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide (200 mg, 0.57 mmol) was dissolved in anhydrous THF (15 mL) Then, methanesulfonyl chloride (78 mg, 0.68 mmol), pyridine (90 mg, 1.14 mmol) was added, and the reaction was continued for 8 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (20 mL), and washed with saturated aqueous ammonium chloride (10 mL). saturated NaHCO 3 (10mL) wash, water (10 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 1) to give 127 mg of a white solid, The yield was 52.0%, and the melting point was 165-166 °C.

1H-NMR(500MHz,CDCl 3)δ(ppm):10.80(s,1H),8.46(s,1H),8.32(d,J＝2.0Hz,1H),8.01(s,1H),7.86(brs,2H),7.65(dd,J＝9.0,2.0Hz,1H),7.47(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),7.33(d,J＝3.0Hz,1H),7.29(d,J＝8.0Hz,1H),4.83(d,J＝5.5Hz,2H),2.95(s,3H),2.68(s,6H)；HR-MS(ESI):m/z,calcd.For C 20H 22O 3N 4S 2431.1206[M+H] +,Found:431.1199。 1 H-NMR (500MHz, CDCl 3) δ (ppm): 10.80 (s, 1H), 8.46 (s, 1H), 8.32 (d, J = 2.0Hz, 1H), 8.01 (s, 1H), 7.86 ( Brs, 2H), 7.65 (dd, J = 9.0, 2.0 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 3.0) Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.83 (d, J = 5.5 Hz, 2H), 2.95 (s, 3H), 2.68 (s, 6H); HR-MS (ESI): m/z,calcd. For C 20 H 22 O 3 N 4 S 2 431.1206 [M+H] + , Found: 431.1199.

实施例(化合物)25Example (compound) 25

N-(4-(二甲氨基)-3-((1-苯基乙基)氨基甲酰)苯基)-4,4-二氟哌啶-1-甲酰胺N-(4-(Dimethylamino)-3-((1-phenylethyl)carbamoyl)phenyl)-4,4-difluoropiperidine-1-carboxamide

Figure PCTCN2018088561-appb-000085
Figure PCTCN2018088561-appb-000085

a)2-(二甲氨基)-5-硝基-N-(1-苯基乙基)苯酰胺a) 2-(Dimethylamino)-5-nitro-N-(1-phenylethyl)benzamide

将2-(二甲氨基)-5-硝基苯甲酸(500mg,2.388mmol)加入无水DMF(25mL)，加入EDC(914mg,4.76mmol)，加入HOBt(643mg,4.76mmol)和DIEA(0.83mL,4.76mmol)，加入化合物1-苯基乙胺(0.365mL,2.85mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(50mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P:D＝1:3:1)，得到黄色固体600mg，产率80.5％。Add 2-(dimethylamino)-5-nitrobenzoic acid (500 mg, 2.388 mmol) to dry DMF (25 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc The compound 1-phenylethylamine (0.365 mL, 2.85 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate (50 mL×2). (30 mL × 2) washed, dried over anhydrous magnesium sulfate, concentrated, and then purified by column chromatography (E: P: D = 1:3:1)

1H-NMR(400MHz,CDCl 3)δ(ppm):8.51(d,J＝2.0Hz,1H),8.14(dd,J 1＝9.2Hz,J 2＝2.4Hz,1H),7.29-7.39(m,5H),6.95(d,J＝8.8Hz,1H),5.30-5.38(m,1H),2.85(s,6H),1.61(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.51 (d, J = 2.0 Hz, 1H), 8.14 (dd, J 1 = 9.2 Hz, J 2 = 2.4 Hz, 1H), 7.29-7.39 ( m, 5H), 6.95 (d, J = 8.8 Hz, 1H), 5.30-5.38 (m, 1H), 2.85 (s, 6H), 1.61 (d, J = 6.8 Hz, 3H).

b)5-氨基-2-(二甲氨基)-N-(1-苯基乙基)苯酰胺b) 5-amino-2-(dimethylamino)-N-(1-phenylethyl)benzamide

将2-(二甲氨基)-5-硝基-N-(1-苯基乙基)苯酰胺(520mg)，加入EtOH(25mL)，加入10％Pd/C(156mg)，常温常压下氢化反应，4h后停止反应，过滤，浓缩，得到土黄色固体450mg，产率95.7％。2-(Dimethylamino)-5-nitro-N-(1-phenylethyl)benzamide (520 mg) was added to EtOH (25 mL), and 10% Pd/C (156 mg) was added at normal temperature and pressure. The hydrogenation reaction was carried out, and the reaction was stopped after 4 h, filtered, and concentrated to give a white solid (yield: 450 mg).

1H-NMR(400MHz,CDCl 3)δ(ppm):10.97(s,1H),7.56(d,J＝2.4Hz,1H),7.31-7.39(m,5H),7.22-7.25(m,1H),7.08(d,J＝8.4Hz,1H),6.73(dd,J 1＝8.4Hz,J 2＝2.8Hz,1H),5.27-5.35(m,1H),2.60(s,6H),1.56(d,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.97 (s, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.31-7.39 (m, 5H), 7.22-7.25 (m, 1H ), 7.08 (d, J = 8.4 Hz, 1H), 6.73 (dd, J 1 = 8.4 Hz, J 2 = 2.8 Hz, 1H), 5.27-5.35 (m, 1H), 2.60 (s, 6H), 1.56 (d, J = 6.8 Hz, 3H).

c)4-硝基苯基(4-(二甲氨基)-3-((1-苯基乙基)苯酰胺)苯基)氨基甲酸酯c) 4-nitrophenyl (4-(dimethylamino)-3-((1-phenylethyl)benzamide)phenyl)carbamate

将5-氨基-2-(二甲氨基)-N-(1-苯基乙基)苯酰胺(57mg,0.2mmol)置于反应瓶中，加入DCM(5mL)，加入吡啶(0.24mL,3mmol)，氩气保护下加入化合物4-硝基苯基氯甲酯(60.5mg,0.3mmol)，加毕，室温搅拌反应，4h后停止反应，浓缩，加水，有固体，抽滤，滤饼水洗，用乙酸乙酯重结晶，得到白色固体50mg，产率55.8％。 1H-NMR(400MHz,CDCl 3)δ(ppm):10.86(d,J＝6.4Hz,1H),9.26(s,1H),8.36(s,1H),8.25(d,J＝8.8Hz,2H),8.11(d,J＝7.6Hz,1H),7.24-7.33(m,8H),5.50-5.54(m,1H),2.64(s,6H),1.54(d,J＝6.8Hz,3H). 5-Amino-2-(dimethylamino)-N-(1-phenylethyl)benzamide (57 mg, 0.2 mmol) was placed in a reaction flask, DCM (5 mL) was added and pyridine (0.24mL, 3mmol) The compound 4-nitrophenylchloromethyl ester (60.5 mg, 0.3 mmol) was added under argon atmosphere. After the addition, the reaction was stirred at room temperature. After 4 h, the reaction was stopped, concentrated, water was added, filtered, filtered, and washed with filter cake. Recrystallization from ethyl acetate gave 50 mg of a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.86 (d, J = 6.4 Hz, 1H), 9.26 (s, 1H), 8.36 (s, 1H), 8.25 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 7.6 Hz, 1H), 7.24 - 7.33 (m, 8H), 5.50 - 5.54 (m, 1H), 2.64 (s, 6H), 1.54 (d, J = 6.8 Hz, 3H ).

d)叔-丁基4,4-二氟哌啶-1-羧酸酯d) tert-butyl 4,4-difluoropiperidine-1-carboxylate

将N-Boc-4-氧代哌啶(199mg,1mmol)置于反应液中，加入DCM(10mL)，冰浴下将DAST(0.26mL,2mmol)的DCM(2mL)溶液滴加入反应瓶中，滴毕，冰浴下搅拌反应30min后升温至室温反应，1.5h后停止反应，将反应液倒入冰水中，用DCM(20mL×2)萃取，合并有机层用饱和NaCl(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:50，E:P＝1:40)，得到白色固体160mg，产率72.4％。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).

1H-NMR(400MHz,CDCl 3)δ(ppm):3.54(t,J＝5.6Hz,4H),1.88-1.98(m,4H),1.47(s,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 3.54 (t,J = 5.6 Hz, 4H), 1.88-1.98 (m, 4H), 1.47 (s, 9H).

e)4,4-二氟哌啶2,2,2-三氟乙酸盐e) 4,4-difluoropiperidine 2,2,2-trifluoroacetate

将叔-丁基4,4-二氟哌啶-1-羧酸酯(380mg,1.727mmol)置于反应瓶中，加入DCM(15mL)，加入TFA(1.28mL,17.27mmol)，室温搅拌反应，2h后停止反应，浓缩，加入乙醚，有固体洗出，抽滤，滤饼用乙醚洗，得到白色固体325mg，产率79.8％。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.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.23(brs,2H),3.23(t,J＝8.0Hz,4H),2.14-2.25(m,4H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 8.23 (brs, 2H), 3.23 (t, J = 8.0Hz, 4H), 2.14-2.25 (m, 4H).

f)N-(4-(二甲氨基)-3-((1-苯基乙基)氨基甲酰)苯基)-4,4-二氟哌啶-1-甲酰胺f) N-(4-(Dimethylamino)-3-((1-phenylethyl)carbamoyl)phenyl)-4,4-difluoropiperidine-1-carboxamide

将4-硝基苯基(4-(二甲氨基)-3-((1-苯基乙基)苯酰胺)苯基)氨基甲酸酯(45mg,0.1mmol)，加入DCM(10mL)，加入4,4-二氟哌啶2,2,2-三氟乙酸盐(35mg,0.15mmol)以及DIEA(0.05mL,0.3mmol)室温搅拌反应，30min后停止反应，加入DCM(20mL)，用饱和NaCl(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1)，得到固体30mg，产率69.7％。4-Nitrophenyl(4-(dimethylamino)-3-((1-phenylethyl)benzamide)phenyl)carbamate (45 mg, 0.1 mmol) 4,4-Difluoropiperidine 2,2,2-trifluoroacetic acid salt (35 mg, 0.15 mmol) and DIEA (0.05 mL, 0.3 mmol) were added and the mixture was stirred at room temperature. After 30 min, the reaction was stopped and DCM (20 mL) was added. The organic layer was washed with EtOAc (EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):10.63(d,J＝7.2Hz,1H),7.88(d,J＝7.2Hz,1H),7.76(s,1H),7.32-7.36(m,5H),7.21(d,J＝8.8Hz,1H),6.86(s,1H),5.28-5.32(m,1H),3.98(s,0.5H),3.69-3.70(m,0.5H),3.59(t,J＝5.2Hz,3H),2.64(s,6H),2.37(brs,0.5H),1.95-2.04(m,3.5H),1.56(d,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 10.63 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.32-7.36 ( m, 5H), 7.21 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 5.28-5.32 (m, 1H), 3.98 (s, 0.5H), 3.69-3.70 (m, 0.5H) , 3.59 (t, J = 5.2 Hz, 3H), 2.64 (s, 6H), 2.37 (brs, 0.5H), 1.95-2.04 (m, 3.5H), 1.56 (d, J = 6.8 Hz, 3H).

实施例(化合物)26Example (compound) 26

N-(4-(二甲氨基)-3-((1-苯基乙基)氨基甲酰)苯基)-3,3-二氟哌啶-1-甲酰胺N-(4-(Dimethylamino)-3-((1-phenylethyl)carbamoyl)phenyl)-3,3-difluoropiperidine-1-carboxamide

Figure PCTCN2018088561-appb-000086
Figure PCTCN2018088561-appb-000086

a)叔-丁基3,3-二氟哌啶-1-羧酸酯a) tert-butyl 3,3-difluoropiperidine-1-carboxylate

将N-Boc-3-氧代哌啶(598mg,3mmol)置于反应液中，加入DCM(20mL)，氩气保护下冰浴下将DAST(0.78mL,6mmol)的DCM(5mL)溶液滴加入反应瓶中，滴毕，冰浴下搅拌反应1h后停止反应，将反应液倒入冰水中，用DCM(30mL×2)萃取，合并有机层用饱和NaCl(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:50)，得到无色油状物体330mg，产率49.7％。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.

1H-NMR(400MHz,CDCl 3)δ(ppm):3.62(t,J＝11.6Hz,2H),3.41(t,J＝4.8Hz,2H),1.93-2.02(m,2H),1.70-1.77(m,2H),1.47(s,9H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 3.62 (t, J = 11.6Hz, 2H), 3.41 (t, J = 4.8Hz, 2H), 1.93-2.02 (m, 2H), 1.70- 1.77 (m, 2H), 1.47 (s, 9H).

b)3,3-二氟哌啶2,2,2-三氟乙酸盐b) 3,3-difluoropiperidine 2,2,2-trifluoroacetate

将叔-丁基3,3-二氟哌啶-1-羧酸酯(250mg,1.13mmol)置于反应瓶中，加入DCM(10mL)，加入TFA(0.84mL,11.3mmol)，室温搅拌反应，2h后停止反应，浓缩，加入乙醚，有固体洗出，抽滤，滤饼用乙醚洗，得到白色固体250mg，产率93.9％。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.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.41(brs,2H),3.52(t,J＝12.0Hz,2H),3.07(t,J＝5.2Hz,2H),2.05-2.15(m,2H),1.82-1.86(m,2H) 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.41 (brs, 2H), 3.52 (t, J = 12.0Hz, 2H), 3.07 (t, J = 5.2Hz, 2H), 2.05- 2.15(m, 2H), 1.82-1.86 (m, 2H)

c)N-(4-(二甲氨基)-3-((1-苯基乙基)氨基甲酰)苯基)-3,3-二氟哌啶-1-甲酰胺c) N-(4-(Dimethylamino)-3-((1-phenylethyl)carbamoyl)phenyl)-3,3-difluoropiperidine-1-carboxamide

将5-氨基-2-(二甲氨基)-N-(1-苯基乙基)苯酰胺(75mg,0.167mmol)，加入DCM(15mL)，加入3,3-二氟哌啶2,2,2-三氟乙酸盐(59mg,0.25mmol)以及DIEA(0.09mL,0.5mmol)室温搅拌反应，30min后停止反应，加入DCM(20mL)，用饱和NaCl(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到固体50mg，产率70.4％。熔点：76-78℃5-Amino-2-(dimethylamino)-N-(1-phenylethyl)benzamide (75 mg, 0.167 mmol) was added to DCM (15 mL) and 3,3-difluoropiperidine 2,2 The reaction was stirred at rt. EtOAc (EtOAc (EtOAc) (EtOAc) The residue was dried over MgSO.sub.4. Melting point: 76-78 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):10.61(d,J＝8.4Hz,1H),7.87(d,J＝8.8Hz,1H),7.74(s,1H),7.31-7.35(m,5H),7.20(d,J＝8.8Hz,1H),6.66(s,1H),5.29-5.33(m,1H),3.69(t,J＝11.6Hz,2H),3.46(t,J＝5.2Hz,2H),2.63(s,6H),1.99-2.08(m,2H),1.76-1.83(m,2H),1.56(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.61 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.31 - 7.35 ( m,5H), 7.20 (d, J=8.8Hz, 1H), 6.66(s,1H), 5.29-5.33(m,1H), 3.69(t,J=11.6Hz,2H), 3.46(t,J = 5.2 Hz, 2H), 2.63 (s, 6H), 1.99-2.08 (m, 2H), 1.76-1.83 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H).

实施例(化合物)27Example (compound) 27

N-(4-(二甲氨基)-3-((1-苯基乙基)氨基甲酰)苯基)-3,3-二氟吡咯烷-1-甲酰胺N-(4-(Dimethylamino)-3-((1-phenylethyl)carbamoyl)phenyl)-3,3-difluoropyrrolidine-1-carboxamide

Figure PCTCN2018088561-appb-000087
Figure PCTCN2018088561-appb-000087

a)叔-丁基3,3-二氟吡咯烷-1-羧酸酯a) tert-butyl 3,3-difluoropyrrolidine-1-carboxylate

将N-Boc-3-氧代四氢吡咯(1.48g,8mmol)置于反应液中，加入DCM(40mL)，氩气保护下冰浴下将DAST(2.08mL,16mmol)的DCM(10mL)溶液滴加入反应瓶中，滴毕，冰浴下搅拌后逐渐升至室温反应，将反应液倒入冰水中，用DCM(50mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:50)，得到无色油状物体1.0g，产率60.6％。</RTI> The solution was added dropwise to the reaction flask, and the mixture was added dropwise. The mixture was stirred in an ice bath and gradually warmed to room temperature. The reaction mixture was poured into ice water and extracted with DCM (50 mL×2), and the organic layer was washed with saturated NaCl (30 mL×2). Drying with anhydrous magnesium sulfate, EtOAc (EtOAc:EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):3.62-3.68(m,2H),3.57(brs,2H),2.26-2.37(m,2H),1.47(s,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 3.62-3.68 (m, 2H), 3.57 (brs, 2H), 2.26-2.37 (m, 2H), 1.47 (s, 9H).

b)3,3-二氟吡咯烷2,2,2-三氟乙酸盐b) 3,3-difluoropyrrolidine 2,2,2-trifluoroacetate

将叔-丁基3,3-二氟吡咯烷-1-羧酸酯(830mg,4mmol)置于反应瓶中，加入DCM(20mL)，加入TFA(2.96mL,40mmol)，室温搅拌反应，2h后停止反应，浓缩，加入乙醚，无固体洗出，置于冰箱冷冻层静置，有固体析出，抽滤，滤饼用乙醚洗，得到白色固体600mg，产率67.8％。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%).

1H-NMR(400MHz,CDCl 3)δ(ppm):10.26(brs,2H),3.48-3.56(m,4H),2.42-2.58(m,2H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 10.26 (brs, 2H), 3.48-3.56 (m, 4H), 2.42-2.58 (m, 2H).

c)N-(4-(二甲氨基)-3-((1-苯基乙基)氨基甲酰)苯基)-3,3-二氟吡咯烷-1-甲酰胺c) N-(4-(Dimethylamino)-3-((1-phenylethyl)carbamoyl)phenyl)-3,3-difluoropyrrolidine-1-carboxamide

将5-氨基-2-(二甲氨基)-N-(1-苯基乙基)苯酰胺(75mg,0.167mmol)，加入DCM(15mL)，加入3,3-二氟吡咯烷2,2,2-三氟乙酸盐(55mg,0.25mmol)以及DIEA(0.09mL,0.5mmol)室温搅拌反应，30min后停止反应，加入DCM(20mL)，用饱和NaCl(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到白色粘稠固体50mg，产率71.9％。5-Amino-2-(dimethylamino)-N-(1-phenylethyl)benzamide (75 mg, 0.167 mmol) was added to DCM (15 mL) and 3,3-difluoropyrrolidine 2,2 The reaction was stirred at rt. EtOAc (EtOAc m. Dry over magnesium sulfate, concentrate, andm~~~~~~~~~

1H-NMR(400MHz,CDCl 3)δ(ppm):10.64(d,J＝6.8Hz,1H),7.96(d,J＝7.6Hz,1H),7.76(s,1H),7.31-7.35(m,5H),7.21(d,J＝8.8Hz,1H),6.66(s,1H),5.27-5.31(m,1H),3.80(t,J＝12.8Hz,2H),3.66(t,J＝7.2Hz,2H),2.63(s,6H),2.35-2.44(m,2H),1.56(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.64 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.31 - 7.35 ( m, 5H), 7.21 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 5.27-5.31 (m, 1H), 3.80 (t, J = 12.8 Hz, 2H), 3.66 (t, J) = 7.2 Hz, 2H), 2.63 (s, 6H), 2.35-2.44 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H).

实施例(化合物)28Example (compound) 28

2-乙氧基-5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000088
Figure PCTCN2018088561-appb-000088

将2-乙氧基-5-异丁酰氨基苯甲酸(80mg,0.32mmol)加入无水DMF(15mL)，加入EDC(123mg,0.64mmol)，加入HOBt(86mg,0.64mmol)和DIEA(0.14mL,0.8mmol)，加入(3-(噻唑-2-基)苯基)甲胺(182mg,0.96mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯30mL×2萃取，合并有机层用饱和NaCl 30mL×2洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝75:1)，得到白色固体70mg，产率51.8％。熔点：157-158℃2-Ethoxy-5-isobutyrylaminobenzoic acid (80 mg, 0.32 mmol) was added to dry DMF (15 mL), EDC (123 mg, 0.64 mmol) was added, and HOBt (86 mg, 0.64 mmol) and DIEA (0.14) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The organic layer was washed with EtOAc EtOAc (EtOAc)EtOAc. Melting point: 157-158 ° C

1H-NMR(400MHz,CDCl 3)δPPm:8.49(s,1H),8.23(d,J＝7.2Hz,1H),7.99(s,1H),7.87-7.91(m,3H),7.59(s,1H),7.42-7.48(m,2H),7.35(d,J＝2.8Hz,1H),6.93(d,J＝ 8.8Hz,1H),4.73(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),2.50-2.55(m,1H),1.31(t,J＝6.8Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR δPPm (400MHz, CDCl 3): 8.49 (s, 1H), 8.23 (d, J = 7.2Hz, 1H), 7.99 (s, 1H), 7.87-7.91 (m, 3H), 7.59 (s , 1H), 7.42-7.48 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H), 2.50 - 2.55 (m, 1H), 1.31 (t, J = 6.8 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)29Example (compound) 29

5-苯甲酰氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-benzoylamino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000089
Figure PCTCN2018088561-appb-000089

a)2-乙氧基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺a) 2-ethoxy-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-硝基苯甲酸(300mg,1.42mmol)溶于DCM(20mL)中，依次加入DIEA(275mg,2.13mmol)、HATU(703mg,1.85mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(296mg,1.56mmol)，室温反应12h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:5)纯化得白色固体481mg，收率为88.3％，熔点：131-132℃。 2-Ethoxy-5-nitrobenzoic acid (300 mg, 1.42 mmol) was dissolved in DCM (20 mL), then DIEA (275 mg, 2.13 mmol), HATU (703 mg, 1.85 mmol). (3-(thiazol-2-yl)phenyl)methanamine (296 mg, 1.56 mmol) was added, and the mixture was reacted at room temperature for 12 hr. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate Ester-petroleum ether, volume ratio 2:5) was purified to give 481 mg of white solid,yield: 88.3%, m.p.: 131-132.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.13(d,J＝2.8Hz,1H),8.31(dd,J＝9.2,3.2Hz,1H),8.13(s,1H),8.01(s,1H),7.90-7.87(m,2H),7.52-7.41(m,2H),7.36(d,J＝3.2Hz,1H),7.04(d,J＝9.2Hz,1H),4.75(d,J＝5.2Hz,2H),4.27(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H)；ESI-MS m/z:384.10[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 9.13 (d, J = 2.8 Hz, 1H), 8.31 (dd, J = 9.2, 3.2 Hz, 1H), 8.13 (s, 1H), 8.01 ( s, 1H), 7.90-7.87 (m, 2H), 7.52-7.41 (m, 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 4.75 (d , J = 5.2 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 384.10 [M+H] + .

b)5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺b) 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(260mg,0.68mmol)溶于THF(15mL)中，加入Pd/C 130mg，在室温下通入氢气，反应过夜，过滤，滤液浓缩，得黄绿色油状物232mg，收率为96.7％。2-Ethoxy-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide (260 mg, 0.68 mmol) was dissolved in THF (15 mL). Hydrogen was introduced at room temperature, and the reaction was allowed to stand overnight, filtered, and the filtrate was concentrated to give 232 mg (yield:

1H-NMR(400MHz,CDCl 3)δ(ppm):8.54(s,1H),7.97(s,1H),7.87(t,J＝5.2Hz,2H),7.59(d,J＝2.0Hz,1H),7.47-7.39(m,2H),7.33(d,J＝3.2Hz,1H),6.76(d,J＝3.6Hz,2H),4.71(d,J＝5.6Hz,2H),4.04(q,J＝7.2Hz,2H),3.48(s,2H),1.26(t,J＝7.2Hz,3H)；ESI-MS m/z:354.13[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.54 (s, 1H), 7.97 (s, 1H), 7.87 (t, J = 5.2Hz, 2H), 7.59 (d, J = 2.0Hz, 1H), 7.47-7.39 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.76 (d, J = 3.6 Hz, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.04 ( q, J = 7.2 Hz, 2H), 3.48 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 354.13 [M+H] + .

c)5-苯甲酰氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 5-Benzoylamino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

将5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(200mg,0.57mmol)溶于无水THF(10mL)中，冰浴下依次加入TEA(115mg,1.14mmol)，苯甲酰氯(121 mg,0.86mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体177mg，收率为68.6％，熔点：143-144℃。 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (200 mg, 0.57 mmol) was dissolved in anhydrous THF (10 mL) TEA (115 mg, 1.14 mmol), benzoyl chloride (121 mg, 0.86 mmol), EtOAc (EtOAc, m. 3 (20 mL), washed with water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:3) to give white solid 177 mg The yield was 68.6%, and the melting point was 143-144 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.48(s,1H),8.37(brs,2H),8.10(d,J＝2.4Hz,1H),7.92-7.86(m,5H),7.52-7.39(m,5H),7.34(d,J＝3.2Hz,1H),6.98(d,J＝8.8Hz,1H),4.60(d,J＝5.2Hz,2H),4.15(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 26H 23O 3N 3S 458.1533[M+H] +,Found:458.1515。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.48 (s, 1H), 8.37 (brs, 2H), 8.10 (d, J = 2.4Hz, 1H), 7.92-7.86 (m, 5H), 7.52-7.39 (m, 5H), 7.34 (d, J = 3.2 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H), 4.15 (q, J) = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 26 H 23 O 3 N 3 S 458.1533 [M+H] + , Found: 458.1515.

实施例(化合物)30Example (compound) 30

(4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨甲酰基)苯基)氨基甲酸丙酯(4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamate

Figure PCTCN2018088561-appb-000090
Figure PCTCN2018088561-appb-000090

将5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(133mg,0.38mmol)溶于无水THF(10mL)中，冰浴下依次加入TEA(77mg,0.76mmol)，氯甲酸丙酯(70mg,0.57mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体72mg，收率为43.6％，熔点：182-183℃。 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (133 mg, 0.38 mmol) was dissolved in anhydrous THF (10 mL) TEA (77 mg, 0.76 mmol), propyl chloroformate (70 mg, 0.57 mmol), EtOAc (EtOAc) (EtOAc) 3 (20 mL), washed with water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:3) The yield was 43.6%, and the melting point was 182-183 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.52(s,1H),7.99(d,J＝3.6Hz,3H),7.89-7.86(m,2H),7.45-7.41(m,2H),7.34(d,J＝3.2Hz,1H),7.21(s,1H),6.92(d,J＝9.2Hz,1H),4.76(d,J＝5.6Hz,2H),4.14-4.08(m,4H),1.71-1.63(m,2H),1.30(t,J＝7.2Hz,3H),0.94(t,J＝7.6Hz,3H)；HR-MS(ESI):m/z,calcd.For C 23H 25O 4N 3S 440.1639[M+H] +,Found:424.1623。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.52 (s, 1H), 7.99 (d, J = 3.6 Hz, 3H), 7.89-7.86 (m, 2H), 7.45-7.41 (m, 2H) ), 7.34 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.76 (d, J = 5.6 Hz, 2H), 4.14 - 4.08 (m) , 4H), 1.71-1.63 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.6 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 23 H 25 O 4 N 3 S 440.1639 [M+H] + , Found: 424.1623.

实施例(化合物)31Example (compound) 31

5-(3,3-二甲基脲基)-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺)5-(3,3-Dimethylureido)-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide)

Figure PCTCN2018088561-appb-000091
Figure PCTCN2018088561-appb-000091

将5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(160mg,0.45mmol)溶于无水THF(10mL)中，冰浴下，依次加入TEA(136mg,1.35mmol)，N,N-二甲基甲酰氯(97mg,0.90mmol)，50℃反应7h，过滤，滤液浓缩，加入乙酸乙酯(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(二氯甲烷-甲醇，体积比50:1)纯化，得白色固体107mg，收率为55.7％，熔点：108-109℃。 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (160 mg, 0.45 mmol) was dissolved in anhydrous THF (10 mL) TEA (136 mg, 1.35 mmol), N,N-dimethylformyl chloride (97 mg, 0.90 mmol) was added, and the mixture was reacted at 50 ° C for 7 h, filtered, and the filtrate was concentrated and diluted with ethyl acetate (30 mL). (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash with saturated brine (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (dichloromethane - methanol, a volume ratio of 50: 1) Purification gave 107 mg of a white solid, yield: 55.7%, m.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.50(brs,1H),8.03-7.98(m,2H),7.89-7.86(m,2H),7.77(d,J＝2.8Hz,1H),7.44(brs,2H),7.34(d,J＝3.2Hz,1H),6.91(d,J＝9.2Hz,1H),6.41(s,1H),4.72(d,J＝5.4Hz,2H),4.12(q,J＝6.8Hz,2H),3.02(s,6H),1.30(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 24O 3N 4S 425.1642[M+H] +,Found:425.1627。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.50 (brs, 1H), 8.03-7.98 (m, 2H), 7.89-7.86 (m, 2H), 7.77 (d, J = 2.8 Hz, 1H) ), 7.44 (brs, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.41 (s, 1H), 4.72 (d, J = 5.4 Hz, 2H) ), 4.12 (q, J = 6.8 Hz, 2H), 3.02 (s, 6H), 1.30 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 22 H 24 O 3 N 4 S 425.1642 [M+H] + , Found: 425.1627.

实施例(化合物)32Example (compound) 32

3-((4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)氨基甲酰)吡咯烷-1-羧酸叔丁酯3-((4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Figure PCTCN2018088561-appb-000092
Figure PCTCN2018088561-appb-000092

将(dl)-N-Boc-β-脯氨酸(185mg,0.86mmol)溶于DCM(15mL)中，依次加入DIEA(147mg,1.14mmol)、HATU(346mg,0.91mmol)，室温反应30min后，加入5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(200mg,0.57mmol)，室温反应10h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体251mg，收率为 80.4％，熔点：135-136℃。 (dl)-N-Boc-β-valine (185 mg, 0.86 mmol) was dissolved in DCM (15 mL), then DIEA (147 mg, 1.14 mmol), HATU (346 mg, 0.91 mmol). 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (200 mg, 0.57 mmol) was added. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 251 mg of white solid,yield: 80.4%, m.p.: 135-136.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.51(s,1H),8.21(brs,2H),7.97-7.95(m,2H),7.86(d,J＝3.2Hz,2H),7.42(d,J＝4.8Hz,2H),7.33(d,J＝3.2Hz,1H),6.92(d,J＝8.4Hz,1H),4.71(d,J＝5.6Hz,2H),4.13(q,J＝6.8Hz,2H),3.65(brs,3H),3.31(brs,1H),3.06(s,1H),2.13(s,2H),1.45(s,9H),1.31(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 29H 34O 5N 4S 551.2323[M+H] +,Found:551.2302。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.51 (s, 1H), 8.21 (brs, 2H), 7.97-7.95 (m, 2H), 7.86 (d, J = 3.2 Hz, 2H), 7.42 (d, J = 4.8 Hz, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H), 4.13 ( q, J = 6.8 Hz, 2H), 3.65 (brs, 3H), 3.31 (brs, 1H), 3.06 (s, 1H), 2.13 (s, 2H), 1.45 (s, 9H), 1.31 (t, J = 6.8Hz, 3H); HR- MS (ESI): m / z, calcd.For C 29 H 34 O 5 N 4 S 551.2323 [m + H] +, Found: 551.2302.

实施例(化合物)33Example (compound) 33

N-(4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)吡咯烷-3-甲酰胺·盐酸盐N-(4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)pyrrolidine-3-carboxamide hydrochloride

Figure PCTCN2018088561-appb-000093
Figure PCTCN2018088561-appb-000093

将3-((4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)氨基甲酰)吡咯烷-1-羧酸叔丁酯(100mg,0.18mmol)溶于DCM(10mL)/乙醇(2mL)中，加入HCl的EA溶液(1mL)，室温下反应8h，浓缩，加入乙醚(20mL)析出浅绿色固体，过滤得86mg，收率为96.6％，熔点：142-144℃。3-((4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester ( 100 mg, 0.18 mmol), dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) It is 96.6%, melting point: 142-144 °C.

1H-NMR(400MHz,DMSO)δ(ppm):10.38(s,1H),9.47(s,1H),9.18(s,1H),8.69(t,J＝5.6Hz,1H),7.98(d,J＝2.4Hz,1H),7.95(s,1H),7.93(d,J＝2.4Hz,1H),7.85(brs,1H),7.80(d,J＝2.0Hz,1H),7.75(d,J＝8.6Hz,1H),7.48(d,J＝4.4Hz,2H),7.11(d,J＝8.8Hz,1H),4.59(d,J＝5.6Hz,2H),4.13(q,J＝6.8Hz,2H),3.43-3.38(m,1H),3.33-3.27(m,2H),3.26-3.17(m,2H),2.26-2.21(m,1H),2.08-2.01(m,1H),1.29(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 24H 26O 3N 4S 451.1798[M+H] +,Found:451.1784。 1 H-NMR (400 MHz, DMSO) δ (ppm): 10.38 (s, 1H), 9.47 (s, 1H), 9.18 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 7.98 (d) , J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.85 (brs, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.75 (d , J = 8.6 Hz, 1H), 7.48 (d, J = 4.4 Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H), 3.43 - 3.38 (m, 1H), 3.33 - 3.27 (m, 2H), 3.26 - 3.17 (m, 2H), 2.26 - 2.21 (m, 1H), 2.08 - 2.01 (m, 1H) ), 1.29 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 24 H 26 O 3 N 4 S 451.1798 [M+H] + , Found: 451.1784.

实施例(化合物)34Example (compound) 34

(1-((4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨甲酰基)苯基)氨基)-1-羰基丙烷-2-基)氨基甲酸叔丁酯(1-((4-Ethyloxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)amino)-1-carbonylpropan-2-yl)carbamic acid Butyl ester

Figure PCTCN2018088561-appb-000094
Figure PCTCN2018088561-appb-000094

将N-Boc-DL-丙氨酸(219mg,1.02mmol)，溶于DCM(15mL)中，依次加入DIEA(175mg,1.36mmol)、HATU(414mg,1.09mmol)，室温反应30min后，加入5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(240mg,0.68mmol)，室温反应10h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得得白色固体297mg，收率为79.4％，熔点：98-99℃。 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). Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 297 mg of white solid,yield: 79.4%, m.p.: 98-99.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(s,1H),8.39(s,1H),8.11(dd,J＝8.8,2.8Hz,1H),7.98(s,1H),7.93(d,J＝2.8Hz,1H),7.88-7.86(m,2H),7.44-7.40(m,2H),7.33(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),5.03(s,1H),4.73(d,J＝5.2Hz,2H),4.33(s,1H),4.12(q,J＝6.8Hz,2H),1.46(s,9H),1.43(d,J＝6.8Hz,3H),1.31(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 27H 32O 5N 4S 525.2166[M+H] +,Found:525.2153。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (s, 1H), 8.39 (s, 1H), 8.11 (dd, J = 8.8,2.8Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.88-7.86 (m, 2H), 7.44 - 7.40 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 9.2 Hz) , 1H), 5.03 (s, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.33 (s, 1H), 4.12 (q, J = 6.8 Hz, 2H), 1.46 (s, 9H), 1.43 (d, J = 6.8 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, cald. For C 27 H 32 O 5 N 4 S 525.2166 [M+ H] + , Found: 525.2153.

实施例(化合物)35Example (compound) 35

5-(2-氨基丙酰氨基)-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺·盐酸盐5-(2-Aminopropionylamino)-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide hydrochloride

Figure PCTCN2018088561-appb-000095
Figure PCTCN2018088561-appb-000095

将(1-((4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨甲酰基)苯基)氨基)-1-羰基丙烷-2-基)氨基甲酸叔丁酯(80mg,0.15mmol)溶于DCM(10mL)/乙醇(2mL)中，加入HCl的EA溶液(1mL)，室温下反应8h，浓缩，加入乙醚(20mL)析出浅绿色固体，过滤得白色固体69mg，收率为98.6％，熔点：141-142℃。(1-((4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)amino)-1-carbonylpropan-2-yl)carbamic acid The tert-butyl ester (80 mg, 0.15 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) White solid 69 mg, yield 98.6%, m.p.: 141 - 142.

1H-NMR(400MHz,DMSO)δ(ppm):10.66(s,1H),8.71(brs,1H),8.31(s,3H),7.99(d,J＝2.4Hz,1H),7.95(s,1H),7.92(brs,1H),7.84(brs,1H),7.79(brs,1H),7.74(dd,J＝8.8,2.4Hz,1H),7.47(d,J＝3.2Hz,2H),7.15(d,J＝9.2Hz,1H),4.59(d,J＝6.0Hz,2H),4.14(q,J＝7.2Hz,2H),4.02(brs,1H),1.46(d,J＝6.8Hz,3H),1.31(t,J＝ 6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 24O 3N 4S 425.1642[M+H] +,Found:425.1625。 1 H-NMR (400MHz, DMSO ) δ (ppm): 10.66 (s, 1H), 8.71 (brs, 1H), 8.31 (s, 3H), 7.99 (d, J = 2.4Hz, 1H), 7.95 (s , 1H), 7.92 (brs, 1H), 7.84 (brs, 1H), 7.79 (brs, 1H), 7.74 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (d, J = 3.2 Hz, 2H) , 7.15 (d, J = 9.2 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 4.02 (brs, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.31 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, cald. For C 22 H 24 O 3 N 4 S 425.1642 [M+H] + ,Found : 425.1625.

实施例(化合物)36Example (compound) 36

2-((4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)氨基甲酰)吡咯烷-1-羧酸叔丁酯2-((4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

Figure PCTCN2018088561-appb-000096
Figure PCTCN2018088561-appb-000096

将(dl)-N-Boc-脯氨酸(163mg,0.86mmol)，溶于DCM(15mL)中，依次加入DIEA(147mg,1.14mmol)、HATU(346mg,0.91mmol)，室温反应30min后，加入5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(200mg,0.57mmol)，室温反应10h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体233mg，收率为78.5％，熔点：152-153℃。 (dl)-N-Boc-valine (163 mg, 0.86 mmol) was dissolved in DCM (15 mL), then DIEA (147 mg, 1.14 mmol), HATU (346 mg, 0.91 mmol). 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (200 mg, 0.57 mmol) was added. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 233 mg of white solid,yield: 78.5%, m.p.: 152-153.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.16(s,1H),8.44(brs,1H),8.10(d,J＝7.2Hz,1H),7.98(s,1H),7.92(s,1H),7.88-7.86(m,2H),7.44-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),4.72(d,J＝5.6Hz,2H),4.44(brs,1H),4.12(q,J＝6.8Hz,2H),3.49(s,2H),2.47(brs,2H),1.93(brs,2H),1.48(s,9H),1.31(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 29H 34O 5N 4S 551.2323[M+H] +,Found:551.2308。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.16 (s, 1H), 8.44 (brs, 1H), 8.10 (d, J = 7.2Hz, 1H), 7.98 (s, 1H), 7.92 ( s, 1H), 7.88-7.86 (m, 2H), 7.44-7.41 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.72 (d) , J = 5.6 Hz, 2H), 4.44 (brs, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.49 (s, 2H), 2.47 (brs, 2H), 1.93 (brs, 2H), 1.48 (s, 9H), 1.31 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 29 H 34 O 5 N 4 S 551.2323 [M+H] + ,Found :551.2308.

实施例(化合物)37Example (compound) 37

N-(4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)吡咯烷-2-甲酰胺·盐酸盐N-(4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)pyrrolidine-2-carboxamide hydrochloride

Figure PCTCN2018088561-appb-000097
Figure PCTCN2018088561-appb-000097

将2-((4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯基)氨基甲酰)吡咯烷-1-羧酸 叔丁酯(80mg,0.15mmol)溶于DCM(10mL)/乙醇(2mL)中，加入HCl的EA溶液(1mL)，室温下反应8h，浓缩，加入乙醚(20mL)析出浅绿色固体，过滤得白色固体67mg，收率为94.4％，熔点：149-150℃。2-((4-Ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester ( 80 mg, 0.15 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) The yield was 94.4%, and the melting point was 149-150 °C.

1H-NMR(400MHz,DMSO)δ(ppm):10.84(s,1H),10.02(s,1H),8.71(brs,1H),8.66(s,1H),8.00(s,1H),7.96(s,1H),7.93(d,J＝2.0Hz,1H),7.84(s,1H),7.80(d,J＝2.8Hz,1H),7.74(d,J＝8.8Hz,1H),7.48(d,J＝4.4Hz,2H),7.15(d,J＝8.8Hz,1H),4.59(d,J＝5.6Hz,2H),4.36(brs,1H),4.14(q,J＝6.8Hz,2H),3.26(brs,2H),2.40(brs,1H),1.95(brs,3H),1.30(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 24H 26O 3N 4S 451.1798[M+H] +,Found:451.1783。 1 H-NMR (400 MHz, DMSO) δ (ppm): 10.84 (s, 1H), 10.02 (s, 1H), 8.71 (brs, 1H), 8.66 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 4.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 4.36 (brs, 1H), 4.14 (q, J = 6.8 Hz) , 2H), 3.26 (brs, 2H), 2.40 (brs, 1H), 1.95 (brs, 3H), 1.30 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 24 H 26 O 3 N 4 S 451.1798 [M+H] + , Found: 451.1783.

实施例(化合物)38Example (compound) 38

2-乙氧基-5-(4-甲氧基苯甲酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(4-methoxybenzoylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000098
Figure PCTCN2018088561-appb-000098

将5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(100mg,0.28mmol)溶于无水THF(10mL)中，冰浴下，依次加入TEA(85mg,0.84mmol)，4-甲氧基苯甲酰氯(95mg,0.56mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化，得白色固体82mg，收率为59.4％，熔点：148-149℃。 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (100 mg, 0.28 mmol) was dissolved in anhydrous THF (10 mL) TEA (85 mg, 0.84 mmol), 4-methoxybenzoyl chloride (95 mg, 0.56 mmol) was added, and the reaction was continued for 1 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (30 mL), Washed, washed with saturated NaHCO 3 (20 mL), washed with water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:1) The white solid was 82 mg, the yield was 59.4%, and the melting point was 148-149 °C.

1H-NMR(400MHz,CDCl 3))δ(ppm):8.49(brs,1H),8.34(dd,J＝8.8,2.4Hz,1H),8.15(s,1H),8.04(d,J＝2.8Hz,1H),7.95(s,1H),7.89-7.85(m,4H),7.47-7.39(m,2H),7.34(d,J＝3.2Hz,1H),6.98-6.95(m,3H),4.66(d,J＝5.6Hz,2H),4.15(q,J＝6.8Hz,2H),3.85(s,3H),1.32(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 27H 25O 4N 3S 488.1639[M+H] +,Found:488.1619。 1 H-NMR (400MHz, CDCl 3)) δ (ppm): 8.49 (brs, 1H), 8.34 (dd, J = 8.8,2.4Hz, 1H), 8.15 (s, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.95 (s, 1H), 7.89-7.85 (m, 4H), 7.47-7.39 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.98-6.95 (m, 3H) ), 4.66 (d, J = 5.6 Hz, 2H), 4.15 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 1.32 (t, J = 6.8 Hz, 3H); HR-MS (ESI) ): m/z, calcd. For C 27 H 25 O 4 N 3 S 488.1639 [M+H] + , Found: 488.1619.

实施例(化合物)39Example (compound) 39

2-乙氧基-5-环丁甲酰胺基-N-(1-(3-(噻唑-2-基)苯基)甲基)苯甲酰胺2-ethoxy-5-cyclobutyramide-N-(1-(3-(thiazol-2-yl)phenyl)methyl)benzamide

Figure PCTCN2018088561-appb-000099
Figure PCTCN2018088561-appb-000099

a)2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)甲基)苯甲酰胺a) 2-ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)methyl)benzamide

2-乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)甲基)苯甲酰胺(200mg，0.52mmol)溶于DCM(2ml)/EtOH(8ml)/H 2O(1ml)，加入Fe粉(175mg，3.13mmol)，NH 4Cl(28mg，0.52mmol)，70℃回流反应2h。原料消失。过滤，浓缩，加入EA(15ml)稀释，水洗(15ml×2),无水硫酸镁干燥，浓缩，加入石油醚，析出白色固体153mg，收率83％。 2-Ethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)methyl)benzamide (200 mg, 0.52 mmol) dissolved in DCM (2 mL) /EtOAc 8 ml) / H 2 O (1 ml), Fe powder (175 mg, 3.13 mmol), NH 4 Cl (28 mg, 0.52 mmol), and refluxed at 70 ° C for 2 h. The raw materials disappeared. Filtration, concentration, EA (15 ml), EtOAc (EtOAc m.

1H NMR(400MHZ，DMSO-d 6)δ(ppm):8.65(t,J＝6.0Hz,1H),7.92-7.94(m,2H),7.83(d,J＝6.0Hz,1H),7.7983(d,J＝6.0Hz,1H),7.79(d,J＝3.2Hz,1H),7.46-7.49(m,2H),7.07(d,J＝2.8Hz,1H),6.85(d,J＝8.4Hz,1H),6.66(dd,J 1＝2.8Hz,J 2＝8.4Hz,1H),4.85(s,2H),4.57(d,J＝5.6Hz,2H),4.00(q,J＝6.8Hz,2H),1.22(t,J＝6.8Hz,3H).m.p.124-126℃. 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.65 (t, J = 6.0 Hz, 1H), 7.92 - 7.94 (m, 2H), 7.83 (d, J = 6.0 Hz, 1H), 7.7983 (d, J = 6.0 Hz, 1H), 7.79 (d, J = 3.2 Hz, 1H), 7.46-7.49 (m, 2H), 7.07 (d, J = 2.8 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.66 (dd, J 1 = 2.8 Hz, J 2 = 8.4 Hz, 1H), 4.85 (s, 2H), 4.57 (d, J = 5.6 Hz, 2H), 4.00 (q, J = 6.8 Hz, 2H), 1.22 (t, J = 6.8 Hz, 3H). mp 124-126 ° C.

b)2-乙氧基-5-环丁甲酰胺基-N-(1-(3-(噻唑-2-基)苯基)甲基)苯甲酰胺b) 2-ethoxy-5-cyclobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)methyl)benzamide

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)甲基)苯甲酰胺(60mg，0.17mmol)溶于THF(4mL)，冰浴下加入TEA(51mg，0.51mmol)，搅拌下逐滴加入环丁甲酰氯(24mg，0.20mmol)，室温下搅拌反应10min。蒸馏水(15mL×2)洗，无水硫酸镁干燥，浓缩，加入石油醚，得到白色固体65mg，收率86％。2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)methyl)benzamide (60 mg, 0.17 mmol) dissolved in THF (4 mL) TEA (51 mg, 0.51 mmol) was added, and cyclobutyroyl chloride (24 mg, 0.20 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. Distilled water (15 mL × 2) was washed, dried over anhydrous magnesium sulfate, and concentrated, and petroleum ether was added to give 65 mg of white solid.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.50(d,J＝4.8Hz,1H),8.25(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),7.99(s,1H),7.86-7.90(m,2H),7.44-7.45(m,2H),7.39(brs,1H),7.35(d,J＝3.2Hz,1H),6.93(d,J＝9.2Hz,1H),4.74(d,J＝5.2Hz,2H),4.13(q,J＝2.8Hz,2H),3.10-3.21(m,1H),2.33-2.38(m,1H),2.17-2.23(m,1H),1.31(t,J＝6.8Hz,3H).m.p.166-168. 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.50 (d, J = 4.8 Hz, 1H), 8.25 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 7.99 (s, 1H) ), 7.86-7.90 (m, 2H), 7.44-7.45 (m, 2H), 7.39 (brs, 1H), 7.35 (d, J = 3.2 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H) , 4.74 (d, J = 5.2 Hz, 2H), 4.13 (q, J = 2.8 Hz, 2H), 3.10 - 3.21 (m, 1H), 2.33 - 2.38 (m, 1H), 2.17 - 2.23 (m, 1H) ), 1.31 (t, J = 6.8 Hz, 3H). mp166-168.

实施例(化合物)40Example (compound) 40

5-(环戊甲酰胺基)-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-(cyclopentamcarbamido)-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000100
Figure PCTCN2018088561-appb-000100

将环戊基甲酸(72mg,0.63mmol)溶于DCM(15mL)中，依次加入DIEA(163 mg,1.26mmol)、HATU(319mg,0.84mmol)，室温反应30min后，加入5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(150mg,0.42mmol)，室温反应10h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化得白色固体63mg，收率为33.2％，熔点：171-172℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.49(brs,1H),8.22(d,J＝7.2Hz,1H),7.98(s,1H),7.88(brs,3H),7.51(s,1H),7.44(brs,2H),7.34(d,J＝3.2Hz,1H),6.92(d,J＝9.0Hz,1H),4.73(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),2.73-2.65(m,1H),1.95-1.83(m,4H),1.79-1.73(m,2H),1.64-1.58(m,2H),1.31(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 25H 27O 3N 3S 450.1846[M+H] +,Found:450.1838。 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. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether was purified by a white solid (yield: 3:3) to give a white solid (yield: 33. 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.49 (brs, 1H), 8.22 (d, J = 7.2Hz, 1H), 7.98 (s, 1H), 7.88 (brs, 3H), 7.51 ( s, 1H), 7.44 (brs, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.13 ( q, J = 6.8 Hz, 2H), 2.73 - 2.65 (m, 1H), 1.95-1.83 (m, 4H), 1.79-1.73 (m, 2H), 1.64-1.58 (m, 2H), 1.31 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 25 H 27 O 3 N 3 S 450.1846 [M+H] + , Found: 450.1838.

实施例(化合物)41Example (compound) 41

2-乙氧基-5-(2-甲氧基丙酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(2-methoxypropionylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000101
Figure PCTCN2018088561-appb-000101

将2-甲氧基丙酸(87mg,0.84mmol)溶于DCM(10mL)中，依次加入DIEA(163mg,1.26mmol)，HATU(400mg,1.05mmol)，室温反应30min后，加入5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(150mg,0.42mmol)，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比3:2)纯化得白色固体116mg，收率为62.4％，熔点：149-151℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.46(s,1H),8.41(s,1H),8.22(dd,J＝9.0,2.8Hz,1H),7.99(s,1H),7.93(d,J＝2.4Hz,1H),7.89-7.86(m,2H),7.45-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.94(d,J＝9.2Hz,1H),4.73(d,J＝5.6Hz,2H),4.14(q,J＝6.8Hz,2H),3.86(q,J＝6.8Hz,1H),3.48(s,3H),1.46(d,J＝6.8Hz,3H),1.32(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 23H 25O 4N 3S 440.1639[M+H] +,Found:440.1631。 2-Methoxypropionic acid (87 mg, 0.84 mmol) was dissolved in DCM (10 mL), then DIEA (163 mg, 1.26 mmol), HATU (400 mg, 1.05 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). DCM was added (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20mL) wash with saturated brine (20mL) wash, dried over anhydrous Na 2 SO 4, column chromatography ( Ethyl acetate-petroleum ether (3:2 by volume) was purified to give a white solid, 116 mg, yield: 62.4%, m.p.: 149-151. 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.46 (s, 1H), 8.41 (s, 1H), 8.22 (dd, J = 9.0,2.8Hz, 1H), 7.99 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.89-7.86 (m, 2H), 7.45-7.41 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.94 (d, J = 9.2 Hz) , 1H), 4.73 (d, J = 5.6 Hz, 2H), 4.14 (q, J = 6.8 Hz, 2H), 3.86 (q, J = 6.8 Hz, 1H), 3.48 (s, 3H), 1.46 (d) , J = 6.8 Hz, 3H), 1.32 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, cald. For C 23 H 25 O 4 N 3 S 440.1639 [M+H] +, Found: 440.1631.

实施例(化合物)42Example (compound) 42

2-乙氧基-5-(甲基磺酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(methylsulfonylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000102
Figure PCTCN2018088561-appb-000102

将5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(160mg,0.45mmol)溶于无水THF(15mL)中，冰浴下，依次加入甲磺酰氯(103mg,0.90mmol)，吡啶(178mg,2.25mmol)，室温搅拌反应8h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，饱和氯化铵溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水洗(10mL)，饱和食盐水洗(10mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比3:2)纯化得白色固体142mg，收率为72.8％，熔点：164-165℃。 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (160 mg, 0.45 mmol) was dissolved in anhydrous THF (15 mL) Methanesulfonyl chloride (103 mg, 0.90 mmol), pyridine (178 mg, 2.25 mmol) was added, and the mixture was stirred at room temperature for 8 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (20 mL), and washed with saturated ammonium chloride (10 mL) NaHCO 3 (10mL) wash, water (10 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 3: 2) to give a white solid 142 mg, yield The rate was 72.8%, and the melting point was 164-165 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.63(s,1H),8.34(d,J＝2.8Hz,1H),8.13(s,1H),8.00(s,1H),7.89-7.85(m,2H),7.63(d,J＝8.8Hz,1H),7.46-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.96(d,J＝8.8Hz,1H),4.81(d,J＝5.6Hz,2H),4.15(q,J＝6.8Hz,2H),2.92(s,3H),1.33(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 20H 21O 4N 3S 2 432.1046[M+H] +,Found:432.1042。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.63 (s, 1H), 8.34 (d, J = 2.8Hz, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.89- 7.85 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.46-7.41 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H) ), 4.81 (d, J = 5.6 Hz, 2H), 4.15 (q, J = 6.8 Hz, 2H), 2.92 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); HR-MS (ESI) ): m/z, calcd. For C 20 H 21 O 4 N 3 S 2 432.1046 [M+H] + , Found: 432.1042.

实施例(化合物)43Example (compound) 43

2-乙氧基-5-(异丙基磺酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(isopropylsulfonylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000103
Figure PCTCN2018088561-appb-000103

将5-氨基-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(100mg,0.28mmol)溶于无水THF(10mL)中，冰浴下，依次加入异丙基磺酰氯(80mg,0.56mmol)，吡啶(111mg,1.40mmol)，搅拌反应8h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，HCl(0.5N)溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水洗(10mL)，饱和食盐水洗(10mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比3:2)纯化得白色固体84mg，收率为64.6％，熔点：158-159℃。 5-Amino-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (100 mg, 0.28 mmol) was dissolved in anhydrous THF (10 mL) Isopropylsulfonyl chloride (80 mg, 0.56 mmol), pyridine (111 mg, 1.40 mmol), EtOAc (EtOAc,EtOAc) , saturated NaHCO 3 (10mL) wash, water (10 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 3: 2) to give a white solid 84mg The yield was 64.6%, and the melting point was 158-159 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.61(s,1H),8.29(d,J＝2.8Hz,1H),8.07(s,1H),8.00(s,1H),7.89-7.85(m,2H),7.68(dd,J＝8.8,2.8Hz,1H),7.48-7.41(m,2H),7.33(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),4.80(d,J＝5.2Hz,2H),4.13(q,J＝ 6.8Hz,2H),3.23-3.16(m,1H),1.35(d,J＝6.8Hz,6H),1.31(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 25O 4N 3S 2 460.1359[M+H] +,Found:460.1345。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.61 (s, 1H), 8.29 (d, J = 2.8Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.89- 7.85 (m, 2H), 7.68 (dd, J = 8.8, 2.8 Hz, 1H), 7.48-7.41 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 9.2 Hz) , 1H), 4.80 (d, J = 5.2 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H), 3.23-3.16 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H), 1.31 (t, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 22 H 25 O 4 N 3 S 2 460.1359 [M+H] + , Found: 460.1345.

实施例(化合物)44Example (compound) 44

2-乙氧基-5-(2-羰基吡咯烷-1-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(2-carbonylpyrrolidin-1-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000104
Figure PCTCN2018088561-appb-000104

a)5-(4-氯丁酰氨基)-2-乙氧基苯甲酸甲酯a) Methyl 5-(4-chlorobutyrylamino)-2-ethoxybenzoate

将5-氨基-2-乙氧基苯甲酸甲酯(600mg,3.08mmol)溶于无水THF(10mL)中，冰浴下，依次加入4-氯丁酰氯(651mg,4.62mmol)，TEA(778mg,7.70mmol)，继续反应2h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，0.5N的HCl水溶液(10mL)洗，饱和NaHCO 3(10mL)洗，水洗(10mL)，饱和食盐水洗(10mL)，无水Na 2SO 4干燥，浓缩，PE/EA重结晶得浅褐色固体899mg，收率为97.4％，熔点：95-96℃。 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 ℃.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.78(d,J＝2.8Hz,1H),7.73(dd,J＝8.8,2.8Hz,1H),7.35(s,1H),6.92(d,J＝8.8Hz,1H),4.09(q,J＝6.8Hz,2H),3.87(s,3H),3.66(t,J＝6.0Hz,2H),2.54(t,J＝7.2Hz,2H),2.30-2.10(m,2H),1.43(t,J＝7.2Hz,3H)；ESI-MS m/z:300.10[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.78 (d, J = 2.8Hz, 1H), 7.73 (dd, J = 8.8,2.8Hz, 1H), 7.35 (s, 1H), 6.92 ( d, J = 8.8 Hz, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.87 (s, 3H), 3.66 (t, J = 6.0 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.30-2.10 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 300.10 [M+H] + .

b)2-乙氧基-5-(2-羰基吡咯烷-1-基)苯甲酸b) 2-ethoxy-5-(2-carbonylpyrrolidin-1-yl)benzoic acid

将5-(4-氯丁酰氨基)-2-乙氧基苯甲酸甲酯(400mg,1.33mmol)溶于THF(15mL)/水(2mL)中，搅拌下加入NaOH(213mg,5.33mmol)，室温反应6h，合并反应1和2，浓缩，加入水(10mL)稀释，乙醚(10mL×2)洗涤水层，水层用盐酸调pH＝3，析出固体377mg，收率为90.6％，熔点：132-133℃。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.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.39(dd,J＝9.2,2.8Hz,1H),7.90(d,J＝2.8Hz,1H),7.06(d,J＝9.2Hz,1H),4.34(q,J＝7.2Hz,2H),3.89(t,J＝7.2Hz,2H),2.61(t,J＝8.0Hz,2H),2.26-2.08(m,2H),1.56(t,J＝7.2Hz,3H)；ESI-MS m/z:248.09[M-H] -。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.39 (dd, J = 9.2, 2.8 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 9.2 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.89 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 2.26-2.08 (m, 2H), 1.56 ( t, J = 7.2Hz, 3H) ; ESI-MS m / z: 248.09 [MH] -.

c)2-乙氧基-5-(2-羰基吡咯烷-1-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-ethoxy-5-(2-carbonylpyrrolidin-1-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-(2-羰基吡咯烷-1-基)苯甲酸(262mg,1.05mmol)溶于DCM(20mL) 中，依次加入DIEA(204mg,1.58mmol)、HATU(600mg,1.58mmol)，搅拌反应20min后加入(3-(噻唑-2-基)苯基)甲胺(200mg,1.05mmol)，室温搅拌过夜。浓缩，加入DCM(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体237mg，收率53.5％，熔点：144-145℃。 2-Ethoxy-5-(2-carbonylpyrrolidin-1-yl)benzoic acid (262 mg, 1.05 mmol) was dissolved in DCM (20 mL). 1.58 mmol), after stirring for 20 min, (3-(thiazol-2-yl)phenyl)methanamine (200 mg, 1.05 mmol). Concentrated, diluted were added DCM (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purification by volume ratio 1:3) gave 237 mg of white solid, yield 53.5%, m.p.: 144-145.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.48(s,1H),8.23(dd,J＝9.0,2.8Hz,1H),7.98(d,J＝2.8Hz,2H),7.87(brs,2H),7.45-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.96(d,J＝8.8Hz,1H),4.73(d,J＝5.2Hz,2H),4.15(q,J＝7.2Hz,2H),3.91(t,J＝7.2Hz,2H),2.60(t,J＝8.4Hz,2H),2.20-2.12(m,2H),1.32(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 23H 23O 3N 3S 422.1533[M+H] +,Found:422.1526。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.48 (s, 1H), 8.23 (dd, J = 9.0,2.8Hz, 1H), 7.98 (d, J = 2.8Hz, 2H), 7.87 ( Brs, 2H), 7.45-7.41 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (t, J = 7.2 Hz, 2H), 2.60 (t, J = 8.4 Hz, 2H), 2.20-2.12 (m, 2H), 1.32 (t, J) = 7.2Hz, 3H); HR- MS (ESI): m / z, calcd.For C 23 H 23 O 3 N 3 S 422.1533 [m + H] +, Found: 422.1526.

实施例(化合物)45Example (compound) 45

2-乙氧基-5-(异丁基氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(isobutylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000105
Figure PCTCN2018088561-appb-000105

a)2-乙氧基-5-(异丁基氨基)苯甲酸甲酯a) Methyl 2-ethoxy-5-(isobutylamino)benzoate

反应1：将5-氨基-2-乙氧基苯甲酸甲酯(200mg,1.03mmol)，异丁醛(81mg,1.03mmol)溶于异丙醇(10mL)/水(1mL)中，依次加入甲酸铵(649mg,10.3mmol)，Pd/C(200mg)，室温反应4h，原料消失。反应2：将5-氨基-2-乙氧基苯甲酸甲酯(400mg,2.06mmol)，异丁醛(162mg,2.06mmol)溶于异丙醇(10mL)/水(1mL)中，依次加入甲酸铵(1.3g,20.60mmol)，Pd/C(400mg)，室温反应4h，原料消失。反应3：与反应2相同，合并反应1、2和3，浓缩，加入EA(50mL)稀释，水洗(20mL×2)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:7)纯化，得浅绿色油状物898mg，收率70.2％。 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). Ammonium formate (1.3 g, 20.60 mmol), Pd/C (400 mg), reacted at room temperature for 4 h, and the starting material disappeared. 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).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.03(d,J＝3.2Hz,1H),6.85(d,J＝8.8Hz,1H),6.71(dd,J＝8.8,3.2Hz,1H),4.01(q,J＝7.2Hz,2H),3.88(s,3H),3.69(s,1H),2.90(d,J＝6.8Hz,2H),1.91-1.81(m,1H),1.39(t,J＝7.2Hz,3H),0.98(d,J＝6.8Hz,6H)；ESI-MS m/z:252.16[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.03 (d, J = 3.2 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.8, 3.2 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.69 (s, 1H), 2.90 (d, J = 6.8 Hz, 2H), 1.91-1.81 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.98 (d, J = 6.8 Hz, 6H); ESI-MS m/z: 252.16 [M+H] + .

b)2-乙氧基-5-(异丁基氨基)苯甲酸b) 2-ethoxy-5-(isobutylamino)benzoic acid

反应1：将2-乙氧基-5-(异丁基氨基)苯甲酸甲酯(160mg,0.64mmol)溶于THF(10mL)/水(1mL)中，搅拌下加入NaOH(102mg,2.56mmol)，室温反应6h。反应2：将2-乙氧基-5-(异丁基氨基)苯甲酸甲酯(500mg,2.00mmol)溶于THF(15mL)/水(2mL)中，搅拌下加入NaOH(320mg,8.00mmol)，室温反应6h，合并反应1和2，浓缩，加入水(10mL)稀释，乙醚(10mL×2)洗涤水层，水层用盐酸调pH＝3，析出固体531mg，收率为85.2％，熔点：80-81℃。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.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.39(d,J＝3.2Hz,1H),6.89(d,J＝8.8Hz,1H),6.79(dd,J＝8.9,3.2Hz,1H),4.23(q,J＝7.2Hz,2H),2.93(d,J＝6.8Hz,2H),1.92-1.82(m,1H),1.50(t,J＝7.2Hz,3H),0.98(d,J＝6.8Hz,6H)；ESI-MS m/z:236.13[M-H] -。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.39 (d, J = 3.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 8.9, 3.2 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 2.93 (d, J = 6.8 Hz, 2H), 1.92-1.82 (m, 1H), 1.50 (t, J = 7.2 Hz, 3H), 0.98 ( d, J = 6.8 Hz, 6H); ESI-MS m/z: 236.13 [MH] - .

c)2-乙氧基-5-(异丁基氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-ethoxy-5-(isobutylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-(异丁基氨基)苯甲酸(249mg,1.05mmol)溶于DCM(20mL)中，依次加入DIEA(204mg,1.58mmol)、HATU(600mg,1.58mmol)，搅拌反应20min后加入(3-(噻唑-2-基)苯基)甲胺(200mg,1.05mmol)，室温搅拌过夜。浓缩，加入DCM(20mL)稀释，HCl(0.5N)(10mL)洗，饱和NaHCO 3(10mL)洗，水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体181mg，收率42.2％，熔点：89-90℃。 2-Ethoxy-5-(isobutylamino)benzoic acid (249 mg, 1.05 mmol) was dissolved in DCM (20 mL), then DIEA (204 mg, 1.58 mmol), HATU (600 mg, 1.58 mmol) After reacting for 20 min, (3-(thiazol-2-yl)phenyl)methanamine (200 mg, 1.05 mmol). Concentrated, diluted were added DCM (20mL), HCl (0.5N ) (10mL) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether Purified by volume ratio 1:3), 181 mg of white solid was obtained, yield 42.2%, melting point: 89-90 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.58(s,1H),7.97(s,1H),7.86(brs,2H),7.54(d,J＝2.8Hz,1H),7.48-7.37(m,2H),7.33(d,J＝3.2Hz,1H),6.81(d,J＝8.8Hz,1H),6.71(dd,J＝8.8,2.8Hz,1H),4.72(d,J＝5.6Hz,2H),4.03(q,J＝7.2Hz,2H),2.94(d,J＝6.8Hz,2H),1.93-1.83(m,1H),1.26(t,J＝7.2Hz,3H),0.97(d,J＝6.4Hz,6H)；HR-MS(ESI):m/z,calcd.For C 23H 27O 2N 3S 410.1897[M+H] +,Found:410.1891。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.58 (s, 1H), 7.97 (s, 1H), 7.86 (brs, 2H), 7.54 (d, J = 2.8Hz, 1H), 7.48- 7.37 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.8, 2.8 Hz, 1H), 4.72 (d, J) = 5.6 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 2.94 (d, J = 6.8 Hz, 2H), 1.93-1.83 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H) ), 0.97 (d, J = 6.4 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 23 H 27 O 2 N 3 S 410.1897 [M+H] + , Found: 410.1891.

实施例(化合物)46Example (compound) 46

4-乙氧基-N 1,N 1-二甲基-N 3-(3-(噻唑-2-基)苯甲基)异酞酰胺 4-ethoxy-N 1 ,N 1 -dimethyl-N 3 -(3-(thiazol-2-yl)benzyl)isodecanoylamide

Figure PCTCN2018088561-appb-000106
Figure PCTCN2018088561-appb-000106

a)2-乙氧基-5-甲酰基苯甲酸甲酯a) Methyl 2-ethoxy-5-formylbenzoate

将2-羟基-5-甲酰基苯甲酸甲酯(2g,11.11mmol)溶于无水DMF(20mL)中，依 次加入K 2CO 3(3.07g,22.22mmol)、C 2H 5I(5.20g,33.33mmol)，加热至60℃反应10h，冷却，加水析出白色固体，过滤，水(20mL)洗涤滤饼，得白色固体1.77g，收率为76.9％，熔点：64-65℃。 A mixture of 2-hydroxy-5-formylbenzoate (2g, 11.11mmol) was dissolved in anhydrous DMF (20mL) added sequentially K 2 CO 3 (3.07g, 22.22mmol ), C 2 H 5 I (5.20 g, 33.33 mmol), heated to 60 ° C for 10 h, cooled, water was added to precipitate a white solid, filtered, water (20mL) washed filter cake to give white solid 1.77 g, yield 76.9%, melting point: 64-65 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.90(s,1H),8.31(d,J＝2.0Hz,1H),7.99(dd,J＝8.8,2.0Hz,1H),7.08(d,J＝8.8Hz,1H),4.22(q,J＝7.2Hz,2H),3.92(s,3H),1.51(t,J＝7.2Hz,3H)；ESI-MS m/z:209.08[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.90 (s, 1H), 8.31 (d, J = 2.0Hz, 1H), 7.99 (dd, J = 8.8,2.0Hz, 1H), 7.08 ( d, J = 8.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 209.08 [ M+H] + .

b)4-乙氧基-3-(甲氧羰基)苯甲酸b) 4-ethoxy-3-(methoxycarbonyl)benzoic acid

将2-乙氧基-5-甲酰基苯甲酸甲酯(600mg,2.88mmol)溶于DMF(15mL)中，加入单过硫酸氢钾复合盐(3.54g,5.76mmol)，室温下反应3h，过滤，加入HCl(2N)(15mL)，再加入EA(25mL×3)萃取，无水Na 2SO 4干燥有机相，浓缩，重结晶得白色固体375mg，收率为58.0％，熔点：185-187℃。 The methyl 2-ethoxy-5-formylbenzoate (600 mg, 2.88 mmol) was dissolved in DMF (15 mL). filtration, HCl (2N) (15mL), was added and then EA (25mL × 3) was extracted, was dried over anhydrous Na 2 SO 4 organic phase was concentrated and recrystallized to give 375 mg of a white solid, yield 58.0%, mp: 185- 187 ° C.

1H-NMR(400MHz,DMSO)δ(ppm):12.90(s,1H),8.21(s,1H),8.06(d,J＝8.8Hz,1H),7.24(d,J＝8.8Hz,1H),4.19(q,J＝6.8Hz,2H),1.35(t,J＝6.8Hz,3H)；ESI-MS m/z:223.06[M-H] -。 1 H-NMR (400 MHz, DMSO) δ (ppm): 12.90 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H) ), 4.19 (q, J = 6.8 Hz, 2H), 1.35 (t, J = 6.8 Hz, 3H); ESI-MS m/z: 223.06 [MH] - .

c)5-(二甲基氨基甲酰)-2-乙氧基苯甲酸甲酯c) Methyl 5-(dimethylcarbamoyl)-2-ethoxybenzoate

将4-乙氧基-3-(甲氧羰基)苯甲酸(300mg,1.05mmol)溶于DCM(20mL)中，依次加入DIEA(519mg,4.02mmol)、HATU(1.02g,2.68mmol)，室温反应30min后，加入二甲胺的盐酸盐(164mg,2.01mmol)，氩气保护下，室温反应5h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得白色固体317mg，收率为94.3％，熔点：55-57℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):7.89(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.4Hz,1H),6.97(d,J＝8.8Hz,1H),4.15(q,J＝7.2Hz,2H),3.88(s,3H),3.05(s,6H),1.47(t,J＝7.2Hz,3H)；ESI-MS m/z:252.12[M+H] +。 4-Ethoxy-3-(methoxycarbonyl)benzoic acid (300 mg, 1.05 mmol) was dissolved in DCM (20 mL) EtOAc (EtOAc) After reacting for 30 min, the hydrochloride salt of dimethylamine (164 mg, 2.01 mmol) was added, and the mixture was reacted under argon atmosphere for 5 hr. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate Ester-petroleum ether, volume ratio 1:2) was purified to give 317 mg of white solid, yield: 94.3%, m.p. 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.8, 2.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.05 (s, 6H), 1.47 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 252.12 [ M+H] + .

d)5-(二甲基氨基甲酰)-2-乙氧基苯甲酸d) 5-(Dimethylcarbamoyl)-2-ethoxybenzoic acid

将5-(二甲基氨基甲酰)-2-乙氧基苯甲酸甲酯(300mg,1.20mmol)溶于THF(20mL)/水(10mL)中，搅拌下加入NaOH(192mg,4.80mmol)，室温反应6h，浓缩，加入乙醚(20mL)洗涤水层，水层用盐酸调pH＝3，析出固体244mg，产率为86.2％，熔点：102-103℃。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.

1H-NMR(400MHz,DMSO)δ(ppm):12.72(s,1H),7.65(s,1H),7.54(d,J＝8.8Hz,1H),7.14(d,J＝8.4Hz,1H),4.14(q,J＝7.2Hz,2H),2.95(s,6H),1.34(t,J＝6.8Hz, 3H)；ESI-MS m/z:236.09[M-H] -。 1 H-NMR (400MHz, DMSO ) δ (ppm): 12.72 (s, 1H), 7.65 (s, 1H), 7.54 (d, J = 8.8Hz, 1H), 7.14 (d, J = 8.4Hz, 1H ), 4.14 (q, J = 7.2 Hz, 2H), 2.95 (s, 6H), 1.34 (t, J = 6.8 Hz, 3H); ESI-MS m/z: 236.09 [MH] - .

e)4-乙氧基-N 1,N 1-二甲基-N 3-(3-(噻唑-2-基)苯甲基)异酞酰胺 e) 4- ethoxy -N 1, N 1 - dimethyl -N 3 - (3- (thiazol-2-yl) benzyl) isophthalic amide

将5-(二甲基氨基甲酰)-2-乙氧基苯甲酸(200mg,0.84mmol)溶于DCM(20mL)中，依次加入DIEA(217mg,1.68mmol)、HATU(479mg,1.26mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(160mg,0.84mmol)，氩气保护下，室温反应5h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体319mg，收率为88.6％，熔点：78-79℃。 5-(Dimethylcarbamoyl)-2-ethoxybenzoic acid (200 mg, 0.84 mmol) was dissolved in DCM (20 mL)EtOAc. After reacting for 30 min at room temperature, (3-(thiazol-2-yl)phenyl)methanamine (160 mg, 0.84 mmol) was added, and the mixture was reacted under argon atmosphere for 5 h at room temperature. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 319 mg of white solid, yield: 88.6%, m.p.: 78-79.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.32(d,J＝2.0Hz,2H),7.99(s,1H),7.87(brs,2H),7.61(dd,J＝8.4,2.4Hz,1H),7.44(brs,2H),7.34(d,J＝3.2Hz,1H),6.98(d,J＝8.4Hz,1H),4.73(d,J＝5.2Hz,2H),4.18(q,J＝6.8Hz,2H),3.07(brs,6H),1.34(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 23O 3N 3S 410.1533[M+H] +,Found:410.1521。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.32 (d, J = 2.0 Hz, 2H), 7.99 (s, 1H), 7.78 (brs, 2H), 7.61 (dd, J = 8.4, 2.4 Hz, 1H), 7.44 (brs, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.18 ( q, J = 6.8 Hz, 2H), 3.07 (brs, 6H), 1.34 (t, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 22 H 23 O 3 N 3 S 410.1533 [M+H] + , Found: 410.1521.

实施例(化合物)47Example (compound) 47

4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯甲基(异丙基)氨基甲酸苄酯Benzyl 4-ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)benzyl (isopropyl)carbamate

Figure PCTCN2018088561-appb-000107
Figure PCTCN2018088561-appb-000107

a)2-乙氧基-5-((异丙基氨基)甲基)苯甲酸甲酯a) Methyl 2-ethoxy-5-((isopropylamino)methyl)benzoate

将2-乙氧基-5-甲酰基苯甲酸甲酯(500mg,2.40mmol)溶于三氟乙醇(20mL)中，加入异丙基胺(1.42g,24mmol)，室温反应2h后，加入NaBH 4(180mg,4.80mmol)，继续反应2h，原料反应完毕。合并反应1和2，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化得浅绿色油状物477mg，收率为71.9％。 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. The combined reaction 1 and 2, saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 3) The pale green oil was purified to be 477 mg, yield 71.9%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.72(d,J＝2.0Hz,1H),7.42(dd,J＝8.4,2.0Hz,1H),6.92(d,J＝8.4Hz,1H),4.10(q,J＝7.2Hz,2H),3.88(s,3H),3.73(s,2H),2.90-2.79(m,1H),1.44(t,J＝7.2Hz,3H),1.10(d,J＝6.4Hz,5H)；ESI-MS m/z: 252.16[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.72 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.73 (s, 2H), 2.90-2.79 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 6.4 Hz, 5H); ESI-MS m/z: 252.16 [M+H] + .

b)5-((((苄氧基)羰基)(异丙基)氨基)甲基)-2-乙氧基苯甲酸甲酯b) Methyl 5-(((benzyloxy))carbonyl)(isopropyl)amino)methyl)-2-ethoxybenzoate

将2-乙氧基-5-((异丙基氨基)甲基)苯甲酸甲酯(450mg,0.08mmol)溶于无水THF(10mL)中，依次加入CbzCl(612mg,3.60mmol)、TEA(545mg,5.40mmol)，室温反应3h，原料反应完毕。浓缩，加入EA(30mL)稀释，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:10)纯化得无色油状物677mg，收率为98.1％。 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. Dried and concentrated, diluted with addition of EA (30mL), saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1 : 10) Purified 677 mg of colorless oil, yield 98.1%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.64(s,1H),7.44-7.15(m,6H),6.88(s,1H),5.14(s,2H),4.37(brs,3H),4.09(q,J＝7.2Hz,2H),1.45(t,J＝6.8Hz,3H),1.11(d,J＝6.4Hz,6H)；ESI-MS m/z:386.20[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64 (s, 1H), 7.44 - 7.15 (m, 6H), 6.88 (s, 1H), 5.14 (s, 2H), 4.37 (brs, 3H) ), 4.09 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H), 1.11 (d, J = 6.4 Hz, 6H); ESI-MS m/z: 386.20 [M+H ] + .

c)5-((((苄氧基)羰基)(异丙基)氨基)甲基)-2-乙氧基苯甲酸c) 5-(((benzyloxy)carbonyl)(isopropyl)amino)methyl)-2-ethoxybenzoic acid

将5-((((苄氧基)羰基)(异丙基)氨基)甲基)-2-乙氧基苯甲酸甲酯(630mg,1.63mmol)溶于甲醇(20mL)/水(10mL)中，搅拌下加入NaOH(326mg,8.15mmol)，室温反应6h，浓缩，加入乙醚(20mL)洗涤水层，用盐酸调pH＝3，加入EA(25mL×3)萃取，浓缩得无色油状物533mg，收率为87.8％。Methyl 5-((((benzyloxy)))(isopropyl)amino)methyl)-2-ethoxybenzoate (630 mg, 1.63 mmol) was dissolved in methanol (20 mL) / water (10 mL) NaOH (326 mg, 8.15 mmol) was added with stirring, and the mixture was stirred at room temperature for 6 h, then concentrated, EtOAc (20 mL) 533 mg, the yield was 87.8%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.04(s,1H),7.53-7.11(m,7H),6.94(s,1H),5.12(brs,2H),4.69(s,1H),4.40(brs,2H),4.29(brs,2H),1.54(t,J＝6.0Hz,3H),1.11(d,J＝6.4Hz,6H)；ESI-MS m/z:370.17[M-H] -。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.04 (s, 1H), 7.53-7.11 (m, 7H), 6.94 (s, 1H), 5.12 (brs, 2H), 4.69 (s, 1H ), 4.40 (brs, 2H), 4.29 (brs, 2H), 1.54 (t, J = 6.0 Hz, 3H), 1.11 (d, J = 6.4 Hz, 6H); ESI-MS m/z: 370.17 [MH. ] - .

d)4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯甲基(异丙基)氨基甲酸苄酯d) Benzyl 4-ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)benzyl (isopropyl)carbamate

将5-((((苄氧基)羰基)(异丙基)氨基)甲基)-2-乙氧基苯甲酸(300mg,0.81mmol)溶于DCM(20mL)中，依次加入DIEA(157mg,1.22mmol)、HATU(400mg,1.05mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(169mg,0.89mmol)，氩气保护下，室温反应5h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得无色油状物303mg，收率为69.1％。 5-((((Benzyloxy)carbonyl)(isopropyl)amino)methyl)-2-ethoxybenzoic acid (300 mg, 0.81 mmol) was dissolved in DCM (20 mL). , 1.22 mmol), HATU (400 mg, 1.05 mmol), reacted at room temperature for 30 min, then added (3-(thiazol-2-yl)phenyl)methanamine (169 mg, 0.89 mmol). The raw materials disappeared. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether was purified in a volume ratio of 1:2 to obtain 303 mg of a colorless oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.42(brs,1H),8.13(s,1H),7.99(s,1H),7.89-7.86(m,2H),7.47-7.41(m,2H),7.30(brs,6H),6.84(s,1H),5.15(s,2H),4.73(d,J＝5.2Hz,2H),4.42(brs,3H),4.12(q,J＝6.8Hz,2H),1.32(t,J＝7.2Hz,3H),1.12(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 31H 33O 4N 3S 544.2265[M+H] +,Found:544.2259。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.42 (brs, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.89-7.86 (m, 2H), 7.47-7.41 (m) , 2H), 7.30 (brs, 6H), 6.84 (s, 1H), 5.15 (s, 2H), 4.73 (d, J = 5.2 Hz, 2H), 4.42 (brs, 3H), 4.12 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.12 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 31 H 33 O 4 N 3 S 544.2265 [M+H] + , Found: 544.2259.

实施例(化合物)48Example (compound) 48

2-乙氧基-5-((异丙基氨基)甲基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺·氢溴酸盐2-Ethoxy-5-((isopropylamino)methyl)-N-(3-(thiazol-2-yl)benzyl)benzamide hydrobromide

Figure PCTCN2018088561-appb-000108
Figure PCTCN2018088561-appb-000108

将4-乙氧基-3-((3-(噻唑-2-基)苯甲基)氨基甲酰)苯甲基(异丙基)氨基甲酸苄酯(80mg,0.15mmol)溶于乙醇(5mL)中，搅拌下加入HBr的乙酸溶液(30％)(1.0mL)，回流反应6h，浓缩，加入乙醚(20mL)析出红色固体，过滤得54mg，收率为75.0％，熔点：139-140℃。Benzyl 4-ethoxy-3-((3-(thiazol-2-yl)benzyl)carbamoyl)benzyl (isopropyl)carbamate (80 mg, 0.15 mmol) was dissolved in ethanol ( In 5 mL), an acetic acid solution (30%) (1.0 mL) of HBr was added under stirring, and the mixture was refluxed for 6 hr, concentrated, and then diethyl ether (20 mL) was added to precipitate a red solid, which was filtered to yield 54 mg, yield: 75.0%, melting point: 139-140 °C.

1H-NMR(400MHz,DMSO)δ(ppm):8.72(s,1H),8.63(s,2H),7.98(s,1H),7.94(s,2H),7.85(s,1H),7.81(s,1H),7.61(d,J＝7.6Hz,1H),7.49(s,2H),7.24(d,J＝7.6Hz,1H),4.62(s,2H),4.21(brs,2H),4.15(s,2H),3.32(brs,1H),1.34(brs,3H),1.28(d,J＝5.2Hz,6H)；HR-MS(ESI):m/z,calcd.For C 23H 27O 2N 3S 410.1897[M+H] +,Found:410.1886。 1 H-NMR (400MHz, DMSO ) δ (ppm): 8.72 (s, 1H), 8.63 (s, 2H), 7.98 (s, 1H), 7.94 (s, 2H), 7.85 (s, 1H), 7.81 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.49 (s, 2H), 7.24 (d, J = 7.6 Hz, 1H), 4.62 (s, 2H), 4.21 (brs, 2H) , 4.15 (s, 2H), 3.32 (brs, 1H), 1.34 (brs, 3H), 1.28 (d, J = 5.2 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 23 H 27 O 2 N 3 S 410.1897 [M+H] + , Found: 410.1886.

实施例(化合物)49Example (compound) 49

4-乙氧基-N 1-异丙基-N 3-(3-(噻唑-2-基)苯甲基)异酞酰胺 4-ethoxy-N 1 -isopropyl-N 3 -(3-(thiazol-2-yl)benzyl)isoindoleamide

Figure PCTCN2018088561-appb-000109
Figure PCTCN2018088561-appb-000109

a)2-乙氧基-5-(异丙基氨基甲酰)苯甲酸甲酯a) Methyl 2-ethoxy-5-(isopropylcarbamoyl)benzoate

将4-乙氧基-3-(甲氧羰基)苯甲酸(300mg,1.34mmol)溶于DCM(20mL)中，依次加入DIEA(260mg,2.01mmol)、HATU(764mg,2.01mmol)，室温反应30min后，加入异丙基胺(95mg,1.61mmol)，氩气保护下，室温反应5h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体311mg，收率为87.6％，熔点：107-108℃。 4-Ethoxy-3-(methoxycarbonyl)benzoic acid (300 mg, 1.34 mmol) was dissolved in DCM (20 mL) EtOAc (EtOAc, EtOAc. After 30 min, isopropylamine (95 mg, 1.61 mmol) was added, and the mixture was reacted under argon atmosphere for 5 h at room temperature. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 311 mg of white solid, yield: 87.6%, m.p.: 107-108.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.11(d,J＝2.4Hz,1H),7.96(dd,J＝8.8,2.4Hz,1H),6.99(d,J＝8.8Hz,1H),4.35-4.21(m,1H),4.16(q,J＝7.2Hz,2H),3.89(s,3H), 1.47(t,J＝7.2Hz,3H),1.25(t,J＝7.2Hz,6H)；ESI-MS m/z:266.14[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.11 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.8, 2.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.35-4.21 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2) Hz, 6H); ESI-MS m/z: 266.14 [M+H] + .

b)2-乙氧基-5-(异丙基氨基甲酰)苯甲酸b) 2-ethoxy-5-(isopropylcarbamoyl)benzoic acid

将2-乙氧基-5-(异丙基氨基甲酰)苯甲酸甲酯(310mg,1.17mmol)溶于甲醇(20mL)/水(10mL)中，搅拌下加入NaOH(234mg,5.85mmol)，室温反应6h，浓缩，加入乙醚(20mL)洗涤水层，用盐酸调pH＝3，析出固体，过滤，得白色固体239mg，收率为81.3％，熔点：175-176℃。Methyl 2-ethoxy-5-(isopropylcarbamoyl)benzoate (310 mg, 1.17 mmol) was dissolved in methanol (20 mL) / water (10 mL). The mixture was reacted at room temperature for 6 h, concentrated, and the aqueous layer was washed with diethyl ether (20 mL), and the mixture was adjusted to pH 3 with hydrochloric acid to precipitate a solid, which was filtered to give a white solid 239 mg,yield of 81.3%, melting point: 175-176 °C.

1H-NMR(400MHz,DMSO)δ(ppm):12.71(s,1H),8.21(d,J＝7.6Hz,1H),8.14(s,1H),7.97(d,J＝8.8Hz,1H),7.15(d,J＝8.8Hz,1H),4.14(q,J＝6.8Hz,2H),4.07(dt,J＝13.2,6.8Hz,1H),1.34(t,J＝6.8Hz,3H),1.15(d,J＝6.8Hz,6H)；ESI-MS m/z:250.11[M-H] -。 1 H-NMR (400 MHz, DMSO) δ (ppm): 12.71 (s, 1H), 8.21. (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H) ), 7.15 (d, J = 8.8 Hz, 1H), 4.14 (q, J = 6.8 Hz, 2H), 4.07 (dt, J = 13.2, 6.8 Hz, 1H), 1.34 (t, J = 6.8 Hz, 3H) ), 1.15 (d, J = 6.8 Hz, 6H); ESI-MS m/z: 250.11 [MH] - .

c)4-乙氧基-N 1-异丙基-N 3-(3-(噻唑-2-基)苯甲基)异酞酰胺 c) 4-Ethoxy-N 1 -isopropyl-N 3 -(3-(thiazol-2-yl)benzyl)isodecanoylamide

将2-乙氧基-5-(异丙基氨基甲酰)苯甲酸(200mg,0.80mmol)溶于DCM(20mL)中，依次加入DIEA(206mg,1.60mmol)、HATU(456mg,1.20mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(151mg,0.80mmol)，氩气保护下，室温反应5h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体232mg，收率为68.8％，熔点：132-133℃。 2-Ethoxy-5-(isopropylcarbamoyl)benzoic acid (200 mg, 0.80 mmol) was dissolved in DCM (20 mL) EtOAc (EtOAc) After reacting at room temperature for 30 min, (3-(thiazol-2-yl)phenyl)methanamine (151 mg, 0.80 mmol) was added, and the mixture was reacted under argon atmosphere for 5 h at room temperature. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 232 mg of white solid, yield 68.8%, m.p.: 132-133.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.48(d,J＝2.4Hz,1H),8.39(s,1H),8.10(dd,J＝8.4,2.4Hz,1H),8.00(s,1H),7.88-7.86(m,2H),7.46-7.42(m,2H),7.36(d,J＝3.6Hz,1H),7.02(d,J＝8.8Hz,1H),6.11(d,J＝7.2Hz,1H),4.74(d,J＝5.2Hz,2H),4.32-4.25(m,1H),4.21(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H),1.25(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 23H 25O 3N 3S 424.1689[M+H] +,Found:424.1673。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.48 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 8.10 (dd, J = 8.4, 2.4 Hz, 1H), 8.00 ( s, 1H), 7.88-7.86 (m, 2H), 7.46-7.42 (m, 2H), 7.36 (d, J = 3.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.11 (d) , J = 7.2 Hz, 1H), 4.74 (d, J = 5.2 Hz, 2H), 4.32-4.25 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz) , 3H), 1.25 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd. For C 23 H 25 O 3 N 3 S 424.1689 [M+H] + , Found: 424.1673 .

实施例(化合物)50Example (compound) 50

5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-bromo-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000110
Figure PCTCN2018088561-appb-000110

a)5-溴-2-乙氧基苯甲酸a) 5-bromo-2-ethoxybenzoic acid

将5-溴水杨酸(10g,46.00mmol)溶于无水DMF(20mL)中，依次加入K 2CO 3(12.70g,92.00mmol)、C 2H 5I(14.40g,92.00mmol)，加热至60℃反应10h，反应完毕冷却至室温，依次加入水(5mL)，NaOH(3.68g,92.00mmol)，继续搅拌反应2h，浓缩，加入盐酸调pH＝3，析出固体，过滤，得白色固体6.71g，收率为59.4％，熔点：128-130℃。 5-bromo-salicylic acid (10g, 46.00mmol) was dissolved in anhydrous DMF (20mL) added sequentially K 2 CO 3 (12.70g, 92.00mmol ), C 2 H 5 I (14.40g, 92.00mmol), The mixture was heated to 60 ° C for 10 h. After the reaction was cooled to room temperature, water (5 mL), NaOH (3.68 g, 92.00 mmol) was added successively, stirring was continued for 2 h, concentrated, hydrochloric acid was added to adjust pH = 3, solids were precipitated, and filtered to obtain white. The solid was 6.71 g, the yield was 59.4%, and the melting point was 128-130 °C.

1H-NMR(400MHz,DMSO)δ(ppm):12.88(s,1H),7.73-7.68(m,1H),7.63(dd,J＝8.8,1.6Hz,1H),7.09(d,J＝8.8Hz,1H),4.08(q,J＝6.8Hz,2H),1.31(t,J＝6.8Hz,3H)；ESI-MS m/z:242.97[M-H] -。 1 H-NMR (400 MHz, DMSO) δ (ppm): 12.88 (s, 1H), 7.73-7.68 (m, 1H), 7.63 (dd, J = 8.8, 1.6 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 4.08 (q, J = 6.8 Hz, 2H), 1.31 (t, J = 6.8 Hz, 3H); ESI-MS m/z: 242.97 [MH] - .

b)5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺b) 5-Bromo-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

将5-溴-2-乙氧基苯甲酸(360mg,1.89mmol)溶于DCM(20mL)中，依次加入DIEA(488mg,3.78mmol)、HATU(1.08g,2.84mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(463mg,1.89mmol)，室温反应10h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:5)纯化得白色固体609mg，收率为77.3％，熔点：104-105℃。 5-Bromo-2-ethoxybenzoic acid (360 mg, 1.89 mmol) was dissolved in DCM (20 mL), then DIEA (488 mg, 3.78 mmol), HATU (1.08 g, 2.84 mmol). (3-(thiazol-2-yl)phenyl)methanamine (463 mg, 1.89 mmol) was added, and the mixture was reacted at room temperature for 10 h. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate Ester-petroleum ether, volume ratio 2:5) was purified to give 609 mg of white solid,yield: 77.3%, m.p.: 104-105.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.36(s,1H),8.30(s,1H),7.98(s,1H),7.87(s,2H),7.50(d,J＝8.8Hz,1H),7.44(brs,2H),7.34(d,J＝2.4Hz,1H),6.82(d,J＝8.8Hz,1H),4.72(d,J＝5.2Hz,2H),4.12(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 19H 17O 2N 2BrS 417.0267[M+H] +,Found:417.0259。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.36 (s, 1H), 8.30 (s, 1H), 7.98 (s, 1H), 7.87 (s, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.44 (brs, 2H), 7.34 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.72 (d, J = 5.2 Hz, 2H), 4.12 ( q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 19 H 17 O 2 N 2 BrS 417.0267 [M+H ] + , Found: 417.0259.

实施例(化合物)51Example (compound) 51

5-(3,3-二氟吡咯烷-1-基)-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-(3,3-difluoropyrrolidin-1-yl)-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000111
Figure PCTCN2018088561-appb-000111

反应1：将3,3-二氟吡咯烷·三氟乙酸盐(265mg,1.20mmol)，Pd 2(dba) 3(22mg,0.024mmol)，BINAP(30mg,0.048mmol)，叔丁醇钠(58mg,5.25mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12mmol)加入至无水甲苯(25mL)中，氩气保护下，100℃反应5h。反应2：将3,3-二氟吡咯烷·三氟乙酸盐(2.28g, 10.30mmol)，Pd 2(dba) 3(183mg,0.20mmol)，BINAP(250mg,0.40mmol)，叔丁醇钠(495mg,5.15mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(430mg,1.03mmol)加入至无水甲苯(30mL)中，氩气保护下，100℃反应5h。合并反应1和2，加入DCM(30mL)稀释，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得浅黄色固体179mg，35.2％，熔点：124-125℃。 Reaction 1: 3,3-difluoropyrrolidine·trifluoroacetate (265 mg, 1.20 mmol), Pd 2 (dba) 3 (22 mg, 0.024 mmol), BINAP (30 mg, 0.048 mmol), sodium tert-butoxide (58 mg, 5.25 mmol), 5-bromo-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol). The reaction was carried out at 100 ° C for 5 h under argon gas protection. Reaction 2: 3,3-difluoropyrrolidine·trifluoroacetate (2.28 g, 10.30 mmol), Pd 2 (dba) 3 (183 mg, 0.20 mmol), BINAP (250 mg, 0.40 mmol), tert-butanol Sodium (495 mg, 5.15 mmol), 5-bromo-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (430 mg, 1.03 mmol). In the argon atmosphere, the reaction was carried out at 100 ° C for 5 h. The combined reaction 1 and 2, was added DCM (30mL) diluted with saturated brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 2) to give a pale yellow solid 179mg , 35.2%, melting point: 124-125 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.59(s,1H),7.98(s,1H),7.89-7.86(m,2H),7.50(d,J＝3.2Hz,1H),7.49-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.89(d,J＝8.8Hz,1H),6.63(dd,J＝8.8,3.2Hz,1H),4.73(d,J＝5.6Hz,2H),4.07(q,J＝7.2Hz,2H),3.67(t,J＝13.2Hz,2H),3.52(t,J＝7.2Hz,2H),2.54-2.43(m,2H),1.29(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 23H 23O 2N 3F 2S 444.1552[M+H] +,Found:444.1535。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.59 (s, 1H), 7.98 (s, 1H), 7.89-7.86 (m, 2H), 7.50 (d, J = 3.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 8.8, 3.2 Hz, 1H), 4.73 (d , J=5.6Hz, 2H), 4.07(q, J=7.2Hz, 2H), 3.67(t, J=13.2Hz, 2H), 3.52(t, J=7.2Hz, 2H), 2.54-2.43(m , 2H), 1.29 (t, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 23 H 23 O 2 N 3 F 2 S 444.1552 [M+H] + ,Found :444.1535.

实施例(化合物)52Example (compound) 52

5-(4,4-二氟哌啶-1-基)-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-(4,4-Difluoropiperidin-1-yl)-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000112
Figure PCTCN2018088561-appb-000112

反应1：将4,4-二氟哌啶·盐酸盐(189mg,1.20mmol)，Pd 2(dba) 3(22mg,0.024mmol)，BINAP(30mg,0.048mmol)，叔丁醇钠(115mg,1.20mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12mmol)加入至无水甲苯(25mL)中，氩气保护下，90℃反应5h。反应2：将4,4-二氟哌啶·盐酸盐(756mg,4.80mmol)，Pd 2(dba) 3(220mg,0.24mmol)，BINAP(299mg,0.48mmol)，叔丁醇钠(1.15g,12.0mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(500mg,1.20mmol)加入至无水甲苯(30mL)中，氩气保护下，90℃反应5h。合并反应1和2，加入DCM(30mL)稀释，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得浅黄色固体149mg，24.8％，熔点：130-131℃。 Reaction 1: 4,4-Difluoropiperidine hydrochloride (189 mg, 1.20 mmol), Pd 2 (dba) 3 (22 mg, 0.024 mmol), BINAP (30 mg, 0.048 mmol), sodium tert-butoxide (115 mg) , 1.20 mmol), 5-bromo-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol). The reaction was carried out at 90 ° C for 5 h under argon gas protection. Reaction 2: 4,4-Difluoropiperidine hydrochloride (756 mg, 4.80 mmol), Pd 2 (dba) 3 (220 mg, 0.24 mmol), BINAP (299 mg, 0.48 mmol), sodium tert-butoxide (1.15) g, 12.0 mmol), 5-bromo-2-ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (500 mg, 1.20 mmol). Under argon protection, react at 90 ° C for 5 h. The combined reaction 1 and 2, was added DCM (30mL) diluted with saturated brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 2) to give a pale yellow solid 149mg , 24.8%, melting point: 130-131 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.52(s,1H),7.98(s,1H),7.87(dd,J＝6.8,3.2Hz,3H),7.51-7.39(m,2H),7.34(d,J＝3.2Hz,1H),7.02(dd,J＝8.8,3.2Hz,1H),6.88(d,J＝8.8Hz,1H),4.73(d,J＝5.6Hz,2H),4.09(q,J＝7.2Hz,2H),3.37-3.22(m,4H),2.15-2.05(m,4H),1.30(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For  C 23H 23O 2N 3F 2S 444.1552[M+H] +,Found:444.1535。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.52 (s, 1H), 7.78 (s, 1H), 7.78 (dd, J = 6.8, 3.2 Hz, 3H), 7.51-7.39 (m, 2H) ), 7.34 (d, J = 3.2 Hz, 1H), 7.02 (dd, J = 8.8, 3.2 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.73 (d, J = 5.6 Hz, 2H) ), 4.09 (q, J = 7.2 Hz, 2H), 3.37 - 3.22 (m, 4H), 2.15 - 2.05 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H); HR-MS (ESI) : m/z,calcd.For C 23 H 23 O 2 N 3 F 2 S 444.1552 [M+H] + , Found: 444.1535.

实施例(化合物)53Example (compound) 53

2-乙氧基-5-(吡啶-4-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(pyridin-4-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000113
Figure PCTCN2018088561-appb-000113

反应1：将4-吡啶硼酸(148mg,1.2mmol)，Pd(PPh 3) 4(14mg,0.012mmol)，Na 2CO 3(64mg,0.6mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12mmol)加入至二氧六环(10mL)/水(3mL)中，氩气保护下，100℃反应5h。反应2：将4-吡啶硼酸(886mg,7.20mmol)，Pd(PPh 3) 4(83mg,0.072mmol)，Na 2CO 3(763mg,7.20mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(300mg,0.72mmol)加入至二氧六环(30mL)/水(8mL)中，氩气保护下，100℃反应5h。合并反应1和2，浓缩，加入EA(30mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(丙酮-石油醚，体积比1:2)纯化得浅黄色固体233mg，66.6％，熔点：167-168℃。 Reaction 1: 4-pyridineboronic acid (148 mg, 1.2 mmol), Pd(PPh 3 ) 4 (14 mg, 0.012 mmol), Na 2 CO 3 (64 mg, 0.6 mmol), 5-bromo-2-ethoxy-N -(3-(thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol) was added to dioxane (10 mL) / water (3 mL). Reaction 2: 4-pyridineboronic acid (886 mg, 7.20 mmol), Pd(PPh 3 ) 4 (83 mg, 0.072 mmol), Na 2 CO 3 (763 mg, 7.20 mmol), 5-bromo-2-ethoxy-N -(3-(thiazol-2-yl)benzyl)benzamide (300 mg, 0.72 mmol) was added to dioxane (30 mL) / water (8 mL). 1 and 2, reactions were combined, concentrated, and EA (30mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (acetone - petroleum ether, the volume ratio of 1: 2) to give 233 mg as a pale yellow solid, 66.6%, melting point: 167-168 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.65(d,J＝5.6Hz,2H),8.61(d,J＝2.4Hz,1H),8.39(s,1H),8.01(s,1H),7.90-7.87(m,2H),7.74(dd,J＝8.8,2.4Hz,1H),7.56(d,J＝5.6Hz,2H),7.49-7.43(m,2H),7.35(d,J＝3.2Hz,1H),7.07(d,J＝8.8Hz,1H),4.76(d,J＝5.4Hz,2H),4.22(q,J＝6.8Hz,2H),1.38(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 24H 21O 2N 3S 416.1427[M+H] +,Found:416.1417。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.65 (d, J = 5.6Hz, 2H), 8.61 (d, J = 2.4Hz, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.90-7.87 (m, 2H), 7.74 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (d, J = 5.6 Hz, 2H), 7.49 - 7.43 (m, 2H), 7.35 (d) , J = 3.2 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.76 (d, J = 5.4 Hz, 2H), 4.22 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.8Hz, 3H); HR- MS (ESI): m / z, calcd.For C 24 H 21 O 2 N 3 S 416.1427 [m + H] +, Found: 416.1417.

实施例(化合物)54Example (compound) 54

2-乙氧基-5-(吡啶-3-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(pyridin-3-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000114
Figure PCTCN2018088561-appb-000114

反应1：将3-吡啶硼酸(148mg,1.2mmol)，Pd(PPh 3) 4(14mg,0.012mmol)，Na 2CO 3(64mg,0.6mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12 mmol)加入至二氧六环(10mL)/水(3mL)中，氩气保护下，100℃反应5h。反应2：将3-吡啶硼酸(886mg,7.20mmol)，Pd(PPh 3) 4(83mg,0.072mmol)，Na 2CO 3(763mg,7.20mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(300mg,0.72mmol)加入至二氧六环(30mL)/水(8mL)中，氩气保护下，100℃反应5h。合并反应1和2，浓缩，加入EA(30mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(丙酮-石油醚，体积比1:2)纯化得浅黄色固体217mg，62.0％，熔点：121-122℃。 Reaction 1: 3-pyridineboronic acid (148 mg, 1.2 mmol), Pd(PPh 3 ) 4 (14 mg, 0.012 mmol), Na 2 CO 3 (64 mg, 0.6 mmol), 5-bromo-2-ethoxy-N -(3-(thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol) was added to dioxane (10 mL) / water (3 mL). Reaction 2: 3-pyridineboronic acid (886 mg, 7.20 mmol), Pd(PPh 3 ) 4 (83 mg, 0.072 mmol), Na 2 CO 3 (763 mg, 7.20 mmol), 5-bromo-2-ethoxy-N -(3-(thiazol-2-yl)benzyl)benzamide (300 mg, 0.72 mmol) was added to dioxane (30 mL) / water (8 mL). 1 and 2, reactions were combined, concentrated, and EA (30mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (acetone - petroleum ether, the volume ratio of 1: 2) to give 217 mg as a pale yellow solid, 62.0%, melting point: 121-122 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.86(s,1H),8.57(d,J＝4.0Hz,1H),8.52(d,J＝2.4Hz,1H),8.41(s,1H),8.01(s,1H),7.93-7.86(m,2H),7.66(dd,J＝8.8,2.4Hz,1H),7.47-7.42(m,2H),7.37-7.34(m,2H),7.06(d,J＝8.8Hz,1H),4.76(d,J＝5.6Hz,2H),4.21(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 24H 21O 2N 3S 416.1427[M+H] +,Found:416.1419。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.86 (s, 1H), 8.57 (d, J = 4.0Hz, 1H), 8.52 (d, J = 2.4Hz, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.93-7.86 (m, 2H), 7.66 (dd, J = 8.8, 2.4 Hz, 1H), 7.47-7.42 (m, 2H), 7.37-7.34 (m, 2H) , 7.06 (d, J = 8.8 Hz, 1H), 4.76 (d, J = 5.6 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); HR - MS (ESI): m/z, calcd. For C 24 H 21 O 2 N 3 S 416.1427 [M+H] + , Found: 416.1419.

实施例(化合物)55Example (compound) 55

2-乙氧基-5-(1H-吡唑-5-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(1H-pyrazol-5-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000115
Figure PCTCN2018088561-appb-000115

反应1：将(1H-吡唑-5-基)硼酸(27mg,0.24mmol)，Pd(PPh 3) 4(28mg,0.024mmol)，Na 2CO 3(64mg,0.6mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12mmol)加入至二氧六环(10mL)/水(3mL)中，氩气保护下，100℃反应5h。反应2：将(1H-吡唑-5-基)硼酸(161mg,1.44mmol)，Pd(PPh 3) 4(166mg,0.144mmol)，Na 2CO 3(382mg,3.60mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(300mg,0.72mmol)加入至二氧六环(30mL)/水(8mL)中，氩气保护下，100℃反应5h。合并反应1和2，浓缩，加入EA(30mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-二氯甲烷-甲醇，体积比15:15:1)纯化得浅黄色固体177mg，52.2％，熔点：192-193℃。 Reaction 1: (1H-pyrazol-5-yl)boronic acid (27 mg, 0.24 mmol), Pd(PPh 3 ) 4 (28 mg, 0.024 mmol), Na 2 CO 3 (64 mg, 0.6 mmol), 5-bromo- 2-Ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol) was added to dioxane (10 mL) / water (3 mL). The reaction was carried out at 100 ° C for 5 h. Reaction 2: (1H-pyrazol-5-yl)boronic acid (161 mg, 1.44 mmol), Pd(PPh 3 ) 4 (166 mg, 0.144 mmol), Na 2 CO 3 (382 mg, 3.60 mmol), 5-bromo- 2-Ethoxy-N-(3-(thiazol-2-yl)benzyl)benzamide (300 mg, 0.72 mmol) was added to dioxane (30 mL) / water (8 mL). The reaction was carried out at 100 ° C for 5 h. 1 and 2, reactions were combined, concentrated, and EA (30mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - dichloromethane - methanol, a volume ratio of 15: 15: 1) Purified pale yellow solid 177 mg, 52.2%, m.p.: 192-193.

1H-NMR(400MHz,DMSO)δ(ppm):12.83(s,1H),8.72(s,1H),8.15(s,1H),7.98(s,1H),7.93(brs,1H),7.85-7.76(m,3H),7.50-7.46(m,2H),7.17(d,J＝7.6Hz,1H),6.66(s,1H),4.60(d,J＝5.6Hz,2H),4.18(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)； HR-MS(ESI):m/z,calcd.For C 22H 20O 2N 4S 405.1380[M+H] +,Found:405.1371。 1 H-NMR (400MHz, DMSO ) δ (ppm): 12.83 (s, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.93 (brs, 1H), 7.85 -7.76 (m, 3H), 7.50-7.46 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.18 ( q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 22 H 20 O 2 N 4 S 405.1380 [M+H ] + , Found: 405.1371.

实施例(化合物)56Example (compound) 56

2-乙氧基-5-(1H-咪唑-1-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(1H-imidazol-1-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000116
Figure PCTCN2018088561-appb-000116

反应1：将咪唑(82mg,1.20mmol)，1,10-phenanthroline(216mg,1.20mmol)，K 2CO 3(166mg,1.20mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12mmol)，CuI(228mg,1.2mmol)加入至无水DMF(10mL)中，氩气保护下，120℃反应8h。反应1：将咪唑(653mg,9.6mmol)，1,10-phenanthroline(1.73g,9.6mmol)，K 2CO 3(1.32g,9.6mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(400mg,0.96mmol)，CuI(1.82g,9.6mmol)溶于无水DMF(20mL)中，氩气保护下，120℃反应8h，合并反应1和2，浓缩，加入EA(30mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-二氯甲烷-甲醇，体积比25:25:1)纯化得白色固体245mg，56.1％，熔点：136-137℃。 Reaction 1: Imidazole (82 mg, 1.20 mmol), 1,10-phenanthroline (216 mg, 1.20 mmol), K 2 CO 3 (166 mg, 1.20 mmol), 5-bromo-2-ethoxy-N-(3- (thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol), EtOAc (EtOAc, EtOAc) Reaction 1: Imidazole (653 mg, 9.6 mmol), 1,10-phenanthroline (1.73 g, 9.6 mmol), K 2 CO 3 (1.32 g, 9.6 mmol), 5-bromo-2-ethoxy-N- ( 3-(thiazol-2-yl)benzyl)benzamide (400 mg, 0.96 mmol), CuI (1.82 g, 9.6 mmol) dissolved in anhydrous DMF (20 mL). , reaction of 1 and 2 were combined, concentrated, and EA (30mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - dichloromethane - methanol, a volume ratio of 25: 25: 1 Purified white solid 245 mg, 56.1%, m.p.: 136-137.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.41(s,1H),8.32(d,J＝2.8Hz,1H),8.01(s,1H),7.89-7.85(m,3H),7.46-7.43(m,3H),7.35(d,J＝3.2Hz,1H),7.29(s,1H),7.20(s,1H),7.05(d,J＝8.8Hz,1H),4.75(d,J＝5.6Hz,2H),4.20(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 20O 2N 4S 405.1380[M+H] +,Found:405.1363。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.41 (s, 1H), 8.32 (d, J = 2.8Hz, 1H), 8.01 (s, 1H), 7.89-7.85 (m, 3H), 7.46-7.43 (m, 3H), 7.35 (d, J = 3.2 Hz, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 7.05 (d, J = 8.8 Hz, 1H), 4.75 (d) , J = 5.6 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, cald. For C 22 H 20 O 2 N 4 S 405.1380 [M+H] + , Found: 405.1363.

实施例(化合物)57Example (compound) 57

2-乙氧基-5-(1H-吡唑-4-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(1H-pyrazol-4-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000117
Figure PCTCN2018088561-appb-000117

反应1：将4-吡唑硼酸频哪酯(47mg,0.24mmol)，Pd(PPh 3) 4(28mg,0.024mmol)，Na 2CO 3(51mg,0.48mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50 mg,0.12mmol)加入至二氧六环(10mL)/水(3mL)中，氩气保护下，100℃反应7h。反应2：将4-吡唑硼酸频哪酯(282mg,1.44mmol)，Pd(PPh 3) 4(166mg,0.144mmol)，Na 2CO 3(306mg,2.88mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(300mg,0.72mmol)加入至二氧六环(30mL)/水(8mL)中，氩气保护下，100℃反应5h。合并反应1和2，浓缩，加入EA(30mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-二氯甲烷-甲醇，体积比15:15:1)纯化得浅黄色固体179mg，53.3％，熔点：159-160℃。 Reaction 1: 4-pyrazoleboronic acid pinacol ester (47 mg, 0.24 mmol), Pd(PPh 3 ) 4 (28 mg, 0.024 mmol), Na 2 CO 3 (51 mg, 0.48 mmol), 5-bromo-2-ethyl Oxy-N-(3-(thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol) was added to dioxane (10 mL) / water (3 mL). The reaction was carried out at 100 ° C for 7 h. Reaction 2: 4-pyrazoleboronic acid pinacol ester (282 mg, 1.44 mmol), Pd(PPh 3 ) 4 (166 mg, 0.144 mmol), Na 2 CO 3 (306 mg, 2.88 mmol), 5-bromo-2-ethyl Oxy-N-(3-(thiazol-2-yl)benzyl)benzamide (300 mg, 0.72 mmol) was added to dioxane (30 mL) / water (8 mL). °C reaction for 5h. 1 and 2, reactions were combined, concentrated, and EA (30mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - dichloromethane - methanol, a volume ratio of 15: 15: 1) Purified to pale yellow solid 179 mg, 53.3%, m.p.: 159-160.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.46(s,1H),8.39(d,J＝2.0Hz,1H),8.00(s,1H),7.87(s,4H),7.56(dd,J＝8.0,2.0Hz,1H),7.48-7.42(m,2H),7.34(d,J＝3.2Hz,1H),6.96(d,J＝8.0Hz,1H),4.76(d,J＝5.6Hz,2H),4.16(q,J＝7.2Hz,2H),1.34(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 20O 2N 4S 405.1380[M+H] +,Found:405.1372。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.46 (s, 1H), 8.39 (d, J = 2.0Hz, 1H), 8.00 (s, 1H), 7.87 (s, 4H), 7.56 ( Dd, J = 8.0, 2.0 Hz, 1H), 7.48-7.42 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.76 (d, J) = 5.6 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); HR-MS (ESI): m/z, cald. For C 22 H 20 O 2 N 4 S 405.1380 [M+H] + , Found: 405.1372.

实施例(化合物)58Example (compound) 58

2-乙氧基-5-(1H-吡唑-1-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(1H-pyrazol-1-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000118
Figure PCTCN2018088561-appb-000118

反应1：将吡唑(82mg,1.20mmol)，乙酰丙酮合铁(424mg,1.20mmol)，Cs 2CO 3(391mg,1.20mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(50mg,0.12mmol)，CuO(95mg,1.20mmol)加入至无水DMF(10mL)中，氩气保护下，90℃反应12h。反应2：将吡唑(490mg,7.2mmol)，乙酰丙酮合铁(1.25g,3.60mmol)，Cs 2CO 3(2.35g,7.20mmol)，5-溴-2-乙氧基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(300mg,0.72mmol)，CuO(282mg,3.6mmol)加入至无水DMF(20mL)中，氩气保护下，90℃反应12h，合并反应1和2，浓缩，加入EA(30mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(石油醚-丙酮，体积比7:1)纯化得白色固体58mg，17.2％，熔点：108-109℃。 Reaction 1: Pyrazole (82 mg, 1.20 mmol), iron acetylacetonate (424 mg, 1.20 mmol), Cs 2 CO 3 (391 mg, 1.20 mmol), 5-bromo-2-ethoxy-N-(3- (thiazol-2-yl)benzyl)benzamide (50 mg, 0.12 mmol), EtOAc (EtOAc, m. Reaction 2: Pyrazole (490 mg, 7.2 mmol), iron acetylacetonate (1.25 g, 3.60 mmol), Cs 2 CO 3 (2.35 g, 7.20 mmol), 5-bromo-2-ethoxy-N- ( 3-(thiazol-2-yl)benzyl)benzamide (300 mg, 0.72 mmol), EtOAc (EtOAc) 1 and 2, reactions were combined, concentrated, and EA (30mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (petroleum ether - acetone, volume ratio 7: 1) to give a white solid 58mg, 17.2 %, melting point: 108-109 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.78(brs,1H),8.46(s,1H),8.12(d,J＝2.4Hz,1H),7.98(s,1H),7.93(d,J＝3.2Hz,1H),7.89(dd,J＝8.8,2.4Hz,1H),7.85(d,J＝6.4Hz,1H),7.79(d,J＝2.8Hz,1H),7.72(s,1H),7.54-7.45(m,2H),7.26(d,J＝8.8 Hz,1H),6.52(s,1H),4.61(d,J＝6.0Hz,2H),4.20(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 20O 2N 4S 405.1380[M+H] +,Found:405.1369。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.78 (brs, 1H), 8.46 (s, 1H), 8.12 (d, J = 2.4Hz, 1H), 7.98 (s, 1H), 7.93 ( d, J = 3.2 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.85 (d, J = 6.4 Hz, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.72 ( s, 1H), 7.54-7.45 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 6.52 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.20 (q, J) = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H); HR-MS (ESI): m/z, calcd. For C 22 H 20 O 2 N 4 S 405.1380 [M+H] + , Found: 405.1369.

实施例(化合物)59Example (compound) 59

2-乙氧基-5-(1H-咪唑-2-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(1H-imidazol-2-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000119
Figure PCTCN2018088561-appb-000119

a)2-乙氧基-5-(1H-咪唑-2-基)苯甲酸甲酯a) Methyl 2-ethoxy-5-(1H-imidazol-2-yl)benzoate

将2-乙氧基-5-甲酰基苯甲酸甲酯(500mg,2.40mmol)溶于甲醇(25mL)中，加入乙二醛(6.96g,120mmol)，室温搅拌下，逐滴加入NH3·H2O(4.20g,120mmol)，继续反应12h，停止反应。加入水(20mL)稀释，EA(30mL×3)萃取，饱和食盐水(20mL)洗有机相，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-二氯甲烷-甲醇，体积比15:15:1)纯化得微黄固体67mg，收率为10.3％，熔点：149-150℃。 Methyl 2-ethoxy-5-formylbenzoate (500 mg, 2.40 mmol) was dissolved in methanol (25 mL), then glydialdehyde (6.96 g, 120 mmol) was added, and the mixture was stirred at room temperature and NH3·H2O was added dropwise. (4.20 g, 120 mmol), the reaction was continued for 12 h and the reaction was stopped. Dilution was added water (20mL), (30mL × 3 ) extracted with EA, saturated brine (20mL) The organic phase was washed, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - dichloromethane - methanol, a volume ratio of 15: 15:1) Purified to give a yellowish solid, 67 mg, yield 10.3%, m.p.: 149-150.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.21(d,J＝2.0Hz,1H),8.02(dd,J＝8.8,1.6Hz,1H),7.13(s,2H),6.97(d,J＝8.8Hz,1H),4.12(q,J＝6.8Hz,2H),3.85(s,3H),1.45(t,J＝7.2Hz,3H)；ESI-MS m/z:247.11[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.21. (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 8.8, 1.6 Hz, 1H), 7.13 (s, 2H), 6.97 ( d, J = 8.8 Hz, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.85 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 247.11 [ M+H] + .

b)2-乙氧基-5-(1H-咪唑-2-基)苯甲酸b) 2-ethoxy-5-(1H-imidazol-2-yl)benzoic acid

反应1：将2-乙氧基-5-(1H-咪唑-2-基)苯甲酸甲酯(50mg,0.20mmol)溶于甲醇(15mL)/水(5mL)中，搅拌下加入NaOH(40mg,1.00mmol)，室温反应6h，浓缩，加入水(5mL)稀释，乙醚(20mL)洗涤水层，水层用盐酸调pH＝3，析出固体，得微褐色固体23mg，收率为48.9％。反应2：将2-乙氧基-5-(1H-咪唑-2-基)苯甲酸甲酯(70mg,0.28mmol)溶于甲醇(15mL)/水(5mL)中，搅拌下加入NaOH(56mg,1.40mmol)，室温反应6h，浓缩，加入水(5mL)稀释，乙醚(20mL)洗涤水层，水层用盐酸调pH＝3，析出固体，得微褐色固体41mg，收率为62.1％，熔点：261-262℃。Reaction 1: Methyl 2-ethoxy-5-(1H-imidazol-2-yl)benzoate (50 mg, 0.20 mmol) was dissolved in methanol (15 mL) / water (5 mL). The mixture was concentrated at room temperature for 6 h, concentrated, diluted with water (5 mL), and the aqueous layer was washed with diethyl ether (20 mL), and the aqueous layer was adjusted to pH 3 with hydrochloric acid to give a solid. Reaction 2: Methyl 2-ethoxy-5-(1H-imidazol-2-yl)benzoate (70 mg, 0.28 mmol) was dissolved in methanol (15 mL) / water (5 mL). , 1.40 mmol), reacted at room temperature for 6 h, concentrated, diluted with water (5 mL), and the aqueous layer was washed with diethyl ether (20 mL), and the aqueous layer was adjusted to pH 3 with hydrochloric acid to give a solid solid, 41 mg, yield 62.1%. Melting point: 261-262 °C.

1H-NMR(400MHz,DMSO)δ(ppm):8.42(brs,2H),7.72(s,2H),7.39(d,J＝8.8Hz,1H),4.22(q,J＝6.8Hz,2H),1.36(t,J＝6.8Hz,3H)；ESI-MS m/z:231.08[M-H] -。 1 H-NMR (400MHz, DMSO ) δ (ppm): 8.42 (brs, 2H), 7.72 (s, 2H), 7.39 (d, J = 8.8Hz, 1H), 4.22 (q, J = 6.8Hz, 2H ), 1.36 (t, J = 6.8 Hz, 3H); ESI-MS m/z: 231.08 [MH] - .

c)2-乙氧基-5-(1H-咪唑-2-基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-ethoxy-5-(1H-imidazol-2-yl)-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-(1H-咪唑-2-基)苯甲酸(50mg,0.22mmol)溶于DCM(10mL)中，加入DIEA(43mg,0.33mmol)，加入HATU(110mg,0.29mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(46mg,0.24mmol)，氩气保护下，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-二氯甲烷-甲醇，体积比15:15:1)纯化得17mg，收率为19.5％，熔点：240-241℃。 2-Ethoxy-5-(1H-imidazol-2-yl)benzoic acid (50 mg, 0.22 mmol) was dissolved in DCM (10 mL), DIEA (43 mg, 0.33 mmol) was added, and HATU (110 mg, 0.29 mmol) After reacting for 30 min at room temperature, (3-(thiazol-2-yl)phenyl)methanamine (46 mg, 0.24 mmol) was added, and the mixture was reacted under argon atmosphere for 8 h at room temperature, and the material disappeared. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-dichloromethane-methanol was used to purify 17 mg in a volume ratio of 15:15:1. The yield was 19.5% and the melting point was 240-241 °C.

1H-NMR(400MHz,DMSO)δ(ppm):12.44(s,1H),8.71(brs,1H),8.27(s,1H),7.98(brs,2H),7.91(d,J＝3.2Hz,1H),7.83(d,J＝6.4Hz,1H),7.77(d,J＝3.2Hz,1H),7.53-7.42(m,2H),7.20(d,J＝8.8Hz,1H),7.16(s,1H),6.96(s,1H),4.59(d,J＝6.0Hz,2H),4.18(q,J＝6.8Hz,2H),1.31(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C 22H 20O 2N 4S 405.1380[M+H] +,Found:405.1368。 1 H-NMR (400MHz, DMSO ) δ (ppm): 12.44 (s, 1H), 8.71 (brs, 1H), 8.27 (s, 1H), 7.98 (brs, 2H), 7.91 (d, J = 3.2Hz , 1H), 7.83 (d, J = 6.4 Hz, 1H), 7.77 (d, J = 3.2 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 6.96 (s, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.18 (q, J = 6.8 Hz, 2H), 1.31 (t, J = 6.8 Hz, 3H); HR - MS (ESI): m/z, calcd. For C 22 H 20 O 2 N 4 S 405.1380 [M+H] + , Found: 405.1368.

实施例(化合物)60Example (compound) 60

2-乙氧基-5-(N-甲基异丁酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-(N-methylisobutyrylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000120
Figure PCTCN2018088561-appb-000120

a)2-乙氧基-5-异丁酰氨基苯甲酸甲酯a) Methyl 2-ethoxy-5-isobutyrylaminobenzoate

将5-氨基-2-乙氧基苯甲酸甲酯(300mg,1.54mmol)溶于无水THF(15mL)中，冰浴下依次加入TEA(622mg,6.16mmol)，异丁酰氯(328mg,3.08mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，HCl(0.5N)水溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化得白色固体337mg，收率为82.8％，熔点：88-89℃。 Methyl 5-amino-2-ethoxybenzoate (300 mg, 1.54 mmol) was dissolved in anhydrous THF (15 mL). EtOAc (EtOAc, EtOAc. mmol), the reaction was continued IH, filtered and the filtrate was concentrated, diluted with ethyl acetate was added (20mL), HCl (0.5N) aqueous solution (10 mL) washed saturated NaHCO 3 (10mL) wash, water (10mL) washed saturated brine ( It was washed with anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:3) to yield 337 mg of white solid,yield of 82.8%, melting point: 88-89 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.78(d,J＝6.8Hz,2H),7.22(s,1H),6.92(d,J＝9.6Hz,1H),4.09(q,J＝7.2Hz,2H),3.87(s,3H),2.51-2.46(m,1H),1.43(t,J＝7.2Hz,3H),1.24(d,J＝6.8Hz,6H)；ESI-MS m/z:266.14[M+H] +。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.78 (d, J = 6.8 Hz, 2H), 7.22 (s, 1H), 6.92 (d, J = 9.6 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 2.51-2.46 (m, 1H), 1.43 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H); MS m/z: 266.14 [M+H] + .

b)2-乙氧基-5-异丁酰氨基苯甲酸b) 2-ethoxy-5-isobutyrylaminobenzoic acid

将2-乙氧基-5-异丁酰氨基苯甲酸甲酯(300mg,1.13mmol)溶于无水DMF(10mL) 中，加入NaH(54mg,2.26mmol)，室温反应20min，加入CH 3I(160mg,1.13mmol)，继续反应4h，原料反应完毕，然后依次加入NaOH(226mg,5.65mmol)，水(5mL)搅拌反应1h。用盐酸调pH＝3，EA(25mL×2)萃取，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，浓缩得白色固体238mg，收率为79.3％，熔点：98-99℃。 The amido ethoxy-5-isobutoxy benzoic acid methyl ester (300mg, 1.13mmol) was dissolved in anhydrous DMF (10mL) was added NaH (54mg, 2.26mmol), stirred at rt for 20min, was added CH 3 I (160 mg, 1.13 mmol), the reaction was continued for 4 h, the reaction of the starting material was completed, then NaOH (226 mg, 5.65 mmol) was added sequentially, and water (5 mL) was stirred for 1 h. 98-99 ℃: 3, EA (25mL × 2) and extracted, washed with brine (20 mL), dried over anhydrous Na 2 SO 4, and concentrated to give a white solid 238 mg, 79.3% yield, m.p. adjusted with hydrochloric acid pH =.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.04(s,1H),7.38(d,J＝7.6Hz,1H),7.09(d,J＝8.0Hz,1H),4.37(q,J＝6.8Hz,2H),3.23(s,3H),2.43(s,1H),1.60(t,J＝6.8Hz,3H),1.02(d,J＝6.0Hz,6H)；ESI-MS m/z:264.12[M-H] -。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.04 (s, 1H), 7.38 (d, J = 7.6Hz, 1H), 7.09 (d, J = 8.0Hz, 1H), 4.37 (q, J=6.8 Hz, 2H), 3.23 (s, 3H), 2.43 (s, 1H), 1.60 (t, J = 6.8 Hz, 3H), 1.02 (d, J = 6.0 Hz, 6H); ESI-MS m /z:264.12[MH] - .

c)2-乙氧基-5-(N-甲基异丁酰氨基)-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-ethoxy-5-(N-methylisobutyrylamino)-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(150mg,0.57mmol)溶于DCM(15mL)中，依次加入DIEA(111mg,0.86mmol)，HATU(258mg,0.68mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(108mg,0.57mmol)，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得白色固体185mg，收率为74.9％，熔点：96-97℃。 2-Ethoxy-5-isobutyrylaminobenzoic acid (150 mg, 0.57 mmol) was dissolved in DCM (15 mL). EtOAc (EtOAc, EtOAc. Then, (3-(thiazol-2-yl)phenyl)methanamine (108 mg, 0.57 mmol) was added, and the mixture was reacted at room temperature for 8 h, and the material disappeared. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether, volume ratio 1:2) was purified to give 185 mg of a white solid,yield of 74.9%, m.p.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.40(s,1H),8.12(s,1H),8.01(s,1H),7.88(brs,2H),7.47(brs,2H),7.36(s,1H),7.24(s,1H),6.98(d,J＝8.8Hz,1H),4.74(d,J＝5.2Hz,2H),4.19(q,J＝6.8Hz,2H),3.24(s,3H),2.52-2.45(m,1H),1.37(t,J＝6.8Hz,3H),1.03(d,J＝6.4Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 3N 3S 438.1846[M+H] +,Found:438.1848。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.40 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.88 (brs, 2H), 7.47 (brs, 2H), 7.36(s,1H), 7.24(s,1H), 6.98(d,J=8.8Hz,1H), 4.74(d,J=5.2Hz,2H), 4.19(q,J=6.8Hz,2H), 3.24 (s, 3H), 2.52-2.45 (m, 1H), 1.37 (t, J = 6.8 Hz, 3H), 1.03 (d, J = 6.4 Hz, 6H); HR-MS (ESI): m/z ,calcd.For C 24 H 27 O 3 N 3 S 438.1846 [M+H] + , Found: 438.1848.

实施例(化合物)61Example (compound) 61

2-乙氧基-5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000121
Figure PCTCN2018088561-appb-000121

将2-乙氧基-5-异丁酰氨基苯甲酸(125mg,0.5mmol)加入无水DMF(15mL)，加入EDC(192mg,1.0mmol)，加入HOBt(135mg,1.0mmol)和DIEA(0.22mL,1.25mmol)，加入1-(3-(噻唑-2-基)苯基)乙胺(128mg,0.625mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯30mL×2萃取，合并有机层用饱和NaCl 30mL×2洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1)，得到白色固体190mg，产率84％。熔点：89-90℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (125 mg, 0.5 mmol) was added to dry DMF (15 mL). E.sub.2 (192 mg, 1.0 mmol) was added, and HOBt (135 mg, 1.0 mmol) and DIEA (0.22) were added. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The combined organic layers were washed with EtOAc EtOAc EtOAc (EtOAc) Melting point: 89-90 ° C.

1H-NMR(400MHz,CDCl 3)δPPm:8.56(d,J＝6.8Hz,1H),8.23(d,J＝8.8Hz,1H),8.01(s,1H),7.84-7.87(m,3H),7.67(s,1H),7.40-7.48(m,2H),7.34(s,1H),6.93(d,J＝9.2Hz,1H),5.34-5.38(m,1H),4.16(q,J＝6.8Hz,2H),2.44-2.52(m,1H),1.63(d,J＝7.2Hz,3H),1.42(t,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ PPm: 8.56 (d, J = 6.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.84-7.87 (m, 3H) ), 7.67 (s, 1H), 7.40-7.48 (m, 2H), 7.34 (s, 1H), 6.93 (d, J = 9.2 Hz, 1H), 5.34 - 5.38 (m, 1H), 4.16 (q, J = 6.8 Hz, 2H), 2.44-2.52 (m, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 6H).

实施例(化合物)61-1Example (compound) 61-1

(+)-2-乙氧基-5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(+)-2-ethoxy-5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

实施例(化合物)61-2Example (compound) 61-2

(-)-2-乙氧基-5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(-)-2-ethoxy-5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将实施例61所示化合物2-乙氧基-5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺采用正相手性柱(ChiralPak AD-H 5μm 10mm×250mm)拆分得到实施例(化合物)61-1和实施例(化合物)61-2。具体过程如下：将化合物实施例61溶解于无水丙酮中，全溶后有机滤膜过滤进样。流动相采用异丙醇和正己烷(体积比：3/7)，流速为3.0mL/min，采用波长为254nm检测。分别收集获得化合物61-1及化合物61-2。化合物61-1的比旋光度为[α] 589 20(MeOH)＝+24.6，化合物61-2的比旋光度为[α] 589 20(MeOH)＝-22.6。 The compound of Example 61, 2-ethoxy-5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide, was used as a normal phase chiral column ( Chiral Pak AD-H 5 μm 10 mm × 250 mm) was resolved to give Example (Compound) 61-1 and Example (Compound) 61-2. The specific procedure was as follows: Compound Example 61 was dissolved in anhydrous acetone, and the organic filter was completely filtered and filtered. The mobile phase was isopropanol and n-hexane (volume ratio: 3/7), the flow rate was 3.0 mL/min, and the wavelength was 254 nm. Compound 61-1 and compound 61-2 were separately collected. The specific optical rotation of the compound 61-1 was [α] 589 20 (MeOH) = +24.6, and the specific optical rotation of the compound 61-2 was [α] 589 20 (MeOH) = -22.6.

实施例(化合物)62Example (compound) 62

2-乙氧基-5-乙酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-acetamido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000122
Figure PCTCN2018088561-appb-000122

a)2-乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-ethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-乙氧基-5-硝基苯甲酸(475mg,2.25mmol)溶于DCM(25mL)，加入HATU(1.285g，3.38mmol)，DIEA(872mg，6.75mmol)，室温反应30min，加入1-(3-甲基苯基)乙基-1-胺(690mg，3.38mmol)，室温反应过夜。0.5N HCl(20mL)洗，水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝2:1-1:1)，得白色固体756mg，收率85％。熔点：137-138℃2-Ethoxy-5-nitrobenzoic acid (475 mg, 2.25 mmol) was dissolved in DCM (25 mL), EtOAc (1, EtOAc, EtOAc, EtOAc) -(3-Methylphenyl)ethyl-1-amine (690 mg, 3.38 mmol) was reacted at room temperature overnight. Wash with 0.5 N HCl (20 mL), EtOAc (EtOAc) Column chromatography (P: E = 2: 1-1: 1) gave 756 mg of white solid. Melting point: 137-138 ° C

1H NMR(500MHZ,CDCl 3)δ(ppm):9.07(d,J＝3.0Hz,1H),8.29(dd,J 1＝3.0Hz,J 2＝9.0Hz,1H),8.04(s,1H)7.84-7.87(m,2H),7.46-7.47(m,2H),7.04(d,J＝9.0Hz,1H),5.35-5.40(m,1H),4.27-4.32(m,2H),1.66(d,J＝7.0Hz,3H),1.50(t,J＝7.5Hz, 3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 9.07 (d, J = 3.0 Hz, 1H), 8.29 (dd, J 1 = 3.0 Hz, J 2 = 9.0 Hz, 1H), 8.04 (s, 1H) ) 7.84-7.87 (m, 2H), 7.46-7.47 (m, 2H), 7.04 (d, J = 9.0 Hz, 1H), 5.35-5.40 (m, 1H), 4.27-4.32 (m, 2H), 1.66 (d, J = 7.0 Hz, 3H), 1.50 (t, J = 7.5 Hz, 3H).

b)2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(400mg，1.01mmol)溶于THF(15mL)，H 2/室温下反应8h。原料消失。过滤，浓缩，加入石油醚，析出白色固体294mg，滤液柱层析，得44mg，共得338mg，收率91％。熔点：125-127℃. 2-ethoxy-5-nitro -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (400mg, 1.01mmol) was dissolved in THF (15mL), H 2 / reaction at room temperature for 8 h. The raw materials disappeared. Filtration, concentration, and petroleum ether were added to precipitate 294 mg of a white solid, and the filtrate was subjected to column chromatography to give 44 mg of 338 mg, yield 91%. Melting point: 125-127 ° C.

1H NMR(500MHZ,DMSO-d 6)δ(ppm):8.64(d,J＝7.5Hz,1H),7.99(s,1H),7.95(d,J＝2.5Hz,1H),7.85(d,J＝7.5Hz,1H),7.81(d,J＝7.5Hz,1H),7.49-7.54(m,2H),7.05(d,J＝2.0Hz,1H),6.89(d,J＝10.5Hz,1H),6.69(dd,J 1＝2.0Hz,J 2＝10.5Hz,1H),5.20(t,J＝7.0Hz,1H),4.87(s,1H),4.05(q,J＝6.5Hz,2H),1.52(d,J＝6.5Hz,3H),1.32(d,J＝7.0Hz,3H). 1 H NMR (500 MHZ, DMSO-d 6 ) δ (ppm): 8.64 (d, J = 7.5 Hz, 1H), 7.99 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.85 (d) , J=7.5Hz, 1H), 7.81 (d, J=7.5Hz, 1H), 7.49-7.54(m, 2H), 7.05(d, J=2.0Hz, 1H), 6.89(d, J=10.5Hz , 1H), 6.69 (dd, J 1 =2.0 Hz, J 2 = 10.5 Hz, 1H), 5.20 (t, J = 7.0 Hz, 1H), 4.87 (s, 1H), 4.05 (q, J = 6.5 Hz) , 2H), 1.52 (d, J = 6.5 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H).

c)2-乙氧基-5-乙酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-ethoxy-5-acetamido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(100mg，0.27mmol)溶于THF(3mL)，冰浴下加入TEA(82mg，0.81mmol)，搅拌下逐滴加入乙酰氯(26mg，0.33mmol)，室温下搅拌反应30min。蒸馏水(5mL×2)洗，无水硫酸镁干燥。得黄白色固体60mg，收率55％。熔点：156-158℃.2-ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (100 mg, 0.27 mmol) dissolved in THF (3 mL) TEA (82 mg, 0.81 mmol) was added, and acetyl chloride (26 mg, 0.33 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 30 min. Distilled water (5 mL × 2) was washed and dried over anhydrous magnesium sulfate. A yellow-white solid was obtained in a yield of 55%. Melting point: 156-158 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.54(d,J＝6.5Hz,1H),8.13(d,J＝7.5Hz,1H),8.01(s,1H),7.82-7.86(m,3H),7.66(brs,1H),7.40-7.44(m,2H),7.33(d,J＝6.5Hz,1H),6.92(d,J＝9.0Hz,1H),5.35(t,J＝7.0Hz,1H),4.16(d,J＝6.5Hz,2H),2.12(s,3H),1.62(d,J＝6.5Hz,3H),1.43(t,J＝6.0Hz,3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 8.54 (d, J = 6.5 Hz, 1H), 8.13 (d, J = 7.5 Hz, 1H), 8.01 (s, 1H), 7.82-7.86 (m) , 3H), 7.66 (brs, 1H), 7.40-7.44 (m, 2H), 7.33 (d, J = 6.5 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.35 (t, J = 7.0 Hz, 1H), 4.16 (d, J = 6.5 Hz, 2H), 2.12 (s, 3H), 1.62 (d, J = 6.5 Hz, 3H), 1.43 (t, J = 6.0 Hz, 3H).

实施例(化合物)63Example (compound) 63

2-乙氧基-5-丙酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-propionamido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000123
Figure PCTCN2018088561-appb-000123

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(100mg，0.27mmol)溶于THF(3mL)，冰浴下加入TEA(82mg，0.81mmol)，搅拌下逐滴加入丙酰氯(31mg，0.33mmol)，室温下搅拌反应30min。蒸馏水(5mL×2)洗，无水硫酸镁干燥。得微黄色固体88mg，收率77％。熔点：153-155℃.2-ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (100 mg, 0.27 mmol) dissolved in THF (3 mL) TEA (82 mg, 0.81 mmol) was added, propionyl chloride (31 mg, 0.33 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Distilled water (5 mL × 2) was washed and dried over anhydrous magnesium sulfate. A yellowish solid 88 mg was obtained in a yield of 77%. Melting point: 153-155 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.64(d,J＝7.0Hz,1H),8.18(d,J＝7.0Hz,1H),8.01(s,1H),7.83-7.87(m,2H),7.64(brs,1H),7.41-7.46(m,2H),7.42(t,J＝7.0 Hz,3H),7.33(d,J＝8.0Hz,1H),6.92(d,J＝9.0Hz,1H),5.35(t,J＝7.0Hz,1H),4.16(t,J＝7.0Hz,1H),2.34(q,J＝7.5Hz,2H),1.62(d,J＝7.0Hz,3H),1.19(t,J＝7.5Hz,3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 8.64 (d, J = 7.0 Hz, 1H), 8.18 (d, J = 7.0 Hz, 1H), 8.01 (s, 1H), 7.83-7.87 (m) , 2H), 7.64 (brs, 1H), 7.41-7.46 (m, 2H), 7.42 (t, J = 7.0 Hz, 3H), 7.33 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.35 (t, J = 7.0 Hz, 1H), 4.16 (t, J = 7.0 Hz, 1H), 2.34 (q, J = 7.5 Hz, 2H), 1.62 (d, J = 7.0 Hz) , 3H), 1.19 (t, J = 7.5 Hz, 3H).

实施例(化合物)64Example (compound) 64

2-乙氧基-5-环丙甲酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-cyclopropylamido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000124
Figure PCTCN2018088561-appb-000124

2-乙氧基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(100mg，0.27mmol)溶于THF(3mL)，冰浴下加入TEA(82mg，0.81mmol)，搅拌下逐滴加入环丙甲酰氯(35mg，0.33mmol)，室温下搅拌反应30min。蒸馏水(5mL×2)洗，无水硫酸镁干燥。得白色固体95mg，收率81％。熔点：202-203℃.2-Ethoxy-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (100 mg, 0.27 mmol) was dissolved in THF (3 mL). TEA (82 mg, 0.81 mmol) was added dropwise with cyclopropanoyl chloride (35 mg, 0.33 mmol), and the mixture was stirred at room temperature for 30 min. Distilled water (5 mL × 2) was washed and dried over anhydrous magnesium sulfate. A white solid of 95 mg was obtained in a yield of 81%. Melting point: 202-203 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.54(d,J＝5.5Hz,1H),8.17(d,J＝7.5Hz,1H),8.06(brs,1H),8.00(s,1H),7.83-7.88(m,3H),7.41-7.43(m,2H),7.33(s,1H),6.90(d,J＝10.5Hz,1H),5.36(t,J＝6.5Hz,1H),4.16(d,J＝6.5Hz,2H),1.62(d,J＝7.0Hz,3H),1.52(brs,1H),1.42(t,J＝6.0Hz,3H),1.03(s,1H),0.76(d,J＝4.5Hz,2H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 8.54 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.06 (brs, 1H), 8.00 (s, 1H) ), 7.83-7.88 (m, 3H), 7.41-7.43 (m, 2H), 7.33 (s, 1H), 6.90 (d, J = 10.5 Hz, 1H), 5.36 (t, J = 6.5 Hz, 1H) , 4.16 (d, J = 6.5 Hz, 2H), 1.62 (d, J = 7.0 Hz, 3H), 1.52 (brs, 1H), 1.42 (t, J = 6.0 Hz, 3H), 1.03 (s, 1H) , 0.76 (d, J = 4.5 Hz, 2H).

实施例(化合物)65Example (compound) 65

2-乙氧基-5-环丁甲酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-cyclobutyramide-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000125
Figure PCTCN2018088561-appb-000125

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(100mg，0.27mmol)溶于THF(3mL)，冰浴下加入TEA(82mg，0.81mmol)，搅拌下逐滴加入环丁甲酰氯(39mg，0.33mmol)，室温下搅拌反应30min。蒸馏水(5mL×2)洗，无水硫酸镁干燥。得白色固体60mg，收率83％。熔点：168-170℃.2-ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (100 mg, 0.27 mmol) dissolved in THF (3 mL) TEA (82 mg, 0.81 mmol) was added, and cyclobutyroyl chloride (39 mg, 0.33 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 30 min. Distilled water (5 mL × 2) was washed and dried over anhydrous magnesium sulfate. A white solid of 60 mg was obtained in a yield of 83%. Melting point: 168-170 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.53(d,J＝6.0Hz,1H),8.21(d,J＝8.0Hz,1H),8.02(s,1H),7.85(d,J＝11.0Hz,2H),7.41-7.45(m,2H),7.34(s,1H),6.92(d,J＝9.0Hz,1H),5.36(t,J＝6.5Hz,1H),4.16(d,J＝5.0Hz,2H),3.12-3.15(m,1H),2.33-2.35(m,2H),1.90-1.99(m,2H),1.63(t,J＝6.0Hz,3H),1.42(t,J＝6.5Hz,3H). 1 H NMR (500MHZ, CDCl 3 ) δ (ppm): 8.53 (d, J = 6.0Hz, 1H), 8.21 (d, J = 8.0Hz, 1H), 8.02 (s, 1H), 7.85 (d, J =11.0 Hz, 2H), 7.41-7.45 (m, 2H), 7.34 (s, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.36 (t, J = 6.5 Hz, 1H), 4.16 (d) , J = 5.0 Hz, 2H), 3.12-3.15 (m, 1H), 2.33 - 2.35 (m, 2H), 1.90 - 1.99 (m, 2H), 1.63 (t, J = 6.0 Hz, 3H), 1.42 ( t, J = 6.5 Hz, 3H).

实施例(化合物)66Example (compound) 66

2-乙氧基-5-环戊甲酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-cyclopentancarboxamide-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000126
Figure PCTCN2018088561-appb-000126

2-乙氧基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(60mg，0.16mmol)溶于无水THF(5mL)，冰浴下加入TEA(49mg，0.48mmol)，搅拌下逐滴加入环戊基甲酰氯(22mg，0.20mmol)，室温下搅拌反应10min。浓缩，加入EA(15mL)稀释，蒸馏水(15mL×2)洗，无水硫酸镁干燥，浓缩，加入石油醚，得到白色固体58mg，收率78％。熔点：172-174℃.2-Ethoxy-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (60 mg, 0.16 mmol) dissolved in anhydrous THF (5 mL) After adding TEA (49 mg, 0.48 mmol), cyclopentylcarbonyl chloride (22 mg, 0.20 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. After concentration, it was diluted with EA (15 mL), washed with distilled water (15 mL×2), dried over anhydrous magnesium sulfate, and evaporated. Melting point: 172-174 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.53(d,J＝7.2Hz,1H),8.20(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),8.03(s,1H),7.87-7.88(m,2H),7.79(d,J＝9.2Hz,1H),7.41-7.48(m,2H),7.37(brs,1H),7.35(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),5.32-5,39(m,1H),4.17(q,J＝6.8Hz,2H),2.63-2.69(m,1H),1.85-1.93(m,4H),1.74-1.81(m,2H),1.83(d,J＝6.8Hz,3H),1.59-1.61(m,2H),1.43(d,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.53 (d, J = 7.2 Hz, 1H), 8.20 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 8.03 (s, 1H) ), 7.87-7.88 (m, 2H), 7.79 (d, J = 9.2 Hz, 1H), 7.41-7.48 (m, 2H), 7.37 (brs, 1H), 7.35 (d, J = 3.2 Hz, 1H) , 6.92 (d, J = 9.2 Hz, 1H), 5.32-5, 39 (m, 1H), 4.17 (q, J = 6.8 Hz, 2H), 2.63 - 2.69 (m, 1H), 1.85-1.93 (m , 4H), 1.74-1.81 (m, 2H), 1.83 (d, J = 6.8 Hz, 3H), 1.59-1.61 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H).

实施例(化合物)67Example (compound) 67

2-乙氧基-5-乙磺酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-ethanesulfonylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000127
Figure PCTCN2018088561-appb-000127

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(80mg，0.22mmol)溶于THF(2mL)，冰浴下加入TEA(67mg，0.66mmol)，搅拌下逐滴加入乙磺酰氯(33mg，0.26mmol)，室温下搅拌反应30min。蒸馏水(20mL×2)洗，无水硫酸镁干燥，得白色固体62mg，收率61％。熔点：160-162℃.2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (80 mg, 0.22 mmol) dissolved in THF (2 mL) TEA (67 mg, 0.66 mmol) was added, and ethanesulfonyl chloride (33 mg, 0.26 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 30 min. Distilled water (20 mL × 2) was washed and dried over anhydrous magnesium sulfate to give a white solid. Melting point: 160-162 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.67(d,J＝7.5Hz,1H),8.20(s,1H),8.05(s,1H),7.63(d,J＝8.5Hz,1H),7.51(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),7.34(d,J＝2.5Hz,1H),6.94(d,J＝8.5Hz,1H),5.49-5.52(m,1H),4.18(d,J＝6.0Hz,2H),3.02(q,J＝7.5Hz,2H),1.63(d,J＝6.5Hz,3H),1.45(t,J＝7.0Hz,3H),1.31(t,J＝7.5Hz,3H). 1 H NMR (500MHZ, CDCl 3 ) δ (ppm): 8.67 (d, J = 7.5Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.63 (d, J = 8.5Hz, 1H ), 7.51 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.49-5.52 (m, 1H), 4.18 (d, J = 6.0 Hz, 2H), 3.02 (q, J = 7.5 Hz, 2H), 1.63 (d, J = 6.5 Hz, 3H), 1.45 (t, J) =7.0 Hz, 3H), 1.31 (t, J = 7.5 Hz, 3H).

实施例(化合物)68Example (compound) 68

4-乙氧基-3-((1-(3-(噻唑-2-基)苯基)乙基)氨基甲酰基)苯基氨基甲酸乙酯Ethyl 4-ethoxy-3-((1-(3-(thiazol-2-yl)phenyl)ethyl)carbamoyl)phenylcarbamate

Figure PCTCN2018088561-appb-000128
Figure PCTCN2018088561-appb-000128

2-乙氧基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(80mg，0.22mmol)溶于THF(5mL)，冰浴下加入TEA(66mg，0.65mmol)，搅拌下逐滴加入焦碳酸二乙酯(36mg，0.22mmol)，室温下搅拌反应5h。蒸馏水(15mL×2)洗，无水硫酸镁干燥，得类白色固体30mg，收率31％。熔点：167-170℃.2-Ethoxy-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (80 mg, 0.22 mmol) was dissolved in THF (5 mL). TEA (66 mg, 0.65 mmol) was added dropwise to diethyl carbonate (36 mg, 0.22 mmol), and the mixture was stirred at room temperature for 5 h. Distilled water (15 mL × 2) was washed and dried over anhydrous magnesium sulfate to give 30 mg of white solid. Melting point: 167-170 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.55(d,J＝6.5Hz,1H),8.02(s,1H),7.93(brs,1H),7.86(s,3H),7.41-7.47(m,2H),7.33(d,J＝1.0Hz,1H),6.85(brs,1H),5.37-5.40(m,1H),4.21(q,J＝7.5Hz,2H),4.15(q,J＝3.5Hz,2H),1.63(d,J＝6.5Hz,3H),1.42(t,J＝7.0Hz,3H),1.29(t,J＝7.0Hz,3H). 1 H NMR (500MHZ, CDCl 3 ) δ (ppm): 8.55 (d, J = 6.5Hz, 1H), 8.02 (s, 1H), 7.93 (brs, 1H), 7.86 (s, 3H), 7.41-7.47 (m, 2H), 7.33 (d, J = 1.0 Hz, 1H), 6.85 (brs, 1H), 5.37-5.40 (m, 1H), 4.21 (q, J = 7.5 Hz, 2H), 4.15 (q, J = 3.5 Hz, 2H), 1.63 (d, J = 6.5 Hz, 3H), 1.42 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H).

实施例(化合物)69Example (compound) 69

4-乙氧基-3-((1-(3-(噻唑-2-基)苯基)乙基)氨基甲酰基)苯基氨基甲酸异丙酯4-Ethoxy-3-((1-(3-(thiazol-2-yl)phenyl)ethyl)carbamoyl)phenylcarbamic acid isopropyl ester

Figure PCTCN2018088561-appb-000129
Figure PCTCN2018088561-appb-000129

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(80mg，0.22mmol)溶于THF(5mL)，冰浴下加入TEA(66mg，0.66mmol)，搅拌下逐滴加入氯甲酸异丙酯(32mg，0.26mmol)，室温下搅拌反应30min。蒸馏水(15mL×2)洗，无水硫酸镁干燥，得白色固体75mg，收率76％。m.p.165-167℃.2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (80 mg, 0.22 mmol) dissolved in THF (5 mL) TEA (66 mg, 0.66 mmol) was added, and isopropyl chloroformate (32 mg, 0.26 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 30 min. The mixture was washed with distilled water (15 mL × 2) and dried over anhydrous magnesium sulfate M.p.165-167°C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.54(d,J＝7.2Hz,1H),8.02(s,1H),7.92(brs,1H),7.86(d,J＝5.2Hz,1H),7.83-7.84(m,1H),7.40-7.47(m,2H),7.33(d,J＝3.2Hz,1H),6.92(d,J＝8.8Hz,1H),8.74(brs,1H),5.34-5.41(m,1H),4.97-5.03(m,1H),4.15(q,J＝7.2Hz,2H),1.63(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H),1.28(t,J＝6.4Hz,6H). 1 H NMR (500MHZ, CDCl 3 ) δ (ppm): 8.54 (d, J = 7.2Hz, 1H), 8.02 (s, 1H), 7.92 (brs, 1H), 7.86 (d, J = 5.2Hz, 1H ), 7.83-7.84 (m, 1H), 7.40-7.47 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 8.74 (brs, 1H) , 5.34-5.41 (m, 1H), 4.97-5.03 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8) Hz, 3H), 1.28 (t, J = 6.4 Hz, 6H).

实施例(化合物)70Example (compound) 70

2-乙氧基-N-(1-(3-(噻唑-2-基)苯基)乙基)-5(2,2,2-三氟乙酰氨基)苯甲酰2-ethoxy-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-5(2,2,2-trifluoroacetamido)benzoyl

Figure PCTCN2018088561-appb-000130
Figure PCTCN2018088561-appb-000130

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(80mg，0.22mmol)溶于THF(5mL)，冰浴下加入TEA(66mg，0.65mmol)，搅拌下逐滴加入三氟乙酸酐(139mg，0.66mmol)，室温下搅拌反应5h。蒸馏水(20mL×2)洗，无水硫酸镁干燥，得类白色固体90mg，收率88％。熔点：177-179℃.2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (80 mg, 0.22 mmol) dissolved in THF (5 mL) After adding TEA (66 mg, 0.65 mmol), trifluoroacetic anhydride (139 mg, 0.66 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 5 h. Distilled water (20 mL × 2) was washed and dried over anhydrous magnesium sulfate to give a white solid. Melting point: 177-179 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.56(brs,1H),8.47(d,J＝6.5Hz,1H),7.06(d,J＝6.5Hz,2H),7.98(s,1H),7.87(d,J＝2.5Hz,2H),7.82(d,J＝6.0Hz,2H),7.42(d,J＝6.0Hz,1H),7.33(d,J＝3.0Hz,1H),6.96(d,J＝9.5Hz,1H),5.33-5.36(m,1H),4.18(d,J＝6.5Hz,2H),1.62(d,J＝7.0Hz,3H),1.44(t,J＝7.0Hz,3H). 1 H NMR (500MHZ, CDCl 3 ) δ (ppm): 8.56 (brs, 1H), 8.47 (d, J = 6.5Hz, 1H), 7.06 (d, J = 6.5Hz, 2H), 7.98 (s, 1H ), 7.87 (d, J = 2.5 Hz, 2H), 7.82 (d, J = 6.0 Hz, 2H), 7.42 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 9.5 Hz, 1H), 5.33-5.36 (m, 1H), 4.18 (d, J = 6.5 Hz, 2H), 1.62 (d, J = 7.0 Hz, 3H), 1.44 (t, J) =7.0Hz, 3H).

实施例(化合物)71Example (compound) 71

N-(3-溴苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(3-bromobenzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000131
Figure PCTCN2018088561-appb-000131

将2-乙氧基-5-异丁酰氨基苯甲酸(440mg,1.76mmol)加入无水DMF(20mL)，加入EDC(676mg,3.52mmol)，加入HOBt(475mg,3.52mmol)和DIEA(0.92mL,5.28mmol)，加入化合物间溴苯乙胺(424mg,2.29mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(60mL×2)萃取，合并有机层用饱和NaCl溶液(50mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5,E:P＝1:1.5)，得到白色固体520mg，产率70.7％。熔点：153-155℃2-Ethoxy-5-isobutyrylaminobenzoic acid (440 mg, 1.76 mmol) was added to dry DMF (20 mL). E.sub.2 (676 mg, 3.52 mmol). mL, 5.28 mmol), the compound m-bromophenethylamine (424 mg, 2.29 mmol) was added and stirred at room temperature overnight. The reaction solution was poured into water and extracted with a mixture of ethyl acetate:methanol=10:1 (60 mL×2) The combined organic layer was washed with a saturated NaCI solution (50 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and then purified by column chromatography (E:P=1:2.5, E:P=1:1.5) The rate is 70.7%. Melting point: 153-155 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.22(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.69(s,1H),7.51(t,J＝1.6Hz,1H),7.39-7.40(m,0.5H),7.37-7.38(m,0.5H),7.30-7.31(m,0.5H),7.28-7.29(m,0.5H),7.21(t,J＝8.0Hz,1H),6.93(t,J＝9.2Hz,1H),5.25-5.29(m,1H),4.18(q,J＝6.8Hz,2H),2.46-2.50(m,1H),1.55(d,J＝6.8Hz,3H),1.46(t,J＝6.8Hz,3H),1.19(dd,J 1＝6.8Hz,J 1＝2.0Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.84 (d, J=2.8 Hz, 1H), 7.69 (s, 1H), 7.51 (t, J=1.6 Hz, 1H), 7.39-7.40 (m, 0.5H), 7.37-7.38 (m, 0.5H), 7.30-7.31 (m, 0.5H), 7.28-7.29 (m, 0.5H), 7.21 (t, J = 8.0 Hz, 1H), 6.93 (t, J = 9.2 Hz, 1H), 5.25-5.29 (m, 1H), 4.18 (q, J = 6.8 Hz, 2H), 2.46-2.50 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.46 (t, J = 6.8 Hz, 3H), 1.19 (dd, J 1 = 6.8 Hz, J 1 = 2.0 Hz, 6H).

实施例(化合物)72Example (compound) 72

N-(1-(3-溴苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-bromophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000132
Figure PCTCN2018088561-appb-000132

将2-乙氧基-5-异丁酰氨基苯甲酸(900mg,3.60mmol)加入无水DMF(50mL)，加入EDC(1.38mg,7.2mmol)，加入HOBt(972mg,7.2mmol)和DIEA(1.90mL,10.8mmol)，加入化合物(21)(931mg,4.68mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(60mL×2)萃取，合并有机层用饱和NaCl溶液(50mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3,E:P＝1:2)，得到白色固体1.2g，产率76.9％。熔点：142-144℃2-Ethoxy-5-isobutyrylaminobenzoic acid (900 mg, 3.60 mmol) was added to dry DMF (50 mL). E.sub.2 (1.38 mg, 7.2 mmol) was added and HOBt (972mg, 7.2mmol) and DIEA ( 1.90 mL, 10.8 mmol), the compound (21) (931 mg, 4.68 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water, and extracted with a mixture of ethyl acetate:methanol = 10:1 (60 mL×2). The combined organic layer was washed with aq. EtOAc (EtOAc) (EtOAc (EtOAc) The rate is 76.9%. Melting point: 142-144 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.22(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.69(s,1H),7.51(t,J＝1.6Hz,1H),7.39-7.40(m,0.5H),7.37-7.38(m,0.5H),7.30-7.31(m,0.5H),7.28-7.29(m,0.5H),7.21(t,J＝8.0Hz,1H),6.93(t,J＝9.2Hz,1H),5.25-5.29(m,1H),4.18(q,J＝6.8Hz,2H),2.46-2.50(m,1H),1.55(d,J＝6.8Hz,3H),1.46(t,J＝6.8Hz,3H),1.19(dd,J 1＝6.8Hz,J 1＝20Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.84 (d, J=2.8 Hz, 1H), 7.69 (s, 1H), 7.51 (t, J=1.6 Hz, 1H), 7.39-7.40 (m, 0.5H), 7.37-7.38 (m, 0.5H), 7.30-7.31 (m, 0.5H), 7.28-7.29 (m, 0.5H), 7.21 (t, J = 8.0 Hz, 1H), 6.93 (t, J = 9.2 Hz, 1H), 5.25-5.29 (m, 1H), 4.18 (q, J = 6.8 Hz, 2H), 2.46-2.50 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.46 (t, J = 6.8 Hz, 3H), 1.19 (dd, J 1 = 6.8 Hz, J 1 = 20 Hz, 6H).

实施例(化合物)73Example (compound) 73

2-乙氧基-5-异丁酰氨基-N-(3-(2-羰基哌啶-1-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-(2-carbonylpiperidin-1-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000133
Figure PCTCN2018088561-appb-000133

将2-乙氧基-5-异丁酰氨基苯甲酸(60mg,0.24mmol)加入无水DMF(10mL)，加入EDC(92mg,0.48mmol)，加入HOBt(65mg,0.48mmol)和DIEA(0.125mL,0.72mmol)，加入1-(3-(氨基甲基)苯基)哌啶-2-酮(54mg,0.264mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(20mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝40:1,D:M＝30:1)，得到白色固体70mg，产率66.6％。熔点：179-181℃ 1H-NMR(500MHz,CDCl 3)δ(ppm):8.38(s,1H),8.21(d,J＝9.0Hz,1H),7.86(s,1H),7.75-7.79(m,1H),7.37(d,J＝7.5Hz,1H),7.24-7.29(m,2H),7.17(d,J＝7.5Hz,1H),6.88(d,J＝9.0Hz,1H),4.66(d,J＝5.0Hz,2H),4.09(q,J＝6.5Hz,2H),3.64(s,2H),2.50-2.56(m,3H),2.05(brs,4H),1.32(t,J＝6.5Hz,3H),1.21(d,J＝6.5Hz,6H). 2-Ethoxy-5-isobutyrylaminobenzoic acid (60 mg, 0.24 mmol) was added to dry DMF (10 mL). E.sub.2 (92 mg, 0.48 mmol) was added to HOBt (65 mg, 0.48 mmol) and DIEA (0.125) mL, 0.72 mmol), 1-(3-(aminomethyl)phenyl)piperidin-2-one (54 mg, 0.264 mmol). The mixture was extracted with a mixture of 10:1 (20 mL×2), and the combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=60:1, D: M = 40:1, D: M = 30:1) gave 70 mg of white solid, yield 66.6%. Melting point: 179-181 ° C 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 8.38 (s, 1H), 8.21. (d, J = 9.0 Hz, 1H), 7.86 (s, 1H), 7.75-7.79 (m, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.24 - 7.29 (m, 2H), 7.17 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 9.0 Hz, 1H) , 4.66 (d, J = 5.0 Hz, 2H), 4.09 (q, J = 6.5 Hz, 2H), 3.64 (s, 2H), 2.50 - 2.56 (m, 3H), 2.05 (brs, 4H), 1.32 ( t, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 6H).

实施例(化合物)74Example (compound) 74

2-乙氧基-5-异丁酰氨基-N-(1-(3-(2-羰基哌啶-1-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(2-carbonylpiperidin-1-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000134
Figure PCTCN2018088561-appb-000134

将N-(1-(3-溴苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(150mg,0.347mmol)置于反应瓶中，加入dioxane(15mL)，氩气保护下加入Pd 2(dba) 3(63mg,0.07mmol)，xantphos(80mg,0.14mmol)，K 3PO 4(184mg,0.87mmol)以及piperidin-2-one(52mg,0.52mmol)，升温至100℃反应，次日停止反应，过滤，浓缩，柱层析(D:M＝50:1,D:M＝40:1)，得到淡黄色固体9mg。熔点：105-107℃ N-(1-(3-Bromophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (150 mg, 0.347 mmol) was placed in a reaction flask and dioxane (15 mL) was added. Pd 2 (dba) 3 (63 mg, 0.07 mmol), xantphos (80 mg, 0.14 mmol), K 3 PO 4 (184 mg, 0.87 mmol) and piperidin-2-one (52 mg, 0.52 mmol) were added under argon. The reaction was carried out to 100 ° C, and the reaction was stopped the next day, filtered, concentrated, and purified by column chromatography (D:M=50:1, D:M=40:1) Melting point: 105-107 ° C

1H-NMR(500MHz,CDCl 3)δPPm:8.44(d,J＝7.0Hz,1H),8.18(d,J＝7.0Hz,1H),7.80(s,1H),7.32-7.39(m,2H),7.26-7.28(m,2H),7.15(d,J＝7.5Hz,1H),6.92(d,J＝9.0Hz,1H),5.37-5.41(m,1H),4.15(q,J＝7.0Hz,2H),3.63(s,2H),2.55(s,2H),2.48-2.51(m,1H),1.94(s,4H),1.65(d,J＝7.0Hz,3H),1.43(t,J＝7.0Hz,3H),1.22(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δPPm: 8.44 (d, J = 7.0 Hz, 1H), 8.18 (d, J = 7.0 Hz, 1H), 7.80 (s, 1H), 7.32-7.39 (m, 2H) ), 7.26-7.28 (m, 2H), 7.15 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.37 - 5.41 (m, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.63 (s, 2H), 2.55 (s, 2H), 2.48-2.51 (m, 1H), 1.94 (s, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.43 ( t, J = 7.0 Hz, 3H), 1.22 (d, J = 6.5 Hz, 6H).

实施例(化合物)75Example (compound) 75

2-乙氧基-5-异丁酰氨基-N-(3-(2-羰基吡咯烷-1-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-(2-carbonylpyrrolidin-1-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000135
Figure PCTCN2018088561-appb-000135

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入1-(3-(氨基甲基)苯基)吡咯烷-2-酮(106mg,0.56mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝40:1)，得到白色固体85mg，产率49.4％。熔点：157-159℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(3-(aminomethyl)phenyl)pyrrolidin-2-one (106 mg, 0.56 mmol) was added and stirred at room temperature overnight. The mixture was extracted with a mixture of 10:1 (30 mL×2), and the combined organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=60:1, D: M = 40: 1) gave a white solid, 85 mg, yield 49.4%. Melting point: 157-159 ° C

1H-NMR(500MHz,CDCl 3)δPPm:8.44(s,1H),8.22(d,J＝7.0Hz,1H),7.91(s,1H),7.67(s,1H),7.62(s,1H),7.53(d,J＝8.0Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(d,J＝7.5Hz,1H),6.92(d,J＝9.0Hz,1H),4.67(d,J＝5.5Hz,2H),4.13(q,J＝7.0Hz,2H),3.86(t,J＝7.0Hz,2H),2.61(t,J＝8.0Hz,2H),2.51-2.54(m,1H),2.14-2.19(m,2H),1.33(t,J＝6.5Hz,3H),1.22(d,J＝7.0Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δPPm: 8.44 (s, 1H), 8.22 (d, J = 7.0 Hz, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H) ), 7.53 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.86 (t, J = 7.0 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 2.51 2.54 (m, 1H), 2.14-2.19 (m, 2H), 1.33 (t, J = 6.5 Hz, 3H), 1.22 (d, J = 7.0 Hz, 6H).

实施例(化合物)76Example (compound) 76

2-乙氧基-5-异丁酰氨基-N-(1-(3-(2-羰基吡咯烷-1-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(2-carbonylpyrrolidin-1-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000136
Figure PCTCN2018088561-appb-000136

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入1-(3-(1-氨基乙基)苯基)吡咯烷-2-酮(110mg,0.54mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝100:1,D:M＝75:1)，得到白色固体100mg，产率57.1％。熔点：93-95℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(3-(1-aminoethyl)phenyl)pyrrolidin-2-one (110 mg, 0.54 mmol), EtOAc The mixture was extracted with a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate D: M = 75: 1) gave a white solid, 100 mg, yield 57.1%. Melting point: 93-95 ° C

1H-NMR(400MHz,DMSO-d 6)δPPm:9.79(s,1H),8.54(d,J＝8.0Hz,1H),7.90(d,J＝2.8Hz,1H),7.75(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.69(s,1H),7.51(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.17(d,J＝7.6Hz,1H),7.07(d,J＝9.2Hz,1H),5.09-5.13(m,1H),4.12(q,J＝6.8Hz,2H),3.83(td,J 1＝8.0Hz,J 2＝2.0Hz,1H),2.50-2.56(m,1H),2.46-2.50(m,2H),2.03-2.09(m,2H),1.46(d,J＝7.2Hz,3H),1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ PPm: 9.79 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.75 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.69 (s, 1H), 7.51 (dd, J 1 = 8.8 Hz, J 2 = 2.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H) ), 7.17 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 5.09-5.13 (m, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.83 (td) , J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H), 2.50-2.56 (m, 1H), 2.46-2.50 (m, 2H), 2.03-2.09 (m, 2H), 1.46 (d, J = 7.2 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)77Example (compound) 77

2-乙氧基-5-异丁酰氨基-N-(3-(吡咯烷-1-基)苯甲基)苯酰胺2-ethoxy-5-isobutyrylamino-N-(3-(pyrrolidin-1-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000137
Figure PCTCN2018088561-appb-000137

将N-(3-溴苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(110mg,0.26mmol)置于反应瓶中，加入甲苯(15mL)，氩气保护下加入Pd 2(dba) 3(47mg,0.052mmol)，xantphos(59mg,0.104mmol)，叔丁醇钠(75mg,0.78mmol)以及四氢吡咯(0.54mL,6.5mmol)，升温至90℃反应，5h后停止反应，过滤，浓缩，柱层析(E:P＝1:3,E:P＝1:1.5)，得到白色固体83mg，产率78.3％。熔点：194-196℃ N-(3-Bromobenzyl)-2-ethoxy-5-isobutyrylaminobenzamide (110 mg, 0.26 mmol) was placed in a reaction flask, and toluene (15 mL) was added and added under argon Pd 2 (dba) 3 (47 mg, 0.052 mmol), xantphos (59 mg, 0.104 mmol), sodium tert-butoxide (75 mg, 0.78 mmol) and tetrahydropyrrole (0.54 mL, 6.5 mmol), warmed to 90 ° C, 5h After the reaction was stopped, the mixture was filtered, concentrated, and purified (jjjjjjjjj Melting point: 194-196 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.40(d,J＝4.0Hz,1H),8.23(dd,J 1＝9.0Hz,J 1＝3.0Hz,1H),7.62(s,1H),7.20(t,J＝7.5Hz,1H),6.91(d,J＝9.0Hz,1H),6.67(brs,1H),6.51-6.55(m,2H),4.61(d,J＝5.5Hz,2H),4.12(q,J＝7.0Hz,2H),3.28(brs,4H),2.52-2.55(m,1H),2.00(brs,4H),1.33(t,J＝7.0Hz,3H),1.23(d,J＝6.5Hz, 6H). 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 8.40 (d, J = 4.0 Hz, 1H), 8.23 (dd, J 1 = 9.0 Hz, J 1 = 3.0 Hz, 1H), 7.62 (s, 1H), 7.20 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.67 (brs, 1H), 6.51-6.55 (m, 2H), 4.61 (d, J = 5.5) Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.28 (brs, 4H), 2.52-2.55 (m, 1H), 2.00 (brs, 4H), 1.33 (t, J = 7.0 Hz, 3H) ), 1.23 (d, J = 6.5 Hz, 6H).

实施例(化合物)78Example (compound) 78

2-乙氧基-5-异丁酰氨基-N-(1-(3-(吡咯烷-1-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(pyrrolidin-1-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000138
Figure PCTCN2018088561-appb-000138

将N-(1-(3-溴苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(110mg,0.255mmol)置于反应瓶中，加入甲苯(15mL)，氩气保护下加入Pd 2(dba) 3(46mg,0.051mmol)，xantphos(58mg,0.102mmol)，叔丁醇钠(74mg,0.77mmol)以及四氢吡咯(0.53mL,6.4mmol)，升温至90℃反应，5h后停止反应，过滤，浓缩，柱层析(E:P＝1:3,E:P＝1:2)，得到白色固体60mg，产率55.5％。熔点：100-102℃ N-(1-(3-Bromophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (110 mg, 0.255 mmol) was placed in a reaction flask and toluene (15 mL) was added. Pd 2 (dba) 3 (46 mg, 0.051 mmol), xantphos (58 mg, 0.102 mmol), sodium tert-butoxide (74 mg, 0.77 mmol) and tetrahydropyrrole (0.53 mL, 6.4 mmol) were added under argon. The reaction was carried out at 90 ° C, and the reaction was quenched after 5 h, filtered, concentrated, EtOAc (EtOAc:EtOAc: Melting point: 100-102 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.48(d,J＝7.5Hz,1H),8.22(dd,J 1＝9.0Hz,J 1＝2.5Hz,1H),7.86(d,J＝2.5Hz,1H),7.63(s,1H),7.20(t,J＝8.0Hz,1H),6.91(d,J＝9.0Hz,1H),6.69(brs,1H),6.56(brs,1H),6.48(brs,1H),5.22-5.26(m,1H),4.09-4.17(m,2H),3.28(s,4H),2.50-2.53(m,1H),1.99(s,4H),1.57(d,J＝7.0Hz,3H),1.41(t,J＝7.0Hz,3H),1.21(d,J 1＝6.5Hz,J 2＝2.0Hz,6H). 1 H-NMR (500MHz, CDCl 3) δ (ppm): 8.48 (d, J = 7.5Hz, 1H), 8.22 (dd, J 1 = 9.0Hz, J 1 = 2.5Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.63 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.69 (brs, 1H), 6.56 (brs, 1H), 6.48 (brs, 1H), 5.22-5.26 (m, 1H), 4.09-4.17 (m, 2H), 3.28 (s, 4H), 2.50-2.53 (m, 1H), 1.99 (s, 4H) , 1.57 (d, J = 7.0 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.21 (d, J 1 = 6.5 Hz, J 2 = 2.0 Hz, 6H).

实施例(化合物)79Example (compound) 79

叔-丁基4-(3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯基)哌嗪-1-羧酸酯Tert-butyl 4-(3-((2-ethoxy-5-isobutyrylaminobenzoylamino)methyl)phenyl)piperazine-1-carboxylate

Figure PCTCN2018088561-appb-000139
Figure PCTCN2018088561-appb-000139

将N-(3-溴苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(100mg,0.24mmol)置于反应瓶中，加入甲苯(15mL)，氩气保护下加入Pd 2(dba) 3(45mg,0.048mmol)，xantphos(55mg,0.096mmol)，叔丁醇钠(69mg,0.72mmol)以及N-Boc哌嗪(133mg,0.72mmol)，升温至100℃反应，5h后停止反应，过滤，浓缩，柱层析(D:M＝80:1,D:M＝70:1)，得到淡黄色固体50mg，产率39.7％。熔点：186-187℃ N-(3-Bromobenzyl)-2-ethoxy-5-isobutyrylaminobenzamide (100 mg, 0.24 mmol) was placed in a reaction flask, and toluene (15 mL) was added and added under argon Pd 2 (dba) 3 (45 mg, 0.048 mmol), xantphos (55 mg, 0.096 mmol), sodium tert-butoxide (69 mg, 0.72 mmol) and N-Boc piperazine (133 mg, 0.72 mmol), warmed to 100 ° C, After 5 h, the reaction was quenched, filtered, concentrated and purified (jjjjjjjjj Melting point: 186-187 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.39(brs,1H),8.22(dd,J 1＝8.5Hz,J 1＝2.5Hz,1H),7.89(d,J＝2.5Hz,1H),7.52(s,1H),7.24-7.27(m,1H),6.85-6.93(m,4H),4.61(d,J＝5.5Hz,2H),4.12(q,J＝7.0Hz,2H),3.58(s,4H),3.14(s,4H),2.51-2.54(m, 1H),1.48(s,9H),1.32(t,J＝7.0Hz,3H),1.23(d,J＝7.0Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.39 (brs, 1H), 8.22 (dd, J 1 = 8.5 Hz, J 1 = 2.5 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.52 (s, 1H), 7.24-7.27 (m, 1H), 6.85-6.93 (m, 4H), 4.61 (d, J = 5.5 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H) ), 3.58 (s, 4H), 3.14 (s, 4H), 2.51-2.54 (m, 1H), 1.48 (s, 9H), 1.32 (t, J = 7.0 Hz, 3H), 1.23 (d, J = 7.0Hz, 6H).

实施例(化合物)80Example (compound) 80

2-乙氧基-5-异丁酰氨基-N-(3-(哌嗪-1-基)苯甲基)苯酰胺2,2,2-三氟乙酸盐2-ethoxy-5-isobutyrylamino-N-(3-(piperazin-1-yl)benzyl)benzamide 2,2,2-trifluoroacetate

Figure PCTCN2018088561-appb-000140
Figure PCTCN2018088561-appb-000140

将叔-丁基4-(3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯基)哌嗪-1-羧酸酯(190mg,0.36mmol)，加入DCM(5mL)，加入TFA(0.27mL,3.6mmol)，室温搅拌反应，次日停止反应，加入乙醚，无固体析出，浓缩至干，加入乙醚，有固体析出，抽滤，得到类白色固体180mg，产率93.3％。熔点：160-162℃tert-Butyl 4-(3-((2-ethoxy-5-isobutyrylaminobenzoylamino)methyl)phenyl)piperazine-1-carboxylate (190 mg, 0.36 mmol), Add DCM (5 mL), add TFA (0.27 mL, 3.6 mmol), and then the mixture was stirred at room temperature. The reaction was stirred at room temperature, and the mixture was evaporated to dryness. 180 mg, yield 93.3%. Melting point: 160-162 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.82(s,1H),8.89(s,1H),8.54(t,J＝5.6Hz,1H),7.97(d,J＝2.8Hz,1H),7.72(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.23(t,J＝8.0Hz,1H),7.07(d,J＝9.2Hz,1H),6.97(s,1H),6.86-6.91(m,2H),4.46(d,J＝6.0Hz,2H),4.10(q,J＝7.2Hz,2H),3.32-3.35(m,4H),3.24-3.26(m,4H),2.50-2.57(m,1H),1.28(t,J＝7.2Hz,3H),1.09(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.82 (s, 1H), 8.89 (s, 1H), 8.54 (t, J = 5.6Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.72 (dd, J 1 = 8.8 Hz, J 1 = 2.8 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.97 ( s, 1H), 6.86-6.91 (m, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.32-3.35 (m, 4H), 3.24 - 3.26 (m, 4H), 2.50-2.57 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.09 (d, J = 6.8 Hz, 6H).

实施例(化合物)81Example (compound) 81

叔-丁基4-(3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯基)哌嗪-1-羧酸酯Tert-Butyl 4-(3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)phenyl)piperazine-1-carboxylate

Figure PCTCN2018088561-appb-000141
Figure PCTCN2018088561-appb-000141

将N-(1-(3-溴苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(300mg,0.69mmol)置于反应瓶中，加入甲苯(25mL)，氩气保护下加入Pd 2(dba) 3(127mg,0.14mmol)，xantphos(159mg,0.28mmol)，叔丁醇钠(200mg,2.08mmol)以及N-Boc哌嗪(387mg,2.08mmol)，升温至100℃反应，8h后停止反应，过滤，浓缩，柱层析(E:P＝1:3,E:P＝1:1.5)，得到淡黄色固体180mg，产率48.5％。熔点：63-65℃ N-(1-(3-Bromophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (300 mg, 0.69 mmol) was placed in a reaction flask and toluene (25 mL) was added. Pd 2 (dba) 3 (127 mg, 0.14 mmol), xantphos (159 mg, 0.28 mmol), sodium tert-butoxide (200 mg, 2.08 mmol) and N-Boc piperazine (387 mg, 2.08 mmol) were added under argon. The reaction was carried out to 100 ° C. After 8 h, the reaction was quenched, filtered, concentrated, EtOAcjjjjjjj Melting point: 63-65 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.44(d,J＝7.0Hz,1H),8.21(dd,J 1＝9.0Hz,J 1＝2.5Hz,1H),7.84(d,J＝2.5Hz,1H),7.56(s,1H),7.25(t,J＝8.0Hz,1H),6.89-6.93(m,3H),6.82(d,J＝8.0Hz,1H),5.23-5.27(m,1H),4.11-4.16(m,2H),3.57(s,4H),3.13(s,4H),2.48-2.52(m,1H),1.56(d,J＝6.5Hz,3H),1.48(s,9H),1.41(t,J＝7.0 Hz,3H),1.21(d,J＝6.5Hz,6H). 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 8.44 (d, J = 7.0 Hz, 1H), 8.21. (dd, J 1 = 9.0 Hz, J 1 = 2.5 Hz, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.56 (s, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.89 - 6.93 (m, 3H), 6.82 (d, J = 8.0 Hz, 1H), 5.23 5.27(m,1H),4.11-4.16(m,2H),3.57(s,4H),3.13(s,4H),2.48-2.52(m,1H),1.56(d,J=6.5Hz,3H) , 1.48 (s, 9H), 1.41 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 6.5 Hz, 6H).

实施例(化合物)82Example (compound) 82

2-乙氧基-5-异丁酰氨基-N-(1-(3-(哌嗪-1-基)苯基)乙基)苯甲酰胺2,2,2-三氟乙酸盐2-ethoxy-5-isobutyrylamino-N-(1-(3-(piperazin-1-yl)phenyl)ethyl)benzamide 2,2,2-trifluoroacetate

Figure PCTCN2018088561-appb-000142
Figure PCTCN2018088561-appb-000142

将叔-丁基4-(3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯基)哌嗪-1-羧酸酯(120mg,0.22mmol)，加入DCM(5mL)，加入TFA(0.16mL,2.2mmol)，室温搅拌反应，次日停止反应，加入乙醚，有固体析出，抽滤，滤饼乙醚洗，得到灰色固体110mg，产率90.9％。tert-Butyl 4-(3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)phenyl)piperazine-1-carboxylate (120 mg, 0.22 mmol) Add DCM (5 mL), add TFA (0.16 mL, 2.2 mmol), and then the mixture was stirred at room temperature. The reaction was stopped the next day, and the mixture was evaporated to give diethyl ether. The solid was precipitated, filtered, and washed with diethyl ether. %.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.81(s,1H),8.85(brs,2H),8.48(d,J＝8.0Hz,1H),7.93(d,J＝2.8Hz,1H),7.72(dd,J 1＝9.2Hz,J 1＝2.8Hz,1H),7.23(t,J＝7.6Hz,1H),7.07(d,J＝9.2Hz,1H),7.01(s,1H),6.91(d,J＝7.6Hz,1H),6.87(dd,J 1＝7.6Hz,J 1＝2.0Hz,1H),5.05-5.09(m,1H),4.11(q,J＝6.4Hz,2H),3.33-3.46(m,4H),3.23-3.26(m,4H),2.51-2.57(m,1H),1.44(d,J＝6.8Hz,3H),1.33(t,J＝7.2Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.81 (s, 1H), 8.85 (brs, 2H), 8.48 (d, J = 8.0Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.72 (dd, J 1 = 9.2 Hz, J 1 = 2.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 7.01 ( s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.87 (dd, J 1 = 7.6 Hz, J 1 = 2.0 Hz, 1H), 5.05-5.09 (m, 1H), 4.11 (q, J) = 6.4 Hz, 2H), 3.33 - 3.46 (m, 4H), 3.23 - 3.26 (m, 4H), 2.51-2.57 (m, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)83Example (compound) 83

3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸甲酯Methyl 3-((2-ethoxy-5-isobutyrylaminobenzoylamino)methyl)benzoate

Figure PCTCN2018088561-appb-000143
Figure PCTCN2018088561-appb-000143

将2-乙氧基-5-异丁酰氨基苯甲酸(530mg,2.12mmol)加入无水DMF(30mL)，加入EDC(814mg,4.24mmol)，加入HOBt(572mg,4.24mmol)和DIEA(1.1mL,6.36mmol)，加入3-(氨基甲基)苯甲酸甲酯(403mg,2.44mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(60mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1)，得到白色固体480mg，产率56.9％。熔点：131-133℃2-Ethoxy-5-isobutyrylaminobenzoic acid (530 mg, 2.12 mmol) was added to dry DMF (30 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc mL, 6.36 mmol), methyl 3-(aminomethyl)benzoate (403 mg, 2.44 mmol) was added, stirred at room temperature overnight, and the mixture was poured into water and mixed with ethyl acetate:methanol = 10:1 ( 60 mL × 2), the organic layer was washed with a saturated NaCI solution (30 mL × 2), dried over anhydrous magnesium sulfate. . Melting point: 131-133 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.52(t,J＝5.2Hz,1H),8.21(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),8.03(brs,1H),7.97(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.91(brs,1H), 7.65(brs,1H),7.56-7.58(m,1H),7.43(t,J＝7.6Hz,1H),6.94(d,J＝8.8Hz,1H),4.71(d,J＝5.6Hz,2H),4.14(q,J＝7.2Hz,2H),3.92(s,3H),2.48-2.56(m,1H),1.33(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.52 (t, J = 5.2 Hz, 1H), 8.21. (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 8.03 (brs, 1H), 7.97 (td, J 1 = 7.6 Hz, J 2 = 1.6 Hz, 1H), 7.91 (brs, 1H), 7.65 (brs, 1H), 7.56-7.58 (m, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 2.48-2.56 (m, 1H), 1.33 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)84Example (compound) 84

3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯甲酸甲酯Methyl 3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)benzoate

Figure PCTCN2018088561-appb-000144
Figure PCTCN2018088561-appb-000144

将2-乙氧基-5-异丁酰氨基苯甲酸(320mg,1.28mmol)加入无水DMF(20mL)，加入EDC(492mg,2.56mmol)，加入HOBt(346mg,2.56mmol)和DIEA(0.67mL,3.84mmol)，加入3-(1-氨基乙基)苯甲酸甲酯(341mg,1.92mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(60mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝75:1)，得到白色固体500mg，产率94.7％。熔点：105-107℃2-Ethoxy-5-isobutyrylaminobenzoic acid (320 mg, 1.28 mmol) was added to dry DMF (20 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc mL, 3.84 mmol), methyl 3-(1-aminoethyl)benzoate (341 mg, 1.92 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water and mixed with ethyl acetate:methanol = 10:1 The mixture was extracted with EtOAc (3 mL, EtOAc). 94.7%. Melting point: 105-107 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.52(d,J＝7.6Hz,1H),8.21(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),8.05-8.06(m,1H),,7.95-7.96(m,0.5H),7.93-7.94(m,0.5H),7.81(d,J＝2.8Hz,1H),7.57(d,J＝7.6Hz,1H),7.52(s,1H),7.42(d,J＝8.0Hz,1H),6.93(d,J＝9.2Hz,1H),5.32-5.36(m,1H),4.14-4.20(m,2H),3.90-3.92(m,3H),2.45-2.50(m,1H),1.59(d,J＝6.8Hz,3H),1.45(t,J＝7.2Hz,3H),1.21(dd,J 1＝6.8Hz,J 2＝1.6Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.52 (d, J = 7.6 Hz, 1H), 8.21. (dd, J 1 = 8.8 Hz, J 1 = 2.8 Hz, 1H), 8.05-8.06 ( m,1H),, 7.95-7.96 (m, 0.5H), 7.93-7.94 (m, 0.5H), 7.81 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 5.32 - 5.36 (m, 1H), 4.14 - 4.20 (m, 2H), 3.90 -3.92 (m, 3H), 2.45-2.50 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H), 1.21 (dd, J 1 = 6.8 Hz , J 2 = 1.6 Hz, 6H).

实施例(化合物)85Example (compound) 85

3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸3-((2-ethoxy-5-isobutyrylaminobenzoylamino)methyl)benzoic acid

Figure PCTCN2018088561-appb-000145
Figure PCTCN2018088561-appb-000145

将3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸甲酯(350mg,0.878mmol)，加入MeOH(5mL),THF(5mL)，将LiOH(31.6mg,1.32mmol)溶于H 2O(3mL)加入反应瓶中，加毕，室温搅拌反应，次日，停止反应，浓缩，加水，用乙醚15mL萃取，水层用稀HCl溶液调PH值至2左右，无固体生成，用二氯甲烷:甲醇＝10:1的混合液(60mL×2)萃取，合并有机层，无水硫酸镁干燥，浓缩，得到白色固体 310mg，产率91.9％。熔点：187-189℃ Methyl 3-((2-ethoxy-5-isobutyrylaminobenzoylamino)methyl)benzoate (350 mg, 0.878 mmol), MeOH (5 mL) 31.6mg, 1.32mmol) dissolved in H 2 O (3mL) was added to the reaction flask, added, stirred at room temperature, the next day, the reaction was stopped, concentrated, added water, extracted with 15mL of ether, the water layer was adjusted with PH The mixture was extracted with a mixture of dichloromethane:methanol = 10:1 (60 mL × 2). Melting point: 187-189 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.94(s,1H),9.80(s,1H),8.66(t,J＝5.6Hz,1H),7.95(s,1H),7.90(d,J＝2.8Hz,1H),7.83(d,J＝7.6Hz,1H),7.77(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.60(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.07(d,J＝8.8Hz,1H),4.56(d,J＝6.0Hz,2H),4.11(q,J＝6.8Hz,2H),2.53-2.57(m,1H),1.30(t,J＝6.8Hz,3H),1.09(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 12.94 (s, 1H), 9.80 (s, 1H), 8.66 (t, J = 5.6Hz, 1H), 7.95 (s, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.77 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.60 (d, J = 7.6) Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.11 (q, J = 6.8 Hz, 2H), 2.53-2.57 (m, 1H), 1.30 (t, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 6H).

实施例(化合物)86Example (compound) 86

3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯甲酸3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)benzoic acid

Figure PCTCN2018088561-appb-000146
Figure PCTCN2018088561-appb-000146

将3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯酸甲酯(250mg,0.606mmol)，加入MeOH(4mL),THF(4mL)，将LiOH(21.8mg,0.909mmol)溶于H 2O(2.5mL)加入反应瓶中，加毕，室温搅拌反应，次日，停止反应，浓缩，加水，用乙醚15mL萃取，水层用稀HCl溶液调PH值至2左右，抽滤，滤饼水洗，得到白色固体220mg，产率91.2％。熔点：99-101℃ Methyl 3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)benzoate (250 mg, 0.606 mmol), MeOH (4 mL) LiOH (21.8 mg, 0.909 mmol) was dissolved in H 2 O (2.5 mL) and added to the reaction flask. After the addition was completed, the reaction was stirred at room temperature. The next day, the reaction was stopped, concentrated, water was added, and extracted with 15 mL of diethyl ether. The pH was adjusted to about 2, suction filtration, and the filter cake was washed with water to give a white solid, 220 mg, yield 91.2%. Melting point: 99-101 ° C

1H-NMR(500MHz,DMSO-d 6)δ(ppm):12.96(brs,1H),9.78(s,1H),8.58(d,J＝7.0Hz,1H),7.85(s,1H),7.83(d,J＝7.5Hz,1H),7.76(d,J＝8.5Hz,1H),7.65(d,J＝7.5Hz,1H),7.47(t,J＝7.5Hz,1H),7.07(d,J＝9.0Hz,1H),5.16-5.19(m,1H),4.10-4.13(m,2H),2.52-2.55(m,1H),1.47(d,J＝7.0Hz,3H),1.34(t,J＝6.5Hz,3H),1.08(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, DMSO -d 6) δ (ppm): 12.96 (brs, 1H), 9.78 (s, 1H), 8.58 (d, J = 7.0Hz, 1H), 7.85 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.07 ( d, J = 9.0 Hz, 1H), 5.16-5.19 (m, 1H), 4.10-4.13 (m, 2H), 2.52-2.55 (m, 1H), 1.47 (d, J = 7.0 Hz, 3H), 1.34 (t, J = 6.5 Hz, 3H), 1.08 (d, J = 6.5 Hz, 6H).

实施例(化合物)87Example (compound) 87

N-(3-氨基甲酰苯甲基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(3-carbamoylbenzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000147
Figure PCTCN2018088561-appb-000147

将3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸(80mg,0.208mmol)加入无水DMF(10mL)，加入EDC(78mg,0.408mmol)，加入HOBt(55mg,0.408mmol)和DIEA(0.18mL,1.04mmol)，加入化合物氨水(0.05mL,0.408mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×8)萃取，合 并有机层用无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝20:1)，得到白色固体14mg，产率17.5％。熔点：184-186℃3-((2-Ethoxy-5-isobutyrylaminobenzoylamino)methyl)benzoic acid (80 mg, 0.208 mmol) was added EtOAc (EtOAc) Add HOBt (55 mg, 0.408 mmol) and DIEA (0.18 mL, 1.04 mmol), add compound aqueous ammonia (0.05 mL, 0.408 mmol), stir at room temperature overnight, pour the reaction solution into water, using ethyl acetate: methanol = 10:1 The mixture was extracted (30 mL×8), EtOAcjjjjjjjjjjjjjj 17.5%. Melting point: 184-186 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.80(s,1H),8.62(t,J＝6.8Hz,1H),7.95(s,1H),7.92(d,J＝2.4Hz,1H),7.68(s,1H),7.74-7.79(m,2H),7.50(d,J＝7.2Hz,1H),7.40(t,J＝7.6Hz,1H),7.34(s,1H),7.07(d,J＝8.8Hz,1H),4.54(d,J＝5.6Hz,2H),4.11(q,J＝6.8Hz,2H),2.53-2.57(m,1H),1.29(t,J＝6.8Hz,3H),1.09(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.80 (s, 1H), 8.62 (t, J = 6.8Hz, 1H), 7.95 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.74-7.79 (m, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.34 (s, 1H) ), 7.07 (d, J = 8.8 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.11 (q, J = 6.8 Hz, 2H), 2.53-2.57 (m, 1H), 1.29 (t) , J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 6H).

实施例(化合物)88Example (compound) 88

N-(1-(3-氨基甲酰苯基)乙基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(1-(3-carbamoylphenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000148
Figure PCTCN2018088561-appb-000148

将3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯酸甲酯(100mg,0.24mmol)置于微波反应管中，加入7M氨的甲醇溶液(3.5mL,24.5mmol)微波反应，Temp 100℃,time 3+3+3h，仍有大量原料剩余，浓缩柱层析(D:M＝50:1，D:M＝25:1)得到产物40mg。熔点：134-136℃Methyl 3-(1-(2-ethoxy-5-isobutyrylbenzoylamino)ethyl)benzoate (100 mg, 0.24 mmol) was placed in a microwave reaction tube, and a solution of 7 M ammonia in methanol was added. (3.5mL, 24.5mmol) microwave reaction, Temp 100 ° C, time 3 + 3 + 3h, there is still a large amount of raw materials remaining, concentrated column chromatography (D: M = 50: 1, D: M = 25: 1) to obtain the product 40mg. Melting point: 134-136 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.79(d,J＝6.4Hz,1H),8.56(brs,1H),7.90-7.96(m,3H),7.76-7.78(m,2H),7.56(brs,1H),7.34-7.43(m,2H),7.08(brs,1H),5.16(brs,1H),4.12(brs,2H),2.51(brs,1H),1.49(brs,3H),1.35(brs,3H),1.09(brs,6H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.79 (d, J = 6.4 Hz, 1H), 8.56 (brs, 1H), 7.90-7.96 (m, 3H), 7.76-7.78 (m) , 2H), 7.56 (brs, 1H), 7.34-7.43 (m, 2H), 7.08 (brs, 1H), 5.16 (brs, 1H), 4.12 (brs, 2H), 2.51 (brs, 1H), 1.49 ( Brs, 3H), 1.35 (brs, 3H), 1.09 (brs, 6H).

实施例(化合物)89Example (compound) 89

2-乙氧基-5-异丁酰氨基-N-(3-(甲基氨基甲酰)苯甲基)苯酰胺2-ethoxy-5-isobutyrylamino-N-(3-(methylcarbamoyl)benzyl)benzamide

Figure PCTCN2018088561-appb-000149
Figure PCTCN2018088561-appb-000149

将3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸(90mg,0.234mmol)加入无水DMF(10mL)，加入EDC(90mg,0.468mmol)，加入HOBt(63mg,0.468mmol)和DIEA(0.20mL,1.17mmol)，加入甲胺盐酸盐(31mg,0.468mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1, D:M＝30:1)，得到白色固体49mg，产率52.6％。熔点：185-187℃3-((2-Ethoxy-5-isobutyrylaminobenzoylamino)methyl)benzoic acid (90 mg, 0.234 mmol) was added EtOAc (EtOAc) Add HOBt (63 mg, 0.468 mmol) and DIEA (0.20 mL, 1.17 mmol), EtOAc (EtOAc, m. The mixture was extracted with a mixture of 1 (30 mL × 2), and the combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (D:M=60:1, D:M=30) :1), 49 mg of a white solid was obtained, yield 52.6%. Melting point: 185-187 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.47(d,J＝5.2Hz,1H),8.17(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.88(d,J＝2.4Hz,1H),7.77(s,1H),7.65-7.68(m,2H),7.47(d,J＝7.6Hz,1H),7.39(t,J＝7.6Hz,1H),6.90(d,J＝9.2Hz,1H),6.34(brs,1H),4.68(d,J＝5.6Hz,2H),4.11(q,J＝7.2Hz,2H),2.99(d,J＝4.8Hz,3H),2.51-2.55(m,1H),1.32(t,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.47 (d, J = 5.2Hz, 1H), 8.17 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.65-7.68 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 6.90 ( d, J = 9.2 Hz, 1H), 6.34 (brs, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 2.99 (d, J = 4.8 Hz, 3H), 2.51-2.55 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)90Example (compound) 90

2-乙氧基-5-异丁酰氨基-N-(1-(3-(甲基氨基甲酰)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(methylcarbamoyl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000150
Figure PCTCN2018088561-appb-000150

将3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯甲酸(80mg,0.201mmol)加入无水DMF(10mL)，加入EDC(77mg,0.402mmol)，加入HOBt(54mg,0.402mmol)和DIEA(0.21mL,1.206mmol)，加入化合物甲胺盐酸盐(20.4mg,0.301mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝30:1)，得到白色固体35mg，产率42.7％。熔点：249-251℃Add 3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)benzoic acid (80 mg, 0.201 mmol) to dry DMF (10 mL). Add HOBt (54mg, 0.402mmol) and DIEA (0.21mL, 1.206mmol), add the compound methylamine hydrochloride (20.4mg, 0.301mmol), stir at room temperature overnight, pour the reaction solution into water with ethyl acetate The mixture was extracted with a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate D: M = 30: 1) gave 35 mg of a white solid, yield 42.7%. Melting point: 249-251 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.79(s,1H),8.55(d,J＝7.6Hz,1H),7.88(d,J＝2.8Hz,1H),7.85(s,1H),7.76(dd,J 1＝9.2Hz,J 1＝2.4Hz,1H),7.69(d,J＝7.6Hz,1H),7.54(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),7.07(d,J＝8.8Hz,1H),5.13-5.18(m,1H),4.11(q,J＝7.2Hz,2H),2.78(d,J＝4.4Hz,3H),2.52-2.56(m,1H),1.48(d,J＝6.8Hz,3H),1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 9.79 (s, 1H), 8.85 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.85 ( s, 1H), 7.76 (dd, J 1 = 9.2 Hz, J 1 = 2.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 ( t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.13-5.18 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.78 (d, J = 4.4) Hz, 3H), 2.52-2.56 (m, 1H), 1.48 (d, J = 6.8 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)91Example (compound) 91

N-(3-(二甲基氨基甲酰)苯甲基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(3-(Dimethylcarbamoyl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000151
Figure PCTCN2018088561-appb-000151

将3-((2-乙氧基-5-异丁酰氨基苯甲酰氨基)甲基)苯甲酸(90mg,0.234mmol)加入无水DMF(10mL)，加入EDC(90mg,0.468mmol)，加入HOBt(63mg,0.468mmol) 和DIEA(0.20mL,1.17mmol)，加入化合物二甲胺盐酸盐(39mg,0.468mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝30:1)，得到白色固体40mg，产率41.6％。熔点：150-152℃3-((2-Ethoxy-5-isobutyrylaminobenzoylamino)methyl)benzoic acid (90 mg, 0.234 mmol) was added EtOAc (EtOAc) HOBt (63 mg, 0.468 mmol) and DIEA (0.20 mL, 1.17 mmol) were added, and the compound dimethylamine hydrochloride (39 mg, 0.468 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was extracted with a mixture of 10:1 (30 mL×2). 40 mg, yield 41.6%. Melting point: 150-152 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.42(t,J＝4.8Hz,1H),8.21(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.87(d,J＝2.8Hz,1H),7.63(s,1H),7.45(s,1H),7.37-7.40(m,2H),7.26-7.31(m,1H),6.90(d,J＝9.2Hz,1H),4.68(d,J＝5.2Hz,2H),4.10(q,J＝7.2Hz,2H),3.11(brs,3H),2.97(brs,3H),2.51-2.54(m,1H),1.31(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.42 (t, J = 4.8 Hz, 1H), 8.21. (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.87 (d, J=2.8 Hz, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.37-7.40 (m, 2H), 7.26-7.31 (m, 1H), 6.90 (d, J = 9.2 Hz, 1H) ), 4.68 (d, J = 5.2 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.11 (brs, 3H), 2.97 (brs, 3H), 2.51-2.54 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)92Example (compound) 92

N-(1-(3-(二甲基氨基甲酰)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(Dimethylcarbamoyl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000152
Figure PCTCN2018088561-appb-000152

将3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯甲酸(90mg,0.226mmol)加入无水DMF(10mL)，加入EDC(87mg,0.45mmol)，加入HOBt(61mg,0.45mmol)和DIEA(0.35mL,1.356mmol)，加入化合物二甲胺盐酸盐(28mg,0.34mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝30:1)，得到白色固体50mg，产率52.1％。熔点：67-69℃ 1H-NMR(400MHz,CDCl 3)δ(ppm):8.47(d,J＝7.2Hz,1H),8.19(dd,J 1＝8.8Hz,J 1＝2.4Hz,1H),7.80(d,J＝2.8Hz,1H),7.43-7.47(m,3H),7.37(t,J＝7.2Hz,1H),7.29(d,J＝7.6Hz,1H),6.92(d,J＝8.8Hz,1H),5.30-5.34(m,1H),4.16(q,J＝6.8Hz,2H),3.09(brs,3H),2.96(brs,3H),1.57(d,J＝6.8Hz,3H),1.47(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H). Add 3-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)benzoic acid (90 mg, 0.226 mmol) to dry DMF (10 mL). Add HOBt (61 mg, 0.45 mmol) and DIEA (0.35 mL, 1.356 mmol), add the compound dimethylamine hydrochloride (28 mg, 0.34 mmol), stir at room temperature overnight, pour the mixture into water and ethyl acetate The mixture was extracted with a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate D: M = 30: 1) gave 50 mg of a white solid, yield 521. Melting point: 67-69 ° C 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.47 (d, J = 7.2 Hz, 1H), 8.19 (dd, J 1 = 8.8 Hz, J 1 = 2.4 Hz, 1H ), 7.80 (d, J = 2.8 Hz, 1H), 7.43 - 7.47 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.92 (d) , J = 8.8 Hz, 1H), 5.30-5.34 (m, 1H), 4.16 (q, J = 6.8 Hz, 2H), 3.09 (brs, 3H), 2.96 (brs, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.47 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)93Example (compound) 93

2-乙氧基-N-(1-(3-((2-羟基乙基)氨基甲酰)苯基)乙基)-5-异丁酰氨基苯甲酰胺2-ethoxy-N-(1-(3-((2-hydroxyethyl))carbamoyl)phenyl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000153
Figure PCTCN2018088561-appb-000153

将3-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)苯酸甲酯(230mg,0.56mmol)加入异丙醇(8mL)，加入乙醇胺(36mg,0.586mmol)以及K 3PO 4(59mg,0.28mmol)，加热回流反应，6h后停止反应，浓缩，柱层析(D:M＝30:1)得到粘稠状固体120mg，产率48.5％。 Methyl 3-(1-(2-ethoxy-5-isobutyrylbenzoylamino)ethyl)benzoate (230 mg, 0.56 mmol) was added to isopropanol (8 mL) and ethanolamine (36 mg, 0.586 mmol) and K 3 PO 4 (59 mg, 0.28 mmol) were heated to reflux. After 6 h, the reaction was quenched and concentrated and purified by column chromatography (D:M=30:1) to give vis.

1H-NMR(500MHz,CDCl 3)δ(ppm):8.57(d,J＝7.0Hz,1H),8.40(s,1H),8.19(dd,J 1＝8.5Hz,J 1＝2.0Hz,1H),7.76(s,1H),7.63(d,J＝7.5Hz,1H),7.59(s,1H),7.41(d,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),6.87(d,J＝9.0Hz,1H),5.13-5.16(m,1H),4.14(q,J＝7.0Hz,2H),3.81(s,2H),3.68-3.72(m,1H),3.51-3.55(m,1H),2.55-2.58(m,1H),1.53(d,J＝6.5Hz,3H),1.47(t,J＝7.0Hz,3H),1.17-1.19(m,6H). 1 H-NMR (500MHz, CDCl 3) δ (ppm): 8.57 (d, J = 7.0Hz, 1H), 8.40 (s, 1H), 8.19 (dd, J 1 = 8.5Hz, J 1 = 2.0Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 5.13-5.16 (m, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.81 (s, 2H), 3.68-3.72 (m, 1H) ), 3.51-3.55 (m, 1H), 2.55-2.58 (m, 1H), 1.53 (d, J = 6.5 Hz, 3H), 1.47 (t, J = 7.0 Hz, 3H), 1.7-1.19 (m, 6H).

实施例(化合物)94Example (compound) 94

N-(1-(3-(4,5-二氢噁唑-2-基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(4,5-Dihydrooxazol-2-yl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000154
Figure PCTCN2018088561-appb-000154

将DDQ(68mg,0.3mmol)，PPh 3(78mg,0.3mmol)置于反应瓶中，加入DCM(5mL)，室温搅拌片刻后，将2-乙氧基-N-(1-(3-((2-羟基乙基)氨基甲酰)苯基)乙基)-5-异丁酰氨基苯甲酰胺(90mg,0.20mmol)溶于THF(5mL)中加入反应瓶中，加毕，室温搅拌反应，次日，TLC显示仍有大量原料剩余，浓缩，加入DCM(30mL)，用饱和NaHCO 3溶液(10mL)洗，饱和NaCL溶液(10mL)洗，无水硫酸镁干燥，浓缩，用THF(5mL)溶解滴加入有化合物DDQ(136mg,0.6mmol)，PPh 3(156mg,0.6mmo)的DCM(5mL)的反应瓶中，升温至40℃反应，次日，原料消失，浓缩至干，加入DCM(30mL)，用饱和NaHCO 3溶液(10mL)洗，饱和NaCL溶液(10mL)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1,D:M＝75:1,D:M＝60:1,D:M＝35:1)得到类白色固体40mg，产率47％。熔点：75-77℃ DDQ (68 mg, 0.3 mmol), PPh 3 (78 mg, 0.3 mmol) was placed in a reaction flask, DCM (5 mL) was added and stirred at room temperature for a while, then 2-ethoxy-N-(1-(3-( (2-Hydroxyethyl)carbamoyl)phenyl)ethyl)-5-isobutyrylaminobenzamide (90 mg, 0.20 mmol) was dissolved in THF (5 mL). The reaction, the next day, still a lot of starting material remaining display TLC, concentrated, DCM (30mL), washed with saturated NaHCO 3 solution (10 mL), saturated NaCL solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated, washed with THF ( 5 mL) A reaction flask containing compound DDQ (136 mg, 0.6 mmol), PPh 3 (156 mg, 0.6 mmo) in DCM (5 mL) was added dropwise, and the mixture was warmed to 40 ° C. The next day, the starting material disappeared, concentrated to dryness, and added. Was washed with saturated NaHCO 3 (10 mL), washed with saturated NaCI solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=90:1, D:M=75:1) , D: M = 60: 1, D: M = 35: 1) gave 40 mg of white solid, yield 47%. Melting point: 75-77 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.49(d,J＝7.6Hz,1H),8.20(dd,J 1＝9.2Hz,J 1＝2.8Hz,1H),7.97(s,1H),7.85(d,J＝8.0Hz,1H),7.81(d,J＝2.8Hz,1H),7.57(s,1H),7.50(d,J＝8.0Hz,1H),7.40(t,J＝8.0Hz,1H),6.92(d,J＝9.2Hz,1H), 5.30-5.34(m,1H),4.43(t,J＝9.6Hz,2H),4.16(q,J＝6.8Hz,2H),4.06(t,J＝9.2Hz,2H),2.47-2.51(m,1H),1.59(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.21(dd,J 1＝7.2Hz,J 2＝1.6Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.49 (d, J = 7.6 Hz, 1H), 8.20 (dd, J 1 = 9.2 Hz, J 1 = 2.8 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 5.30-5.34 (m, 1H), 4.43 (t, J = 9.6 Hz, 2H), 4.16 (q, J = 6.8 Hz, 2H), 4.06 (t, J = 9.2 Hz, 2H), 2.47-2.51 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.21. Dd, J 1 = 7.2 Hz, J 2 = 1.6 Hz, 6H).

实施例(化合物)95Example (compound) 95

2-乙氧基-5-异丁酰氨基-N-(3-甲基苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-methylbenzyl)benzamide

Figure PCTCN2018088561-appb-000155
Figure PCTCN2018088561-appb-000155

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入化合物3-甲基苄胺(106mg,0.878mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到白色固体130mg，产率83.9％。熔点：168-170℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), the compound 3-methylbenzylamine (106 mg, 0.878 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water, and a mixture of ethyl acetate:methanol = 10:1 (30 mL × 2) The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc) Melting point: 168-170 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.41(t,J＝4.4Hz,1H),8.25(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.95(d,J＝2.8Hz,1H),7.82(s,1H),7.23(d,J＝7.6Hz,1H),7.14-7.17(m,2H),7.10(d,J＝7.6Hz,1H),6.92(d,J＝9.2Hz,1H),4.63(d,J＝5.6Hz,2H),4.12(q,J＝6.8Hz,2H),2.50-2.57(m,1H),2.35(s,3H),1.32(t,J＝6.8Hz,3H),1.21(d,J＝7.2Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.41 (t, J = 4.4 Hz, 1H), 8.25 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.82 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.14 - 7.17 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.92 ( d, J = 9.2 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 4.12 (q, J = 6.8 Hz, 2H), 2.50-2.57 (m, 1H), 2.35 (s, 3H), 1.32 (t, J = 6.8 Hz, 3H), 1.21 (d, J = 7.2 Hz, 6H).

实施例(化合物)96Example (compound) 96

2-乙氧基-5-异丁酰氨基-N-(1-(m-苯甲基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(m-benzyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000156
Figure PCTCN2018088561-appb-000156

将2-乙氧基-5-异丁酰氨基苯甲酸(900mg,3.585mmol)加入无水DMF(40mL)，加入EDC(1.38g,7.17mmol)，加入HOBt(968mg,7.17mmol)和DIEA(1.87mL,10.76mmol)，加入1-(间-苯甲基)乙胺(630mg,4.66mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(60mL×2)萃取，合并有机层用饱和NaCl溶液(40mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3,E:P＝1:1.5)，得到白色固体1.09g，产率82.5％。熔点：161-163℃2-Ethoxy-5-isobutyrylaminobenzoic acid (900 mg, 3.585 mmol) was added to dry DMF (40 mL), EtOAc (EtOAc: EtOAc, 1.87 mL, 10.76 mmol), 1-(m-phenylmethyl)ethylamine (630 mg, 4.66 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water, and a mixture mixture of ethyl acetate:methanol = 10:1 (60 mL × 2), the combined organic layer was washed with a saturated NaCI solution (40 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:3, E:P=1:1.5) A white solid was obtained, 1.09 g, yield 82.5%. Melting point: 161-163 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.46(d,J＝7.0Hz,1H),8.22(dd,J 1＝9.0Hz,J 1＝2.5Hz,1H),7.86-7.87(m,1H),7.61(brs,1H),7.24(t,J＝7.5Hz,1H),7.16-7.18(m,2H),7.08(d,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,1H),5.25-5.28(m,1H),4.11-4.18(m,2H),2.48-2.51(m,1H),2.35(s,3H),1.57(d,J＝6.5Hz,3H),1.41(t,J＝7.0Hz,3H),1.22(dd,J 1＝5.6Hz,J 1＝2.4Hz,6H). 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 8.46 (d, J = 7.0 Hz, 1H), 8.22 (dd, J 1 = 9.0 Hz, J 1 = 2.5 Hz, 1H), 7.86-7.87 ( m,1H), 7.61 (brs, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.16-7.18 (m, 2H), 7.08 (d, J = 7.0 Hz, 1H), 6.92 (d, J) = 9.0 Hz, 1H), 5.25-5.28 (m, 1H), 4.11-4.18 (m, 2H), 2.48-2.51 (m, 1H), 2.35 (s, 3H), 1.57 (d, J = 6.5 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.22 (dd, J 1 = 5.6 Hz, J 1 = 2.4 Hz, 6H).

实施例(化合物)97Example (compound) 97

5-(2-环丙基乙酰氨基)-2-乙氧基-N-(1-(3-甲基苯基)乙基)苯甲酰胺5-(2-cyclopropylacetamido)-2-ethoxy-N-(1-(3-methylphenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000157
Figure PCTCN2018088561-appb-000157

a)2-乙氧基-5-硝基-N-(1-(3-甲基苯基)乙基)苯甲酰胺a) 2-ethoxy-5-nitro-N-(1-(3-methylphenyl)ethyl)benzamide

将2-乙氧基-5-硝基苯甲酸(600mg，2.84mmol)溶于DCM(25mL)，加入HATU(1.620g，4.26mmol)，DIEA(1.10g，8.52mmol)，室温反应20min，加入1-(3-甲基苯基)乙基-1-胺(576mg，4.26mmol)，室温反应过夜。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝3:1)，得白色固体740mg，收率79％。熔点：82-84℃.2-Ethoxy-5-nitrobenzoic acid (600 mg, 2.84 mmol) was dissolved in DCM (25 mL), EtOAc (1. EtOAc, &lt;RTIgt; 1-(3-Methylphenyl)ethyl-1-amine (576 mg, 4.26 mmol) was reacted at room temperature overnight. Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 3:1) gave 740 mg of white solid. Melting point: 82-84 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):9.10(d,J＝3.2Hz,1H),8.29(dd,J 1＝3.2Hz,J 2＝9.2Hz,1H),8.11(d,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),7.03(d,J＝9.2Hz,1H),5.24-5.31(m,1H),4.22-4.33(m,1H),2.36(s,3H),1.69(d,J＝7.2Hz,1H),1.49(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 9.10 (d, J = 3.2 Hz, 1H), 8.29 (dd, J 1 = 3.2 Hz, J 2 = 9.2 Hz, 1H), 8.11 (d) , J = 7.2 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.03 (d, J) = 9.2 Hz, 1H), 5.24 - 5.31 (m, 1H), 4.22-4.33 (m, 1H), 2.36 (s, 3H), 1.69 (d, J = 7.2 Hz, 1H), 1.49 (t, J = 7.2 Hz, 3H).

b)2-乙氧基-5氨基-N-(1-(3-甲基苯基)乙基)苯甲酰胺b) 2-Ethoxy-5amino-N-(1-(3-methylphenyl)ethyl)benzamide

2-乙氧基-5-硝基-N-(1-(m-甲基苯基)乙基)苯甲酰胺(200mg，0.47mmol)溶于THF(10mL)，H 2/50℃反应17h。原料消失。过滤，浓缩，柱层析(P:E＝1:1)，得微黄色固体129mg，收率70％。熔点：121-123℃. 2-ethoxy-5-nitro -N- (1- (m- methylphenyl) ethyl) benzamide (200mg, 0.47mmol) was dissolved in THF (10mL), the reaction 17h H 2/50 ℃ . The raw materials disappeared. Filtration, concentration and column chromatography (P: E = 1:1) gave 129 mg ofyellow solid. Melting point: 121-123 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.79(d,J＝7.6Hz,1H),7.97(d,J＝1.6Hz,1H),7.92(d,J＝3.2Hz,1H),7.82(dt,J 1＝1.6Hz,J 2＝7.2Hz 1H),7.79(d,J＝3.2Hz,1H),7.45-7.53(m,2H),7.09(d,J＝3.2Hz,1H),5.16-5.23(m,1H),3.84(d,J＝7.2Hz,2H),1.51(d,J＝7.2Hz,3H),1.16-1.25(m,1H),0.46-0.51(m,2H),0.29-0.30(m,2H). 1H NMR (400MHZ, CDCl 3 ) δ (ppm): 8.79 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.82 (dt, J 1 =1.6 Hz, J 2 =7.2 Hz 1H), 7.79 (d, J = 3.2 Hz, 1H), 7.45-7.53 (m, 2H), 7.09 (d, J = 3.2 Hz, 1H), 5.16-5.23(m,1H), 3.84(d,J=7.2Hz,2H), 1.51(d,J=7.2Hz,3H),1.16-1.25(m,1H),0.46-0.51(m,2H) , 0.29-0.30 (m, 2H).

c)5-(2-环丙基乙酰氨基)-2-乙氧基-N-(1-(3-甲基苯基)乙基)苯甲酰胺c) 5-(2-cyclopropylacetamido)-2-ethoxy-N-(1-(3-methylphenyl)ethyl)benzamide

将环丙基乙酸(24mg，0.24mmol)溶于DCM(2mL)，加入HATU(111mg，0.29mmol)，DIEA(62mg，0.48mmol)，室温反应1h，加入2-乙氧基-5-氨基-N-(1-(3- 甲基)苯基)乙胺)苯甲酰胺(80mg，0.29mmol)，室温反应过夜。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体40mg，收率44％。熔点：185-187℃.Cyclopropylacetic acid (24 mg, 0.24 mmol) was dissolved in DCM (2 mL), EtOAc (EtOAc, EtOAc (EtOAc) N-(1-(3-methyl)phenyl)ethylamine)benzamide (80 mg, 0.29 mmol). Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave 40 mg of white solid. Melting point: 185-187 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.45(d,J＝7.2Hz,1H),8.17(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),7.80(d,J＝2.8Hz,1H),7.49(s,1H),7.23(d,J＝7.6Hz,1H),7.18(d,J＝8.8Hz,1H),7.08(d,J＝7.6Hz,1H),6.90(d,J＝8.8Hz,1H),5.23-5.30(m,1H),4.10-4.18(m,2H),2.35(s,3H),1.57(d,J＝6.8Hz,3H),1.44(d,J＝3.6Hz,3H),1.41(d,J＝7.2Hz,3H),1.29(q,J＝2.8Hz,2H),0.67(q,J＝2.8Hz,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.45 (d, J = 7.2 Hz, 1H), 8.17 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 7.80 (d, J) = 2.8 Hz, 1H), 7.49 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.23-5.30 (m, 1H), 4.10-4.18 (m, 2H), 2.35 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.44 (d, J = 3.6 Hz, 3H), 1.41 (d, J = 7.2 Hz, 3H), 1.29 (q, J = 2.8 Hz, 2H), 0.67 (q, J = 2.8 Hz, 2H).

实施例(化合物)98Example (compound) 98

2-乙氧基-5-(1-甲基环丙基-1-甲酰胺)-N-(1-(m-甲基苯基)乙基)苯甲酰胺2-ethoxy-5-(1-methylcyclopropyl-1-carboxamide)-N-(1-(m-methylphenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000158
Figure PCTCN2018088561-appb-000158

将1-甲基环丙基甲酸(24mg，0.24mmol)溶于DCM(2mL)，加入HATU(111mg，0.29mmol)，DIEA(62mg，0.48mmol)，室温反应1h，加入2-乙氧基-5-氨基-N-(1-(3-甲基)苯基)乙胺)苯甲酰胺(80mg，0.29mmol)，室温反应3.5h。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体82mg，收率90％。熔点：168-170℃.1-Methylcyclopropyl-formic acid (24 mg, 0.24 mmol) was dissolved in DCM (2 mL), EtOAc (EtOAc, EtOAc (EtOAc) 5-Amino-N-(1-(3-methyl)phenyl)ethylamine)benzamide (80 mg, 0.29 mmol). Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid (yield: 82). Melting point: 168-170 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.47(d,J＝7.2Hz,1H),8.22(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),7.83(d,J＝7.6Hz,2H),7.23(d,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,1H),7.08(d,J＝7.2Hz,1H),6.93(d,J＝8.8Hz,1H),5.22-5.29(m,1H),4.10-4.19(m,2H),2.35(s,3H),2.31(d,J＝7.2Hz,3H),1.57(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),0.99-1.07(m,1H),0.66-0.71(q,J＝6.5Hz,2H),0.25-0.29(q,J＝6.5Hz,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.47 (d, J = 7.2 Hz, 1H), 8.22 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 7.83 (d, J) = 7.6 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.22-5.29 (m, 1H), 4.10-4.19 (m, 2H), 2.35 (s, 3H), 2.31 (d, J = 7.2 Hz, 3H), 1.57 (d, J = 6.8 Hz) , 3H), 1.42 (t, J = 6.8 Hz, 3H), 0.99 - 1.07 (m, 1H), 0.66 - 0.71 (q, J = 6.5 Hz, 2H), 0.25 - 0.29 (q, J = 6.5 Hz, 2H).

实施例(化合物)99Example (compound) 99

N-(4-乙氧基-3-((1-间甲基苯基)乙基)氨基甲酰基)苯基)噻唑-5-甲酰胺N-(4-Ethoxy-3-((1-m-methylphenyl)ethyl)carbamoyl)phenyl)thiazole-5-carboxamide

Figure PCTCN2018088561-appb-000159
Figure PCTCN2018088561-appb-000159

将5-噻唑甲酸(31mg，0.24mmol)溶于DCM(3mL)，加入HATU(111mg，0.29mmol)，DIEA(62mg，0.48mmol)，室温反应20min，加入1-(3-甲基苯基) 乙基-1-胺(80mg，0.29mmol)的DCM溶液(2mL)，室温反应6h。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体77mg，收率78％。熔点：111-113℃.5-thiazolecarboxylic acid (31 mg, 0.24 mmol) was dissolved in DCM (3 mL), EtOAc (EtOAc (EtOAc) Ethyl-1-amine (80 mg, 0.29 mmol) in EtOAc (2 mL). Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid (yield: 77). Melting point: 111-113 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.97(brs,1H),8.89(s,1H),8.53(s,1H),8.48(d,J＝8.4Hz,1H),8.21(d,J＝8.4Hz,1H),8.09(d,J＝2.8Hz,1H),7.15(t,J＝7.6Hz,1H),7.02(d,J＝11.6Hz,3H),6.94(d,J＝9.2Hz,1H),5.06-5.13(m,1H),4.12-4.19(m,2H),2.28(s,3H),1.47(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.97 (brs, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.21. , J = 8.4 Hz, 1H), 8.09 (d, J = 2.8 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 11.6 Hz, 3H), 6.94 (d, J = 9.2 Hz, 1H), 5.06-5.13 (m, 1H), 4.12-4.19 (m, 2H), 2.28 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8Hz, 3H).

实施例(化合物)100Example (compound) 100

N-(4-乙氧基-3-((1-(3-甲基苯基)乙基)氨基甲酰基)苯基)噻唑-4-甲酰胺N-(4-Ethoxy-3-((1-(3-methylphenyl)ethyl)carbamoyl)phenyl)thiazole-4-carboxamide

Figure PCTCN2018088561-appb-000160
Figure PCTCN2018088561-appb-000160

将4-噻唑甲酸(31mg，0.24mmol)溶于DCM(3mL)，加入HATU(111mg，0.29mmol)，DIEA(62mg，0.48mmol)，室温反应20min，加入1-(3-甲基苯基)乙基-1-胺(80mg，0.29mmol)的DCM溶液(2mL)，室温反应过夜。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体76mg，收率77％。熔点：125-127℃.4-thiazolecarboxylic acid (31 mg, 0.24 mmol) was dissolved in DCM (3 mL), EtOAc (EtOAc, EtOAc (EtOAc) Ethyl-1-amine (80 mg, 0.29 mmol) in EtOAc (2 mL) Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid, 76 mg, yield 77%. Melting point: 125-127 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.80(d,J＝2.0Hz,1H),8.44(d,J＝7.6Hz,1H),8.34(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),8.25(d,J＝2.0Hz,1H),8.03(d,J＝3.2Hz,1H),7.23(d,J＝7.6Hz,1H),7.19(d,J＝8.4Hz,1H),7.08(d,J＝7.2Hz,1H),6.98(d,J＝8.8Hz,1H),5.25-5.32(m,1H),4.13-4.21(m,2H),2.36(s,3H),1.58(d,J＝6.8Hz,3H),1.43(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.80 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.34 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 3.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 8.4) Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.25-5.32 (m, 1H), 4.13-4.21 (m, 2H), 2.36 (s) , 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 6.8 Hz, 3H).

实施例(化合物)101Example (compound) 101

N-(3-(二氟甲氧基)苯甲基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(3-(Difluoromethoxy)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000161
Figure PCTCN2018088561-appb-000161

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20 mmol)，加入化合物(3-(二氟甲氧基)苯基)甲胺(104mg,0.6mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到白色固体120mg，产率61.7％。熔点：123-125℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) The compound (3-(difluoromethoxy)phenyl)methanamine (104 mg, 0.6 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate: methanol = 10: The mixture was extracted with EtOAc (3 mL, EtOAc) (EtOAc) The yield was 61.7%. Melting point: 123-125 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.45(brs,1H),8.23(dd,J 1＝9.0Hz,J 1＝2.5Hz,1H),7.89(d,J＝2.5Hz,1H),7.57(brs,1H),7.35(t,J＝7.5Hz,1H),7.21(d,J＝8.0Hz,1H),7.12(s,1H),7.05(d,J＝8.0Hz,1H),6.94(d,J＝9.0Hz,1H),4.67(d,J＝5.5Hz,2H),4.15(q,J＝7.0Hz,2H),2.49-2.53(m,1H),1.35(t,J＝6.5Hz,3H),1.23(d,J＝7.0Hz,6H). 1 H-NMR (500MHz, CDCl 3) δ (ppm): 8.45 (brs, 1H), 8.23 (dd, J 1 = 9.0Hz, J 1 = 2.5Hz, 1H), 7.89 (d, J = 2.5Hz, 1H), 7.57 (brs, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.15 (q, J = 7.0 Hz, 2H), 2.49-2.53 (m, 1H), 1.35 ( t, J = 6.5 Hz, 3H), 1.23 (d, J = 7.0 Hz, 6H).

实施例(化合物)102Example (compound) 102

N-(1-(3-(二氟甲氧基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(Difluoromethoxy)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000162
Figure PCTCN2018088561-appb-000162

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入化合物1-(3-(二氟甲氧基)苯基)乙胺(90mg,0.48mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5,E:P＝1:2)，得到白色固体70mg，产率41.6％。熔点：137-139℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) The compound 1-(3-(difluoromethoxy)phenyl)ethylamine (90 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was extracted with a 10:1 mixture (30 mL×2), and the combined organic layer was washed with saturated NaCI (30mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:2.5, E:P =1: 2), 70 mg of a white solid was obtained, yield 41.6%. Melting point: 137-139 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.47(d,J＝7.6Hz,1H),8.21(d,J＝9.2Hz,1H),7.85(s,1H),7.68(s,1H),7.34(td,J 1＝8.0Hz,J 1＝1.6Hz,1H),7.22(d,J＝7.6Hz,1H),7.12(s,1H),7.01(d,J＝8.0Hz,1H),6.93(dd,J 1＝8.8Hz,J 1＝1.2Hz,1H),5.28-5.32(m,1H),4.17(q,J＝6.8Hz,2H),2.47-2.51(m,1H),1.56(d,J＝6.8Hz,3H),1.44(t,J＝6.8Hz,3H),1.20(dd,J 1＝6.8Hz,J 2＝2.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.47 (d, J = 7.6Hz, 1H), 8.21 (d, J = 9.2Hz, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.34 (td, J 1 = 8.0 Hz, J 1 = 1.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.93 (dd, J 1 = 8.8 Hz, J 1 = 1.2 Hz, 1H), 5.28-5.32 (m, 1H), 4.17 (q, J = 6.8 Hz, 2H), 2.47-2.51 (m, 1H) ), 1.56 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 6.8 Hz, 3H), 1.20 (dd, J 1 = 6.8 Hz, J 2 = 2.8 Hz, 6H).

实施例(化合物)103Example (compound) 103

2-乙氧基-5-异丁酰氨基-N-(3-甲氧苄基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-methoxybenzyl)benzamide

Figure PCTCN2018088561-appb-000163
Figure PCTCN2018088561-appb-000163

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.4mmol)加入无水DMF(15mL)，加入EDC(154mg,0.8mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.60mL,3.2mmol)，加入间甲氧基苄胺(71mg,0.52mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5,D:M＝60:1)，得到白色固体120mg，产率81％。熔点：152-154℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.4 mmol) was added to dry DMF (15 mL). E.sub.2 (154 mg, 0.8 mmol) was added to HOBt (108 mg, 0.80 mmol) and DIEA (0.60) mL, 3.2 mmol), m-methoxybenzylamine (71 mg, 0.52 mmol) was added and stirred at room temperature overnight. The reaction solution was poured into water and extracted with a mixture of ethyl acetate:methanol=10:1 (40 mL×2) The combined organic layer was washed with a saturated NaCI solution (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (E:P=1:2.5, D:M=60:1) The rate is 81%. Melting point: 152-154 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.43(brs,1H),8.24(dd,J 1＝8.8,J 2＝2.8,1H),7.91(d,J＝2.8Hz,1H),7.66(s,1H),7.27(t,J＝8.0Hz,1H),6.89-6.95(m,3H),6.81-6.84(m,1H),4.64(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),3.83(s,3H),2.51-2.55(m,1H),1.33(t,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.43 (brs, 1H), 8.24 (dd, J 1 = 8.8, J 2 = 2.8,1H), 7.91 (d, J = 2.8Hz, 1H) , 7.66 (s, 1H), 7.27 (t, J = 8.0 Hz, 1H), 6.89-6.95 (m, 3H), 6.81-6.84 (m, 1H), 4.64 (d, J = 5.2 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H), 3.83 (s, 3H), 2.51-2.55 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H) ).

实施例(化合物)104Example (compound) 104

2-乙氧基-5-异丁酰氨基-N-(1-(3-甲氧苯基)乙基)苯酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-methoxyphenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000164
Figure PCTCN2018088561-appb-000164

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(10mL)，加入EDC(156mg,0.8mmol)，加入HOBt(108mg,0.8mmol)和DIEA(0.21mL,1.20mmol)，加入1-(3-甲氧苯基)乙胺(121mg,0.8mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1)，得到白色固体140mg，产率90.9％。熔点：138-140℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (10 mL). E.sub.2 (156 mg, 0.8 mmol) was added to HOBt (108 mg, 0.8 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(3-methoxyphenyl)ethylamine (121 mg, 0.8 mmol) was added, and stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate: methanol = 10:1 mixture (30 mL × 2), the combined organic layer was washed with saturated NaCI (15 mL × 2), dried over anhydrous magnesium sulfate. %. Melting point: 138-140 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.47(d,J＝7.6Hz,1H),8.22(dd,J 1＝9.2Hz,J 1＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.66(s,1H),7.27(t,J＝7.6Hz,1H),6.95-6.97(m,1H),6.90-6.93(m,2H),6.78-6.82(m,1H),5.26-5.29(m,1H),4.11-4.18(M,2H),3.80(s,3H),2.46-2.51(m,1H),1.56(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.20(dd,J 1＝6.8Hz,J 2＝2.0Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.47 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 9.2Hz, J 1 = 2.8Hz, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.66 (s, 1H), 7.27 (t, J=7.6 Hz, 1H), 6.95-6.97 (m, 1H), 6.90-6.93 (m, 2H), 6.78-6.82 (m) , 1H), 5.26-5.29 (m, 1H), 4.11-4.18 (M, 2H), 3.80 (s, 3H), 2.46-2.51 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.20 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 6H).

实施例(化合物)105Example (compound) 105

2-乙氧基-5-异丁酰氨基-N-(3-(吡啶-2-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-(pyridin-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000165
Figure PCTCN2018088561-appb-000165

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入(3-(吡啶-2-基)苯基)甲胺(216mg,0.8mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到白色固体80mg，产率47.9％。熔点：119-121℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) (3,1,20 mmol), (3-(pyridin-2-yl)phenyl)methanamine (216 mg, 0.8 mmol) was added and stirred at room temperature overnight, then poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (30 mL×2), EtOAc (EtOAc m. The yield was 47.9%. Melting point: 119-121 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.70(d,J＝5.2Hz,1H),8.49(t,J＝5.0Hz,1H),8.23(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),8.03(s,1H),7.90-7.94(m,2H),7.73-7.78(m,2H),7.48(t,J＝7.6Hz,1H),7.42-7.45(m,1H),7.24-7.28(m,1H),6.92(d,J＝9.2Hz,1H),4.75(d,J＝5.2Hz,2H),4.11(q,J＝7.2Hz,2H),2.51-2.55(m,1H),1.28(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.70 (d, J = 5.2 Hz, 1H), 8.49 (t, J = 5.0 Hz, 1H), 8.23 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1H), 8.03 (s, 1H), 7.90-7.94 (m, 2H), 7.73-7.78 (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.42-7.45 (m) , 1H), 7.24-7.28 (m, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.75 (d, J = 5.2 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 2.51 -2.55 (m, 1H), 1.28 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)106Example (compound) 106

2-乙氧基-5-异丁酰氨基-N-(1-(3-(吡啶-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(pyridin-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000166
Figure PCTCN2018088561-appb-000166

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入1-(3-(吡啶-2-基)苯基)乙烷-1-胺(95mg,0.48mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到白色固体105mg，产率60.7％。熔点：185-187℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(3-(pyridin-2-yl)phenyl)ethane-1-amine (95 mg, 0.48 mmol). The mixture was extracted with a mixture of methanol and 10:1 (30 mL×2). The combined organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate , 105 mg of a white solid was obtained in a yield of 60.7%. Melting point: 185-187 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):9.75(s,1H),8.62-8.63(m,1H),8.56(d,J＝6.8Hz,1H),8.09(s,1H),7.91-7.93(m,2H),7.82-7.85(m,2H),7.72(td,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.42-7.44(m,2H),7.29-7.33(m,1H),7.03(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),5.16-5.19(m,1H),4.04-4.10(m,2H),2.48-2.52(m,1H),1.48(d,J＝5.2Hz,3H), 1.27(t,J＝7.2Hz,3H),1.04(d,J＝6.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.75 (s, 1H), 8.62-8.63 (m, 1H), 8.56 (d, J = 6.8Hz, 1H), 8.09 (s, 1H), 7.91-7.93 (m, 2H), 7.82-7.85 (m, 2H), 7.72 (td, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.42-7.44 (m, 2H), 7.29-7.33 ( m,1H), 7.03 (dd, J 1 =8.8 Hz, J 2 =2.0 Hz, 1H), 5.16-5.19 (m, 1H), 4.04-4.10 (m, 2H), 2.48-2.52 (m, 1H) , 1.48 (d, J = 5.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.04 (d, J = 6.4 Hz, 6H).

实施例(化合物)107Example (compound) 107

2-乙氧基-5-异丁酰氨基-N-(3-(哒嗪-3-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-(pyridazin-3-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000167
Figure PCTCN2018088561-appb-000167

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入(3-(哒嗪-3-基)苯基)甲胺(120mg,0.65mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝50:1)，得到白色固体45mg，产率26.9％。熔点：128-130℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) (1,20 mmol), (3-(pyridazin-3-yl)phenyl)methanamine (120 mg, 0.65 mmol), mp. The mixture was extracted with EtOAc (3 mL, EtOAc) :1), 45 mg of a white solid was obtained in a yield of 26.9%. Melting point: 128-130 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):9.18(s,1H),8.52(s,1H),8.21(d,J＝7.5Hz,1H),8.13(s,1H),7.98(s,1H),7.91(s,1H),7.88(d,J＝8.5Hz,1H),7.51-7.59(m,4H),6.92(d,J＝8.5Hz,1H),4.77(s,2H),4.12-4.13(m,2H),2.50-2.58(m,1H),1.31(brs,3H),1.23(d,J＝5.5Hz,6H). 1 H-NMR (500MHz, CDCl 3) δ (ppm): 9.18 (s, 1H), 8.52 (s, 1H), 8.21 (d, J = 7.5Hz, 1H), 8.13 (s, 1H), 7.98 ( s, 1H), 7.91 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.51 - 7.59 (m, 4H), 6.92 (d, J = 8.5 Hz, 1H), 4.77 (s, 2H) ), 4.12-4.13 (m, 2H), 2.50-2.58 (m, 1H), 1.31 (brs, 3H), 1.23 (d, J = 5.5 Hz, 6H).

实施例(化合物)108Example (compound) 108

2-乙氧基-5-异丁酰氨基-N-(1-(3-(哒嗪-3-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(pyridazin-3-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000168
Figure PCTCN2018088561-appb-000168

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入1-(3-(哒嗪-3-基)苯基)乙烷-1-胺(119mg,0.6mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1)，得到白色固体32mg，产率18.6％。熔点：65-67℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(3-(pyridazin-3-yl)phenyl)ethane-1-amine (119 mg, 0.6 mmol) was added and stirred at room temperature overnight. The ester was extracted with a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate ), 32 mg of a white solid was obtained in a yield of 18.6%. Melting point: 65-67 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):9.16(d,J＝4.5Hz,1H),8.56(d,J＝7.0Hz,1H),8.19(d,J＝9.0Hz,1H),8.16(s,1H),7.92(d,J＝6.5Hz,1H),7.86(d,J＝8.5Hz,1H), 7.81(s,1H),7.50-7.56(m,3H),7.39-7.43(m,1H),6.92(d,J＝9.0Hz,1H),5.37-5.41(m,1H),4.17(q,J＝7.0Hz,2H),2.48-2.51(m,1H),1.65(d,J＝7.0Hz,3H),1.43(t,J＝7.0Hz,3H),1.22(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 9.16 (d, J = 4.5 Hz, 1H), 8.56 (d, J = 7.0 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H) , 8.16 (s, 1H), 7.92 (d, J = 6.5 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.50 - 7.56 (m, 3H), 7.39- 7.43 (m, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.37-5.41 (m, 1H), 4.17 (q, J = 7.0 Hz, 2H), 2.48-2.51 (m, 1H), 1.65 (d, J = 7.0 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.22 (d, J = 6.5 Hz, 6H).

实施例(化合物)109Example (compound) 109

N-(3-(1H-吡唑-3-基)苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(3-(1H-pyrazol-3-yl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000169
Figure PCTCN2018088561-appb-000169

将N-(3-溴苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(125mg,0.3mmol)置于反应瓶中，加入dioxane(10mL)，氩气保护下加入Pd(PPh 3) 4(70mg,0.06mmol)，(1H-pyrazol-3-yl)boronic acid(50mg,0.45mmol)，将Na 2CO 3(80g,12mmol)溶于水(2.5mL)中加入反应瓶中，升温至100℃反应，次日TLC与3h时TLC无差别，原料仍有剩余，停止反应，浓缩，加入DCM(60mL)，用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，柱层析(D:M＝100:1,D:M＝60:1)，得到淡黄色固体25mg，产率20.5％。熔点：195-197℃ N-(3-Bromobenzyl)-2-ethoxy-5-isobutyrylaminobenzamide (125 mg, 0.3 mmol) was placed in a reaction flask, dioxane (10 mL) was added and added under argon Pd(PPh 3 ) 4 (70mg, 0.06mmol), (1H-pyrazol-3-yl)boronic acid (50mg, 0.45mmol), Na 2 CO 3 (80g, 12mmol) was dissolved in water (2.5mL) In the reaction flask, the temperature was raised to 100 ° C. The next day TLC was not different from TLC at 3 h. The starting material remained, the reaction was stopped, concentrated, DCM (60 mL) was added, and washed with saturated NaCl solution (30 mL×2). Magnesium was dried, column chromatography (D: M = 100:1, D: M = 60:1) to afford 25 mg of pale yellow solid. Melting point: 195-197 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.48(s,1H),8.21(d,J＝7.0Hz,1H),7.92(s,1H),7.81(s,1H),7.67(d,J＝7.0Hz,1H),7.62(s,2H),7.40(t,J＝7.5Hz,1H),7.33(d,J＝7.5Hz,1H),6.90(d,J＝9.0Hz,1H),6.62(s,1H),4.71(d,J＝5.0Hz,2H),4.07-4.13(m,2H),2.51-2.54(m,1H),1.28(t,J＝7.0Hz,3H),1.24(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.48 (s, 1H), 8.21. (d, J = 7.0 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.67 ( d, J = 7.0 Hz, 1H), 7.62 (s, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.62 (s, 1H), 4.71 (d, J = 5.0 Hz, 2H), 4.07-4.13 (m, 2H), 2.51-2.54 (m, 1H), 1.28 (t, J = 7.0 Hz, 3H) ), 1.24 (d, J = 6.5 Hz, 6H).

实施例(化合物)110Example (compound) 110

N-(1-(3-(1H-吡唑-3-基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(1H-pyrazol-3-yl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000170
Figure PCTCN2018088561-appb-000170

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入化合物(35)(57mg,0.305mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝50:1,D:M＝35:1,D:M＝25:1)， 得到无色粘稠状液体90mg，产率53％。熔点：114-116℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) The compound (35) (57 mg, 0.305 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water, and extracted with a mixture of ethyl acetate:methanol = 10:1 (30 mL×2). The organic layer was washed with a saturated NaCI solution (30 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (D:M=50:1, D:M=35:1, D:M=25:1), A colorless viscous liquid of 90 mg was obtained in a yield of 53%. Melting point: 114-116 ° C

1H-NMR(400MHz,CDCl 3)δPPm:8.55(d,J＝7.2Hz,1H),8.19(dd,J 1＝9.2Hz,J 1＝1.6Hz,1H),7.88-7.90(m,2H),7.85(s,1H),7.58-7.62(m,2H),7.31-7.39(m,2H),6.87(d,J＝8.8Hz,1H),6.57(d,J＝1.6Hz,1H),5.31-5.38(m,1H),4.07-4.14(m,2H),2.48-2.51(m,1H),1.59(d,J＝6.8Hz,3H),1.38(t,J＝7.2Hz,3H),1.21(dd,J 1＝6.8Hz,J 2＝1.2Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ PPm: 8.55 (d, J = 7.2 Hz, 1H), 8.19 (dd, J 1 = 9.2 Hz, J 1 = 1.6 Hz, 1H), 7.88-7.90 (m, 2H) ), 7.85 (s, 1H), 7.58-7.62 (m, 2H), 7.31-7.39 (m, 2H), 6.87 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 1.6 Hz, 1H) , 5.31-5.38 (m, 1H), 4.07-4.14 (m, 2H), 2.48-2.51 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H ), 1.21 (dd, J 1 = 6.8 Hz, J 2 = 1.2 Hz, 6H).

实施例(化合物)111Example (compound) 111

N-(3-(5-((二甲氨基)甲基)噻唑-2-基)苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(3-(5-((Dimethylamino)methyl)thiazol-2-yl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000171
Figure PCTCN2018088561-appb-000171

a)2-溴-5-(溴甲基)噻唑a) 2-bromo-5-(bromomethyl)thiazole

将2-溴-5-甲基噻唑(354mg,2mmol)，加入CCl 4(15mL)，乙腈(3mL)，NBS(392mg,2.2mmol)以及AIBN(66mg,0.4mmol)，加热回流反应，4h后停止反应，浓缩，加入EA(40mL)，用用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:100)，得到淡黄色固体320mg，产率62.8％。熔点：59-60℃ 2-Bromo-5-methylthiazole (354 mg, 2 mmol) was added to CCl 4 (15 mL), EtOAc (3 mL), EtOAc (EtOAc (EtOAc) The reaction was quenched, concentrated, EtOAc EtOAc (EtOAc m. 62.8%. Melting point: 59-60 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.77(s,1H),5.03(s,2H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.77 (s, 1H), 5.03 (s, 2H).

b)1-(2-溴噻唑-5-基)-N,N-二甲基甲胺b) 1-(2-bromothiazole-5-yl)-N,N-dimethylmethylamine

将2-溴-5-(溴甲基)噻唑(300mg,1.18mmol)置于反应瓶中，加入DCM(15mL)，化合物不溶解，加入丙酮(7.5mL)，加入二甲胺盐酸盐(191mg,2.36mmol)，K 2CO 3(488mg,3.54mmol)，室温搅拌反应，次日停止反应，过滤，滤液浓缩，柱层析(D:M＝30:1)，得到淡黄色油状物210mg，产率80.7％。 2-Bromo-5-(bromomethyl)thiazole (300 mg, 1.18 mmol) was placed in a reaction flask, DCM (15 mL) was added, the compound was not dissolved, acetone (7.5 mL) was added, and dimethylamine hydrochloride was added ( 191 mg, 2.36 mmol), K 2 CO 3 (488 mg, 3.54 mmol), EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m The yield was 80.7%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.37(s,1H),3.61(s,2H),2.27(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.37 (s, 1H), 3.61 (s, 2H), 2.27 (s, 6H).

c)N-(3-(5-((二甲氨基)甲基)噻唑-2-基)苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.4mmol)加入无水DMF(15mL)，加入EDC(154mg,0.8mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.60mL,3.2mmol)，加入1-(2-(3-(氨基甲基)苯基)噻唑-5-基)-N,N-二甲基甲胺(170mg,0.60mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝30:1,D:M＝25:1)，得到白色固体55mg，产率28.6％。熔点： 134-136℃c) N-(3-(5-((Dimethylamino)methyl)thiazol-2-yl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide 2-ethoxy Add 5-OH-isobutyrylaminobenzoic acid (100 mg, 0.4 mmol) to dry DMF (15 mL), EtOAc (EtOAc EtOAc (EtOAc) Add 1-(2-(3-(aminomethyl)phenyl)thiazol-5-yl)-N,N-dimethylmethylamine (170 mg, 0.60 mmol), stir at room temperature overnight, and pour the reaction solution The mixture was extracted with a mixture of ethyl acetate:methanol = 10:1 (40 mL×2). M = 30:1, D: M = 25:1) afforded 55 mg of white solid. Melting point: 134-136°C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.33(s,1H),8.12(d,J＝7.6Hz,1H),7.94(s,1H),7.86(d,J＝2.4Hz,1H),7.80-7.83(m,1H),7.61(s,1H),7.38-7.40(m,2H),7.21-7.24(m,1H),6.91(d,J＝8.8Hz,1H),4.70(d,J＝5.6Hz,2H),4.10-4.15(m,2H),3.68(s,2H),2.48-2.52(m,1H),2.31(s,6H),1.28-1.32(m,3H),1.23-1.25(m,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.33 (s, 1H), 8.12 (d, J = 7.6Hz, 1H), 7.94 (s, 1H), 7.86 (d, J = 2.4Hz, 1H), 7.80-7.83 (m, 1H), 7.61 (s, 1H), 7.38-7.40 (m, 2H), 7.21-7.24 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.70 (d, J=5.6 Hz, 2H), 4.10-4.15 (m, 2H), 3.68 (s, 2H), 2.48-2.52 (m, 1H), 2.31 (s, 6H), 1.28-1.32 (m, 3H) ), 1.23 - 1.25 (m, 6H).

实施例(化合物)112Example (compound) 112

N-(1-(3-(5-((二甲氨基)甲基)噻唑-2-基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(5-((Dimethylamino)methyl)thiazol-2-yl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000172
Figure PCTCN2018088561-appb-000172

将2-乙氧基-5-异丁酰氨基苯甲酸(63mg,0.25mmol)加入无水DMF(10mL)，加入EDC(96mg,0.5mmol)，加入HOBt(68mg,0.50mmol)和DIEA(0.35mL,2.0mmol)，加入1-(3-(5-((二甲氨基)甲基)噻唑-2-基)苯基)乙胺(70mg,0.21mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝40:1,D:M＝30:1,D:M＝25:1)，得到粘稠状固体40mg，产率38.8％。2-Ethoxy-5-isobutyrylaminobenzoic acid (63 mg, 0.25 mmol) was added to dry DMF (10 mL). E.sub.2 (96 mg, 0.5 mmol) was added to HOBt (68 mg, 0.50 mmol) and DIEA (0.35) mL, 2.0 mmol), 1-(3-(5-((Dimethylamino)methyl)thiazol-2-yl)phenyl)ethylamine (70 mg, 0.21 mmol). The mixture was poured into a mixture of ethyl acetate:methanol=10:1 (30 mL×2), and the organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate :M=40:1, D:M=30:1, D:M=25:1), 40 mg of a viscous solid was obtained, yield 38.8%.

1H-NMR(500MHz,CDCl 3)δ(ppm):8.51(d,J＝6.5Hz,1H),8.20(d,J＝8.0Hz,1H),7.96(s,1H),7.82(s,1H),7.78(d,J＝7.0Hz,1H),7.65(s,1H),7.59(s,1H),7.39-7.43(m,1H),6.92(d,J＝9.0Hz,1H),5.30-5.35(m,1H),4.16(q,J＝6.5Hz,2H),3.80(s,2H),2.49-2.52(m,1H),2.38(s,6H),1.61(d,J＝6.5Hz,3H),1.41(t,J＝6.5Hz,3H),1.21(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3) δ (ppm): 8.51 (d, J = 6.5Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 7.0 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.39-7.43 (m, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.30-5.35 (m, 1H), 4.16 (q, J = 6.5 Hz, 2H), 3.80 (s, 2H), 2.49-2.52 (m, 1H), 2.38 (s, 6H), 1.61 (d, J = 6.5 Hz, 3H), 1.41 (t, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 6H).

实施例(化合物)113Example (compound) 113

N-(3-(4-((二甲氨基)甲基)噻唑-2-基)苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(3-(4-((Dimethylamino)methyl)thiazol-2-yl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000173
Figure PCTCN2018088561-appb-000173

a)2-溴-4-(溴甲基)噻唑a) 2-bromo-4-(bromomethyl)thiazole

将2-溴-4-甲基噻唑(1.78g,10mmol)，加入CCl 4(80mL)，乙腈(15mL)，NBS(1.96 g,11mmol)以及AIBN(324mg,2mmol)，加热回流反应，3h后停止反应，浓缩，加入EA(160mL)，用用饱和NaCl溶液(50mL×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:120)，得到淡黄色固体1.15g，产率45.27％。 2-Bromo-4-methylthiazole (1.78 g, 10 mmol), CCl 4 (80 mL), acetonitrile (15 mL), NBS (1.96 g, 11 mmol) and AIBN (324 mg, 2 mmol) The reaction was quenched, concentrated, EtOAc (EtOAc EtOAc (EtOAc) The rate is 45.27%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.27(s,1H),4.52(s,2H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.27 (s, 1H), 4.52 (s, 2H).

b)1-(2-溴噻唑-4-基)-N,N-二甲基甲胺b) 1-(2-Bromothiazol-4-yl)-N,N-dimethylmethylamine

将2-溴-4-(溴甲基)噻唑(1.05g,4.13mmol)置于反应瓶中，加入DCM(40mL)，加入二甲胺盐酸盐(669mg,8.26mmol)，K 2CO 3(1.7g,12.39mmol)，室温搅拌反应，次日停止反应，过滤，滤液浓缩，柱层析(D:M＝30:1)，得到淡黄色油状物700mg，产率77％。 2-Bromo-4-(bromomethyl)thiazole (1.05 g, 4.13 mmol) was placed in a reaction flask, DCM (40 mL) was added and dimethylamine hydrochloride (669 mg, 8.26 mmol), K 2 CO 3 (1.7 g, 12.39 mmol), the reaction was stirred at room temperature, and then the mixture was filtered, filtered, and the filtrate was concentrated and purified by column chromatography (D:M=30:1)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.09(s,1H),3.57(s,2H),2.30(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.09 (s, 1H), 3.57 (s, 2H), 2.30 (s, 6H).

c)N-(3-(4-((二甲氨基)甲基)噻唑-2-基)苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(156mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入1-(2-(3-(氨基甲基)苯基)噻唑-4-基)-N,N-二甲基甲胺(130mg,0.52mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝20:1,D:M＝15:1)，得到白色固体62mg，产率32.2％。熔点：113-115℃c) N-(3-(4-((Dimethylamino)methyl)thiazol-2-yl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide 2-ethoxy Add 5-OH-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) to dry DMF (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) Add 1-(2-(3-(aminomethyl)phenyl)thiazol-4-yl)-N,N-dimethylmethylamine (130 mg, 0.52 mmol), stir at room temperature overnight, then pour the reaction solution The mixture was extracted with a mixture of ethyl acetate:methanol = 10:1 (40 mL×2). M = 20:1, D: M = 15:1) gave 62 mg as a white solid. Melting point: 113-115 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.54(t,J＝5.2Hz,1H),8.23(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.97(s,1H),7.90(d,J＝2.8Hz,1H),7.85-7.88(m,1H),7.60(s,1H),7.40-7.43(m,2H),7.22(m 1H),6.93(d,J＝8.8Hz,1H),4.72(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),3.73(s,2H),2.51-2.55(m,1H),2.40(s,6H),1.31(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.54 (t, J = 5.2 Hz, 1H), 8.23 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.97 (s, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.85-7.88 (m, 1H), 7.60 (s, 1H), 7.40-7.43 (m, 2H), 7.22 (m 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.72 (d, J = 5.2 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H), 3.73 (s, 2H), 2.51-2.55 (m, 1H), 2.40 ( s, 6H), 1.31 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)114Example (compound) 114

N-(1-(3-(4-((二甲氨基)甲基)噻唑-2-基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(4-((Dimethylamino)methyl)thiazol-2-yl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000174
Figure PCTCN2018088561-appb-000174

将2-乙氧基-5-异丁酰氨基苯甲酸(80mg,0.32mmol)加入无水DMF(10mL)，加入EDC(123mg,0.64mmol)，加入HOBt(86mg,0.64mmol)和DIEA(0.17mL,0.96mmol)，加入1-(3-(4-((二甲氨基)甲基)噻唑-2-基)苯基)乙胺(100mg,0.384mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝30:1,D:M＝25:1)，得到白色固体12mg，产率12.6％。熔点：53-55℃2-Ethoxy-5-isobutyrylaminobenzoic acid (80 mg, 0.32 mmol) was added to dry DMF (10 mL) EtOAc (EtOAc (EtOAc) mL, 0.96 mmol), 1-(3-(4-((dimethylamino)methyl)thiazol-2-yl)phenyl)ethylamine (100 mg, 0.384 mmol). The mixture was poured into a mixture of ethyl acetate:methanol = 10:1 (40 mL×2), and the organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate :M=30:1, D:M=25:1) gave 12 mg as a white solid. Melting point: 53-55 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.54(d,J＝7.2Hz,1H),8.22(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.98(s,1H),7.82-7.85(m,2H),7.53(s,1H),7.38-7.45(m,2H),7.22(m1H),6.93(d,J＝9.2Hz,1H),5.32-5.36(m,1H),4.14-4.20(m,2H),3.73(s,2H),2.47-2.52(m,1H),2.39(s,6H),1.62(d,J＝6.8Hz,3H),1.43(t,J＝7.2Hz,3H),1.21(dd,J 1＝6.8Hz,J 2＝2.0Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.54 (d, J = 7.2Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.98 (s, 1H), 7.82-7.85 (m, 2H), 7.53 (s, 1H), 7.38-7.45 (m, 2H), 7.22 (m1H), 6.93 (d, J = 9.2 Hz, 1H), 5.32-5.36 (m) , 1H), 4.14-4.20 (m, 2H), 3.73 (s, 2H), 2.47-2.52 (m, 1H), 2.39 (s, 6H), 1.62 (d, J = 6.8 Hz, 3H), 1.43 ( t, J = 7.2 Hz, 3H), 1.21 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 6H).

实施例(化合物)115Example (compound) 115

2-乙氧基-5-异丁酰氨基-N-(3-(三氟甲氧基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(3-(trifluoromethoxy)benzyl)benzamide

Figure PCTCN2018088561-appb-000175
Figure PCTCN2018088561-appb-000175

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.4mmol)加入无水DMF(15mL)，加入EDC(154mg,0.8mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.60mL,3.2mmol)，加入间三氟甲氧基苄胺(115mg,0.60mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5,E:P＝1:2)，得到白色固体130mg，产率76.4％。熔点：133-135℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.4 mmol) was added to dry DMF (15 mL). E.sub.2 (154 mg, 0.8 mmol) was added to HOBt (108 mg, 0.80 mmol) and DIEA (0.60) mL, 3.2 mmol), m-trifluoromethoxybenzylamine (115 mg, 0.60 mmol) was added, stirred at room temperature overnight, and the mixture was poured into water, and mixed with ethyl acetate:methanol = 10:1 (40 mL×2) The organic layer was washed with a saturated NaCl solution (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and then purified by column chromatography (E:P=1:2.5, E:P=1:2) The yield was 76.4%. Melting point: 133-135 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.49(d,J＝5.2Hz,1H),8.26(dd,J 1＝9.2,J 2＝2.8,1H),7.94(d,J＝2.8Hz,1H),7.86(s,1H),7.39(t,J＝7.6Hz,1H),7.30(d,J＝7.6Hz,1H),7.21(s,1H),7.14-7.16(m,1H),6.94(d,J＝8.8Hz,1H),4.69(d,J＝5.6Hz,2H),4.15(q,J＝7.2Hz,2H),2.48-2.54(m,1H),1.34(t,J＝7.2Hz,3H),1.20(d,J＝7.2Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.49 (d, J = 5.2 Hz, 1H), 8.26 (dd, J 1 = 9.2, J 2 = 2.8, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.86 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.14 - 7.16 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 2.48-2.54 (m, 1H), 1.34 ( t, J = 7.2 Hz, 3H), 1.20 (d, J = 7.2 Hz, 6H).

实施例(化合物)116Example (compound) 116

N-(3-(1H-咪唑-1-基)苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(3-(1H-imidazol-1-yl)benzyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000176
Figure PCTCN2018088561-appb-000176

将N-(3-溴苯甲基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(125mg,0.3mmol)加入无水DMF(15mL)，氩气保护下加入咪唑(205mg,3mmmol)，1,10-邻二氮菲(540mg,3mmol)，K 2CO 3(415mg,3mmol)以及CuI(570mg,3mmol)加热至120℃反应，8h后停止反应，加水，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝35:1,D:M＝30:1)，得到白色固体52mg，产率42.6％。熔点：201-203℃ Add N-(3-bromobenzyl)-2-ethoxy-5-isobutyrylaminobenzamide (125 mg, 0.3 mmol) to dry DMF (15 mL). 3mmmol), 1,10-phenanthroline (540mg, 3mmol), K 2 CO 3 (415mg, 3mmol) and CuI (570mg, 3mmol) heated to 120 ° C reaction, stopped after 8h, added water, with ethyl acetate The mixture was extracted with a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate D: M = 35:1, D: M = 30:1) gave 52 mg of white solid, yield 42.6%. Melting point: 201-203 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.48-8.52(m,1H),,8.22(dd,J 1＝9.0Hz,J 1＝2.5Hz,1H),7.89(d,J＝2.5Hz,1H),7.86(s,1H),7.61(s,1H),7.46(t,J＝8.0Hz,1H),7.40(s,1H),7.36(d,J＝7.5Hz,1H),7.31(d,J＝7.5Hz,1H),7.28(s,1H),7.20(s,1H),6.94(d,J＝9.0Hz,1H),4.73(d,J＝5.5Hz,2H),4.15(q,J＝7.0Hz,2H),2.50-2.54(m,1H),1.30(t,J＝7.0Hz,3H),1.23(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.48-8.52 (m, 1H), 8.22 (dd, J 1 = 9.0 Hz, J 1 = 2.5 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H) , 7.31 (d, J = 7.5 Hz, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H) , 4.15 (q, J = 7.0 Hz, 2H), 2.50-2.54 (m, 1H), 1.30 (t, J = 7.0 Hz, 3H), 1.23 (d, J = 6.5 Hz, 6H).

实施例(化合物)117Example (compound) 117

N-(1-(3-(吖丁啶-1-基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(azetidin-1-yl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000177
Figure PCTCN2018088561-appb-000177

将N-(1-(3-溴苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(120mg,0.278mmol)置于反应瓶中，加入甲苯(15mL)，氩气保护下加入Pd 2(dba) 3(50mg,0.056mmol)，xantphos(63mg,0.112mmol)，叔丁醇钠(80mg,0.834mmol)以及氮杂环丁烷(79mg,1.39mmol)，升温至100℃反应，1h后停止反应，过滤，浓缩，柱层析(E:P＝1:3,E:P＝1:2)，得到白色固体89mg，产率78％。 N-(1-(3-Bromophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (120 mg, 0.278 mmol) was placed in a reaction flask and toluene (15 mL) was added. Pd 2 (dba) 3 (50 mg, 0.056 mmol), xantphos (63 mg, 0.112 mmol), sodium tert-butoxide (80 mg, 0.834 mmol) and azetidine (79 mg, 1.39 mmol) were added under argon. The reaction was carried out at 100 ° C. After 1 h, the reaction was quenched, filtered, concentrated and purified eluting elute

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.21(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.60(s,1H),7.18(t,J＝8.0Hz,1H),6.91(d,J＝8.8Hz,1H),6.74(d,J＝7.6Hz,1H),6.42(d,J＝2.0Hz,1H),6.33-6.37(m,1H),5.21-5.30(m,1H),4.09-4.18(m,2H),3.87(t,J＝7.6Hz,4H),2.49-2.53(m,1H),2.31-2.39(m,2H),1.56(d,J＝6.8Hz,3H),1.40(t,J＝6.8Hz,3H),1.22(dd,J 1＝6.8Hz,J 2＝2.0Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.45 (d, J = 7.6 Hz, 1H), 8.21. (dd, J 1 = 8.8 Hz, J 1 = 2.8 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H) , 6.42 (d, J = 2.0 Hz, 1H), 6.33 - 6.37 (m, 1H), 5.21-5.30 (m, 1H), 4.09 - 4.18 (m, 2H), 3.87 (t, J = 7.6 Hz, 4H) ), 2.49-2.53 (m, 1H), 2.31-2.39 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H), 1.40 (t, J = 6.8 Hz, 3H), 1.22 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 6H).

实施例(化合物)118Example (compound) 118

N-(1-(3-((二甲氨基)甲基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-((Dimethylamino)methyl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000178
Figure PCTCN2018088561-appb-000178

a)1-(3-(溴甲基)苯基)乙酮a) 1-(3-(bromomethyl)phenyl)ethanone

将间甲基苯乙酮(1.34g,10mmol)，加入CCl 4(50mL)，乙腈(20mL)，NBS(1.96g,11mmol)以及AIBN(328mg,2mmol)，加热回流反应，2h后停止反应，浓缩，加入EA(100mL)，用用饱和NaCl溶液(40mL×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:80,E:P＝1:50)，无水油状物1.6g，产率75.5％。 m-Methylacetophenone (1.34 g, 10 mmol) was added to CCl 4 (50 mL), acetonitrile (20 mL), NBS (1.96 g, 11 mmol) and AIBN (328 mg, 2 mmol) Concentrate, add EA (100 mL), wash with saturated NaCl solution (40 mL×2), dry over anhydrous magnesium sulfate, column chromatography (E:P=1:80, E:P=1:50), anhydrous oil 1.6 g, 75.5% yield.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.98(t,J＝1.2Hz,1H),7.88(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),4.53(s,2H),2.59-2.60(m,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.98 (t, J = 1.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H) , 7.46 (t, J = 8.0 Hz, 1H), 4.53 (s, 2H), 2.59-2.60 (m, 3H).

b)1-(3-((二甲氨基)甲基)苯基)乙酮b) 1-(3-((Dimethylamino)methyl)phenyl)ethanone

将1-(3-(溴甲基)苯基)乙酮(212mg,1mmol)置于反应瓶中，加入DCM(15mL)，加入二甲胺盐酸盐(162mg,2mmol)，K 2CO 3(414mg,3mmol)，室温搅拌反应，次日停止反应，过滤，滤液浓缩，柱层析(D:M＝35:1)，得到淡黄色油状物130mg，产率73.4％。 1-(3-(Bromomethyl)phenyl)ethanone (212 mg, 1 mmol) was placed in a reaction flask, DCM (15 mL) was added and dimethylamine hydrochloride (162 mg, 2 mmol), K 2 CO 3 (414 mg, 3 mmol), the reaction was stirred at room temperature, and then the mixture was filtered, filtered, and the filtrate was concentrated to give a pale-yellow oil (yield: 73.4%).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.89-7.91(m,1H),7.85-7.87(m,1H),7.53-7.55(m,1H),7.40-7.45(m,1H),3.48-3.49(m,2H),2.61-2.62(m,3H),2.25-2.26(m,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.89-7.91 (m, 1H), 7.85-7.87 (m, 1H), 7.53-7.55 (m, 1H), 7.40-7.45 (m, 1H) , 3.48-3.49 (m, 2H), 2.61-2.62 (m, 3H), 2.25-2.26 (m, 6H).

c)N-(1-(3-((二甲氨基)甲基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺c) N-(1-(3-((Dimethylamino)methyl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入1-(3-((二甲氨基)甲基)苯基)乙胺(107mg,0.6mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝35:1,D:M＝20:1)，得到无色粘稠状液体80mg。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(3-((dimethylamino)methyl)phenyl)ethylamine (107 mg, 0.6 mmol). The mixture was extracted with a mixture of 10:1 (30 mL×2), and the combined organic layer was washed with saturated NaCI (30mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=35:1, D: M = 20: 1), 80 mg of a colorless viscous liquid was obtained.

1H-NMR(500MHz,CDCl 3)δ(ppm):8.40(d,J＝6.5Hz,1H),8.22(dd,J 1＝9.0Hz,J 1＝2.5Hz,1H),8.12(s,1H),7.93(d,J＝2.5Hz,1H),7.41(s,1H),7.31-7.35(m,2H),7.28(s,1H),6.92(d,J＝9.0Hz,1H),5.17-5.20(m,1H),4.12-4.18(m,2H),2.56-2.60(m,1H),2.52(s,6H),1.56(d,J＝7.0Hz,3H),1.45(t,J＝6.5Hz,3H),1.21(d,J＝7.0Hz,6H). 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 8.40 (d, J = 6.5 Hz, 1H), 8.22 (dd, J 1 = 9.0 Hz, J 1 = 2.5 Hz, 1H), 8.12 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.41 (s, 1H), 7.31-7.35 (m, 2H), 7.28 (s, 1H), 6.92 (d, J = 9.0 Hz, 1H), 5.17-5.20 (m, 1H), 4.12-4.18 (m, 2H), 2.56-2.60 (m, 1H), 2.52 (s, 6H), 1.56 (d, J = 7.0 Hz, 3H), 1.45 (t, J = 6.5 Hz, 3H), 1.21 (d, J = 7.0 Hz, 6H).

实施例(化合物)119Example (compound) 119

2-乙氧基-5-异丁酰氨基-N-(1-苯基乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-phenylethyl)benzamide

Figure PCTCN2018088561-appb-000179
Figure PCTCN2018088561-appb-000179

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(15mL)，加入EDC(154mg,0.80mmol)，加入HOBt(108mg,0.80mmol)和DIEA(0.21mL,1.20mmol)，加入化合物1-苯基乙胺(63mg,0.52mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3,E:P＝1:2)，得到白色固体120mg，产率84.5％。熔点：146-148℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (15 mL), EDC (154 mg, 0.80 mmol) was added, and HOBt (108 mg, 0.80 mmol) and DIEA (0.21) The compound 1-phenylethylamine (63 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water and mixed with ethyl acetate:methanol = 10:1 (30 mL × 2) The organic layer was washed with a saturated NaCI solution (30 mL×2), dried over anhydrous magnesium sulfate. The yield was 84.5%. Melting point: 146-148 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.48(d,J＝7.0Hz,1H),8.22(d,J＝9.0Hz,1H),7.84-7.85(m,1H),7.57(brs,1H),7.33-7.39(m,4H),7.26-7.28(m,1H),6.92(d,J＝9.0Hz,1H),5.23-5.29(m,1H),4.11-4.18(m,2H),2.48-2.51(m,1H),1.58(d,J＝6.5Hz,3H),1.41(t,J＝6.5Hz,3H),1.21(d,J＝4.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.48 (d, J = 7.0 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.84-7.85 (m, 1H), 7.57 ( Brs,1H),7.33-7.39(m,4H), 7.26-7.28(m,1H), 6.92(d,J=9.0Hz,1H),5.23-5.29(m,1H),4.11-4.18(m, 2H), 2.48-2.51 (m, 1H), 1.58 (d, J = 6.5 Hz, 3H), 1.41 (t, J = 6.5 Hz, 3H), 1.21 (d, J = 4.5 Hz, 6H).

实施例(化合物)120Example (compound) 120

(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯甲基)(甲基)氨基甲酸苄酯(3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)benzyl)(methyl)carbamate

Figure PCTCN2018088561-appb-000180
Figure PCTCN2018088561-appb-000180

a)3-(2-甲基-1,3-二噁戊环-2-基)苯甲腈a) 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile

将3-氰基苯乙酮(435mg,3mmol)，加入苯(20mL)，加入二水和对甲苯磺酸(57mg,0.3mmol)以及乙二醇(0.33mL,6mmol)，安装分水器加热回流反应，2h后停止反应，加入乙酸乙酯50mL，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:30)，得到无色油状物420mg，产率74％。3-cyanoacetophenone (435 mg, 3 mmol) was added to benzene (20 mL), di-water and p-toluenesulfonic acid (57 mg, 0.3 mmol) and ethylene glycol (0.33 mL, 6 mmol) The reaction was refluxed, and the reaction was stopped after 2 h, ethyl acetate (50 mL), EtOAc (EtOAc) The yield was 74%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.79-7.81(m,1H),7.71-7.73(m,1H),7.57-7.61(m,1H),7.43-7.48(m,1H),4.04-4.09(m,2H),3.74-3.78(m,2H),1.63(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.79-7.81 (m, 1H), 7.71-7.73 (m, 1H), 7.57-7.61 (m, 1H), 7.43-7.48 (m, 1H) , 4.04-4.09 (m, 2H), 3.74-3.78 (m, 2H), 1.63 (s, 3H).

b)(3-(2-甲基-1,3-二噁戊环-2-基)苯基)甲胺b) (3-(2-methyl-1,3-dioxolan-2-yl)phenyl)methanamine

将3-(2-甲基-1,3-二噁戊环-2-基)苯甲腈(1.2g)，加入MeOH(50mL)，加入10％Pd/C(0.4g)，常温常压下氢化反应，5h后停止反应，过滤，浓缩，得到淡黄色油状物 1.1g，产率90.1％。3-(2-Methyl-1,3-dioxalan-2-yl)benzonitrile (1.2 g), added to MeOH (50 mL), 10% Pd/C (0.4 g), normal temperature and pressure The hydrogenation reaction was carried out, and the reaction was quenched after 5 h, filtered and concentrated to give a pale yellow oil (1.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.41-7.43(m,1H),7.35-7.38(m,1H),7.29-7.33(m,1H),7.23-7.26(m,1H),4.01-4.05(m,2H),3.88(s,2H),3.76-3.80(m,2H),1.65(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.41-7.43 (m, 1H), 7.35-7.38 (m, 1H), 7.29-7.33 (m, 1H), 7.23-7.26 (m, 1H) , 4.01-4.05 (m, 2H), 3.88 (s, 2H), 3.76-3.80 (m, 2H), 1.65 (s, 3H).

c)3-(2-甲基-1,3-二噁戊环-2-基)苯甲基)氨基甲酸苄酯c) Benzyl 3-(2-methyl-1,3-dioxolan-2-yl)benzyl)carbamate

将(3-(2-甲基-1,3-二噁戊环-2-基)苯基)甲胺(120mg,0.62mmol)，加入乙酸乙酯(8mL)，水(4mL)，加入碳酸氢钠(156mg,1.86mmol)，将CBZ-Cl(0.13mL,0.93mmol)滴加入反应瓶中，滴毕，继续室温搅拌反应，1h后停止反应，加入乙酸乙酯20mL，用饱和NaCl溶液(10mL×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:7,E:P＝1:6)，得到无色油状物100mg，产率49.5％。(3-(2-Methyl-1,3-dioxalan-2-yl)phenyl)methanamine (120 mg, 0.62 mmol) was added ethyl acetate (8 mL), water (4 mL) Sodium hydrogenate (156 mg, 1.86 mmol), CBZ-Cl (0.13 mL, 0.93 mmol) was added dropwise to the reaction flask, and the mixture was added dropwise. The reaction was stirred at room temperature. After 1 h, the reaction was stopped and ethyl acetate (20 mL) was added. After washing with 10 mL × 2), dried over anhydrous magnesium sulfate, EtOAc (EtOAc:EtOAc:

1H-NMR(400MHz,CDCl 3)δ(ppm):7.23-7.40(m,9H),5.15(s,2H),5.10(brs,1H),4.40(d,J＝6.0Hz,2H),4.00-4.03(m,2H),3.76(t,J＝7.2Hz,2H),1.63(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.23-7.40 (m, 9H), 5.15 (s, 2H), 5.10 (brs, 1H), 4.40 (d, J = 6.0 Hz, 2H), 4.00-4.03 (m, 2H), 3.76 (t, J = 7.2 Hz, 2H), 1.63 (s, 3H).

d)甲基(3-(2-甲基-1,3-二噁戊环-2-基)苯甲基)氨基甲酸苄酯d) benzyl (3-(2-methyl-1,3-dioxolan-2-yl)benzyl)carbamate

将3-(2-甲基-1,3-二噁戊环-2-基)苯甲基)氨基甲酸苄酯(80mg,0.244mmol)加入DMF 10mL，氩气保护下，室温下加入NaH(15mg,0.36mmol)，室温搅拌1h，加入碘甲烷(42mg,0.29mmol)，室温搅拌反应，2h后停止反应，加入水，用乙酸乙酯40mL萃取，有机层用饱和NaCl溶液20mL×2洗，无水硫酸镁干燥，柱层析(E:P＝1:6)，得到产物70mg，产率84.3％。Benzyl 3-(2-methyl-1,3-dioxolan-2-yl)benzyl)carbamate (80 mg, 0.244 mmol) was added to 10 mL of DMF under argon, and NaH was added at room temperature. 15 mg, 0.36 mmol), stirred at room temperature for 1 h, MeOH (42 mg, 0.29 mmol), EtOAc (EtOAc, EtOAc) Drying over anhydrous magnesium sulfate and column chromatography (EtOAc:EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.29-7.40(m,8H),7.10-7.20(m,1H),5.19(s,2H),4.51(d,J＝10.4Hz,2H),4.02(t,J＝6.8Hz,2H),3.74-3.76(m,2H),2.87-2.92(m,3H),1.63-1.65(m,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.29-7.40 (m, 8H), 7.10-7.20 (m, 1H), 5.19 (s, 2H), 4.51 (d, J = 10.4 Hz, 2H) ), 4.02 (t, J = 6.8 Hz, 2H), 3.74 - 3.76 (m, 2H), 2.87 - 2.92 (m, 3H), 1.63-1.65 (m, 3H).

e)(3-乙酰基苯甲基)(甲基)氨基甲酸苄酯e) (3-Acetylbenzyl) (methyl) carbamate

将甲基(3-(2-甲基-1,3-二噁戊环-2-基)苯甲基)氨基甲酸苄酯(160mg,0.468mmol)，加入THF(4mL)，H 2O(1mL)，加入2.5N HCl溶液(0.5mL,1.25mmol)，室温搅拌反应，2h后停止反应，加入乙酸乙酯20mL，用饱和NaHCO3溶液10mL×2洗，无水硫酸镁干燥浓缩得到无色油状物120mg，产率86％。 Benzyl methyl (3-(2-methyl-1,3-dioxolan-2-yl)benzyl)carbamate (160 mg, 0.468 mmol) was added to THF (4 mL), H ? 1mL), 2.5N HCl solution (0.5mL, 1.25mmol) was added, and the reaction was stirred at room temperature. After 2h, the reaction was stopped. Ethyl acetate (20 mL) was added, washed with saturated NaHCO3 solution 10 mL×2, dried over anhydrous magnesium sulfate 120 mg, yield 86%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.77-7.87(m,2H),7.32-7.50(m,7H),5.19(s,2H),4.54-4.56(m,2H),2.89-2.93(m,3H),2.53-2.59(m,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.77-7.87 (m, 2H), 7.32-7.50 (m, 7H), 5.19 (s, 2H), 4.54-4.56 (m, 2H), 2.89 -2.93 (m, 3H), 2.53-2.59 (m, 3H).

f)(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯甲基)(甲基)氨基甲酸苄酯f) (3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)benzyl)(methyl)carbamate

将2-乙氧基-5-异丁酰氨基苯甲酸(160mg,0.637mmol)加入无水DMF(15mL)，加入EDC(244mg,1.274mmol)，加入HOBt(172mg,1.274mmol)和DIEA(0.33mL, 1.911mmol)，加入(3-(1-氨基乙基)苯甲基)(甲基)氨基甲酸苄酯(218mg,0.733mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝100:1)，得到粘稠状液体290mg，产率85.7％。2-Ethoxy-5-isobutyrylaminobenzoic acid (160 mg, 0.637 mmol) was added to dry DMF (15 mL) EtOAc (EtOAc EtOAc EtOAc mL, 1.911 mmol), benzyl (3-(1-aminoethyl)benzyl)(methyl)carbamate (218 mg, 0.733 mmol) was added, stirred at room temperature overnight, then poured into water, with ethyl acetate The ester was extracted with a mixture of methanol = 10:1 (40 mL × 2). The combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated. ), 290 mg of a viscous liquid was obtained, and the yield was 85.7%.

1H-NMR(500MHz,CDCl 3)δ(ppm):8.39-8.45(m,1H),8.21(d,J＝7.0,1H),7.82(brs,1H),7.07-7.48(m,10H),6.91(d,J＝8.5,1H),5.28(brs,1H),5.15-5.17(m,2H),4.48(s,2H),4.13(s,2H),2.85-2.90(m,3H),2.48-2.51(m,1H),1.54(s,3H),1.38(s,3H),1.22(d,J＝6.5Hz,6H). 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm): 8.39-8.45 (m, 1H), 8.21 (d, J = 7.0, 1H), 7.82 (brs, 1H), 7.07-7.48 (m, 10H) , 6.91 (d, J = 8.5, 1H), 5.28 (brs, 1H), 5.15-5.17 (m, 2H), 4.48 (s, 2H), 4.13 (s, 2H), 2.85-2.90 (m, 3H) , 2.48-2.51 (m, 1H), 1.54 (s, 3H), 1.38 (s, 3H), 1.22 (d, J = 6.5 Hz, 6H).

实施例(化合物)121Example (compound) 121

2-乙氧基-5-异丁酰氨基-N-(1-(3-((甲基氨基)甲基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-((methylamino)methyl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000181
Figure PCTCN2018088561-appb-000181

将苯甲基(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯甲基)(甲基)氨基甲酸苄酯(235mg)，加入MeOH(15mL)，10％Pd/C(70.5mg)，常温常压下氢化反应，2h后停止反应，过滤，浓缩，柱层析(D:M＝50:1,D:M:氨水＝300:20:1)，得到类白色固体95mg，产率54.3％。熔点：63-65℃Benzyl (3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)benzyl)(methyl)carbamate (235 mg), MeOH (15 mL) ), 10% Pd/C (70.5 mg), hydrogenation at normal temperature and normal pressure, stop reaction after 2 h, filter, concentrate, column chromatography (D: M = 50:1, D: M: ammonia = 300:20: 1) An 95 mg of an off-white solid was obtained with a yield of 54.3%. Melting point: 63-65 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.49(d,J＝7.2Hz,1H),8.22(dd,J 1＝9.2Hz,J 2＝3.2Hz,1H),7.75-7.80(m,2H),7.23-7.34(m,4H),6.91(d,J＝8.8,1H),5.23-5.27(m,1H),4.13-4.16(m,2H),3.78(s,2H),2.52-2.56(m,1H),2.45(s,3H),1.56(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.49 (d, J = 7.2 Hz, 1H), 8.22 (dd, J 1 = 9.2 Hz, J 2 = 3.2 Hz, 1H), 7.75-7.80 ( m, 2H), 7.23 - 7.34 (m, 4H), 6.91 (d, J = 8.8, 1H), 5.23-5.27 (m, 1H), 4.13-4.16 (m, 2H), 3.78 (s, 2H), 2.52-2.56 (m, 1H), 2.45 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H) ).

实施例(化合物)122Example (compound) 122

(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯基)(甲基)氨基甲酸苄酯(3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)phenyl)(methyl)carbamate

Figure PCTCN2018088561-appb-000182
Figure PCTCN2018088561-appb-000182

a)(3-乙酰苯基)氨基甲酸苄酯a) benzyl (3-acetylphenyl)carbamate

将3-氨基苯乙酮(1.35g,10mmol)，加入乙酸乙酯(40mL)，水(20mL)，加入碳酸氢钠(2.52g,30mmol)，将CBZ-Cl(2.1mL,15mmol)滴加入反应瓶中，滴毕， 继续室温搅拌反应，1h后停止反应，加入乙酸乙酯80mL，用饱和NaCl溶液(40mL×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:6,E:P＝1:5)，得到白色固体2.3g，产率85.5％。熔点：108-109℃3-Aminoacetophenone (1.35 g, 10 mmol), EtOAc (40 mL),EtOAc (EtOAc) After the reaction was completed, the reaction was stirred at room temperature. After 1 h, the reaction was stopped, and ethyl acetate (80 mL) was added, and washed with a saturated NaCI solution (40 mL×2), dried over anhydrous magnesium sulfate and column chromatography (E:P=1: 6, E: P = 1: 5) gave 2.3 g of a white solid, yield 85.5%. Melting point: 108-109 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.94(brs,1H),7.67-7.70(m,1H),7.63-7.66(m,1H),7.34-7.42(m,6H),6.91(brs,1H),5.22(s,2H),2.53(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.94 (brs, 1H), 7.67-7.70 (m, 1H), 7.63-7.66 (m, 1H), 7.34-7.42 (m, 6H), 6.91 (brs, 1H), 5.22 (s, 2H), 2.53 (s, 3H).

b)(3-乙酰苯基)(甲基)氨基甲酸苄酯b) Benzyl (3-acetylphenyl)(methyl)carbamate

将(3-乙酰苯基)氨基甲酸苄酯(1.0g,3.72mmol)加入DMF 25mL，氩气保护下，室温下加入(178mg,4.46mmol)NaH，室温搅拌1h，加入(554mg,3.91mmol)碘甲烷，室温搅拌反应，2h后停止反应，加入水，用乙酸乙酯80mL萃取，有机层用饱和NaCl溶液20mL×2洗，无水硫酸镁干燥，柱层析(E:P＝1:7.5,E:P＝1:6)，得到产物770mg，产率87％。Benzyl (3-acetylphenyl)carbamate (1.0 g, 3.72 mmol) was added to 25 mL of DMF, EtOAc (EtOAc, EtOAc. Methyl iodide was stirred at room temperature. After 2 h, the reaction was quenched, water was added, and ethyl acetate (EtOAc) was evaporated and evaporated. , E: P = 1:6), the product was obtained in 770 mg, yield 87%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.85(s,1H),7.77-7.80(m,1H),7.41-7.47(m,2H),7.29-7.35(m,5H),5.18(s,2H),3.36(s,3H),2.56(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.85 (s, 1H), 7.77-7.80 (m, 1H), 7.41-7.47 (m, 2H), 7.29-7.35 (m, 5H), 5.18 (s, 2H), 3.36 (s, 3H), 2.56 (s, 3H).

c)(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯基)(甲基)氨基甲酸苄酯c) (3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)phenyl)(methyl)carbamate

将2-乙氧基-5-异丁酰氨基苯甲酸(230mg,0.916mmol)加入无水DMF(25mL)，加入EDC(352mg,1.832mmol)，加入HOBt(247mg,1.832mmol)和DIEA(0.48mL,2.748mmol)，加入(3-(1-氨基乙基)苯基)(甲基)氨基甲酸苄酯(338mg,1.19mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2,D:M＝75:1)，得到类白色固体420mg，产率88.6％。熔点：58-60℃2-Ethoxy-5-isobutyrylaminobenzoic acid (230 mg, 0.916 mmol) was added to dry DMF (25 mL). E.sub.2 (352 mg, 1.832 mmol) was added to HOBt (247 mg, 1.832 mmol) and DIEA (0.48) Add benzyl (3-(1-aminoethyl)phenyl)(methyl)carbamate (338 mg, 1.19 mmol), stir at room temperature overnight, then poured into water and ethyl acetate The mixture was extracted with a mixture of methanol = 10:1 (40 mL × 2). The combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate D: M = 75: 1) gave 420 mg of white solid, yield 88.6%. Melting point: 58-60 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.43(d,J＝8.0Hz,1H),8.21(d,J＝8.0,1H),7.84(s,1H),7.56-7.62(m,1H),7.21-7.34(m,8H),5.27-5.31(m,1H),5.15(s,2H),4.09-4.13(m,2H),3.31(s,3H),2.48-2.51(m,1H),1.54(d,J＝6.5Hz,3H),1.36(t,J＝6.5Hz,3H),1.21(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.43 (d, J = 8.0 Hz, 1H), 8.21. (d, J = 8.0, 1H), 7.84 (s, 1H), 7.56-7.62 (m) , 1H), 7.21-7.34 (m, 8H), 5.27-5.31 (m, 1H), 5.15 (s, 2H), 4.09-4.13 (m, 2H), 3.31 (s, 3H), 2.48-2.51 (m , 1H), 1.54 (d, J = 6.5 Hz, 3H), 1.36 (t, J = 6.5 Hz, 3H), 1.21 (d, J = 6.5 Hz, 6H).

实施例(化合物)123Example (compound) 123

2-乙氧基-5-异丁酰氨基-N-(1-(3-(甲基氨基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(methylamino)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000183
Figure PCTCN2018088561-appb-000183

将(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯基)(甲基)氨基甲酸苄酯(310mg)， 加入MeOH(15mL)，10％Pd/C(93mg)，常温常压下氢化反应，4h后停止反应，过滤，浓缩，柱层析(D:M＝80:1)，得到白色固体153mg，产率66.8％。熔点：138-140℃Benzyl (3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)phenyl)(methyl)carbamate (310 mg), MeOH (15 mL), 10% Pd/C (93 mg), hydrogenation reaction at normal temperature and normal pressure, the reaction was stopped after 4h, filtered, concentrated, and purified by column chromatography (D:M=80:1) to afford 153 mg of white solid. Melting point: 138-140 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.46(d,J＝7.0Hz,1H),8.21(d,J＝8.5,1H),7.87(s,1H),7.72(s,1H),7.17(t,J＝8.0,1H),6.91(d,J＝9.0,1H),6.73(d,J＝7.0,1H),6.62(s,1H),6.52(d,J＝7.5,1H),5.20-5.24(m,1H),4.10-4.15(m,2H),3.98(brs,1H),2.82(s,3H),2.50-2.53(m,1H),1.56(d,J＝6.5Hz,3H),1.41(t,J＝7.0Hz,3H),1.21(d,J＝5.0Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.46 (d, J = 7.0 Hz, 1H), 8.21. (d, J = 8.5, 1H), 7.87 (s, 1H), 7.72 (s, 1H) ), 7.17 (t, J = 8.0, 1H), 6.91 (d, J = 9.0, 1H), 6.73 (d, J = 7.0, 1H), 6.62 (s, 1H), 6.52 (d, J = 7.5, 1H), 5.20-5.24 (m, 1H), 4.10-4.15 (m, 2H), 3.98 (brs, 1H), 2.82 (s, 3H), 2.50-2.53 (m, 1H), 1.56 (d, J = 6.5 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 5.0 Hz, 6H).

实施例(化合物)124Example (compound) 124

(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯基)氨基甲酸苄酯(3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)phenyl)carbamate

Figure PCTCN2018088561-appb-000184
Figure PCTCN2018088561-appb-000184

将2-乙氧基-5-异丁酰氨基苯甲酸(360mg,1.434mmol)加入无水DMF(30mL)，加入EDC(551mg,2.868mmol)，加入HOBt(387mg,2.868mmol)和DIEA(0.75mL,4.302mmol)，加入(3-(1-氨基乙基)苯基)氨基甲酸苄酯(581mg,2.15mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2,D:M＝50:1)，得到白色固体600mg，产率87％2-Ethoxy-5-isobutyrylaminobenzoic acid (360 mg, 1.434 mmol) was added to dry DMF (30 mL), EDC (551 mg, 2.068 mmol) was added, and HOBt (387 mg, 2.068 mmol) and DIEA (0.75) (3.03 mmol), benzyl (3-(1-aminoethyl)phenyl)carbamate (581 mg, 2.15 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water with ethyl acetate: methanol = 10 The mixture was extracted with 1 ml (40 mL×2), and the combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (E:P=1:2, D:M= 50:1), 600 mg of white solid was obtained, yield 87%

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.76(s,1H),8.52(d,J＝7.6Hz,1H),7.96(s,1H),7.92(d,J＝2.8,1H),7.79(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.52(s,1H),7.31-7.44(m,6H),7.25(t,J＝8.0,1H),7.07(d,J＝9.2,1H),7.04(d,J＝7.6,1H),5.15(s,2H),5.03-5.08(m,1H),4.08-4.15(m,2H),2.53-2.57(m,1H),1.44(d,J＝6.8Hz,3H),1.33(t,J＝7.2Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.76 (s, 1H), 8.52 (d, J = 7.6Hz, 1H), 7.96 (s, 1H), 7.92 (d, J = 2.8 , 1H), 7.79 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.52 (s, 1H), 7.31-7.44 (m, 6H), 7.25 (t, J = 8.0, 1H), 7.07 (d, J=9.2, 1H), 7.04 (d, J=7.6, 1H), 5.15 (s, 2H), 5.03-5.08 (m, 1H), 4.08-4.15 (m, 2H), 2.53-2.57 (m, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)125Example (compound) 125

N-(1-(3-氨基苯基)乙基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(1-(3-Aminophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000185
Figure PCTCN2018088561-appb-000185

将(3-(1-(2-乙氧基-5-异丁酰胺苯甲酰胺基)乙基)苯基)氨基甲酸苄酯(600mg)，加入EtOH(25mL)，10％Pd/C(180mg)，常温常压下氢化反应，次日停止反应，过滤，浓缩，柱层析(D:M＝40:1,DM＝30:1)，得到白色固体320mg，产率72.7％。(3-(1-(2-ethoxy-5-isobutyramide benzamido)ethyl)phenyl)carbamic acid benzyl ester (600 mg), added to EtOH (25 mL), 10% Pd / C ( 180 mg), hydrogenation reaction at normal temperature and normal pressure, the next day, the reaction was stopped, filtered, concentrated, and purified by column chromatography (D:M=40:1, DM=30:1) to give a white solid, 320 mg, yield 72.7%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.50(d,J＝6.0Hz,1H),8.23(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.85(d,J＝2.8,1H),7.81(s,1H),7.12(t,J＝8.0,1H),6.91(d,J＝8.8,1H),6.81(d,J＝5.6,1H),6.77(s,1H),6.62(d,J＝8.0,1H),5.13-5.17(m,1H),4.09-4.18(m,2H),2.50-2.58(m,1H),1.524(d,J＝6.8Hz,3H),1.43(t,J＝6.8Hz,3H),1.22(dd,J 1＝6.8Hz,J 2＝2.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.50 (d, J = 6.0Hz, 1H), 8.23 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.85 (d, J = 2.8, 1H), 7.81 (s, 1H), 7.12 (t, J = 8.0, 1H), 6.91 (d, J = 8.8, 1H), 6.81 (d, J = 5.6, 1H), 6.77 (s) , 1H), 6.62 (d, J = 8.0, 1H), 5.13-5.17 (m, 1H), 4.09-4.18 (m, 2H), 2.50-2.58 (m, 1H), 1.524 (d, J = 6.8 Hz) , 3H), 1.43 (t, J = 6.8 Hz, 3H), 1.22 (dd, J 1 = 6.8 Hz, J 2 = 2.4 Hz, 6H).

实施例(化合物)126Example (compound) 126

2-乙氧基-5-异丁酰氨基-N-(1-(3-(2,2,2-三氟乙氧基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000186
Figure PCTCN2018088561-appb-000186

a)1-(3-(2,2,2-三氟乙氧基)苯基)乙酮a) 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethanone

将3-羟基苯乙酮(953mg,7.0mmol)，加入DMF(30mL)，加入碳酸铯(3.4g,10.5mmol)，加入2,2,2-三氟乙基三氟甲磺酸酯(1.95g,8.4mmol)，室温搅拌反应，30min后停止反应，将反应液倒入水中，有固体析出，抽滤，滤饼水洗，得到白色固体1.4g，产率91.7％。熔点：70-71℃3-Hydroxyacetophenone (953 mg, 7.0 mmol) was added to DMF (30 mL), cesium carbonate (3.4 g, 10.5 mmol) was added, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.95) was added. g, 8.4 mmol), the reaction was stirred at room temperature, and the reaction was stopped after 30 min. The reaction mixture was poured into water, and a solid was precipitated, suction filtered, and the filter cake was washed with water to obtain a white solid (1.4 g, yield: 91.7%). Melting point: 70-71 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.62-7.65(m,1H),7.51-7.53(m,1H),7.43(t,J＝8.0Hz,1H),7.16-7.19(m,1H),4.41(q,J＝8.0Hz,2H),2.61(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.62 - 7.65 (m, 1H), 7.51 - 7.53 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.16-7.19 (m) , 1H), 4.41 (q, J = 8.0 Hz, 2H), 2.61 (s, 3H).

b)2-乙氧基-5-异丁酰氨基-N-(1-(3-(2,2,2-三氟乙氧基)苯基)乙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入1-(3-(2,2,2-三氟乙氧基)苯基)乙胺(192mg,0.876mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3,E:P＝1:1.5)，得到白色固体139mg，产率70％。熔点：75-77℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethylamine (192 mg, 0.876 mmol), mp. Ethyl acetate: a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate 3, E: P = 1: 1.5), 139 mg of a white solid was obtained, yield 70%. Melting point: 75-77 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.46(d,J＝7.2Hz,1H),8.21(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.81(s,1H),7.44(brs,1H),7.30(t,J＝8.0Hz,1H),7.06(d,J＝7.6Hz,1H),6.98-6.99(m,1H),6.93(d,J＝9.2Hz,1H),6.81(dd,J 1＝8.0Hz,J 2＝2.4Hz,1H), 5.24-5.31(m,1H),4.34(q,J＝8.0Hz,2H),4.14-4.20(m,2H),2.45-2.53(m,1H),1.56(d,J＝6.8Hz,3H),1.44(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.46 (d, J = 7.2Hz, 1H), 8.21 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.81 (s, 1H), 7.44 (brs, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.98-6.99 (m, 1H), 6.93 (d, J = 9.2) Hz, 1H), 6.81 (dd, J 1 = 8.0 Hz, J 2 = 2.4 Hz, 1H), 5.24-5.31 (m, 1H), 4.34 (q, J = 8.0 Hz, 2H), 4.14-4.20 (m) , 2H), 2.45-2.53 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)127Example (compound) 127

N-(1-(3-环丙基苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-cyclopropylphenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000187
Figure PCTCN2018088561-appb-000187

a)1-(3-环丙基苯基)乙酮a) 1-(3-cyclopropylphenyl)ethanone

将3-溴苯乙酮(796mg,4mmol)置于反应瓶中，加入甲苯(30mL)，水(1.5mL)，氩气保护下加入环丙基苯硼酸(447mg,5.2mmol)，醋酸钯(90mg,0.4mmol)，三环己基磷(162mg,0.8mmol)以及磷酸钾(2.97mg,14mmol)加热至100℃反应，4h后停止反应，过滤，加入乙酸乙酯(60ml)，用饱和NaCl溶液(20ml×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:80)得到黄色油状物440mg，产率68.7％。3-Bromoacetophenone (796 mg, 4 mmol) was placed in a reaction flask, toluene (30 mL), water (1.5 mL) was added, and cyclopropylphenylboronic acid (447 mg, 5.2 mmol) was added under argon, palladium acetate ( 90 mg, 0.4 mmol), tricyclohexylphosphine (162 mg, 0.8 mmol) and potassium phosphate (2.97 mg, 14 mmol) were heated to 100 ° C. The reaction was stopped after 4 h, filtered, ethyl acetate (60 ml) was added, and saturated NaCl solution was used. (20 ml × 2) washed, dried over anhydrous magnesium sulfate, EtOAc (EtOAc: EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.72(dd,J 1＝7.6Hz,J 1＝1.6Hz,1H),7.67(t,J＝7.6Hz,1H),7.25-7.28(m,1H),2.59(s,3H),1.93-1.98(m,1H),0.98-1.03(m,2H),0.72-0.76(m,2H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.72 (dd, J 1 = 7.6 Hz, J 1 = 1.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.25-7.28 ( m, 1H), 2.59 (s, 3H), 1.93-1.98 (m, 1H), 0.98-1.03 (m, 2H), 0.72-0.76 (m, 2H).

b)N-(1-(3-环丙基苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺b) N-(1-(3-cyclopropylphenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入1-(3-环丙基苯基)乙胺(141mg,0.876mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3.5,E:P＝1:2.5)，得到白色固体120mg，产率69.3％。熔点：143-145℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 1-(3-cyclopropylphenyl)ethylamine (141 mg, 0.876 mmol) was added and stirred at room temperature overnight. The mixture was poured into water and mixed with ethyl acetate:methanol = 10:1 The mixture was extracted with EtOAc (EtOAc) (EtOAc) , 120 mg of a white solid was obtained in a yield of 69.3%. Melting point: 143-145 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝7.2Hz,1H),8.22(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.56(s,1H),7.23(t,J＝7.6Hz,1H),7.15(dt,J 1＝7.6Hz,J 1＝1.2Hz,1H),7.12(d,J＝1.6Hz,1H),6.90-6.94(m,2H),5.24-5.28(m,1H),4.12-4.17(m,2H),2.48-2.52(m,1H),1.86-1.90(m,1H),1.56(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H),1.21(dd,J 1＝7.2Hz,J 1＝2.0Hz,6H),0.92-0.97(m,2H),0.66-0.71(m,2H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (d, J = 7.2Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 1 = 2.8Hz, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.56 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.15 (dt, J 1 = 7.6 Hz, J 1 = 1.2 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.90-6.94 (m, 2H), 5.24-5.28 (m, 1H), 4.12-4.17 (m, 2H), 2.48-2.52 (m, 1H), 1.86-1.90 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8 Hz, 3H), 1.21 (dd, J 1 = 7.2 Hz, J 1 = 2.0 Hz, 6H), 0.92-0.97 ( m, 2H), 0.66-0.71 (m, 2H).

实施例(化合物)128Example (compound) 128

N-(1-(3-(环丙基甲氧基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000188
Figure PCTCN2018088561-appb-000188

a)1-(3-(环丙基甲氧基)苯基)乙酮a) 1-(3-(cyclopropylmethoxy)phenyl)ethanone

将3-羟基苯乙酮(953mg,7mmol)，置于反应瓶中，加入DMF(25ml)，加入Cs 2CO 3(3.4g,10.5mmol)，反应液呈黄色，加入溴甲基环丙烷(0.8mL,8.4mmol)室温搅拌反应，次日，停止反应，将反应液倒入水中，用乙酸乙酯(40ml×2)萃取，合并有机层，用饱和NaCl溶液(20ml×2)洗，无水硫酸镁干燥，柱层析(E:P＝1:50,E:P＝1:25)得到无色油状物1.29g，产率96.9％。 3-Hydroxyacetophenone (953 mg, 7 mmol) was placed in a reaction flask, DMF (25 ml) was added, and Cs 2 CO 3 (3.4 g, 10.5 mmol) was added, the reaction mixture was yellow, and bromomethylcyclopropane was added. 0.8 mL, 8.4 mmol) The reaction was stirred at room temperature, the next day, the reaction was stopped, the reaction mixture was poured into water, and extracted with ethyl acetate (40 ml × 2), and the organic layer was combined and washed with saturated NaCl solution (20 ml × 2) The mixture was dried over MgSO.sub.4.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.50-7.754(m,1H),7.46-7.47(m,1H),7.32-7.38(m,1H),7.09-7.14(m,1H),3.83-3.87(m,2H),2.57-2.59(m,3H),1.25-1.31(m,1H),0.62-0.67(M,2H),0.33-0.38(m,2H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.50-7.754 (m, 1H), 7.46-7.47 (m, 1H), 7.32-7.38 (m, 1H), 7.09-7.14 (m, 1H) , 3.83-3.87 (m, 2H), 2.57-2.59 (m, 3H), 1.25-1.31 (m, 1H), 0.62-0.67 (M, 2H), 0.33-0.38 (m, 2H).

b)N-(1-(3-(环丙基甲氧基)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺b) N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入1-(3-(环丙基甲氧基)苯基)乙胺(167mg,0.876mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3.5,E:P＝1:2.5)，得到白色固体150mg，产率80.6％。熔点：129-130℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 1-(3-(cyclopropylmethoxy)phenyl)ethylamine (167 mg, 0.876 mmol). The mixture was extracted with a 10:1 mixture (30 mL×2), and the combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:3.5, E:P =1: 2.5), 150 mg of a white solid was obtained in a yield of 80.6%. Melting point: 129-130 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.46(d,J＝7.2Hz,1H),8.22(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.68(s,1H),7.25(t,J＝8.0Hz,1H),6.90-6.96(m,3H),6.77-6.80(m,1H),5.23-5.30(m,1H),4.11-4.18(m,2H),3.79(d,J＝6.8Hz,2H),2.46-2.53(m,1H),1.56(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.22-1.28(m,1H),1.20(dd,J 1＝6.8Hz,J 1＝2.0Hz,6H),0.62-0.65(m,2H),0.32-0.36(m,2H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.46 (d, J = 7.2 Hz, 1H), 8.22 (dd, J 1 = 8.8 Hz, J 1 = 2.8 Hz, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.68 (s, 1H), 7.25 (t, J=8.0 Hz, 1H), 6.90-6.96 (m, 3H), 6.77-6.80 (m, 1H), 5.23-5.30 (m) , 1H), 4.11-4.18 (m, 2H), 3.79 (d, J = 6.8 Hz, 2H), 2.46-2.53 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.42 (t, J=6.8 Hz, 3H), 1.22-1.28 (m, 1H), 1.20 (dd, J 1 = 6.8 Hz, J 1 = 2.0 Hz, 6H), 0.62-0.65 (m, 2H), 0.32-0.36 (m) , 2H).

实施例(化合物)129Example (compound) 129

2-乙氧基-5-异丁酰氨基-N-(1-(3-(甲基磺酰氨基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(methylsulfonylamino)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000189
Figure PCTCN2018088561-appb-000189

a)N-(3-乙酰基苯基)甲磺酰胺a) N-(3-acetylphenyl)methanesulfonamide

将3-氨基苯乙酮(1g,7.4mmol)置于反应瓶中，加入DCM(30mL)，加入吡啶(3mL,37.3mmol)，冰浴下降甲磺酰氯(0.86mL,11.2mmol)滴加入反应瓶中，滴毕升至室温反应，4h后停止反应，加入DCM(30mL)，用1N HCl溶液(20mL)洗，饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，用乙醇重结晶，得到橙色固体1.05g，产率66.6％。熔点：93-94℃3-Aminoacetophenone (1 g, 7.4 mmol) was placed in a reaction flask, DCM (30 mL) was added, pyridine (3 mL, 37.3 mmol) was added, and the mixture was added dropwise with methanesulfonyl chloride (0.86 mL, 11.2 mmol). In the flask, the reaction was allowed to rise to room temperature. After 4 h, the reaction was stopped. DCM (30 mL) was added, washed with 1N HCl solution (20 mL), washed with saturated NaCI solution (20 mL×2), dried over anhydrous magnesium sulfate Recrystallization gave 1.05 g of an orange solid, yield 66.6%. Melting point: 93-94 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):7.83(s,1H),7.76(d,J＝7.5Hz,1H),7.48(t,J＝8.0Hz,1H),7.27(s,1H),3.06(s,3H),2.62(s,3H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 7.83 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 3.06 (s, 3H), 2.62 (s, 3H).

b)2-乙氧基-5-异丁酰氨基-N-(1-(3-(甲基磺酰氨基)苯基)乙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(3-(methylsulfonylamino)phenyl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入N-(3-(1-氨基乙基)苯基)甲磺酰胺(175mg,0.818mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝75:1,D:M＝60:1)，得到白色固体150mg，产率76.5％。熔点：84-86℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; Addition of N-(3-(1-aminoethyl)phenyl)methanesulfonamide (175 mg, 0.818 mmol), rt over EtOAc. The mixture was extracted with a 10:1 mixture (30 mL×2), and the combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=75:1, D:M = 60:1) gave 150 mg of a white solid, yield 76.5%. Melting point: 84-86 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.68(d,J＝6.8Hz,1H),8.29(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),8.22(brs,1H),7.95(d,J＝2.8Hz,1H),7.80(brs,1H),7.38(s,1H),7.32(d,J＝5.2Hz,2H),7.13-7.16(m,1H),6.92(d,J＝9.2Hz,1H),5.26-5.31(m,1H),4.14-4.21(m,2H),2.96(s,3H),2.48-2.54(m,1H),1.57(d,J＝6.8Hz,3H),1.47(t,J＝6.8Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.68 (d, J = 6.8Hz, 1H), 8.29 (dd, J 1 = 8.8Hz, J 1 = 2.8Hz, 1H), 8.22 (brs, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.80 (brs, 1H), 7.38 (s, 1H), 7.32 (d, J = 5.2 Hz, 2H), 7.13-7.16 (m, 1H), 6.92 (d, J=9.2 Hz, 1H), 5.26-5.31 (m, 1H), 4.14-4.21 (m, 2H), 2.96 (s, 3H), 2.48-2.54 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.47 (t, J = 6.8 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)130Example (compound) 130

N-(1-(3-(吖丁啶-1-基磺酰)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(3-(azetidin-1-ylsulfonyl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000190
Figure PCTCN2018088561-appb-000190

a)1-(3-(吖丁啶-1-基磺酰)苯基)乙酮a) 1-(3-(azetidin-1-ylsulfonyl)phenyl)ethanone

将氮杂环丁烷(128mg,2.25mmol)置于反应瓶中，加入DCM(10mL)，加入吡啶(0.6mL,7.5mmol)，冰浴下将3-acetylbenzenesulfonyl chloride(327mg,1.5mmol)的DCM(5mL)溶液，滴毕，室温搅拌反应，2h后停止反应，浓缩至干，加入DCM(40mL)，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:7， E:P＝1:5，E:P＝1:4)得到白色蜡状固体310mg，产率86.3％。熔点：65-66℃Azetidine (128 mg, 2.25 mmol) was placed in a reaction flask, DCM (10 mL) was added, pyridine (0.6 mL, 7.5 mmol) was added, and 3- propylbenzenesulfonyl chloride (327 mg, 1.5 mmol) in DCM. (5mL) solution, after completion, the reaction was stirred at room temperature. After 2h, the reaction was stopped and concentrated to dryness. EtOAc (EtOAc) E: P = 1:7, E: P = 1:5, E: P = 1:4) Obtained a white waxy solid, 310 mg, yield 86.3%. Melting point: 65-66 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.38(brs,1H),8.22(d,J＝6.5Hz,1H),8.03-8.05(m,1H),7.71(t,J＝7.5Hz,1H),3.80-3.85(m,4H),2.67-2.68(m,1H),2.09-2.13(m,2H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.38 (brs, 1H), 8.22 (d, J = 6.5 Hz, 1H), 8.03 - 8.05 (m, 1H), 7.71 (t, J = 7.5 Hz, 1H), 3.80-3.85 (m, 4H), 2.67-2.68 (m, 1H), 2.09-2.13 (m, 2H).

b)N-(1-(3-(吖丁啶-1-基磺酰)苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺b) N-(1-(3-(azetidin-1-ylsulfonyl)phenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(39mg,0.155mmol)加入无水DMF(6mL)，加入EDC(59mg,0.31mmol)，加入HOBt(42mg,0.31mmol)和DIEA(0.08mL,0.465mmol)，加入1-(3-(吖丁啶-1-基磺酰)苯基)乙胺(48mg,0.2mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝100:1)，得到白色固体50mg，产率68.4％。熔点：71-73℃2-Ethoxy-5-isobutyrylaminobenzoic acid (39 mg, 0.155 mmol) was added to dry DMF (6 mL), EtOAc (EtOAc, EtOAc (EtOAc) mL, 0.465 mmol), 1-(3-(azetidin-1-ylsulfonyl)phenyl)ethylamine (48 mg, 0.2 mmol). The mixture was extracted with a mixture of methanol = 10:1 (30 mL × 2), and the combined organic layer was washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=100:1) , 50 mg of a white solid was obtained in a yield of 68.4%. Melting point: 71-73 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.53(d,J＝6.8Hz,1H),8.16(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.84(t,J＝1.6Hz,1H),7.77(d,J＝2.8Hz,1H),7.73(dt,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.64-7.67(m,1H),7.55(t,J＝8.0Hz,1H),5.34-5.38(m,1H),4.18-4.24(m,2H),3.75(t,J＝7.6Hz,4H),2.45-2.51(m,1H),2.00-2.09(m,2H),1.60(d,J＝7.2Hz,3H),1.49(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.53 (d, J = 6.8Hz, 1H), 8.16 (dd, J 1 = 8.8Hz, J 1 = 2.8Hz, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.73 (dt, J 1 = 7.6 Hz, J 2 = 1.6 Hz, 1H), 7.64 - 7.67 (m, 1H), 7.55 ( t, J=8.0 Hz, 1H), 5.34-5.38 (m, 1H), 4.18-4.24 (m, 2H), 3.75 (t, J = 7.6 Hz, 4H), 2.45-2.51 (m, 1H), 2.00 -2.09 (m, 2H), 1.60 (d, J = 7.2 Hz, 3H), 1.49 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)131Example (compound) 131

2-乙氧基-5-异丁酰氨基-N-(1-(3-氨磺酰苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-sulfamoylphenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000191
Figure PCTCN2018088561-appb-000191

a)3-乙酰基苯磺酰胺a) 3-acetylbenzenesulfonamide

将3-乙酰基苯磺酰氯(327mg,1.5mmol)，冰浴下加入7M NH 3的甲醇溶液，加毕，室温搅拌反应，15min后停止反应，浓缩，柱层析(D:M＝50:1)，得到白色固体290mg，产率97.3％。m.p.144-146℃ 3-Acetyl-benzenesulfonyl chloride (327mg, 1.5mmol), was added under ice-7M NH 3 in methanol, addition was completed, the reaction was stirred at room temperature, the reaction was stopped after 15min, concentration, column chromatography (D: M = 50: 1) A white solid 290 mg was obtained in a yield of 97.3%. Mp144-146°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.35(t,J＝1.6Hz,1H),8.18(dt,J 1＝8.0Hz,J 1＝1.6Hz,1H),8.04-8.07(m,1H),7.74(t,J＝8.0Hz,1H),7.50(brs,2H),2.64(s,3H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.35 (t, J = 1.6 Hz, 1H), 8.18 (dt, J 1 = 8.0 Hz, J 1 = 1.6 Hz, 1H), 8.04 8.07 (m, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.50 (brs, 2H), 2.64 (s, 3H).

b)2-乙氧基-5-异丁酰氨基-N-(1-(3-氨磺酰苯基)乙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(3-sulfamoylphenyl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(48mg,0.19mmol)加入无水DMF(10mL)，加入 EDC(73mg,0.38mmol)，加入HOBt(51mg,0.38mmol)和DIEA(0.10mL,0.57mmol)，加入3-(1-氨基乙基)苯磺酰胺(50mg,0.258mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝40:1,D:M＝30:1)，得到白色固体50mg，产率60.9％。熔点：93-95℃2-Ethoxy-5-isobutyrylaminobenzoic acid (48 mg, 0.19 mmol) was added to dry DMF (10 mL) EtOAc (EtOAc,EtOAc, mL, 0.57 mmol), 3-(1-aminoethyl)benzenesulfonamide (50 mg, 0.258 mmol) was added, stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate: methanol = 10:1 mixture (30 mL × 2), the combined organic layer was washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=40:1, D:M=30:1) A white solid of 50 mg was obtained in a yield of 60.9%. Melting point: 93-95 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.78(s,1H),8.60(d,J＝7.6Hz,1H),7.87(d,J＝2.8Hz,1H),7.84(s,1H),7.71-7.77(m,2H),7.63(d,J＝7.6Hz,1H),7.54(t,J＝8.0Hz,1H),7.35(s,2H),7.08(d,J＝9.2Hz,1H),5.16-5.21(m,1H),4.12(q,J＝6.8Hz,2H),2.52-2.56(m,1H),1.48(d,J＝7.2Hz,3H),1.37(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.78 (s, 1H), 8.60 (d, J = 7.6Hz, 1H), 7.87 (d, J = 2.8Hz, 1H), 7.84 ( s, 1H), 7.71-7.77 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.35 (s, 2H), 7.08 (d, J) = 9.2 Hz, 1H), 5.16-5.21 (m, 1H), 4.12 (q, J = 6.8 Hz, 2H), 2.52-2.56 (m, 1H), 1.48 (d, J = 7.2 Hz, 3H), 1.37 (t, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)132Example (compound) 132

2-乙氧基-5-异丁酰氨基-N-(1-(3-(四氢呋喃-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(tetrahydrofuran-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000192
Figure PCTCN2018088561-appb-000192

将2-乙氧基-5-异丁酰氨基苯甲酸(120mg,0.48mmol)加入无水DMF(15mL)，加入EDC(184mg,0.96mmol)，加入HOBt(130mg,0.96mmol)和DIEA(0.25mL,1.44mmol)，加入1-(3-(四氢呋喃-2-基)苯基)乙胺(183mg,0.96mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝100:1)，得到白色固体100mg，产率49.2％。熔点：121-123℃2-Ethoxy-5-isobutyrylaminobenzoic acid (120 mg, 0.48 mmol) was added to dry DMF (15 mL), EtOAc (EtOAc, EtOAc, EtOAc mL, 1.44 mmol), 1-(3-(tetrahydrofuran-2-yl)phenyl)ethylamine (183 mg, 0.96 mmol). The mixture was extracted with a mixture of EtOAc (3 mL, EtOAc) (EtOAc (EtOAc) 100 mg, yield 49.2%. Melting point: 121-123 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.46(d,J＝7.5Hz,1H),8.21(d,J＝9.0Hz,1H),7.86(s,1H),7.70(d,J＝7.0Hz,1H),7.32-7.35(m,1H),7.30(d,J＝7.5Hz,1H),7.22-7.27(m,2H),6.91(d,J＝8.5Hz,1H),5.29-5.33(m,1H),4.87(t,J＝7.5Hz,1H),4.04-4.17(m,3H),3.89-3.95(m,1H),2.47-2.53(m,1H),2.28-2.32(m,1H),1.97-2.04(m,2H),1.76-1.81(m,1H),1.57(d,J＝7.0Hz,3H),1.40(t,J＝7.0Hz,3H),1.20(d,J 1＝6.5Hz,J 2＝2.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.46 (d, J = 7.5 Hz, 1H), 8.21. (d, J = 9.0 Hz, 1H), 7.86 (s, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.32 - 7.35 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.22 - 7.27 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 5.29-5.33 (m, 1H), 4.87 (t, J = 7.5 Hz, 1H), 4.04-4.17 (m, 3H), 3.89-3.95 (m, 1H), 2.47-2.53 (m, 1H), 2.28- 2.32 (m, 1H), 1.97-2.04 (m, 2H), 1.76-1.81 (m, 1H), 1.57 (d, J = 7.0 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H), 1.20 (d, J 1 = 6.5 Hz, J 2 = 2.5 Hz, 6H).

实施例(化合物)133Example (compound) 133

2-乙氧基-5-异丁酰氨基-N-(1-(3-(嘧啶-2-基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(pyrimidin-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000193
Figure PCTCN2018088561-appb-000193

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入1-(3-(嘧啶-2-基)苯基)乙胺(192mg,0.876mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1)，得到白色固体135mg，产率71.4％。熔点：161-163℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 1-(3-(pyrimidin-2-yl)phenyl)ethylamine (192 mg, 0.876 mmol). The mixture was extracted with a mixture of EtOAc (1 mL, EtOAc (EtOAc) (EtOAc) 135 mg, yield 71.4%. Melting point: 161-163 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.79(s,1H),8.91(d,J＝4.8Hz,1H),8.44(s,1H),8.29(d,J＝7.6Hz,1H),7.88(d,J＝2.8Hz,1H),7.77(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.58(d,J＝7.2Hz,1H),7.51(t,J＝7.6Hz,1H),7.46(t,J＝4.8Hz,1H),7.08(d,J＝8.8Hz,1H),5.19-5.28(m,1H),4.10-4.15(m,2H),2.52-2.56(m,1H),1.52(d,J＝7.2Hz,3H),1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.79 (s, 1H), 8.91 (d, J = 4.8Hz, 1H), 8.44 (s, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.77 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.51 ( t, J = 7.6 Hz, 1H), 7.46 (t, J = 4.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.19-5.28 (m, 1H), 4.10-4.15 (m, 2H) ), 2.52-2.56 (m, 1H), 1.52 (d, J = 7.2 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)134Example (compound) 134

2-乙氧基-5-异丁酰氨基-N-((6-甲基吡啶-2-基)甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-((6-methylpyridin-2-yl)methyl)benzamide

Figure PCTCN2018088561-appb-000194
Figure PCTCN2018088561-appb-000194

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(10mL)，加入EDC(156mg,0.8mmol)，加入HOBt(108mg,0.8mmol)和DIEA(0.21mL,1.20mmol)，加入化合物(6-甲基吡啶-2-基)甲胺(74mg,0.8mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1,D:M＝50:1,D:M＝40:1)，得到白色固体115mg，产率80.98％。熔点：138-140℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (10 mL). E.sub.2 (156 mg, 0.8 mmol) was added to HOBt (108 mg, 0.8 mmol) and DIEA (0.21) The compound (6-methylpyridin-2-yl)methanamine (74 mg, 0.8 mmol) was added, and the mixture was stirred at room temperature overnight, and poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI solution (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=80:1, D:M=50:1) D: M = 40: 1) gave a white solid, 115 mg, yield: 80.98%. Melting point: 138-140 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):9.01(s,1H),8.23(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.91-7.92(m,1H),7.65(brs,1H),7.56(t,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H),7.07(d,J＝7.6Hz,1H),6.96(d,J＝9.2Hz,1H),4.78(d,J＝4.8Hz,2H),4.22(q,J＝7.2Hz,2H),2.58(s,3H),2.51-2.55(m,1H),1.49(t,J＝6.8Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.01 (s, 1H), 8.23 (dd, J 1 = 8.8Hz, J 1 = 2.8Hz, 1H), 7.91-7.92 (m, 1H), 7.65 (brs, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 9.2) Hz, 1H), 4.78 (d, J = 4.8 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.51-2.55 (m, 1H), 1.49 (t, J = 6.8 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)135Example (compound) 135

2-乙氧基-5-异丁酰氨基-N-(1-(6-甲基吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-methylpyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000195
Figure PCTCN2018088561-appb-000195

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.40mmol)加入无水DMF(10mL)，加入EDC(156mg,0.8mmol)，加入HOBt(108mg,0.8mmol)和DIEA(0.21mL,1.20mmol)，加入1-(6-甲基吡啶-2-基)乙胺(82mg,0.6mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1,D:M＝50:1)，得到白色固体110mg，产率74.8％。熔点：189-191℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.40 mmol) was added to dry DMF (10 mL). E.sub.2 (156 mg, 0.8 mmol) was added to HOBt (108 mg, 0.8 mmol) and DIEA (0.21) mL, 1.20 mmol), 1-(6-methylpyridin-2-yl)ethylamine (82 mg, 0.6 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=80:1, D:M=50: 1) A white solid of 110 mg was obtained in a yield of 74.8%. Melting point: 189-191 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):9.13(d,J＝7.2Hz,1H),8.21(dd,J 1＝8.8Hz,J 1＝2.8Hz,1H),7.87(d,J＝2.8Hz,1H),7.62(s,1H),7.53(t,J＝7.6Hz,1H),7.02-7.08(m,2H),6.94(d,J＝8.8Hz,1H),5.32-5.36(m,1H),4.19-4.25(m,2H),2.56(s,3H),2.51-2.55(m,1H),1.52-1.56(m,6H),1.22(dd,J 1＝6.8Hz,J 2＝2.0Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 9.13 (d, J = 7.2 Hz, 1H), 8.21. (dd, J 1 = 8.8 Hz, J 1 = 2.8 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.62 (s, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.02-7.08 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H), 5.32 5.36 (m, 1H), 4.19-4.25 (m, 2H), 2.56 (s, 3H), 2.51-2.55 (m, 1H), 1.52-1.56 (m, 6H), 1.22 (dd, J 1 = 6.8 Hz , J 2 = 2.0 Hz, 6H).

实施例(化合物)136Example (compound) 136

2-乙氧基-5-异丁酰氨基-N-(1-(4-甲基吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(4-methylpyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000196
Figure PCTCN2018088561-appb-000196

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入1-(4-甲基吡啶-2-基)乙胺(119mg,0.876mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1,D:M＝50:1)，得到白色固体88mg，产率54.6％。熔点：129-131℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 1-(4-methylpyridin-2-yl)ethylamine (119 mg, 0.876 mmol), EtOAc. The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=80:1, D:M=50: 1) A white solid 88 mg was obtained in a yield of 54.6%. Melting point: 129-131 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):9.28(d,J＝6.0Hz,1H),8.42(d,J＝5.0Hz,1H),8.20(d,J＝7.0Hz,1H),7.87(s,1H),7.54(s,1H),7.11(s,1H),7.03(s,1H),6.94(d,J＝9.0Hz,1H),5.30-5.34(m,1H),4.16-4.23(m,2H),2.51-2.54(m,1H),2.36(s,3H),1.56-1.59(m,6H),1.23(d,J＝6.0Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 9.28 (d, J = 6.0 Hz, 1H), 8.42 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 7.0 Hz, 1H) , 7.78 (s, 1H), 7.54 (s, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 6.94 (d, J = 9.0 Hz, 1H), 5.30-5.34 (m, 1H), 4.16-4.23 (m, 2H), 2.51-2.54 (m, 1H), 2.36 (s, 3H), 1.56-1.59 (m, 6H), 1.23 (d, J = 6.0 Hz, 6H).

实施例(化合物)137Example (compound) 137

2-乙氧基-5-异丁酰氨基-N-(1-(6-甲氧基吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-methoxypyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000197
Figure PCTCN2018088561-appb-000197

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入1-(6-甲氧基吡啶-2-基)乙胺(133mg,0.876mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3,E:P＝1:1.5)，得到白色固体130mg，产率76.9％。熔点：178-180℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 1-(6-methoxypyridin-2-yl)ethylamine (133 mg, 0.876 mmol). The mixture was extracted with 1 ml (30 mL×2), and the combined organic layer was washed with saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:3, E:P=1) : 1.5), 130 mg of a white solid was obtained with a yield of 76.9%. Melting point: 178-180 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.73(d,J＝7.6Hz,1H),8.22(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.69(s,1H),7.52(t,J＝7.2Hz,1H),6.94(d,J＝9.2Hz,1H),6.87(d,J＝7.2Hz,1H),6.62(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),5.28-5.36(m,1H),4.14-4.21(m,2H),3.95(s,3H),2.48-2.56(m,1H),1.57(d,J＝6.8Hz,3H),1.43(t,J＝6.8Hz,3H),1.22(dd,J 1＝6.8Hz,J 2＝1.6Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.73 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.69 (s, 1H), 7.52 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H) , 6.62 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 5.28-5.36 (m, 1H), 4.14 - 4.21 (m, 2H), 3.95 (s, 3H), 2.48-2.56 (m , 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 6.8 Hz, 3H), 1.22 (dd, J 1 = 6.8 Hz, J 2 = 1.6 Hz, 6H).

实施例(化合物)138Example (compound) 138

2-乙氧基-5-异丁酰氨基-N-(1-(2-甲氧基吡啶-4-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(2-methoxypyridin-4-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000198
Figure PCTCN2018088561-appb-000198

a)1-(2-甲氧基吡啶-4-基)乙酮a) 1-(2-methoxypyridin-4-yl)ethanone

将2-甲氧基-4-氰基-吡啶(670mg,5mmol)，加入叔丁基甲基醚(10mL)，降温至0℃，氩气保护下将1M甲基溴化镁THF溶液(6mL,6mmol)滴加入反应瓶中，滴毕在0℃下反应3h后补加1M甲基溴化镁THF溶液(0.25mL,0.25mmol)继续0℃下反应5h，加入水6mL后室温下搅拌反应过夜，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NH 4Cl溶液(20mL×2)和洗饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20,E:P＝1:15)，得到无色油状物160mg，产率21.2％。 2-Methoxy-4-cyano-pyridine (670 mg, 5 mmol) was added to tert-butyl methyl ether (10 mL), cooled to 0 ° C, 1 M methyl bromide THF solution (6 mL, 6 mmol) The mixture was added dropwise to the reaction flask, and the reaction was carried out at 0 ° C for 3 h, and then 1 M methylmagnesium bromide THF solution (0.25 mL, 0.25 mmol) was added to continue the reaction at 0 ° C for 5 h. After adding 6 mL of water, the reaction was stirred at room temperature overnight. with ethyl acetate (40mL × 2). The combined organic layers were washed with saturated NH 4 Cl solution (20mL × 2) and washed with saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, and concentrated by column chromatography (E :P=1:20, E:P=1:15), 160 mg of colorless oil was obtained, yield 21.2%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.31(d,J＝5.6Hz,1H),7.30(dd,J 1＝5.6 Hz,J 2＝1.6Hz,1H),7.17-7.18(m,1H),3.98(s,3H),2.58(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.31 (d, J = 5.6 Hz, 1H), 7.30 (dd, J 1 = 5.6 Hz, J 2 = 1.6 Hz, 1H), 7.17-7.18 ( m, 1H), 3.98 (s, 3H), 2.58 (s, 3H).

b)2-乙氧基-5-异丁酰氨基-N-(1-(2-甲氧基吡啶-4-基)乙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(2-methoxypyridin-4-yl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(95mg,0.378mmol)加入无水DMF(10mL)，加入EDC(145mg,0.756mmol)，加入HOBt(102mg,0.756mmol)和DIEA(0.20mL,1.13mmol)，加入1-(2-甲氧基吡啶-4-基)乙胺(86mg,0.57mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D：M＝75:1)，得到白色固体103mg，产率70.5％。熔点：94-96℃2-Ethoxy-5-isobutyrylaminobenzoic acid (95 mg, 0.378 mmol) was added to dry DMF (10 mL) EtOAc (EtOAc EtOAc EtOAc </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; The mixture was extracted with EtOAc (3 mL, EtOAc) (EtOAc m. The yield was 70.5%. Melting point: 94-96 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.78(s,1H),8.54(d,J＝7.6Hz,1H),8.10(dd,J 1＝5.6Hz,J 2＝0.4Hz,1H),7.82(d,J＝2.8Hz,1H),7.75(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.07(d,J＝8.8Hz,1H),7.01(dd,J 1＝5.2Hz,J 2＝1.2Hz,1H),6.80-6.81(m,1H),5.04-5.08(m,1H),4.12(q,J＝7.2Hz,2H),3.83(s,3H),2.52-2.56(m,1H),1.42(d,J＝7.2Hz,3H),1.38(t,J＝7.2Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.78 (s, 1H), 8.54 (d, J = 7.6Hz, 1H), 8.10 (dd, J 1 = 5.6Hz, J 2 = 0.4 Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.75 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.01 ( Dd, J 1 = 5.2 Hz, J 2 = 1.2 Hz, 1H), 6.80-6.81 (m, 1H), 5.04-5.08 (m, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.83 (s) , 3H), 2.52-2.56 (m, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)139Example (compound) 139

N-(1-(2-氨基吡啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(2-Aminopyridin-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000199
Figure PCTCN2018088561-appb-000199

a)1-(2-氨基吡啶-4-基)乙酮a) 1-(2-Aminopyridin-4-yl)ethanone

将2-氨基异尼古丁酸甲酯(608mg,4mmol)置于反应瓶中，加入干燥THF(25mL)，氩气保护-78℃下将1.3M甲基锂的乙醚溶液(12.3mL,16mmol)滴加入反应瓶中，滴毕继续在-78℃下反应1h后升温至0℃反应3h，加入异丙醇(6mL)，加入乙酸乙酯(60mL)，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝50:1)，得到类白色固体110mg，产率20％。m.p.129-130℃Methyl 2-aminoiso-n-butyric acid (608 mg, 4 mmol) was placed in a reaction flask, dry THF (25 mL) was added, and a solution of 1.3 M methyllithium in diethyl ether (12.3 mL, 16 mmol) was added at -78 ° C under argon atmosphere. After adding to the reaction flask, the reaction was continued at -78 ° C for 1 h, then the temperature was raised to 0 ° C for 3 h, isopropyl alcohol (6 mL) was added, ethyl acetate (60 mL) was added, and washed with a saturated NaCI solution (15 mL×2). Drying over anhydrous magnesium sulfate, EtOAc (EtOAc:EtOAc) M.p.129-130°C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.22(dd,J 1＝5.2Hz,J 2＝0.8Hz,1H),7.06(dd,J 1＝5.2Hz,J 2＝1.6Hz,1H),6.94-6.95(m,1H),4.69(brs,2H),2.56(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.22 (dd, J 1 = 5.2 Hz, J 2 = 0.8 Hz, 1H), 7.06 (dd, J 1 = 5.2 Hz, J 2 = 1.6 Hz, 1H), 6.94-6.95 (m, 1H), 4.69 (brs, 2H), 2.56 (s, 3H).

b)N-(1-(2-氨基吡啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺b) N-(1-(2-Aminopyridin-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(90mg,0.36mmol)加入无水DMF(10mL)，加入EDC(138mg,0.72mmol)，加入HOBt(97mg,0.72mmol)和DIEA(0.19mL,1.08mmol)，加入4-(1-氨基乙基)吡啶-2-胺(71mg,0.52mmol)，室温搅拌过夜，将反 应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝35:1,D:M＝20:1)，得到白色固体99mg，产率74.4％。m.p.82-84℃2-Ethoxy-5-isobutyrylaminobenzoic acid (90 mg, 0.36 mmol) was added to dry DMF (10 mL) EtOAc (EtOAc (EtOAc) mL, 1.08 mmol), 4-(1-aminoethyl)pyridin-2-amine (71 mg, 0.52 mmol) was added and stirred at room temperature overnight, then poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=35:1, D:M=20:1) ), a white solid of 99 mg was obtained in a yield of 74.4%. M.p.82-84°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.80(s,1H),8.47(d,J＝8.0Hz,1H),7.91(d,J＝2.8Hz,1H),7.83(d,J＝5.6Hz,1H),7.78(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.08(d,J＝8.8Hz,1H),6.51(dd,J 1＝5.6Hz,J 2＝1.6Hz,1H),6.39-6.40(m,1H),5.87(s,2H),4.91-4.95(m,1H),4.13(q,J＝7.2Hz,2H),2.51-2.56(m,1H),1.35-1.41(m,6H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.80 (s, 1H), 8.47 (d, J = 8.0Hz, 1H), 7.91 (d, J = 2.8Hz, 1H), 7.83 ( d, J = 5.6 Hz, 1H), 7.78 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.51 (dd, J 1 = 5.6 Hz , J 2 =1.6 Hz, 1H), 6.39-6.40 (m, 1H), 5.87 (s, 2H), 4.91-4.95 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.51-2.56 (m, 1H), 1.35 - 1.41 (m, 6H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)140Example (compound) 140

N-(1-(6-氯吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(6-chloropyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000200
Figure PCTCN2018088561-appb-000200

a)6-氯-N-甲氧基-N-甲基甲基吡啶酰胺a) 6-chloro-N-methoxy-N-methylmethylpyridine

将6-氯吡啶-2-甲酸(785mg,5.0mmol)加入无水DMF(40mL)，加入HBTU(3.79g,10.0mmol)，加入HOBt(1.35g,10.0mmol)和DIEA(5.2mL,30.0mmol)，加入N,O-二甲基羟胺(972mg,10.0mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(50mL×2)萃取，合并有机层用饱和NaCl溶液(25mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:5,E:P＝1:4)，得到无色油状物800mg，产率80％。6-Chloropyridine-2-carboxylic acid (785 mg, 5.0 mmol) was added to dry DMF (40 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc , N,O-dimethylhydroxylamine (972 mg, 10.0 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water, and extracted with a mixture of ethyl acetate:methanol=10:1 (50 mL×2), and combined. The organic layer was washed with a saturated NaCI solution (25 mL×2), dried over anhydrous magnesium sulfate. The rate is 80%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.76(t,J＝8.0Hz,1H),7.58(brs,1H),7.41(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),3.80(s,3H),3.38(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.76 (t, J = 8.0 Hz, 1H), 7.58 (brs, 1H), 7.41 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 3.80 (s, 3H), 3.38 (s, 3H).

b)1-(6-氯吡啶-2-基)乙酮b) 1-(6-chloropyridin-2-yl)ethanone

将6-氯-N-甲氧基-N-甲基甲基吡啶酰胺(760mg,3.80mmol)加入干燥THF(25mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(4.94mL,4.94mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:15)，得到无色油状物355mg，产率60.3％。6-Chloro-N-methoxy-N-methylmethylpyridine amide (760 mg, 3.80 mmol) was added to dry THF (25 mL) and 1M methylmagnesium bromide in THF at 0 ° C under argon ( 4.94mL, 4.94mmol) was added dropwise to the reaction flask, and the reaction was stirred at 0 ° C. After 2 h, a saturated ammonium chloride solution was added to the reaction flask, and extracted with EA (40 mL × 2), and the organic layer was combined. The mixture was washed with aq. EtOAc (EtOAc)EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.96(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),7.81(t,J＝6.8Hz,1H),7.51(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),2.71(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.96 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 7.81 (t, J = 6.8 Hz, 1H), 7.51 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 2.71 (s, 3H).

c)N-(1-(6-氯吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺c) N-(1-(6-chloropyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(129mg,0.51mmol)加入无水DMF(20mL)，加入EDC(196mg,1.02mmol)，加入HOBt(138mg,1.02mmol)和DIEA(0.27mL,1.53mmol)，加入1-(6-氯吡啶-2-基)乙胺(100mg,0.64mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝75:1)，得到白色固体165mg，产率83.3％。2-Ethoxy-5-isobutyrylaminobenzoic acid (129 mg, 0.51 mmol) was added to dry DMF (20 mL). E.sub.2 (196 mg, 1.02 mmol). mL, 1.53 mmol), 1-(6-chloropyridin-2-yl)ethylamine (100 mg, 0.64 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted with EtOAc (3 mL, EtOAc) (EtOAc) The rate is 83.3%.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.09(d,J＝7.2Hz,1H),8.20(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.82(d,J＝2.8Hz,1H),7.63(t,J＝8.4Hz,1H),7.41(brs,1H),7.23(d,J＝8.4Hz,2H),5.34-5.42(m,1H),4.21-4.27(m,2H),2.48-2.55(m,1H),1.55-1.62(m,6H),1.24(dd,J 1＝6.8Hz,J 2＝1.2Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.09 (d, J = 7.2Hz, 1H), 8.20 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.41 (brs, 1H), 7.23 (d, J = 8.4 Hz, 2H), 5.34 - 5.42 (m, 1H), 4.21 4.27 (m, 2H), 2.48-2.55 (m, 1H), 1.55-1.62 (m, 6H), 1.24 (dd, J 1 = 6.8 Hz, J 2 = 1.2 Hz, 6H).

实施例(化合物)141Example (compound) 141

N-(1-(2-氨基嘧啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(2-Aminopyrimidin-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000201
Figure PCTCN2018088561-appb-000201

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(10mL)，加入EDC(153mg,0.796mmol)，加入HOBt(107mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入4-(1-氨基乙基)嘧啶-2-胺(99mg,0.717mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝35:1,D:M＝20:1)，得到白色固体100mg，产率68.9％。m.p.192-194℃2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (10 mL), EDC (153 mg, 0.796 mmol) was added, HOBt (107 mg, 0.796 mmol) and DIEA (0.21) mL, 1.19 mmol), 4-(1-aminoethyl)pyrimidin-2-amine (99 mg, 0.717 mmol) was added and stirred at room temperature overnight, then poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=35:1, D:M=20:1) ), a white solid 100 mg was obtained in a yield of 68.9%. M.p.192-194°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.81(s,1H),8.73(d,J＝7.2Hz,1H),8.19(d,J＝5.2Hz,1H),7.97(d,J＝2.8Hz,1H),7.79(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.01(d,J＝8.8Hz,1H),6.62(d,J＝4.8Hz,1H),6.59(s,2H),4.87-4.91(m,1H),4.13-4.19(m,2H),2.53-2.57(m,1H),1.37-1.41(m,6H),1.09(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.81 (s, 1H), 8.73 (d, J = 7.2Hz, 1H), 8.19 (d, J = 5.2Hz, 1H), 7.97 ( d, J = 2.8 Hz, 1H), 7.79 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 4.8 Hz, 1H), 6.59 (s, 2H), 4.87-4.91 (m, 1H), 4.13-4.19 (m, 2H), 2.53-2.57 (m, 1H), 1.37-1.41 (m, 6H), 1.09 (d, J=6.8Hz, 6H).

实施例(化合物)142Example (compound) 142

2-乙氧基-5-异丁酰氨基-N-(1-(6-甲基吡嗪-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-methylpyrazin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000202
Figure PCTCN2018088561-appb-000202

a)N-甲氧基-N,6-二甲基吡嗪-2-甲酰胺a) N-methoxy-N,6-dimethylpyrazine-2-carboxamide

将6-甲基-吡嗪-2-甲酸(414mg,3mmol)加入无水DMF(30mL)，加入EDC(1.15g,6mmol)，加入HOBt(810mg,6mmol)和DIEA(3.1mL,18mmol)，加入N,O-二甲基羟胺(437mg,4.5mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2)，得到白色固体400mg，产率73.7％。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.69(s,1H),3.74(s,3H),3.40(s,3H),2.66(s,3H). 6-Methyl-pyrazine-2-carboxylic acid (414 mg, 3 mmol) was added to dry DMF (30 mL), EtOAc (EtOAc, EtOAc, N,O-dimethylhydroxylamine (437 mg, 4.5 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water, and extracted with a mixture of ethyl acetate:methanol = 10:1 (40 mL × 2) It was washed with a saturated NaCl solution (15 mL × 2), dried over anhydrous magnesium sulfate. 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.69 (s, 1H), 3.74 (s, 3H), 3.40 (s, 3H), 2.66 (s, 3H).

b)1-(6-甲基吡嗪-2-基)乙酮b) 1-(6-methylpyrazin-2-yl)ethanone

将N-甲氧基-N,6-二甲基吡嗪-2-甲酰胺(362mg,2mmol)加入干燥THF(15mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(2.6mL,2.6mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(30mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:10,E:P＝1:6)，得到蜡状固体200mg，产率73.5％。Add N-methoxy-N,6-dimethylpyrazine-2-carboxamide (362 mg, 2 mmol) to dry THF (15 mL), 1 M methyl magnesium bromide in THF at 0 ° C under argon (2.6 mL, 2.6 mmol) was added dropwise to the reaction flask, and the reaction was stirred at 0 ° C. After 2 h, a saturated ammonium chloride solution was added to the reaction flask, and extracted with EA (30 mL×2), and the organic layer was combined. Washed with a saturated NaCl solution (15 mL × 2), dried over anhydrous magnesium sulfate, and evaporated. .

1H-NMR(400MHz,CDCl 3)δ(ppm):9.03(s,1H),8.62(s,1H),2.71(s,3H),2.65(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.03 (s, 1H), 8.62 (s, 1H), 2.71 (s, 3H), 2.65 (s, 3H).

c)2-乙氧基-5-异丁酰氨基-N-(1-(6-甲基吡嗪-2-基)乙基)苯甲酰胺c) 2-ethoxy-5-isobutyrylamino-N-(1-(6-methylpyrazin-2-yl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(80mg,0.32mmol)加入无水DMF(15mL)，加入EDC(123mg,0.64mmol)，加入HOBt(86mg,0.64mmol)和DIEA(0.17mL,0.96mmol)，加入1-(6-甲基吡嗪-2-基)乙胺(66mg,0.48mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1,D:M＝40:1)，得到白色固体34mg，产率50.7％。2-Ethoxy-5-isobutyrylaminobenzoic acid (80 mg, 0.32 mmol) was added to dry DMF (15 mL), EDC (123 mg, 0.64 mmol) was added, and HOBt (86 mg, 0.64 mmol) and DIEA (0.17) were added. </ RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; The mixture was extracted with 1 ml (30 mL×2), and the combined organic layer was washed with saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=70:1, D:M=40) :1), 34 mg of a white solid was obtained with a yield of 50.7%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.97(d,J＝7.6Hz,1H),8.43(s,1H),8.36(s,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.81(s,1H),7.36-7.43(m,1H),6.95(d,J＝9.2Hz,1H),5.42-5.47(m,1H),4.21-4.25(m,2H),2.59(s,3H),2.48-2.55(m,1H),1.54-1.59(m,6H),1.21(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.97 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.21. (dd, J 1 = 8.8 Hz , J 2 = 2.8 Hz, 1H), 7.81 (s, 1H), 7.36-7.43 (m, 1H), 6.95 (d, J = 9.2 Hz, 1H), 5.42 - 5.47 (m, 1H), 4.21-4.25 (m, 2H), 2.59 (s, 3H), 2.48-2.55 (m, 1H), 1.54-1.59 (m, 6H), 1.21 (d, J = 6.8 Hz, 6H).

实施例(化合物)143Example (compound) 143

2-乙氧基-5-异丁酰氨基-N-(1-(2-甲基嘧啶-4-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(2-methylpyrimidin-4-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000203
Figure PCTCN2018088561-appb-000203

a)N-甲氧基-N,2-二甲基嘧啶-4-甲酰胺a) N-methoxy-N,2-dimethylpyrimidine-4-carboxamide

将2-甲基-嘧啶-4-甲酸(450mg,3.26mmol)加入无水DMF(30mL)，加入EDC(1.25g,6.52mmol)，加入HOBt(880mg,6.52mmol)和DIEA(3.4mL,19.6mmol)，加入N,O-二甲基羟胺(475mg,4.89mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2)，得到淡黄色油状物480mg，产率81.35％。Add 2-methyl-pyrimidine-4-carboxylic acid (450 mg, 3.26 mmol) to dry DMF (30 mL), EtOAc (EtOAc, EtOAc, EtOAc To a solution of the mixture of ethyl acetate:methanol = 10:1 (40 mL×2) The combined organic layer was washed with EtOAc EtOAc (EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.73(d,J＝4.8Hz,1H),7.29(brs,1H),3.70(s,3H),3.35(s,3H),2.75(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.73 (d, J = 4.8Hz, 1H), 7.29 (brs, 1H), 3.70 (s, 3H), 3.35 (s, 3H), 2.75 ( s, 3H).

b)1-(2-甲基嘧啶-4-基)乙酮b) 1-(2-Methylpyrimidin-4-yl)ethanone

将N-甲氧基-N,2-二甲基嘧啶-4-甲酰胺(430mg,2.37mmol)加入干燥THF(15mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(3.09mL,3.09mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(30mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:10,E:P＝1:7.5)，得到无色油状物200mg，产率62.1％。Add N-methoxy-N,2-dimethylpyrimidine-4-carboxamide (430 mg, 2.37 mmol) to dry THF (15 mL), 1 M methylmagnesium bromide in THF at 0 ° C under argon (3.09 mL, 3.09 mmol) was added dropwise to the reaction flask, and the reaction was stirred at 0 ° C. After 2 h, a saturated ammonium chloride solution was added to the reaction flask, and extracted with EA (30 mL×2), and the organic layer was combined. Washed with a saturated NaCl solution (15 mL × 2), dried over anhydrous magnesium sulfate, evaporated, EtOAcjjjjjjjjjj %.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.85(d,J＝5.2Hz,1H),7.67(d,J＝4.8Hz,1H),2.82(s,3H),2.71(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.85 (d, J = 5.2 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 2.82 (s, 3H), 2.71 (s, 3H).

c)2-乙氧基-5-异丁酰氨基-N-(1-(2-甲基嘧啶-4-基)乙基)苯甲酰胺c) 2-ethoxy-5-isobutyrylamino-N-(1-(2-methylpyrimidin-4-yl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(90mg,0.36mmol)加入无水DMF(15mL)，加入EDC(138mg,0.72mmol)，加入HOBt(97mg,0.72mmol)和DIEA(0.19mL,1.08mmol)，加入1-(2-甲基嘧啶-4-基)乙胺(66mg,0.48mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝40:1,D:M＝30:1)，得到白色固体36mg，产率27％。2-Ethoxy-5-isobutyrylaminobenzoic acid (90 mg, 0.36 mmol) was added to dry DMF (15 mL). E.sub.2 (138 mg, 0.72 mmol) was added, and HOBt (97 mg, 0.72 mmol) and DIEA (0.19) were added. mL, 1.08 mmol), 1-(2-methylpyrimidin-4-yl)ethylamine (66 mg, 0.48 mmol). The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=60:1, D:M=40: 1, D: M = 30: 1) gave 36 mg of a white solid, yield 27%.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.01(d,J＝7.6Hz,1H),8.58(d,J＝3.6Hz,1H),8.21(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.81(d,J＝2.8Hz,1H),7.35(s,1H),7.18(d,J ＝5.2Hz,1H),6.97(d,J＝8.8Hz,1H),5.28-5.32(m,1H),4.25(q,J＝7.2Hz,2H),2.75(s,3H),2.47-2.54(m,1H),1.54-1.60(m,6H),1.24(dd,J 1＝6.8Hz,J 2＝0.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.01 (d, J = 7.6Hz, 1H), 8.58 (d, J = 3.6Hz, 1H), 8.21 (dd, J 1 = 9.2Hz, J 2 = 2.8 Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.35 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H) , 5.28-5.32 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.75 (s, 3H), 2.47-2.54 (m, 1H), 1.54-1.60 (m, 6H), 1.24 (dd , J 1 = 6.8 Hz, J 2 = 0.8 Hz, 6H).

实施例(化合物)144Example (compound) 144

2-乙氧基-5-异丁酰氨基-N-(1-(5-甲基噻吩-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(5-methylthien-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000204
Figure PCTCN2018088561-appb-000204

将2-乙氧基-5-异丁酰氨基苯甲酸(90mg,0.358mmol)加入无水DMF(10mL)，加入EDC(137mg,0.716mmol)，加入HOBt(97mg,0.716mmol)和DIEA(0.19mL,1.074mmol)，加入1-(5-甲基噻吩-2-基)乙胺(60mg,0.425mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝150:1)，得到白色固体20mg，产率16.8％。熔点：101-103℃2-Ethoxy-5-isobutyrylaminobenzoic acid (90 mg, 0.358 mmol) was added to dry DMF (10 mL), EDC (137 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.074 mmol), 1-(5-methylthiophen-2-yl)ethylamine (60 mg, 0.425 mmol) was added and stirred at room temperature overnight, then poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (30 mL×2). EtOAc (EtOAc m. The yield was 16.8%. Melting point: 101-103 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝6.8Hz,1H),8.26(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.87(d,J＝2.0,1H),7.59(s,1H),6.91(d,J＝8.8Hz,1H),6.79(d,J＝3.2Hz,1H),6.59(s,1H),5.46-5.53(m,1H),4.10-4.17(m,2H),2.48-2.56(m,1H),2.44(s,3H),1.62(d,J＝6.8Hz,3H),1.41(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (d, J = 6.8Hz, 1H), 8.26 (dd, J 1 = 8.8Hz, J 2 = 2.4Hz, 1H), 7.87 (d, J = 2.0, 1H), 7.59 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 3.2 Hz, 1H), 6.59 (s, 1H), 5.46-5.53 (m , 1H), 4.10-4.17 (m, 2H), 2.48-2.56 (m, 1H), 2.44 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)145Example (compound) 145

N-(1-(2-氨基噻唑-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(2-Aminothiazol-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000205
Figure PCTCN2018088561-appb-000205

a)1-(2-氨基噻唑-5-基)乙酮a) 1-(2-Aminothiazole-5-yl)ethanone

将硫代脲(760mg,10mmol)加入DCM(20ml)中，加入DMF-DMA(3.5mL,26mmol)加热回流反应，4h后停止反应，浓缩至干，用DCM和乙醚重结晶，得到淡黄色固体800mg。将上述固体(580mg,3.12mmol)加入THF(20mL)，加入氯丙酮(0.5mL,6.24mmol)，20℃下搅拌30min后加入三乙胺(0.84mL,6.24mmol)，升温至55℃反应5h后降至室温加入甲胺水溶液(2.9mL)室温搅拌反应1h后加入 DCM(30mL)，无水硫酸镁干燥，柱层析(D:M＝50:1)，得到土黄色固体290mg，产率65.4％。The thiourea (760 mg, 10 mmol) was added to EtOAc (EtOAc) (EtOAc) 800mg. The above solid (580 mg, 3.12 mmol) was added to THF (20 mL), chloroacetone (0.5 mL, 6.24 mmol) was added, and stirred at 20 ° C for 30 min, then triethylamine (0.84 mL, 6.24 mmol) was added and the mixture was warmed to 55 ° C for 5 h. After the mixture was stirred at room temperature, the aqueous solution was added with aq. EtOAc (EtOAc) (m. 65.4%.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):7.99(s,2H),7.91(s,1H),2.34(s,3H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 7.99 (s, 2H), 7.91 (s, 1H), 2.34 (s, 3H).

b)N-(1-(2-氨基噻唑-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺b) N-(1-(2-Aminothiazol-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(10mL)，加入EDC(153mg,0.796mmol)，加入HOBt(107mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入5-(1-氨基乙基)噻唑-2-胺(114mg,0.796mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5)，得到白色固体90mg，产率60.4％。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (10 mL), EDC (153 mg, 0.796 mmol) was added, HOBt (107 mg, 0.796 mmol) and DIEA (0.21) mL, 1.19 mmol), 5-(1-aminoethyl)thiazol-2-amine (114 mg, 0.796 mmol) was added and stirred at room temperature overnight, then poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted with EtOAc (3 mL, EtOAc). The rate is 60.4%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.40(d,J＝7.6Hz,1H),8.18(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),7.86-7.89(m,2H),6.94(s,1H),6.90(d,J＝8.8Hz,1H),5.30-5.41(m,1H),4.10-4.16(m,2H),2.51-2.58(m,1H),1.60(d,J＝6.8Hz,3H),1.43(t,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.40 (d, J = 7.6 Hz, 1H), 8.18 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1H), 7.86 - 7.89 ( m, 2H), 6.94 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.30-5.41 (m, 1H), 4.10-4.16 (m, 2H), 2.51-2.58 (m, 1H) , 1.60 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)146Example (compound) 146

2-乙氧基-5-异丁酰氨基-N-(1-(2-甲硫基唑-4-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(2-methylthiooxazol-4-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000206
Figure PCTCN2018088561-appb-000206

a)1-(2-甲硫基唑-5-基)乙酮a) 1-(2-Methylthioazol-5-yl)ethanone

将硫代乙酰胺(751mg,10mmol)加入DCM(20ml)中，加入DMF-DMA(2.7mL,20mmol)加热回流反应，4h后停止反应，浓缩至干，将上述固体(1.3g,10mmol)加入THF(30mL)，加入氯丙酮(1.6mL,20mmol)，20℃下搅拌30min后加入三乙胺(2.7mL,20mmol)，升温至55℃反应5h后降至室温加入甲胺水溶液(10mL)室温搅拌反应1h后加入DCM(30mL)，无水硫酸镁干燥，柱层析(D:M＝50:1)，得到土黄色固体150mg，产率10.6％。The thioacetamide (751 mg, 10 mmol) was added to DCM (20 mL), EtOAc (EtOAc) THF (30 mL), adding chloroacetone (1.6 mL, 20 mmol), stirring at 20 ° C for 30 min, then adding triethylamine (2.7 mL, 20 mmol), warming to 55 ° C for 5 h, then at room temperature, add methylamine aqueous solution (10 mL), room temperature After stirring for 1 h, DCM (30 mL) was evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.17(s,1H),2.76(s,3H),2.57(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.17 (s, 1H), 2.76 (s, 3H), 2.57 (s, 3H).

b)2-乙氧基-5-异丁酰氨基-N-(1-(2-甲硫基唑-4-基)乙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(2-methylthiothiazol-4-yl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(45mg,0.18mmol)加入无水DMF(10mL)，加入EDC(69mg,0.36mmol)，加入HOBt(49mg,0.36mmol)和DIEA(0.095mL,0.54 mmol)，加入1-(2-甲硫基唑-5-基)乙胺(30mg,0.21mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝60:1,D:M＝50:1)，得到白色固体34mg，产率50.7％。Add 2-ethoxy-5-isobutyrylaminobenzoic acid (45 mg, 0.18 mmol) to dry DMF (10 mL), EtOAc (EtOAc,EtOAc </ RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; The mixture was extracted with 1 ml (30 mL×2), and the combined organic layer was washed with saturated NaCI (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=60:1, D:M=50 :1), 34 mg of a white solid was obtained with a yield of 50.7%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.44(d,J＝8.0Hz,1H),8.20(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.51(s,1H),7.36(s,1H),6.92(d,J＝9.2Hz,1H),5.52-5.59(m,1H),4.15(q,J＝7.2Hz,2H),2.67(s,3H),2.47-2.55(m,1H),1.65(d,J＝6.8Hz,3H),1.43(t,J＝7.2Hz,3H),1.24(d,J＝7.2Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.44 (d, J = 8.0 Hz, 1H), 8.20 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.51 (s, 1H), 7.36 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 5.52-5.59 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 2.47-2.55 (m, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 7.2 Hz, 6H).

实施例(化合物)147Example (compound) 147

N-(1-(苯并[d][1,3]二噁唑-5-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(Benzo[d][1,3]dioxazole-5-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000207
Figure PCTCN2018088561-appb-000207

将2-乙氧基-5-异丁酰氨基苯甲酸(120mg,0.478mmol)加入无水DMF(15mL)，加入EDC(184mg,0.956mmol)，加入HOBt(129mg,0.956mmol)和DIEA(0.25mL,1.434mmol)，加入1-(苯并[d][1,3]二噁唑-5-基)乙胺(126mg,0.765mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2,D:M＝70:1)，得到白色固体150mg，产率78.9％。熔点：72-74℃2-Ethoxy-5-isobutyrylaminobenzoic acid (120 mg, 0.478 mmol) was added to dry DMF (15 mL) EtOAc (EtOAc, EtOAc (EtOAc) mL, 1.344 mmol), 1-(benzo[d][1,3]dioxazole-5-yl)ethylamine (126 mg, 0.765 mmol), EtOAc. Ethyl acetate: a mixture of methanol = 10:1 (40 mL × 2). The combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate 2, D: M = 70: 1), 150 mg of white solid was obtained, yield 78.9%. Melting point: 72-74 ° C

1H-NMR(500MHz,CDCl 3)δ(ppm):8.41(d,J＝6.5Hz,1H),8.21(d,J＝6.5,1H),7.81(s,1H),7.41-7.46(m,1H),6.92(d,J＝8.5Hz,1H),6.84-6.86(m,2H),6.77(d,J＝8.0Hz,1H),5.94(s,2H),5.19-5.22(m,1H),4.12-4.18(m,2H),2.48-2.52(m,1H),1.54(d,J＝7.0Hz,3H),1.43(t,J＝6.5Hz,3H),1.22(d,J＝6.5Hz,6H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 8.41 (d, J = 6.5 Hz, 1H), 8.21 (d, J = 6.5, 1H), 7.81 (s, 1H), 7.41-7.46 (m) , 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.84 - 6.86 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 5.19 - 5.22 (m, 1H), 4.12-4.18 (m, 2H), 2.48-2.52 (m, 1H), 1.54 (d, J = 7.0 Hz, 3H), 1.43 (t, J = 6.5 Hz, 3H), 1.22 (d, J) =6.5Hz, 6H).

实施例(化合物)148Example (compound) 148

N-(1-(2-氨基苯并[d]噻唑-5-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(2-Aminobenzo[d]thiazol-5-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000208
Figure PCTCN2018088561-appb-000208

a)1-(2-氨基苯并[d]噻唑-6-基)乙酮a) 1-(2-Aminobenzo[d]thiazole-6-yl)ethanone

将4-氨基苯乙酮(946mg,7mmol)，加入乙酸(12mL)，室温搅拌至化合物完全溶 解，将1M Br 2的乙酸溶液室温下滴加入反应瓶中，滴毕室温搅拌反应，次日，将反应液倒入冰水中，用氨水调PH值至9左右，过滤，滤饼溶于DCM和甲醇的混合液中，无水硫酸镁干燥，柱层析(D:M＝70:1,D:M＝60:1,D:M＝50:1)，得到淡黄色固体330mg，产率24.5％。 4-Aminoacetophenone (946 mg, 7 mmol) was added to acetic acid (12 mL), and the mixture was stirred at room temperature until the compound was completely dissolved. The 1 M Br 2 acetic acid solution was added dropwise to the reaction flask at room temperature, and the reaction was stirred at room temperature, the next day. Pour the reaction solution into ice water, adjust the pH to about 9 with ammonia water, filter, filter cake dissolved in DCM and methanol mixture, dry over anhydrous magnesium sulfate, column chromatography (D: M=70:1, D :M=60:1, D:M=50:1) gave 330 mg of pale yellow solid, yield 24.5%.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):8.32(d,J＝1.6Hz,1H),7.91(brs,2H),7.83(dd,J 1＝8.4Hz,J 2＝1.6Hz,1H),7.37(d,J＝8.4Hz,1H),2.55(s,3H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 8.32 (d, J = 1.6 Hz, 1H), 7.91 (brs, 2H), 7.83 (dd, J 1 = 8.4 Hz, J 2 = 1.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H).

b)N-(1-(2-氨基苯并[d]噻唑-5-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺b) N-(1-(2-Aminobenzo[d]thiazol-5-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(10mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入5-(1-氨基乙基)苯并[d]噻唑-2-胺(150mg,0.78mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝30:1,D:M＝25:1)，得到白色固体165mg，产率88.2％。熔点：.135-137℃2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (10 mL), EDC (168 mg, &lt;RTI ID=0.0&gt;&gt; mL, 1.314 mmol), 5-(1-aminoethyl)benzo[d]thiazol-2-amine (150 mg, 0.78 mmol) was added and stirred at room temperature overnight. The mixture was extracted with a mixture of 10:1 (30 mL×2), and the combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=30:1, D: M = 25: 1) gave 165 mg of white solid. Melting point: .135-137 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.51(d,J＝6.8Hz,1H),8.17(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.85(s,1H),7.78(s,1H),7.56(s,1H),7.45(d,J＝8.0Hz,1H),7.27-7.30(m,1H),6.90(d,J＝9.2Hz,2H),5.74(brs,2H),5.29-5.33(m,1H),4.10-4.15(m,2H),2.49-2.53(m,1H),1.58(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H),1.19(dd,J 1＝6.8Hz,J 2＝2.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.51 (d, J = 6.8Hz, 1H), 8.17 (dd, J 1 = 8.8Hz, J 2 = 2.4Hz, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.27-7.30 (m, 1H), 6.90 (d, J = 9.2 Hz, 2H), 5.74 (brs, 2H), 5.29-5.33 (m, 1H), 4.10-4.15 (m, 2H), 2.49-2.53 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8 Hz, 3H), 1.19 (dd, J 1 = 6.8 Hz, J 2 = 2.8 Hz, 6H).

实施例(化合物)149Example (compound) 149

N-(1-(2-氨基-1H-苯并[d]咪唑-5-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(2-Amino-1H-benzo[d]imidazol-5-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000209
Figure PCTCN2018088561-appb-000209

a)N-(4-乙酰基-2-硝基苯基)乙酰胺a) N-(4-acetyl-2-nitrophenyl)acetamide

将4-氨基苯乙酮(1.35g,10mmol)置于反应瓶中，加入DCM(50mL)，室温搅拌下加入五水合硝酸铋(4.85g,10mmol)，将醋酐(5.64mL,60mmol)滴加入反应瓶中，滴毕，室温搅拌反应，次日停止反应，将反应液倒入饱和NaHCO3溶液中，用乙酸乙酯(30mL×2)萃取，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:5,E:P＝1:3)，得到淡黄色固体1.59g，产率71.6％。m.p.140-142℃ 1H-NMR(400MHz,CDCl 3)δ(ppm):10.55(s,1H),8.94(d,J＝8.8Hz,1H),8.81(d,J ＝2.0Hz,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),2.64(s,3H),2.34(s,3H). 4-Aminoacetophenone (1.35 g, 10 mmol) was placed in a reaction flask, DCM (50 mL) was added, and cerium nitrate pentahydrate (4.85 g, 10 mmol) was added with stirring at room temperature, and acetic anhydride (5.64 mL, 60 mmol) was added dropwise. After adding to the reaction flask, the reaction was stirred at room temperature, and the reaction was stopped the next day. The reaction solution was poured into a saturated NaHCO3 solution, extracted with ethyl acetate (30 mL×2), and washed with a saturated NaCl solution (15 mL×2). The residue was dried over MgSO.sub.sub. Mp 140-142 ° C 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 10.55 (s, 1H), 8.94 (d, J = 8.8 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.21 (dd, J 1 = 8.8 Hz, J 2 = 2.0 Hz, 1H), 2.64 (s, 3H), 2.34 (s, 3H).

b)1-(4-氨基-3-硝基苯基)乙酮b) 1-(4-Amino-3-nitrophenyl)ethanone

将N-(4-乙酰基-2-硝基苯基)乙酰胺(1.46g,6.57mmol)置于反应瓶中，加入6N HCl(20mL,120mmol)加热回流反应，2h后停止反应，冷却，用NaOH溶液调PH值至8左右，抽滤，滤饼水洗，得到黄色固体1.1g，产率93.2％。m.p.148-150℃N-(4-Acetyl-2-nitrophenyl)acetamide (1.46 g, 6.57 mmol) was placed in a reaction flask, and 6N HCl (20 mL, 120 mmol) was added and the mixture was heated to reflux. After 2 h, the reaction was stopped and cooled. The pH was adjusted to about 8 with a NaOH solution, suction filtered, and the filter cake was washed with water to obtain a yellow solid (1.1 g, yield: 93.2%). M.p.148-150°C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.73(d,J＝2.0Hz,1H),7.98(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),6.85(d,J＝8.8Hz,1H),6.52(brs,2H),2.56(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.73 (d, J = 2.0Hz, 1H), 7.98 (dd, J 1 = 8.8Hz, J 2 = 2.0Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.52 (brs, 2H), 2.56 (s, 3H).

c)1-(3,4-二氨基苯基)乙酮c) 1-(3,4-diaminophenyl)ethanone

将1-(4-氨基-3-硝基苯基)乙酮(300mg)置于反应瓶中，加入甲醇(10mL)，加入Raney Ni常温常压下氢化反应，4h后停止反应，过滤，浓缩，柱层析(D:M＝80:1,D:M＝70:1)得到类白色固体227mg，产率91.1％。m.p.129-131℃1-(4-Amino-3-nitrophenyl)ethanone (300 mg) was placed in a reaction flask, methanol (10 mL) was added, and Raney Ni was added to hydrogenation at normal temperature and normal pressure. After 4 hours, the reaction was stopped, filtered, and concentrated. Column chromatography (D: M = 80:1, D: M = 70:1) afforded 227 mg as white solid. M.p.129-131°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):7.10-7.14(m,2H),6.49-6.52(m,1H),5.36(brs,2H),4.63(brs,2H),2.35(s,3H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 7.10-7.14 (m, 2H), 6.49-6.52 (m, 1H), 5.36 (brs, 2H), 4.63 (brs, 2H), 2.35 (s, 3H).

d)1-(2-氨基-1H-苯并[d]咪唑-5-基)乙酮d) 1-(2-Amino-1H-benzo[d]imidazol-5-yl)ethanone

将1-(3,4-二氨基苯基)乙酮(150mg,1mmol)置于反应瓶中，加入HFIP(6mL)，加入BrCN(157mg,1.5mmol)室温搅拌反应，3日后仍有大量原料剩余，加入H2O(1.5mL)继续室温搅拌反应，次日停止反应，加入DCM(30mL)，无水硫酸镁干燥，浓缩，柱层析(D:M＝35:1,D:M＝15:1)，得到土黄色固体150mg，产率85.7％。m.p.210℃时变色1-(3,4-Diaminophenyl)ethanone (150 mg, 1 mmol) was placed in a reaction flask, HFIP (6 mL) was added, and BrCN (157 mg, 1.5 mmol) was added to stir the reaction at room temperature, and a large amount of raw materials remained after 3 days. After the addition, H2O (1.5 mL) was added and the mixture was stirred at room temperature. The reaction was stirred, and then the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. 1) A 150 mg solid yellow solid was obtained in a yield of 85.7%. M.p. discoloration at 210 ° C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.46(brs,1H),8.30(s,2H),7.82-7.85(m,2H),7.40(d,J＝8.4Hz,1H),2.59(s,3H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 12.46 (brs, 1H), 8.30 (s, 2H), 7.82-7.85 (m, 2H), 7.40 (d, J = 8.4Hz, 1H ), 2.59 (s, 3H).

e)N-(1-(2-氨基-1H-苯并[d]咪唑-5-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺e) N-(1-(2-Amino-1H-benzo[d]imidazol-5-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(55mg,0.22mmol)加入无水DMF(10mL)，加入EDC(85mg,0.44mmol)，加入HOBt(59mg,0.44mmol)和DIEA(0.12mL,0.66mmol)，加入5-(1-氨基乙基)-1H-苯并[d]咪唑-2-胺(77mg,0.44mmol)，室温搅拌过夜，将反应液倒入水中，用二氯甲烷:甲醇＝10:1的混合液(20mL×5)萃取，合并有机层，无水硫酸镁干燥，浓缩，柱层析(D:M＝20:1,D:M:氨水＝15:1:0.125)，得到类白色固体35mg，产率38.9％。m.p.>250℃2-Ethoxy-5-isobutyrylaminobenzoic acid (55 mg, 0.22 mmol) was added to dry DMF (10 mL) EtOAc (EtOAc) mL, 0.66 mmol), 5-(1-aminoethyl)-1H-benzo[d]imidazol-2-amine (77 mg, 0.44 mmol) was added and stirred at room temperature overnight, then poured into water and dichloro Methane: methanol = 10:1 mixture (20 mL × 5) was extracted, the organic layer was combined, dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=20:1, D:M: ammonia = 15:1) : 0.125), 35 mg of an off-white solid was obtained, yield 38.9%. M.p.>250°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):10.67(s,1H),9.82(s,1H),8.49(d,J＝7.6Hz,1H),7.94(s,1H),7.79(d,J＝8.8Hz,1H),7.13(s,1H),7.05(t,J＝8.0Hz,2H),6.90(d,J＝8.0Hz,1H),6.12(brs,2H),5.08-5.13(m,1H),4.06-4.14(m,2H), 2.54-2.56(m,1H),1.47(d,J＝6.4Hz,3H),1.32(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 10.67 (s, 1H), 9.82 (s, 1H), 8.49 (d, J = 7.6Hz, 1H), 7.94 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.12 (brs, 2H), 5.08-5.13 (m, 1H), 4.06-4.14 (m, 2H), 2.54-2.56 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.32 (t, J = 6.8 Hz, 3H) , 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)150Example (compound) 150

2-乙氧基-5-异丁酰氨基-N-(1-(2-甲基-1H-苯并[d]咪唑-5-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000210
Figure PCTCN2018088561-appb-000210

a)1-(2-甲基-1H-苯并[d]咪唑-5-基)乙酮a) 1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethanone

将1-(3,4-二氨基苯基)乙酮(180mg,1.2mmol)置于反应瓶中，加入DMF(6mL)，加入原乙酸三乙酯(2.3mL,12mmol)浓HCl(0.3mL,3.6mmol)室温搅拌反应，4h后停止反应，加水，用乙酸乙酯:甲醇＝10:1的混合液(30mL×4)萃取，无水硫酸镁干燥，浓缩，柱层析(D:M＝40:1,D:M＝30:1)，得到类白色固体135mg，产率64.6％。m.p.191-193℃1-(3,4-Diaminophenyl)ethanone (180 mg, 1.2 mmol) was placed in a reaction flask, DMF (6 mL) was added, and triethyl orthoacetate (2.3 mL, 12 mmol) concentrated HCl (0.3 mL) , 3.6 mmol), the reaction was stirred at room temperature, and the reaction was stopped after 4 h, water was added, extracted with a mixture of ethyl acetate:methanol = 10:1 (30mL×4), dried over anhydrous magnesium sulfate, concentrated, column chromatography (D:M = 40:1, D: M = 30:1) gave 135 mg of white solid, yield 64.6%. M.p.191-193°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.53(s,1H),8.09(s,1H),7.77(dd,J 1＝8.4Hz,J 1＝1.6Hz,1H),7.52(d,J＝8.0Hz,1H),2.61(s,3H),2.53(s,3H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 12.53 (s, 1H), 8.09 (s, 1H), 7.77 (dd, J 1 = 8.4Hz, J 1 = 1.6Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 2.61 (s, 3H), 2.53 (s, 3H).

b)2-乙氧基-5-异丁酰氨基-N-(1-(2-甲基-1H-苯并[d]咪唑-5-基)乙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(60mg,0.24mmol)加入无水DMF(10mL)，加入EDC(92mg,0.48mmol)，加入HOBt(65mg,0.48mmol)和DIEA(0.13mL,0.72mmol)，加入1-(2-甲基-1H-苯并[d]咪唑-5-基)乙胺(84mg,0.48mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝25:1,D:M＝20:1)，得到白色固体50mg，产率51％。m.p.203-205℃2-Ethoxy-5-isobutyrylaminobenzoic acid (60 mg, 0.24 mmol) was added to dry DMF (10 mL). E.sub.2 (92 mg, 0.48 mmol) was added to HOBt (65 mg, 0.48 mmol) and DIEA (0.13) mL, 0.72 mmol), 1-(2-methyl-1H-benzo[d]imidazol-5-yl)ethylamine (84 mg, 0.48 mmol). Ethyl acetate: a mixture of methanol = 10:1 (30 mL × 2). The combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate 1, D: M = 20: 1), 50 mg of a white solid was obtained, yield 51%. M.p.203-205°C

1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.17(s,1H),9.80(s,1H),8.53(d,J＝7.6Hz,1H),7.92(d,J＝2.4Hz,1H),7.78(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.39-7.47(m,2H),7.16(d,J＝8.4Hz,1H),7.07(d,J＝9.2Hz,1H),5.17-5.24(m,1H),4.07-4.14(m,2H),2.52-2.56(m,1H),2.47(s,3H),1.50(d,J＝6.8Hz,3H),1.33(t,J＝7.2Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 12.17 (s, 1H), 9.80 (s, 1H), 8.53 (d, J = 7.6Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.78 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1H), 7.39-7.47 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.07 (d, J) = 9.2 Hz, 1H), 5.17-5.24 (m, 1H), 4.07-4.14 (m, 2H), 2.52-2.56 (m, 1H), 2.47 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

实施例(化合物)151Example (compound) 151

5-异丁酰氨基-2-丙基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺5-isobutyrylamino-2-propyl-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000211
Figure PCTCN2018088561-appb-000211

a)2-丙基-5-硝基苯甲酸甲酯a) Methyl 2-propyl-5-nitrobenzoate

在Ar气保护下，依次将ZnCl2的乙醚溶液(1.36g,10.00mmol)、丙基溴化镁的THF溶液(1.47g,10.00mmol)加入烧瓶中，室温下搅拌反应2h。然后依次将2-溴-5-硝基苯甲酸甲酯(1.04g,4.00mmol)、PdCl 2(dppf)(292mg,0.40mmol)、LiCl(336mg,8.00mmol)加入到上述反应体系中，氩气保护下，升至55℃反应24h，加入饱和NH4Cl(20mL)，EA(30mL)萃取，饱和食盐水洗(20mL)有机相，无水Na 2SO 4干燥，柱色谱(石油醚-乙酸乙酯，体积比50:1)纯化得无色油状物362mg，收率40.1％。 A solution of ZnCl 2 in diethyl ether (1.36 g, 10.00 mmol) and a solution of propylmagnesium bromide in THF (1.47 g, 10.00 mmol) were added to the flask under argon gas, and the mixture was stirred at room temperature for 2 h. Then, methyl 2-bromo-5-nitrobenzoate (1.04 g, 4.00 mmol), PdCl 2 (dppf) (292 mg, 0.40 mmol), LiCl (336 mg, 8.00 mmol) were added to the above reaction system, argon. under protective gas, the reaction was raised to 55 ℃ 24h, added saturated NH4Cl (20mL), EA (30mL ) and extracted, washed with brine (20mL) the organic phase was dried over anhydrous Na 2 SO 4, column chromatography (petroleum ether - ethyl acetate The volume ratio of 50:1) was purified to obtain 362 mg of a colorless oil, yield 40.1%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.73(d,J＝2.4Hz,1H),8.25(dd,J＝8.4,2.4Hz,1H),7.43(d,J＝8.4Hz,1H),3.95(s,3H),3.04(t,J＝7.6Hz,2H),1.65(sext,J＝7.6Hz,2H),0.99(t,J＝7.2Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.73 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 8.4, 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 1.65 (sext, J = 7.6 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H).

b)2-丙基-5-硝基苯甲酸b) 2-propyl-5-nitrobenzoic acid

将2-丙基-5-硝基苯甲酸甲酯(450mg,2.02mmol)溶于甲醇(15mL)/水(8mL)中，搅拌下加入NaOH(404mg,10.10mmol)，室温反应8h，浓缩，加水(5mL)，乙醚(20mL)洗涤水层，水层用盐酸调pH＝3，析出白色固体，过滤得378mg，收率为89.6％，熔点：115-117℃。Methyl 2-propyl-5-nitrobenzoate (450 mg, 2.02 mmol) was dissolved in methanol (15 mL) / water (8 mL). Water (5 mL) and diethyl ether (20 mL) were added and the aqueous layer was washed, and the aqueous layer was adjusted to pH 3 with hydrochloric acid to give a white solid, which was filtered to afford 378 g, yield: 89.

1H-NMR(400MHz,DMSO)δ(ppm):13.58(s,1H),8.51(s,1H),8.29(dd,J＝8.4,2.4Hz,1H),7.61(d,J＝8.4Hz,1H),3.01(t,J＝7.6Hz,2H),1.65(sext,J＝7.6Hz,2H),0.91(t,J＝7.2Hz,3H)；ESI-MS m/z:208.06[M-H] -。 1 H-NMR (400MHz, DMSO ) δ (ppm): 13.58 (s, 1H), 8.51 (s, 1H), 8.29 (dd, J = 8.4,2.4Hz, 1H), 7.61 (d, J = 8.4Hz , 1H), 3.01 (t, J = 7.6 Hz, 2H), 1.65 (sext, J = 7.6 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 208.06 [MH. ] - .

c)5-硝基-2-丙基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 5-nitro-2-propyl-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-丙基-5-硝基苯甲酸(200mg,0.96mmol)溶于DCM(15mL)中，依次加入DIEA(248mg,1.92mmol)、HATU(475mg,1.25mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(182mg,0.96mmol)，氩气保护下，室温反应10h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(石油醚-乙酸乙酯，体积比4:1)纯化得白色固体210mg，收率为57.7％，熔点：135-137℃。 The 2-propyl-5-nitrobenzoic acid (200 mg, 0.96 mmol) was dissolved in DCM (15 mL), then DIEA (248 mg, 1.92 mmol), HATU (475 mg, 1.25 mmol). (3-(thiazol-2-yl)phenyl)methanamine (182 mg, 0.96 mmol), argon atmosphere, reaction at room temperature for 10 h, the material disappeared. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (petroleum ether - Ethyl acetate, 4:1 by volume) was purified to give a white solid (yield: </RTI><RTIgt;

1H-NMR(400MHz,CDCl 3)δ(ppm):8.23(d,J＝1.6Hz,1H),8.18(d,J＝8.4Hz,1H),8.00(s,1H),7.89-7.87(m,2H),7.46(d,J＝4.8Hz,2H),7.41(d,J＝8.4Hz,1H),7.36(d,J＝2.8Hz,1H),6.29(s,1H),4.71(d,J＝5.6Hz,2H),2.86(t,J＝7.6Hz,2H),1.65(sext,J＝7.6Hz,2H),0.92(t,J＝7.2Hz,3H)；ESI-MS m/z:382.12[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.23 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.89 - 7.87 ( m, 2H), 7.46 (d, J = 4.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 6.29 (s, 1H), 4.71 ( d, J = 5.6 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H), 1.65 (sext, J = 7.6 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H); ESI-MS m /z:382.12[M+H] + .

d)5-氨基-2-丙基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺d) 5-amino-2-propyl-N-(3-(thiazol-2-yl)benzyl)benzamide

将5-硝基-2-丙基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(180mg,0.47mmol)溶于THF(20mL)中，加入pd/C(90mg)，通入氢气，室温搅拌过夜，过滤，浓缩，得无色油状物153mg，收率92.7％。5-Nitro-2-propyl-N-(3-(thiazol-2-yl)benzyl)benzamide (180 mg, 0.47 mmol) was dissolved in THF (20 mL). The mixture was stirred with hydrogen, stirred at room temperature overnight, filtered and concentrated to give 153 mg of colorless oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.96(s,1H),7.88-7.86(m,2H),7.44(d,J＝4.8Hz,2H),7.34(d,J＝3.2Hz,1H),7.04-6.96(m,1H),6.70(d,J＝2.4Hz,1H),6.66(dd,J＝8.0,2.4Hz,1H),6.12(brs,1H),4.66(d,J＝6.0Hz,2H),3.44(s,2H),2.63(t,J＝7.6Hz,2H),1.65(sext,J＝7.6Hz,2H),0.87(t,J＝7.2Hz,3H)；ESI-MS m/z:352.15[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.96 (s, 1H), 7.88-7.86 (m, 2H), 7.44 (d, J = 4.8 Hz, 2H), 7.34 (d, J = 3.2) Hz, 1H), 7.04-6.96 (m, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 8.0, 2.4 Hz, 1H), 6.12 (brs, 1H), 4.66 (d) , J=6.0Hz, 2H), 3.44(s, 2H), 2.63(t, J=7.6Hz, 2H), 1.65(sext, J=7.6Hz, 2H), 0.87(t, J=7.2Hz, 3H ESI-MS m/z: 352.15 [M+H] + .

e)5-异丁酰氨基-2-丙基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺e) 5-Isobutyrylamino-2-propyl-N-(3-(thiazol-2-yl)benzyl)benzamide

将5-氨基-2-丙基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(140mg,0.40mmol)溶于无水THF(15mL)中，冰浴下依次加入TEA(121mg,1.20mmol)，异丁酰氯(85mg,0.80mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(30mL)稀释，饱和氯化铵溶液(20mL)洗，饱和NaHCO 3(20mL)洗，水(20mL)洗，饱和食盐水(20mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化，得白色固体91mg，收率为54.2％，熔点：162-163℃。 5-Amino-2-propyl-N-(3-(thiazol-2-yl)benzyl)benzamide (140 mg, 0.40 mmol) was dissolved in anhydrous THF (15 mL). TEA (121 mg, 1.20 mmol), isobutyryl chloride (85 mg, <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:3) The rate was 54.2%, and the melting point was 162-163 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.95(s,1H),7.84(d,J＝3.2Hz,2H),7.56(s,2H),7.48(d,J＝8.0Hz,1H),7.41(brs,2H),7.34(d,J＝3.2Hz,1H),7.14(d,J＝8.4Hz,1H),6.42(brs,1H),4.63(d,J＝6.0Hz,2H),2.70(t,J＝7.6Hz,2H),2.53-2.46(m,1H),1.65(sext,J＝7.6Hz,2H),1.21(d,J＝6.8Hz,6H),0.87(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 2N 3S 422.1897[M+H] +,Found:422.1884。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.95 (s, 1H), 7.84 (d, J = 3.2Hz, 2H), 7.56 (s, 2H), 7.48 (d, J = 8.0Hz, 1H), 7.41 (brs, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.42 (brs, 1H), 4.63 (d, J = 6.0 Hz, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.53-2.46 (m, 1H), 1.65 (sext, J = 7.6 Hz, 2H), 1.21 (d, J = 6.8 Hz, 6H), 0.87 ( t, J = 7.2Hz, 3H) ; HR-MS (ESI): m / z, calcd.For C 24 H 27 O 2 N 3 S 422.1897 [m + H] +, Found: 422.1884.

实施例(化合物)152Example (compound) 152

2-环丙基-5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-cyclopropyl-5-isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000212
Figure PCTCN2018088561-appb-000212

a)2-环丙基-5-硝基苯甲酸a) 2-cyclopropyl-5-nitrobenzoic acid

将2-溴-5-硝基苯甲酸甲酯(500mg,1.90mmol)，PdCl 2(dppf)(280mg,0.38mmol),Na2CO3(600mg,5.70mmol)，环丙基硼酸(330mg,3.80mmol)依次加入到二氧六环(16mL)/水(4mL)中，氩气保护下，100℃反应15h。过滤，浓缩，加入水(10mL)稀释，加入乙醚(10mL×2)洗，水相浓缩，调pH＝3，析出灰色固体，柱色谱(乙酸乙酯-石油醚，体积比1:4)纯化得147mg白色固体，36.9％，熔点：144-145℃。 2-Bromo-5-nitrobenzoic acid methyl ester (500 mg, 1.90 mmol), PdCl 2 (dppf) (280 mg, 0.38 mmol), Na2CO3 (600 mg, 5.70 mmol), cyclopropylboronic acid (330 mg, 3.80 mmol) It was added to dioxane (16 mL)/water (4 mL) in turn, and reacted at 100 ° C for 15 h under argon gas. Filtration, concentration, dilute with water (10 mL), add diethyl ether (10 mL×2), wash the aqueous phase, adjust the pH to 3, and precipitate a gray solid. Purify by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:4) 147 mg of a white solid, 36.9%, m.p.: 144-145.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.86(d,J＝2.0Hz,1H),8.29(dd,J＝8.8,2.0Hz,1H),7.14(d,J＝8.8Hz,1H),3.08-2.94(m,1H),1.28-1.23(m,2H),0.91-0.87(m,2H)；ESI-MS m/z:206.05[M-H] -。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.86 (d, J = 2.0 Hz, 1H), 8.29 (dd, J = 8.8, 2.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 3.08-2.94 (m, 1H), 1.28-1.23 (m, 2H), 0.91-0.87 (m, 2H); ESI-MS m/z: 206.05 [MH] - .

b)2-环丙基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺b) 2-cyclopropyl-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide

反应1：将2-环丙基-5-硝基苯甲酸(50mg,0.24mmol)溶于DCM(10mL)中，依次加入DIEA(62mg,0.48mmol)，HATU(118mg,0.31mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(46mg,0.24mmol)，室温反应8h，原料消失。反应2：将2-环丙基-5-硝基苯甲酸(70mg,0.34mmol)溶于DCM(15mL)中，依次加入DIEA(88mg,0.68mmol)，HATU(167mg,0.44mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(65mg,0.34mmol)，室温反应8h，原料消失。合并反应1和2，加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:3)纯化得白色固体158mg，收率为71.8％，熔点：168-169℃。 Reaction 1: 2-cyclopropyl-5-nitrobenzoic acid (50 mg, 0.24 mmol) was dissolved in DCM (10 mL). EtOAc (EtOAc,EtOAc. After 30 min, (3-(thiazol-2-yl)phenyl)methanamine (46 mg, 0.24 mmol) was obtained. Reaction 2: 2-Cyclopropyl-5-nitrobenzoic acid (70 mg, 0.34 mmol) was dissolved in DCM (15 mL), then DIEA (88 mg, 0.68 mmol), HATU (167 mg, 0.44 mmol) After 30 min, (3-(thiazol-2-yl)phenyl)methanamine (65 mg, 0.34 mmol) was obtained. The combined reaction 1 and 2, was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 Column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) afforded 158 mg of white solid,yield 71.8%, m.p.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.28(d,J＝2.0Hz,1H),8.15(d,J＝8.8Hz,1H),8.01(s,1H),7.88(brs,2H),7.46(d,J＝4.4Hz,2H),7.36(d,J＝3.2Hz,1H),7.02(d,J＝8.8Hz,1H),6.35(s,1H),4.75(d,J＝5.6Hz,2H),2.38(brs,1H),1.15(q,J＝6.4Hz,2H),0.84(q,J＝5.2Hz,2H)；ESI-MS m/z:380.11[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.28 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.88 (brs, 2H), 7.46 (d, J = 4.4 Hz, 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.35 (s, 1H), 4.75 (d, J=5.6 Hz, 2H), 2.38 (brs, 1H), 1.15 (q, J = 6.4 Hz, 2H), 0.84 (q, J = 5.2 Hz, 2H); ESI-MS m/z: 380.11 [M+ H] + .

c)2-环丙基-5-氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-cyclopropyl-5-amino-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-环丙基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(120mg,0.32mmol)溶于THF(15mL)中，加入Pd/C 60mg，在室温下通入氢气，反应过夜，过滤，滤液浓缩，得无色油状物106mg，收率为95.5％。2-Cyclopropyl-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide (120 mg, 0.32 mmol) was dissolved in THF (15 mL). Hydrogen was introduced at room temperature, the reaction was allowed to stand overnight, and the filtrate was concentrated to give a white oil (yield:

1H-NMR(400MHz,CDCl 3)δ(ppm):7.97(s,1H),7.88-7.86(m,2H),7.43(brs,2H),7.34(d,J＝3.2Hz,1H),6.86(d,J＝2.4Hz,1H),6.80(d,J＝8.4Hz,1H),6.64(dd,J＝ 8.4,2.4Hz,1H),6.49(s,1H),4.70(d,J＝5.6Hz,2H),2.11-2.05(m,1H),0.85-0.81(m,2H),0.62-0.59(m,2H)；ESI-MS m/z:350.13[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.97 (s, 1H), 7.88-7.86 (m, 2H), 7.43 (brs, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.4 Hz, 1H), 6.49 (s, 1H), 4.70 (d, J) = 5.6 Hz, 2H), 2.11-2.05 (m, 1H), 0.85-0.81 (m, 2H), 0.62-0.59 (m, 2H); ESI-MS m/z: 350.13 [M+H] + .

d)2-环丙基-5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺d) 2-cyclopropyl-5-isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-环丙基-5-氨基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(100mg,0.29mmol)溶于无水THF(10mL)中，冰浴下依次加入TEA(117mg,1.16mmol)，异丁酰氯(61mg,0.58mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，HCl(0.5N)水溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得白色固体97mg，收率为69.3％，熔点：167-168℃。 2-Cyclopropyl-5-amino-N-(3-(thiazol-2-yl)benzyl)benzamide (100 mg, 0.29 mmol) was dissolved in anhydrous THF (10 mL) TEA (117 mg, 1.16 mmol), isobutyryl chloride (61 mg, 0.58 mmol), EtOAc (EtOAc) 3 (10 mL), washed with water (10 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:2) The yield was 69.3%, and the melting point was 167-168 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.97(s,1H),7.85(brs,2H),7.57(brs,2H),7.47(s,H),7.43-7.40(m,2H),7.34(d,J＝3.2Hz,1H),6.90(d,J＝8.4Hz,1H),6.60(s,1H),4.69(d,J＝5.6Hz,2H),2.52-2.47(m,1H),2.22-2.17(m,1H),1.22(d,J＝6.8Hz,6H),0.94-0.85(m,2H),0.66(q,J＝4.8Hz,2H)；HR-MS(ESI):m/z,calcd.For C 24H 25O 2N 3S 420.1740[M+H] +,Found:420.1734。 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.97 (s, 1H), 7.85 (brs, 2H), 7.57 (brs, 2H), 7.47 (s, H), 7.43-7.40 (m, 2H) ), 7.34 (d, J = 3.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 2.52-2.47 (m) , 1H), 2.22-2.17 (m, 1H), 1.22 (d, J = 6.8 Hz, 6H), 0.94-0.85 (m, 2H), 0.66 (q, J = 4.8 Hz, 2H); HR-MS ( ESI): m / z, calcd.For C 24 H 25 O 2 N 3 S 420.1740 [m + H] +, Found: 420.1734.

实施例(化合物)153Example (compound) 153

2-甲氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-methoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000213
Figure PCTCN2018088561-appb-000213

a)2-甲氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-methoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-甲氧基-5-硝基苯甲酸(177mg，0.90mmol)溶于DCM(15mL)，加入HATU(616mg，1.62mmol)，DIEA(418mg，3.24mmol)，室温反应30min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(690mg，3.38mmol)，室温反应过夜。0.5NHCl(15mL×2)洗，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体285mg，收率83％。熔点：143-145℃.2-methoxy-5-nitrobenzoic acid (177 mg, 0.90 mmol) was dissolved in DCM (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) (3-thiazol-2-yl)phenyl)ethyl-1-amine (690 mg, 3.38 mmol) was reacted at room temperature overnight. Wash with 0.5 N HCl (15 mL × 2), water (20 mL × 2), and dry over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave 285 mg of white solid. Melting point: 143-145 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):9.06(d,J＝2.5Hz,1H),8.32(dd,J 1＝2.5Hz,J 2＝9.0Hz 1H),8.08(s,1H),8.00(d,J＝6.5Hz,1H),8.00(d,J＝6.5Hz,1H),7.87(d,J＝2.5Hz,1H),7.83(d,J＝9.0Hz,1H),7.43-7.46(m,2H),7.35(d,J＝3.0Hz,1H),7.08(d,J＝9.5Hz,1H),5.37-5.43(m,1H),4.11(s,3H),3.31(d,J＝7.0Hz,3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 9.06 (d, J = 2.5 Hz, 1H), 8.32 (dd, J 1 = 2.5 Hz, J 2 = 9.0 Hz 1H), 8.08 (s, 1H) , 8.00 (d, J = 6.5 Hz, 1H), 8.00 (d, J = 6.5 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.43 -7.46 (m, 2H), 7.35 (d, J = 3.0 Hz, 1H), 7.08 (d, J = 9.5 Hz, 1H), 5.37 - 5.43 (m, 1H), 4.11 (s, 3H), 3.31 ( d, J = 7.0 Hz, 3H).

b)2-甲氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Methoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-甲氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(250mg，0.65mmol)溶于THF(15mL)，H 2/50℃反应过夜。原料消失。过滤，浓缩，柱层析(P:E＝1:1-1:2)，得黄色油状物203mg，收率88％。 2-methoxy-5-nitro -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (250mg, 0.65mmol) was dissolved in THF (15mL), H 2 The reaction was allowed to proceed at /50 °C overnight. The raw materials disappeared. Filtration, concentration and column chromatography (P: EtOAc: 1:1: 2)

1H NMR(400MHZ,CDCl 3)δ(ppm):8.58(d,J＝7.6Hz,1H),7.96(d,J＝2.0Hz,1H),7.80-7.84(m,1H),7.79(d,J＝3.2Hz,1H),7.45-7.50(m,2H),7.05(d,J＝2.8Hz,1H),6.85(d,J＝7.6Hz,1H),6.66(dd,J 1＝3.2Hz,J 2＝8.8Hz,1H),5.15-5.22(m,1H),3.92(t,J＝6.4Hz,2H),1.64-1.73(m,2H),1.49(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.58 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.80-7.84 (m, 1H), 7.79 (d) , J = 3.2 Hz, 1H), 7.45-7.50 (m, 2H), 7.05 (d, J = 2.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.66 (dd, J 1 = 3.2 Hz, J 2 = 8.8 Hz, 1H), 5.15 - 5.22 (m, 1H), 3.92 (t, J = 6.4 Hz, 2H), 1.64-1.73 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H).

c)2-甲氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-methoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-甲氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(150mg，0.27mmol)溶于THF(3mL)，冰浴下加入TEA(129mg，1.27mmol)，搅拌下逐滴加入异丁酰氯(45mg，0.51mmol)，室温下搅拌反应2h。蒸馏水(5mL×2)洗，饱和NaCl(15mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝1:1)，得白色固体125mg，收率70％。熔点：140-142℃.2-Methoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (150 mg, 0.27 mmol) dissolved in THF (3 mL) TEA (129 mg, 1.27 mmol) was added, and isobutyryl chloride (45 mg, 0.51 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 2 h. Washed with distilled water (5 mL × 2), washed with saturated NaCl (15 mL × 2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 1:1) gave a white solid, 125 mg, yield 70%. Melting point: 140-142 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.32(d,J＝7.0Hz,1H),8.22(d,J＝10.5Hz,1H),8.03(s,1H),7.81-7.87(m,3H),7.39-7.45(m,3H),7.34(d,J＝3.0Hz,1H),6.96(d,J＝9.0Hz,1H),5.36-5.40(m,1H),3.97(s,3H),2.47-2.52(m,1H),1.63(d,J＝7.0Hz,3H),1.22(d,J＝7.0Hz,6H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 8.32 (d, J = 7.0 Hz, 1H), 8.22 (d, J = 10.5 Hz, 1H), 8.03 (s, 1H), 7.81-7.87 (m) , 3H), 7.39-7.45 (m, 3H), 7.34 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 5.36-5.40 (m, 1H), 3.97 (s, 3H), 2.47-2.52 (m, 1H), 1.63 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 6H).

实施例(化合物)154Example (compound) 154

2-丙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-propoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000214
Figure PCTCN2018088561-appb-000214

a)2-丙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-propoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-甲氧基-5-硝基苯甲酸(307mg，1.36mmol)溶于DCM(20mL)，加入HATU(776mg，2.04mmol)，DIEA(527mg，4.08mmol)，室温反应30min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(335mg，1.64mmol)，室温反应过夜。0.5NHCl(15mL)洗，水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝3:1)，得白色固体477mg，收率85％。熔点：65-66℃.2-methoxy-5-nitrobenzoic acid (307 mg, 1.36 mmol) was dissolved in DCM (20 mL), EtOAc (EtOAc, EtOAc (EtOAc) (3-thiazol-2-yl)phenyl)ethyl-1-amine (335 mg, 1.64 mmol). Wash with 0.5 N HCl (15 mL), EtOAc (EtOAc) Column chromatography (P: E = 3:1) gave 477 mg of white solid. Melting point: 65-66 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):9.09(d,J＝2.5Hz,1H),8.29(dd,J 1＝2.5Hz,J 2＝9.0Hz 1H),8.17(d,J＝6.5Hz,1H),8.03(s,1H)7.85-7.87(m,2H),7.42-7.47(m,2H),7.35(d,J＝3.0Hz,1H),7.04(d,J＝9.0Hz,1H),5.36-5.41(m,1H),4.14-4.21(m,2H),1.84-1.91(m,2H),1.66(d,J＝7.0Hz,3H),0.99(t,J＝7.5Hz,3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 9.09 (d, J = 2.5 Hz, 1H), 8.29 (dd, J 1 = 2.5 Hz, J 2 = 9.0 Hz 1H), 8.17 (d, J = 6.5 Hz, 1H), 8.03 (s, 1H) 7.85-7.87 (m, 2H), 7.42-7.47 (m, 2H), 7.35 (d, J = 3.0 Hz, 1H), 7.04 (d, J = 9.0 Hz) , 1H), 5.36-5.41 (m, 1H), 4.14 - 4.21 (m, 2H), 1.84-1.91 (m, 2H), 1.66 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H).

b)2-丙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-propoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-甲氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(200mg，0.48mmol)溶于THF(10mL)，H 2/50℃反应过夜。原料消失。过滤，浓缩，柱层析(P:E＝1:1)，得微红色固体92mg，收率50％。熔点：140-141℃. 2-methoxy-5-nitro -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg, 0.48mmol) was dissolved in THF (10mL), H 2 The reaction was allowed to proceed at /50 °C overnight. The raw materials disappeared. Filtration, concentration and column chromatography (P: E = 1:1) gave a reddish solid, 92mg, yield 50%. Melting point: 140-141 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.58(d,J＝7.6Hz,1H),7.96(d,J＝2.0Hz,1H),7.80-7.84(m,1H),7.79(d,J＝3.2Hz,1H),7.45-7.50(m,2H),7.05(d,J＝2.8Hz,1H),6.85(d,J＝7.6Hz,1H),6.66(dd,J 1＝3.2Hz,J 2＝8.8Hz 1H),5.15-5.22(m,1H),3.92(t,J＝6.4Hz,2H),1.64-1.73(m,2H),1.49(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H). 1H NMR (400MHZ, CDCl 3 ) δ (ppm): 8.58 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.80-7.84 (m, 1H), 7.79 (d, J = 3.2 Hz, 1H), 7.45-7.50 (m, 2H), 7.05 (d, J = 2.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.66 (dd, J 1 = 3.2 Hz) , J 2 = 8.8 Hz 1H), 5.15 - 5.22 (m, 1H), 3.92 (t, J = 6.4 Hz, 2H), 1.64-1.73 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H) , 0.88 (t, J = 7.2 Hz, 3H).

c)2-丙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-propoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-丙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(60mg，0.15mmol)溶于THF(6mL)，冰浴下加入TEA(48mg，0.47mmol)，搅拌下逐滴加入异丁酰氯(20mg，0.19mmol)，室温下搅拌反应30min。蒸馏水(10mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝1:1)，得白色固体50mg，收率75％。熔点：142-143℃.2-propoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (60 mg, 0.15 mmol) dissolved in THF (6 mL) TEA (48 mg, 0.47 mmol) was added, and isobutyryl chloride (20 mg, 0.19 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 30 min. Distilled water (10 mL × 2) was washed and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 1:1) gave 50 mg of white solid. Melting point: 142-143 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.51(d,J＝6.8Hz,1H),8.20(dd,J 1＝2.8Hz,J 2＝9.2Hz 1H),8.01(s,1H),7.82-7.87(m,3H),7.40-7.46(m,2H),7.34(d,J＝3.2Hz,1H),6.93(d,J＝9.2Hz,1H),5.34-5.41(m,1H),4.06(t,J＝6.4Hz,2H),2.46-2.53(m,1H),1.76-1.84(m,2H),1.63(d,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H),0.96(t,J＝6.4Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.51 (d, J = 6.8 Hz, 1H), 8.20 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz 1H), 8.01 (s, 1H) , 7.82-7.87 (m, 3H), 7.40-7.46 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 5.34 - 5.41 (m, 1H) ), 4.06 (t, J = 6.4 Hz, 2H), 2.46-2.53 (m, 1H), 1.76-1.84 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H), 0.96 (t, J = 6.4 Hz, 3H).

实施例(化合物)155Example (compound) 155

2-异丙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-isopropoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000215
Figure PCTCN2018088561-appb-000215

a)2-异丙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-Isopropoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-异丙氧基-5-硝基苯甲酸(250mg，1.11mmol)溶于DCM(20mL)，加入HATU (633mg，1.66mmol)，DIEA(430mg，3.33mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(272mg，1.33mmol)，室温反应过夜。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝3:1)，得类白色固体387mg，收率85％。熔点：99-101℃.2-Isopropoxy-5-nitrobenzoic acid (250 mg, 1.11 mmol) was dissolved in DCM (20 mL), EtOAc (EtOAc, EtOAc, EtOAc -(3-thiazol-2-yl)phenyl)ethyl-1-amine (272 mg, 1.33 mmol). Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 3:1) gave 387 mg of white solid. Melting point: 99-101 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):9.10(d,J＝2.8Hz,1H),8.29(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),8.13(d,J＝7.2Hz,1H),8.03(t,J＝1.6Hz,1H),7.84-7.87(m,2H),7.45(t,J＝1.6Hz,1H),7.35(d,J＝3.2Hz,1H),7.03(d,J＝9.2Hz,1H),3.97(d,J＝6.4Hz,2H),2.09-2.19(m,1H),1.66(d,J＝7.2Hz,3H),1.01(d,J＝9.8Hz,3H),0.95(d,J＝9.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 9.10 (d, J = 2.8 Hz, 1H), 8.29 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 8.13 (d, J) = 7.2 Hz, 1H), 8.03 (t, J = 1.6 Hz, 1H), 7.84 - 7.87 (m, 2H), 7.45 (t, J = 1.6 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H) ), 7.03 (d, J = 9.2 Hz, 1H), 3.97 (d, J = 6.4 Hz, 2H), 2.09 - 2.19 (m, 1H), 1.66 (d, J = 7.2 Hz, 3H), 1.01 (d) , J = 9.8 Hz, 3H), 0.95 (d, J = 9.8 Hz, 3H).

b)2-异丙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Isopropoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-异丙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(200mg，0.47mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(163mg，2.92mmol)，NH 4Cl(26mg，0.49mmol)，70℃回流反应3h。原料消失。过滤，浓缩，加入EA(,15mL)稀释，水洗(15mL×2),无水硫酸镁干燥，浓缩，柱层析(P:E＝1:1)，得白色固体155mg，收率84％。熔点：134-136℃. 2-Isopropoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (200 mg, 0.47 mmol) dissolved in DCM (2mL) / EtOH (8 mL) / H 2 O (1 mL), Fe powder (163 mg, 2.92 mmol), NH 4 Cl (26 mg, 0.49 mmol), and refluxed at 70 ° C for 3 h. The raw materials disappeared. Filtration, concentration, EA (15 mL), EtOAc (EtOAc) (EtOAc) Melting point: 134-136 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.68(d,J＝7.2Hz,1H),7.96(s,1H),7.92(d,J＝3.2Hz,1H),7.83(d,J＝6.0Hz,1H),7.80(d,J＝3.2Hz,1H),7.48(d,J＝6.0Hz,2H),7.04(d,J＝8.8Hz,1H),6.66(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),5.13-5.18(m,1H),4.89(s,2H),4.47-4.53(m,1H),1.50(d,J＝2.8Hz,3H),1.20(q,J＝6.0Hz,6H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.68 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.83 (d) , J = 6.0 Hz, 1H), 7.80 (d, J = 3.2 Hz, 1H), 7.48 (d, J = 6.0 Hz, 2H), 7.04 (d, J = 8.8 Hz, 1H), 6.66 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 5.13-5.18 (m, 1H), 4.89 (s, 2H), 4.47-4.53 (m, 1H), 1.50 (d, J = 2.8 Hz, 3H) , 1.20 (q, J = 6.0 Hz, 6H).

c)2-异丙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-Isopropoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-异丙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(100mg，0.26mmol)溶于THF(7mL)，冰浴下加入TEA(80mg，0.79mmol)，搅拌下逐滴加入异丁酰氯(34mg，0.32mmol)，室温下搅拌反应10min。浓缩，加入EA(15mL)稀释，蒸馏水(15mL×2)洗，无水硫酸镁干燥，浓缩，加入石油醚，得到白色固体99mg，收率84％。熔点：149-151℃.2-Isopropoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (100 mg, 0.26 mmol) dissolved in THF (7 mL) After adding TEA (80 mg, 0.79 mmol), isobutyryl chloride (34 mg, 0.32 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. After concentration, it was diluted with EA (15 mL), washed with distilled water (15 mL×2), dried over anhydrous magnesium sulfate and evaporated. Melting point: 149-151 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.62(d,J＝6.8Hz,1H),8.20(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),8.01(s,1H),7.86(d,J＝2.4Hz,1H),7.83(d,J＝9.2Hz,1H),7.43(d,J＝7.2Hz,2H),7.33(d,J＝3.2Hz,1H),6.95(d,J＝9.2Hz,1H),5.32-5.39(m,1H),4.67-4.73(m,1H),2.46-2.53(m,1H),1.63(d,J＝6.8Hz,3H),1.34(q,J＝6.0Hz,6H),1.21(d,J＝6.4Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.62 (d, J = 6.8 Hz, 1H), 8.20 (dd, J 1 = 2.4 Hz, J 2 = 8.8 Hz, 1H), 8.01 (s, 1H) ), 7.86 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.95 (d, J=9.2 Hz, 1H), 5.32-5.39 (m, 1H), 4.67-4.73 (m, 1H), 2.46-2.53 (m, 1H), 1.63 (d, J = 6.8 Hz, 3H) , 1.34 (q, J = 6.0 Hz, 6H), 1.21 (d, J = 6.4 Hz, 6H).

实施例(化合物)156Example (compound) 156

2-异丁氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-isobutoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000216
Figure PCTCN2018088561-appb-000216

a)2-异丁氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-isobutoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-异丁氧基-5-硝基苯甲酸(300mg，1.25mmol)溶于DCM(20mL)，加入HATU(713mg，1.88mmol)，DIEA(485mg，3.75mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(282mg，1.38mmol)，室温反应过夜。浓缩，加入EA(20mL)稀释，水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝5:1)，得淡黄色固体470mg，收率88％。2-Isobutoxy-5-nitrobenzoic acid (300 mg, 1.25 mmol) was dissolved in DCM (20 mL), EtOAc (EtOAc, EtOAc (EtOAc) (3-thiazol-2-yl)phenyl)ethyl-1-amine (282 mg, 1.38 mmol) was reacted overnight at room temperature. Concentrated, diluted with EA (20 mL), water (20 mL) Column chromatography (P: E = 5:1) gave 470 mg of pale yellow solid.

1H NMR(400MHZ,CDCl 3)δ(ppm):9.10(d,J＝2.8Hz,1H),8.29(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),8.13(d,J＝7.2Hz,1H),8.03(t,J＝1.6Hz,1H),7.84-7.87(m,2H),7.45(t,J＝1.6Hz,1H),7.35(d,J＝3.2Hz,1H),7.03(d,J＝9.2Hz,1H),3.97(d,J＝6.4Hz,2H),2.09-2.19(m,1H),1.66(d,J＝7.2Hz,3H),1.01(d,J＝9.8Hz,3H),0.95(d,J＝9.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 9.10 (d, J = 2.8 Hz, 1H), 8.29 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 8.13 (d, J) = 7.2 Hz, 1H), 8.03 (t, J = 1.6 Hz, 1H), 7.84 - 7.87 (m, 2H), 7.45 (t, J = 1.6 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H) ), 7.03 (d, J = 9.2 Hz, 1H), 3.97 (d, J = 6.4 Hz, 2H), 2.09 - 2.19 (m, 1H), 1.66 (d, J = 7.2 Hz, 3H), 1.01 (d) , J = 9.8 Hz, 3H), 0.95 (d, J = 9.8 Hz, 3H).

b)2-异丙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Isopropoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-异丁氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(300mg，0.52mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(236mg，4.23mmol)，NH 4Cl(38mg，0.71mmol)，70℃回流反应2h。原料消失。过滤，浓缩，加入EA(20mL)稀释，水洗(15mL×2),无水硫酸镁干燥，浓缩，加入石油醚，析出白色固体240mg，收率86％。熔点：118-120℃. 2-Isobutoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (300 mg, 0.52 mmol) dissolved in DCM (2 mL) / EtOH (8 mL) / H 2 O (1 mL), Fe powder (236 mg, 4.23 mmol), NH 4 Cl (38 mg, 0.71 mmol), and refluxed at 70 ° C for 2 h. The raw materials disappeared. Filtration, concentration, EA (20 mL), EtOAc (EtOAc)EtOAc. Melting point: 118-120 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.55(d,J＝7.6Hz,1H),7.97(s,1H),7.92(d,J＝3.2Hz,1H),7.81-7.83(m,1H),7.79(d,J＝9.6Hz,1H),7.48(d,J＝2.4Hz,1H),7.06(d,J＝2.8Hz,1H),6.84(d,J＝8.4Hz,1H),5.18-5.21(m,1H),4.83(s,2H),3.74(d,J＝6.4Hz,2H),1.94-2.01(m,1H),1.50(d,J＝7.2Hz,3H),0.90(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.55 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.81-7.83 (m, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 8.4 Hz) , 1H), 5.18-5.21 (m, 1H), 4.83 (s, 2H), 3.74 (d, J = 6.4 Hz, 2H), 1.94-2.01 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H).

c)2-异丁氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-Isobutoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-异丁氧基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(100mg，0.25mmol)溶于THF(5mL)，冰浴下加入TEA(76mg，0.75mmol)，搅拌下逐滴加入异丁 酰氯(32mg，0.30mmol)，室温下搅拌反应10min。浓缩，加入EA(15mL)稀释，蒸馏水(10mL×2)洗，无水硫酸镁干燥，浓缩，加入石油醚，得到白色固体103mg，收率89％。熔点：119-121℃.2-Isobutoxy-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (100 mg, 0.25 mmol) was dissolved in THF (5 mL) After adding TEA (76 mg, 0.75 mmol), isobutyryl chloride (32 mg, 0.30 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. After concentration, it was diluted with EA (15 mL), washed with distilled water (10 mL×2), dried over anhydrous magnesium sulfate, and evaporated. Melting point: 119-121 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.47(d,J＝7.2Hz,1H),8.20(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),8.01(s,1H),7.86(d,J＝2.8Hz,1H),7.83(d,J＝6.8Hz,1H),7.39-7.44(m,2H),7.33(d,J＝3.2Hz,1H),6.91(d,J＝9.2Hz,1H),5.35-5.42(m,2H),3.86(d,J＝6.4Hz,2H),2.46-2.53(m,1H),2.02-2.10(m,1H),1.63(d,J＝6.8Hz,3H),1.22(s,6H),0.98(d,J＝6.4Hz,3H),0.93(d,J＝6.4Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.47 (d, J = 7.2 Hz, 1H), 8.20 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 8.01 (s, 1H) ), 7.86 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.39-7.44 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.91 (d) , J=9.2 Hz, 1H), 5.35-5.42 (m, 2H), 3.86 (d, J = 6.4 Hz, 2H), 2.46-2.53 (m, 1H), 2.02-2.10 (m, 1H), 1.63 ( d, J = 6.8 Hz, 3H), 1.22 (s, 6H), 0.98 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H).

实施例(化合物)157Example (compound) 157

2-环丙甲氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺2-cyclopropylmethoxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

Figure PCTCN2018088561-appb-000217
Figure PCTCN2018088561-appb-000217

a)2-环丙甲氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-cyclopropylmethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-环丙甲氧基-5-硝基苯甲酸(230mg，0.97mmol)溶于DCM(15mL)，加入HATU(553mg，1.46mmol)，DIEA(376mg，2.91mmol)，室温反应30min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(237mg，1.16mmol)，室温反应过夜。水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝3:1)，得白色固体399mg，收率98％。熔点：69-71℃.2-Cyclopropylmethoxy-5-nitrobenzoic acid (230 mg, 0.97 mmol) was dissolved in DCM (15 mL), EtOAc (EtOAc, EtOAc, EtOAc 1-(3-thiazol-2-yl)phenyl)ethyl-1-amine (237 mg, 1.16 mmol). Wash with water (20 mL) and dry over anhydrous magnesium sulfate. Column chromatography (P: E = 3:1) gave 399 mg of white solid. Melting point: 69-71 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):9.11(d,J＝2.8Hz,1H),8.46(d,J＝7.2Hz,1H),8.28(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),7.83-7.86(m,2H),7.41-7.49(m,2H),7.34(d,J＝2.8Hz,1H),6.97(d,J＝8.8Hz,1H),5.36-5.43(m,1H),4.00-4.09(m,2H),1.66(d,J＝6.8Hz,3H),1.51(d,J＝7.2Hz,3H),1.33-1.37(m,1H),0.61-0.69(m,2H),0.37-0.42(m,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 9.11 (d, J = 2.8 Hz, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.28 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 7.83-7.86 (m, 2H), 7.41-7.49 (m, 2H), 7.34 (d, J = 2.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.36 -5.43 (m, 1H), 4.00-4.09 (m, 2H), 1.66 (d, J = 6.8 Hz, 3H), 1.51 (d, J = 7.2 Hz, 3H), 1.33-1.37 (m, 1H), 0.61-0.69 (m, 2H), 0.37-0.42 (m, 2H).

b)2-环丙甲氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-cyclopropylmethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-环丙甲氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(200mg，0.47mmol)溶于THF(10mL)，H 2/50℃反应17h。原料消失。过滤，浓缩，柱层析(P:E＝1:1)，得微黄色固体129mg，收率70％。熔点：156-157℃. 2-Cyclopropylmethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (200 mg, 0.47 mmol) was dissolved in THF (10 mL). The reaction was carried out for 17 h at H 2 /50 °C. The raw materials disappeared. Filtration, concentration and column chromatography (P: E = 1:1) gave 129 mg ofyellow solid. Melting point: 156-157 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.79(d,J＝7.6Hz,1H),7.97(d,J＝1.6Hz,1H), 7.92(d,J＝3.2Hz,1H),7.82(dt,J 1＝1.6Hz,J 2＝7.2Hz 1H),7.79(d,J＝3.2Hz,1H),7.45-7.53(m,2H),7.09(d,J＝3.2Hz,1H),5.16-5.23(m,1H),3.84(d,J＝7.2Hz,2H),1.51(d,J＝7.2Hz,3H),1.16-1.25(m,1H),0.46-0.51(m,2H),0.29-0.30(m,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.79 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.82 (dt, J 1 =1.6 Hz, J 2 =7.2 Hz 1H), 7.79 (d, J = 3.2 Hz, 1H), 7.45-7.53 (m, 2H), 7.09 (d, J = 3.2 Hz, 1H) , 5.16-5.23 (m, 1H), 3.84 (d, J = 7.2 Hz, 2H), 1.51 (d, J = 7.2 Hz, 3H), 1.16-1.25 (m, 1H), 0.46-0.51 (m, 2H) ), 0.29-0.30 (m, 2H).

c)2-环丙甲氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺c) 2-cyclopropylmethoxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

2-环丙甲氧基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(80mg，0.20mmol)溶于THF(5mL)，冰浴下加入TEA(61mg，0.60mmol)，搅拌下逐滴加入异丁酰氯(32mg，0.3mmol)，室温下搅拌反应30min。蒸馏水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝1:1)，得白色固体78mg，收率85％。熔点：168-170℃.2-cyclopropylmethoxy-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (80 mg, 0.20 mmol) dissolved in THF (5 mL) After adding TEA (61 mg, 0.60 mmol), isobutyryl chloride (32 mg, 0.3 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. It was washed with distilled water (20 mL) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 1:1) gave a white solid (yield: 78%). Melting point: 168-170 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.76(d,J＝7.6Hz,1H),8.20(dd,J 1＝6.8Hz,J 2＝8.8Hz 1H),8.03(d,J＝1.2Hz,1H),7.82-7.86(m,3H),7.41-7.47(m,3H),7.33(d,J＝1.2Hz,1H),6.86(d,J＝8.8Hz,1H),5.35-5.42(m,1H),3.88-4.00(m,1H),2.46-2.53(m,1H),1.64(d,J＝7.2Hz,3H),1.21(d,J＝6.8Hz,6H),0.55-0.61(m,2H),0.32-0.36(m,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.76 (d, J = 7.6 Hz, 1H), 8.20 (dd, J 1 = 6.8 Hz, J 2 = 8.8 Hz 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.82-7.86 (m, 3H), 7.41-7.47 (m, 3H), 7.33 (d, J = 1.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.35- 5.42 (m, 1H), 3.88-4.00 (m, 1H), 2.46-2.53 (m, 1H), 1.64 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 6.8 Hz, 6H), 0.55 -0.61 (m, 2H), 0.32-0.36 (m, 2H).

实施例(化合物)158Example (compound) 158

2-苯氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺2-phenoxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

Figure PCTCN2018088561-appb-000218
Figure PCTCN2018088561-appb-000218

a)2-苯氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-phenoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-苯氧基-5-硝基苯甲酸(120mg，0.46mmol)溶于DCM(15mL)，加入HATU(213mg，0.56mmol)，DIEA(118mg，0.92mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(113mg，0.56mmol)，室温反应8h。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝5:1)，得微黄色油状物170mg，收率83％。直接投入下一步。2-Phenoxy-5-nitrobenzoic acid (120 mg, 0.46 mmol) was dissolved in DCM (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) (3-thiazol-2-yl)phenyl)ethyl-1-amine (113 mg, 0.56 mmol). Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 5: 1) gave a pale yellow oil (yield: Go directly to the next step.

b)2-苯氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-phenoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-苯氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(150mg，0.33mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(113mg，2.02mmol)，NH 4Cl(18mg，0.33mmol)，60℃回流反应3h。原料消失。过滤，浓缩，加入 EA(15mL)稀释，水洗(10mL×2),无水硫酸镁干燥，柱层析(P:E＝2:1)得微黄色油状物95mg，收率69％。 2-Phenoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (150 mg, 0.33 mmol) dissolved in DCM (2 mL) /EtOAc 8 mL) / H 2 O (1 mL), Fe powder (113 mg, 2.02 mmol), NH 4 Cl (18 mg, 0.33 mmol), and refluxed at 60 ° C for 3 h. The raw materials disappeared. Filtration, concentration, EA (15 mL), EtOAc (EtOAc (EtOAc)EtOAc.

1H NMR(400MHZ，DMSO-d 6)δ(ppm):8.49(d,J＝7.2Hz,1H),7.93(t,J＝3.2Hz,1H),7.89(brs,1H),7.75-7.79(m,2H),7.70-7.74(m,1H),7.66-7.69(m,1H),7.29-7.36(m,2H),7.21-7.26(m,2H),6.96(d,J＝7.6Hz,1H),6.77-5.84(m,4H),6.67(dt,J 1＝2.4Hz,J 2＝8.8Hz,1H),5.21(s,2H),7.21-7.26(m,2H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.49 (d, J = 7.2 Hz, 1H), 7.93 (t, J = 3.2 Hz, 1H), 7.89 (brs, 1H), 7.75-7.79 (m, 2H), 7.70-7.74 (m, 1H), 7.66-7.69 (m, 1H), 7.29-7.36 (m, 2H), 7.21-7.26 (m, 2H), 6.96 (d, J = 7.6 Hz) , 1H), 6.77-5.84 (m, 4H), 6.67 (dt, J 1 = 2.4 Hz, J 2 = 8.8 Hz, 1H), 5.21 (s, 2H), 7.21 - 7.26 (m, 2H).

c)2-苯氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺c) 2-phenoxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

2-苯氧基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(80mg，0.19mmol)溶于THF(2mL)，冰浴下加入TEA(58mg，0.57mmol)，搅拌下逐滴加入异丁酰氯(25mg，0.23mmol)，室温下搅拌反应10min。浓缩，加入EA(10mL)稀释，蒸馏水(10mL×2)洗，无水硫酸镁干燥，柱层析(P:E＝2:1)，得白色固体61mg，收率66％。熔点：93-95℃.2-Phenoxy-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (80 mg, 0.19 mmol) was dissolved in THF (2 mL) TEA (58 mg, 0.57 mmol), isobutyryl chloride (25 mg, 0.23 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. After concentration, it was diluted with EA (10 mL), washed with distilled water (10 mL×2), dried over anhydrous magnesium sulfate, and then purified by column chromatography (P:E=2:1) to give a white solid (yield: 66%). Melting point: 93-95 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.19(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),8.01(d,J＝7.6Hz,1H),7.91(s,1H),7.87(brs,1H),7.86(d,J＝3.2Hz,1H),7.80(dd,J 1＝1.2Hz,J 2＝7.6Hz,1H),7.55(brs,1H),7.29-7.33(m,1H),7.12(d,J＝7.6Hz,1H),6.97(d,J＝8.0Hz,2H),6.92(d,J＝9.2Hz,1H),5.28-5.35(m,1H),2.47-2.54(m,1H),1.51(d,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.19 (dd, J 1 = 2.4 Hz, J 2 = 8.8 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.91 (s) , 1H), 7.87 (brs, 1H), 7.86 (d, J = 3.2 Hz, 1H), 7.80 (dd, J 1 = 1.2 Hz, J 2 = 7.6 Hz, 1H), 7.55 (brs, 1H), 7.29 -7.33 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 9.2 Hz, 1H), 5.28-5.35 (m, 1H), 2.47-2.54 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H).

实施例(化合物)159Example (compound) 159

2-苄氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺2-benzyloxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

Figure PCTCN2018088561-appb-000219
Figure PCTCN2018088561-appb-000219

a)2-苄氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-Benzyloxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-苄氧基-5-硝基苯甲酸(274mg，1.0mmol)溶于DCM(20mL)，加入HATU(570mg，1.5mmol)，DIEA(492mg，3.0mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(340mg，1.66mmol)，室温反应12h。浓缩，加入EA(20mL)稀释，水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝4:1)，得浅黄色固体206mg，收率40％。2-Benzyloxy-5-nitrobenzoic acid (274 mg, 1.0 mmol) was dissolved in DCM (20 mL), EtOAc (EtOAc, EtOAc) 3-thiazol-2-yl)phenyl)ethyl-1-amine (340 mg, 1.66 mmol). Concentrated, diluted with EA (20 mL), water (20 mL) Column chromatography (P: E = 4: 1) gave a pale yellow solid (m.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.75(s,1H),8.36(d,J＝2.4Hz,1H),8.19(dd,J 1＝2.4Hz,J 2＝9.6Hz,1H),8.01(s,1H),7.87(d,J＝3.2Hz,1H),7.44-7.46(m,2H),7.34(d,J＝3.2Hz,1H),7.11(d,J＝9.6Hz,1H),6.55(d,J＝7.2Hz,3H),5.24-5.31(m,1H),2.48-2.54(m,1H),0.84-0.90(m,2H),5.58-5.82(m,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.75 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.19 (dd, J 1 = 2.4 Hz, J 2 = 9.6 Hz, 1H ), 8.01 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.44 - 7.46 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.11 (d, J = 9.6 Hz) , 1H), 6.55 (d, J = 7.2 Hz, 3H), 5.24-5.31 (m, 1H), 2.48-2.54 (m, 1H), 0.84-0.90 (m, 2H), 5.58-5.82 (m, 2H) ).

b)2-苄氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Benzyloxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-苄氧基-5-硝基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺(240mg，0.52mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(175mg，3.13mmol)，NH 4Cl(28mg，0.52mmol)，70℃回流反应2.5h。原料消失。过滤，浓缩，加入EA(15mL)稀释，水洗(15mL×2),无水硫酸镁干燥，浓缩，加入石油醚，析出白色固体170mg，收率76％。熔点：135-137℃. 2-Benzyloxy-5-nitro-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide (240 mg, 0.52 mmol) was dissolved in DCM (2mL) /EtOAc. 8 mL) / H 2 O (1 mL), Fe powder (175 mg, 3.13 mmol), NH 4 Cl (28 mg, 0.52 mmol), and refluxed at 70 ° C for 2.5 h. The raw materials disappeared. Filtration, concentration, EA (15 mL) was added, diluted with water (15 mL×2), dried over anhydrous magnesium sulfate, concentrated, and petroleum ether was added to yield 170 mg of white solid. Melting point: 135-137 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.56(d,J＝7.6Hz,1H),7.91(d,J＝3.2Hz,1H),7.87(s,1H),7.78(d,J＝3.2Hz,2H),7.48(d,J＝7.6Hz,2H),7.31-7.38(m,4H),7.26(d,J＝7.6Hz,1H),7.01(t,J＝2.8Hz,1H),6.68(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),5.08(m,2H),4.87(m,1H),1.26(d,J＝7.2Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.56 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J) =3.2 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.31-7.38 (m, 4H), 7.26 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 2.8 Hz, 1H) ), 6.68 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 5.08 (m, 2H), 4.87 (m, 1H), 1.26 (d, J = 7.2 Hz, 3H).

c)2-苄氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺c) 2-Benzyloxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

2-苄氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(80mg，0.18mmol)溶于THF(5mL)，冰浴下加入TEA(55mg，0.54mmol)，搅拌下逐滴加入异丁酰氯(24mg，0.22mmol)，室温下搅拌反应30min。浓缩，加入EA(15mL)稀释，蒸馏水(10mL×2)洗，无水硫酸镁干燥，浓缩，加入无水乙醚，析出白色固体90mg，收率83％。熔点：162-164℃.2-Benzyloxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (80 mg, 0.18 mmol) was dissolved in THF (5 mL) TEA (55 mg, 0.54 mmol) was added, and isobutyryl chloride (24 mg, 0.22 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 30 min. After concentration, it was diluted with EA (15 mL), washed with distilled water (10 mL×2), dried over anhydrous magnesium sulfate, and evaporated to ethyl ether. Melting point: 162-164 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.39(d,J＝7.6Hz,1H),8.26(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),7.83-7.86(m,3H),7.79(d,J＝8.0Hz,1H),7.48(brs,1H),7.43(dd,J 1＝2.0Hz,J 2＝7.6Hz,2H),7.13(d,J＝8.0Hz,1H),7.07(d,J＝9.2Hz,1H),5.14-5.29(m,2H),2.46-2.53(m,2H),1.30(d,J＝7.2Hz,3H),1.23(d,J＝1.6Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.39 (d, J = 7.6 Hz, 1H), 8.26 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 7.83-7.86 (m) , 3H), 7.79 (d, J = 8.0 Hz, 1H), 7.48 (brs, 1H), 7.43 (dd, J 1 = 2.0 Hz, J 2 = 7.6 Hz, 2H), 7.13 (d, J = 8.0 Hz) , 1H), 7.07 (d, J = 9.2 Hz, 1H), 5.14 - 5.29 (m, 2H), 2.46 - 2.53 (m, 2H), 1.30 (d, J = 7.2 Hz, 3H), 1.23 (d, J=1.6Hz, 3H).

实施例(化合物)160Example (compound) 160

2-苯乙氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺2-Phenylethoxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

Figure PCTCN2018088561-appb-000220
Figure PCTCN2018088561-appb-000220

a)2-苯乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 2-Phenylethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-苯乙氧基-5-硝基苯甲酸(205mg，0.71mmol)溶于DCM(20mL)，加入HATU(407mg，1.07mmol)，DIEA(275mg，2.13mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(220mg，1.07mmol)，室温反应过夜。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝3:2)，得类白色固体387mg，收率85％。2-Phenylethoxy-5-nitrobenzoic acid (205 mg, 0.71 mmol) was dissolved in DCM (20 mL), EtOAc (EtOAc, EtOAc, EtOAc. -(3-thiazol-2-yl)phenyl)ethyl-1-amine (220 mg, 1.07 mmol). Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 3: 2) gave 387 mg of white solid.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.30(dd,J 1＝3.2Hz,J 2＝9.2Hz,1H),8.01(s,1H),7.92(d,J＝7.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.41(t,J＝7.6Hz,1H),7.36(s,1H),7.34(d,J＝1.2Hz,1H),7.25(d,J＝1.6Hz,1H),7.24-7.25(m,1H),7.16(d,J＝1.6Hz,1H),7.14(s,1H),7.08(d,J＝9.2Hz,1H),5.32-5.36(m,1H),4.47-4.53(m,2H),3.19(q,J＝2.8Hz,2H),1.48(d,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.30 (dd, J 1 = 3.2 Hz, J 2 = 9.2 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H) ), 7.84 (d, J = 3.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.34 (d, J = 1.2 Hz, 1H), 7.25 (d, J) =1.6 Hz, 1H), 7.24-7.25 (m, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.14 (s, 1H), 7.08 (d, J = 9.2 Hz, 1H), 5.32-5.36 (m, 1H), 4.47-4.53 (m, 2H), 3.19 (q, J = 2.8 Hz, 2H), 1.48 (d, J = 6.8 Hz, 3H).

b)2-苯乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Phenylethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-苯乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(200mg，0.42mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(142mg，2.53mmol)，NH 4Cl(23mg，0.42mmol)，70℃回流反应3h。原料消失。过滤，浓缩，加入EA(20mL)稀释，水洗(15mL×2),无水硫酸镁干燥，浓缩，加入石油醚，得微黄色固体162mg，收率87％。 2-Phenylethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (200 mg, 0.42 mmol) dissolved in DCM (2 mL) / EtOH (8 mL) / H 2 O (1 mL), Fe powder (142 mg, 2.53 mmol), NH 4 Cl (23 mg, 0.42 mmol), and refluxed at 70 ° C for 3 h. The raw materials disappeared. Filtration, concentration, EA (20 mL), EtOAc (EtOAc)EtOAc.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.43(d,J＝7.6Hz,1H),7.95(s,1H),7.92(d,J＝3.2Hz,1H),7.81(d,J＝3.6Hz,1H),7.78(d,J＝3.2Hz,1H),7.40-7.47(m,2H),7.15-7.26(m,5H),7.03(d,J＝2.8Hz,1H),6.66(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),5.11-5.18(m,1H),4.85(s,2H),4.23(dt,J 1＝2.8Hz,J＝7.6Hz,2H),3.10-3.04(dt,J 1＝3.2Hz,J 2＝7.6Hz,2H),1.37(d,J＝7.6Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.43 (d, J = 7.6 Hz, 1H), 7.95 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.81 (d) , J = 3.6 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.40-7.47 (m, 2H), 7.15-7.26 (m, 5H), 7.03 (d, J = 2.8 Hz, 1H) , 6.66 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 5.11-5.18 (m, 1H), 4.85 (s, 2H), 4.23 (dt, J 1 = 2.8 Hz, J = 7.6 Hz , 2H), 3.10-3.04 (dt, J 1 = 3.2 Hz, J 2 = 7.6 Hz, 2H), 1.37 (d, J = 7.6 Hz, 3H).

c)2-苯乙氧基-5-异丁酰胺基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺c) 2-Phenylethoxy-5-isobutyramido-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide

2-苯乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(60mg，0.14mmol)溶于THF(5mL)，冰浴下加入TEA(41mg，0.41mmol)，搅拌下逐滴加入异丁酰氯(17mg，0.16mmol)，室温下搅拌反应10min。浓缩，加入EA(15mL)稀 释，蒸馏水(15mL×2)洗，无水硫酸镁干燥，浓缩，加入石油醚，得到白色固体44mg，收率64％。熔点：102-105℃.2-Phenylethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (60 mg, 0.14 mmol) dissolved in THF (5 mL) After adding TEA (41 mg, 0.41 mmol), isobutyryl chloride (17 mg, 0.16 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. The mixture was concentrated, diluted with EtOAc EtOAc EtOAc (EtOAc) Melting point: 102-105 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.26(d,J＝7.2Hz,1H),8.22(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),7.98(s,1H),7.81-7.84(m,3H),7.41(brs,1H),7.37(d,J＝7.6Hz,1H),7.34(brs,1H),7.31(d,J＝7.2Hz,1H),7.25(brs,1H),7.20(d,J＝7.2Hz,1H),7.15(d,J＝6.8Hz,1H),6.96(d,J＝9.2Hz,1H),5.28-5.35(m,1H),4.35-4.41(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),5.11-5.18(m,1H),4.85(s,2H),4.23(dt,J 1＝2.8Hz,J 2＝7.6Hz,2H),3.10-3.04(dt,J 1＝3.2Hz,J 2＝7.6Hz,2H),1.37(d,J＝7.6Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.26 (d, J = 7.2 Hz, 1H), 8.22 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 7.98 (s) , 1H), 7.81-7.84 (m, 3H), 7.41 (brs, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.34 (brs, 1H), 7.31 (d, J = 7.2 Hz, 1H) , 7.25 (brs, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 5.28-5.35 (m, 1H), 4.35-4.41 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 5.11-5.18 (m, 1H), 4.85 (s, 2H), 4.23 (dt, J 1 = 2.8 Hz, J 2 = 7.6 Hz, 2H), 3.10-3.04 (dt, J 1 = 3.2 Hz, J 2 = 7.6 Hz, 2H), 1.37 (d, J = 7.6 Hz, 3H).

实施例(化合物)161Example (compound) 161

2-环丙胺基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺2-cyclopropylamino-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000221
Figure PCTCN2018088561-appb-000221

a)2-环丙胺基-5-硝基-苯甲酸的制备a) Preparation of 2-cyclopropylamino-5-nitro-benzoic acid

2-氯-5-硝基水杨酸(500mg，2.48mmol)，加入环丙胺(1.416mg，24.8mmol)，加热至70℃反应12h。两次合并处理，冷却，加入EA(20mL)稀释，水洗(20mL×2)，无水硫酸镁干燥，柱层析(D:M＝30:1)，得黄色固体590mg，收率88％。2-Chloro-5-nitrosalicylic acid (500 mg, 2.48 mmol) was added to cyclopropylamine (1.416 mg, 24.8 mmol) and heated to 70 ° C for 12 h. The mixture was combined twice, cooled, diluted with EA (20 mL), washed with water (20mL×2), dried over anhydrous magnesium sulfate, and then purified by column chromatography (D:M=30:1) to give y.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):7.57(s,1H),7.42(t,J＝1.6Hz,1H),7.03(dd,J 1＝2.0Hz,J 2＝7.6Hz,1H),6.02(dd,J 1＝1.2Hz,J 2＝7.6Hz,1H),3.07(t,J＝4.8Hz,2H),1.37-1.45(m,1H),0.92-0.94(m,2H),0.73-0.75(m,2H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 7.57 (s, 1H), 7.42 (t, J = 1.6 Hz, 1H), 7.03 (dd, J 1 = 2.0 Hz, J 2 = 7.6 Hz , 1H), 6.02 (dd, J 1 = 1.2 Hz, J 2 = 7.6 Hz, 1H), 3.07 (t, J = 4.8 Hz, 2H), 1.37-1.45 (m, 1H), 0.92-0.94 (m, 2H), 0.73-0.75 (m, 2H).

b)2-环丙胺基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 2-Cyclopropylamino-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将2-环丙胺基-5-硝基-苯甲酸(282mg，1.27mmol)溶于DCM(15mL)，加入HATU(726mg，1.91mmol)，DIEA(492mg，3.81mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(340mg，1.66mmol)，室温反应过夜。水(20mL)洗，无水硫酸镁干燥。柱层析(P:E＝1:1)，得浅黄色固体206mg，收率40％。熔点：145-147℃.2-Cyclopropylamino-5-nitro-benzoic acid (282 mg, 1.27 mmol) was dissolved in DCM (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) -(3-thiazol-2-yl)phenyl)ethyl-1-amine (340 mg, 1.66 mmol). Wash with water (20 mL) and dry over anhydrous magnesium sulfate. Column chromatography (P: E = 1:1) gave a pale yellow solid (m. Melting point: 145-147 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.75(s,1H),8.36(d,J＝2.4Hz,1H),8.19(dd,J1＝2.4Hz,J2＝9.6Hz,1H),8.01(s,1H),7.87(d,J＝3.2Hz,1H),7.44-7.46(m,2H),7.34(d,J＝3.2Hz,1H),7.11(d,J＝9.6Hz,1H),6.55(d,J＝7.2Hz,3H),5.24-5.31(m,1H),2.48-2.54(m,1H),0.84-0.90(m,2H),5.58-5.82(m,2H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.75 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.19 (dd, J1 = 2.4 Hz, J2 = 9.6 Hz, 1H), 8.01(s,1H), 7.87(d,J=3.2Hz,1H),7.44-7.46(m,2H),7.34(d,J=3.2Hz,1H),7.11(d,J=9.6Hz,1H ), 6.55 (d, J = 7.2 Hz, 3H), 5.24-5.31 (m, 1H), 2.48-2.54 (m, 1H), 0.84-0.90 (m, 2H), 5.58-5.82 (m, 2H).

c)2-环丙胺基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 2-cyclopropylamino-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-环丙胺基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺(200mg，0.47mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(139mg，2.50mmol)，NH 4Cl(22mg，0.41mmol)，70℃回流反应6h。原料消失。过滤，浓缩，加入EA(15mL)，水洗(15mL×2),得褐色油状物120mg，直接投入下一步。 2-Cyclopropylamino-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (200 mg, 0.47 mmol) was dissolved in DCM (2mL) /EtOAc. 8 mL) / H 2 O (1 mL), Fe powder (139 mg, 2.50 mmol), NH 4 Cl (22 mg, 0.41 mmol), and refluxed at 70 ° C for 6 h. The raw materials disappeared. Filtration, concentration, EA (15 mL), EtOAc (EtOAc)

d)2-环丙胺基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺d) 2-Cyclopropylamino-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

2-环丙胺基-5-氨基-N-(1-(3-(2-噻唑基)苯基)乙胺)苯甲酰胺溶于THF(5mL)，冰浴下加入TEA(79mg，0.78mmol)，搅拌下逐滴加入异丁酰氯(42mg，0.39mmol)，室温下搅拌反应30min。浓缩，加入EA(20mL)稀释，蒸馏水(15mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝5:1)，得白色固体75mg，收率65％。熔点：205-207℃.2-Cyclopropylamino-5-amino-N-(1-(3-(2-thiazolyl)phenyl)ethylamine)benzamide was dissolved in THF (5 mL). EtOAc (EtOAc) Isobutyryl chloride (42 mg, 0.39 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Concentrated, diluted with EA (20 mL), washed with distilled water (15 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 5: 1) gave a white solid, 75 mg, yield 65%. Melting point: 205-207 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.08(s,1H),7.87(d,J＝3.2Hz,1H),7.80-7.83(m,2H),7.43(t,J＝1.6Hz,1H),7.28(dd,J 1＝2.0Hz,J 2＝8.8Hz 1H),7.07(d,J＝8.8Hz,1H),6.47(d,J＝7.2Hz,1H),5.23-5.30(m,1H),2.45-2.52(m,1H),2.34-2.39(m,1H),1.58(d,J＝7.2Hz,3H),1.24(d,J＝6.8Hz,6H),0.69-0.73(m,1H),0.47-0.49(m,1H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.08 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.80-7.83 (m, 2H), 7.43 (t, J = 1.6 Hz) , 1H), 7.28 (dd, J 1 = 2.0 Hz, J 2 = 8.8 Hz 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 7.2 Hz, 1H), 5.23-5.30 ( m,1H), 2.45-2.52 (m, 1H), 2.34-2.39 (m, 1H), 1.58 (d, J = 7.2 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H), 0.69-0.73 (m, 1H), 0.47-0.49 (m, 1H).

实施例(化合物)162Example (compound) 162

2-乙氧基-5-异丁酰氨基-N-甲基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-methyl-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000222
Figure PCTCN2018088561-appb-000222

a)2-乙氧基-N-甲基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺a) 2-Ethoxy-N-methyl-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(300mg,0.78mmol)溶于无水DMF(5mL)中，加入NaH(37mg,1.56mmol)，室温搅拌反应20min，加入CH 3I(111mg,0.78mmol)，继续反应4h，原料反应完毕。加入EA(25mL)稀释，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比2:3)纯化得白色固体201mg，收率为64.6％，熔点：133-135℃。 2-Ethoxy-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide (300 mg, 0.78 mmol) was dissolved in anhydrous DMF (5 mL). 37 mg, 1.56 mmol), the reaction was stirred at room temperature for 20 min, CH 3 I (111 mg, 0.78 mmol) was added and the reaction was continued for 4 h. Add EA (25mL) diluted with saturated brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 2: 3) to give a white solid 201 mg, 64.6% yield, Melting point: 133-135 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.28-8.24(m,2H),7.99(s,1H),7.91-7.84(m,2H),7.52(d,J＝7.2Hz,1H),7.48-7.43(m,1H),7.37(d,J＝3.2Hz,1H),6.98(d,J＝9.8Hz,1H),5.29(brs,1H),4.42(brs,1H),4.18(q,J＝6.8Hz,2H),3.09(s,1H),2.80 (s,2H),1.43(t,J＝7.2Hz,1H),1.37(t,J＝7.2Hz,2H)；ESI-MS m/z:398.12[M+H] +。b)2-乙氧基-5-异丁酰氨基-N-甲基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.28-8.24 (m, 2H), 7.99 (s, 1H), 7.91-7.84 (m, 2H), 7.52 (d, J = 7.2 Hz, 1H) ), 7.48-7.43 (m, 1H), 7.37 (d, J = 3.2 Hz, 1H), 6.98 (d, J = 9.8 Hz, 1H), 5.29 (brs, 1H), 4.42 (brs, 1H), 4.18 (q, J = 6.8 Hz, 2H), 3.09 (s, 1H), 2.80 (s, 2H), 1.43 (t, J = 7.2 Hz, 1H), 1.37 (t, J = 7.2 Hz, 2H); ESI - MS m/z: 398.12 [M+H] + . b) 2-ethoxy-5-isobutyrylamino-N-methyl-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-N-甲基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(140mg,0.35mmol)溶于THF(15mL)中，加入Pd/C 70mg，在室温下通入氢气，反应过夜，过滤，滤液浓缩，得无色油状物110mg，将上述无色油状物(100mg,0.27mmol)溶于无水THF(15mL)中，冰浴下依次加入TEA(136mg,1.35mmol)，异丁酰氯(57mg,0.54mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，HCl(0.5N)水溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:2)纯化得白色固体69mg，收率为58.0％，熔点：168-169℃。 2-Ethoxy-N-methyl-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide (140 mg, 0.35 mmol) was dissolved in THF (15 mL) After adding 70 mg of Pd/C, a hydrogen atmosphere was added at room temperature, and the reaction mixture was filtered, and the filtrate was concentrated to give a white oil (yield: 110 mg). TEA (136 mg, 1.35 mmol), isobutyryl chloride (57 mg, 0.54 mmol) was added to the mixture, and the mixture was stirred for 1 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (20 mL), HCl (0.5N) wash with saturated NaHCO 3 (10mL) wash, water (10mL) wash, brine water (10mL) wash, dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate - petroleum ether, the volume ratio of 1: 2) to give White solid 69 mg, yield 58.0%, m.p.: 168-169.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.00(s,1H),7.95(s,1H),7.87(d,J＝3.6Hz,2H),7.76-7.68(m,1H),7.52(d,J＝7.2Hz,1H),7.45-7.38(m,2H),7.35-7.33(m,1H),7.23(s,1H),6.80(d,J＝8.8Hz,1H),5.35(brs,1H),4.44(s,1H),4.33(brs,1H),4.05-4.01(m,2H),3.03(s,1H),2.82(s,2H),2.53-2.45(m,1H),1.35(t,J＝6.8Hz,1H),1.30(t,J＝6.8Hz,2H),1.19(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 3N 3S 438.1846[M+H] +,Found:438.1826。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.00 (s, 1H), 7.95 (s, 1H), 7.87 (d, J = 3.6Hz, 2H), 7.76-7.68 (m, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.45-7.38 (m, 2H), 7.35-7.33 (m, 1H), 7.23 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.35 (brs, 1H), 4.44 (s, 1H), 4.33 (brs, 1H), 4.05-4.01 (m, 2H), 3.03 (s, 1H), 2.82 (s, 2H), 2.53-2.45 (m, 1H) ), 1.35 (t, J = 6.8 Hz, 1H), 1.30 (t, J = 6.8 Hz, 2H), 1.19 (d, J = 6.8 Hz, 6H); HR-MS (ESI): m/z, calcd .For C 24 H 27 O 3 N 3 S 438.1846 [M+H] + , Found: 438.1826.

实施例(化合物)163Example (compound) 163

2-乙氧基-5-异丁酰胺基-N-(1-(3-甲氧苯基)丙基-2-基)苯甲酰胺2-ethoxy-5-isobutyramido-N-(1-(3-methoxyphenyl)propyl-2-yl)benzamide

Figure PCTCN2018088561-appb-000223
Figure PCTCN2018088561-appb-000223

a)1-(3-甲氧基苯基)丙基-2-胺a) 1-(3-methoxyphenyl)propyl-2-amine

将间甲基苯丙酮(200mg，1.22mmol)溶于乙醇(10mL)/水(5mL)，加入甲酸铵(845mg，13.40mmol)，全部溶解后，加入Pd/C(130mg，0.12mmol)40℃反应10h。停止反应，浓缩，乙醚(10mL×2)洗，水层加入饱和NaHCO 3调至碱性，加二氯甲烷(10mL)搅拌，过滤，D:M＝10:1萃取，合并有机层，无水硫酸镁干燥。得黄色油状物148mg，收率74％。直接投入下一步。 m-Methylpropiophenone (200 mg, 1.22 mmol) was dissolved in ethanol (10 mL) / water (5 mL), and ammonium formate (845 mg, 13.40 mmol) was added. After all dissolved, Pd/C (130 mg, 0.12 mmol) was added at 40 ° C. Reaction for 10 h. The reaction was stopped, concentrated, and diethyl ether (10mL × 2) wash added to the aqueous layer made basic with saturated NaHCO 3, was added dichloromethane (10 mL) was stirred, filtered, D: M = 10: 1, the organic layers were combined, dried over anhydrous Dry over magnesium sulfate. A yellow oil 148 mg was obtained in a yield of 74%. Go directly to the next step.

b)2-乙氧基-5-硝基-N-(1-(3-甲氧苯基)丙基-2-基)苯甲酰胺b) 2-ethoxy-5-nitro-N-(1-(3-methoxyphenyl)propyl-2-yl)benzamide

2-乙氧基-5-硝基苯甲酸(122mg，0.58mmol)溶于DCM(10mL)，加入HATU (331mg，0.87mmol)，DIEA(224mg，1.74mmol)，室温反应10min，加入1-(3-甲氧基苯基)丙基-2-胺(145mg，0.87mmol)的DCM溶液(2mL)，室温反应过夜。浓缩，加入EA(15mL)稀释，水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体170mg，收率84％。熔点：91-93℃.2-Ethoxy-5-nitrobenzoic acid (122 mg, 0.58 mmol) was dissolved in DCM (10 mL), EtOAc (EtOAc, EtOAc, EtOAc, A solution of 3-methoxyphenyl)propyl-2-amine (145 mg, 0.87 mmol) in DCM (2 mL) Concentrated, diluted with EA (15 mL), water (20 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid, 170 mg, yield 84%. Melting point: 91-93 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):9.10(d,J＝2.8Hz,1H),8.29(dd,J 1＝2.8Hz,J 2＝9.2Hz,1H),7.72(d,J＝7.6Hz,1H),8.21(dt,J 1＝0.8Hz,J 2＝7.6Hz,1H),7.02(d,J＝9.2Hz,1H),6.82-6.76(m,3H),4.54-4.47(m,1H),4.25(q,J＝6.8Hz,2H),3.77(s,3H),2.96(dd,J 1＝5.2Hz,J 2＝13.6Hz,1H),2.79(dd,J 1＝7.2Hz,J 2＝13.6Hz,1H),1.43(d,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 9.10 (d, J = 2.8 Hz, 1H), 8.29 (dd, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), 7.72 (d, J) = 7.6 Hz, 1H), 8.21 (dt, J 1 = 0.8 Hz, J 2 = 7.6 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.82 - 6.76 (m, 3H), 4.54-4.47 (m, 1H), 4.25 (q, J = 6.8 Hz, 2H), 3.77 (s, 3H), 2.96 (dd, J 1 = 5.2 Hz, J 2 = 13.6 Hz, 1H), 2.79 (dd, J 1 = 7.2 Hz, J 2 = 13.6 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H).

c)2-乙氧基-5-氨基-N-(1-(3-甲氧苯基)丙基-2-基)苯甲酰胺c) 2-ethoxy-5-amino-N-(1-(3-methoxyphenyl)propyl-2-yl)benzamide

2-乙氧基-5-硝基-N-(1-(3-甲氧苯基)丙基-2-基)苯甲酰胺(160mg，0.45mmol)溶于DCM(2mL)/EtOH(6mL)/H 2O(1mL)，加入Fe粉(150mg，2.68mmol)，NH 4Cl(24mg，0.45mmol)，50℃回流反应2h。原料消失。过滤，浓缩，加入EA(15mL)稀释，水洗(10mL×2),无水硫酸镁干燥，浓缩，收率69％。熔点：98-100℃. 2-Ethoxy-5-nitro-N-(1-(3-methoxyphenyl)propyl-2-yl)benzamide (160 mg, 0.45 mmol) dissolved in DCM (2 mL) /EtOAc /H 2 O (1 mL), Fe powder (150 mg, 2.68 mmol), NH 4 Cl (24 mg, 0.45 mmol), and refluxed at 50 ° C for 2 h. The raw materials disappeared. Filtration, concentration, EA (15 mL), EtOAc (EtOAc) Melting point: 98-100 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.10(d,J＝7.6Hz,1H),7.20(t,J＝8.8Hz,1H),7.09(d,J＝2.8Hz,1H),6.83-6.76(m,4H),6.64(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),4.83(s,2H),4.26-4.19(m,1H),3.96(d,J＝7.2Hz,2H),3.70(s,3H),2.81(q,J＝6.8Hz,1H),2.72(q,J＝6.8Hz,1H),1.22(t,J＝7.2Hz,3H),1.11(d,J＝6.4Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.10 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 8.8 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H) ), 6.83-6.76 (m, 4H), 6.64 (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 4.83 (s, 2H), 4.26-4.19 (m, 1H), 3.96 (d, J = 7.2 Hz, 2H), 3.70 (s, 3H), 2.81 (q, J = 6.8 Hz, 1H), 2.72 (q, J = 6.8 Hz, 1H), 1.22 (t, J = 7.2 Hz, 3H) , 1.11 (d, J = 6.4 Hz, 3H).

d)2-乙氧基-5-异丁酰胺基-N-(1-(3-甲氧苯基)丙基-2-基)苯甲酰胺d) 2-ethoxy-5-isobutyramido-N-(1-(3-methoxyphenyl)propyl-2-yl)benzamide

2-乙氧基-5-氨基-N-(1-(3-甲氧苯基)丙基-2-基)苯甲酰胺(60mg，0.18mmol)溶于THF(3mL)，冰浴下加入TEA(55mg，0.54mmol)，搅拌下逐滴加入异丁酰氯(23mg，0.22mmol)，室温下搅拌反应10min。浓缩，加入EA(10mL)稀释，蒸馏水(10mL×2)洗，无水硫酸镁干燥，得白色固体60mg，收率85％。熔点：111-113℃.2-Ethoxy-5-amino-N-(1-(3-methoxyphenyl)propyl-2-yl)benzamide (60 mg, 0.18 mmol) was dissolved in THF (3 mL) TEA (55 mg, 0.54 mmol), isobutyryl chloride (23 mg, 0.22 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 10 min. After concentration, it was diluted with EA (10 mL), washed with distilled water (10 mL×2) and dried over anhydrous magnesium sulfate. Melting point: 111-113 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.21(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),8.10(d,J＝7.6Hz,1H),7.85(d,J＝2.8Hz,1H),7.50(brs,1H),7.19(dt,J 1＝0.8Hz,J 2＝7.6Hz,1H),6.91(d,J＝9.2Hz,1H),6.80(d,J＝7.6Hz,1H),6.75-6.78(m,2H),4.94-4.50(m,1H),4.11(d,J＝7.2Hz,2H),3.75(s,3H),2.95(dd,J 1＝5.2Hz,J 2＝13.2Hz,1H),2.77(dd,J 1＝7.2Hz,J 2＝13.6Hz,1H),2.48-2.57(m,1H),1.34(t,J＝7.2Hz,3H),1.24(d,J＝7.2Hz,6H),1.19(d,J＝6.8Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.21. (dd, J 1 = 2.8 Hz, J 2 = 8.8 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.85 (d) , J = 2.8 Hz, 1H), 7.50 (brs, 1H), 7.19 (dt, J 1 = 0.8 Hz, J 2 = 7.6 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.80 (d , J = 7.6 Hz, 1H), 6.75-6.78 (m, 2H), 4.94 - 4.50 (m, 1H), 4.11 (d, J = 7.2 Hz, 2H), 3.75 (s, 3H), 2.95 (dd, J 1 = 5.2 Hz, J 2 = 13.2 Hz, 1H), 2.77 (dd, J 1 = 7.2 Hz, J 2 = 13.6 Hz, 1H), 2.48-2.57 (m, 1H), 1.34 (t, J = 7.2) Hz, 3H), 1.24 (d, J = 7.2 Hz, 6H), 1.19 (d, J = 6.8 Hz, 3H).

实施例(化合物)164Example (compound) 164

2-乙氧基-5-异丁酰氨基-N-(2-(m-苯甲基)丙烷-2-基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(2-(m-benzyl)propan-2-yl)benzamide

Figure PCTCN2018088561-appb-000224
Figure PCTCN2018088561-appb-000224

a)2-(m-苯甲基)丙烷-2-胺a) 2-(m-benzyl)propan-2-amine

将三氯化铈(1.47g,6mmol)加入干燥THF(25mL)，在-66℃下氩气保护下将1.6M甲基锂溶液(3.75mL,6mmol)滴加入反应瓶中，滴毕继续在-66℃下反应1.5h，后将间甲基苯腈(0.23mL,2mmol)的THF(5mL)溶液滴加入反应瓶中，滴毕在-66℃下反应0.5h后逐渐升至室温反应，1h后加入氨水，过滤。滤液浓缩，加入乙酸和水，用乙醚萃取，水层用氨水调PH值至9左右，用DCM:MeOH＝10:1的混合液萃取，合并有机层，用无水硫酸镁干燥，浓缩，得到淡黄色油状物150mg，产率50.3％。Add ruthenium trichloride (1.47 g, 6 mmol) to dry THF (25 mL), and add 1.6 M methyllithium solution (3.75 mL, 6 mmol) to the reaction flask under argon atmosphere at -66 ° C. After reacting at -66 ° C for 1.5 h, a solution of m-methylbenzonitrile (0.23 mL, 2 mmol) in THF (5 mL) was added dropwise to the reaction flask, and the reaction was carried out at -66 ° C for 0.5 h, then gradually increased to room temperature. After 1 h, ammonia water was added and filtered. The filtrate was concentrated, and the mixture was combined with EtOAc EtOAc (EtOAc m. Light yellow oil 150 mg, yield 50.3%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.33(s,1H),7.29(d,J＝8.0Hz,1H),7.22(t,J＝7.6Hz,1H),7.04(d,J＝7.6Hz,1H),2.36(s,3H),1.49(s,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.33 (s, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.22 (t, J = 7.6Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 2.36 (s, 3H), 1.49 (s, 6H).

b)2-乙氧基-5-异丁酰氨基-N-(2-(m-苯甲基)丙烷-2-基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(2-(m-benzyl)propan-2-yl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(10mL)，加入EDC(153mg,0.796mmol)，加入HOBt(107mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入2-(m-苯甲基)丙烷-2-胺(118mg,0.79mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5)，得到白色固体90mg，产率59.2％。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (10 mL), EDC (153 mg, 0.796 mmol) was added, HOBt (107 mg, 0.796 mmol) and DIEA (0.21) mL, 1.19 mmol), 2-(m-benzyl)propan-2-amine (118 mg, 0.79 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted with EtOAc (3 mL, EtOAc). The rate is 59.2%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.58(s,1H),8.17(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.73(d,J＝2.8Hz,1H),7.33(s,1H),7.18-7.26(m,3H),7.02-7.04(m,1H),6.93(d,J＝9.2Hz,1H),4.18(q,J＝6.8Hz,2H),2.40-2.48(m,1H),2.34(s,3H),1.78(s,6H),1.44(t,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.58 (s, 1H), 8.17 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.73 (d, J = 2.8Hz, 1H), 7.33 (s, 1H), 7.18-7.26 (m, 3H), 7.02-7.04 (m, 1H), 6.93 (d, J = 9.2 Hz, 1H), 4.18 (q, J = 6.8 Hz, 2H) ), 2.40-2.48 (m, 1H), 2.34 (s, 3H), 1.78 (s, 6H), 1.44 (t, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 6H).

实施例(化合物)165Example (compound) 165

2-乙氧基-5-异丁酰氨基-N-(1-(m-苯甲基)丙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(m-benzyl)propyl)benzamide

Figure PCTCN2018088561-appb-000225
Figure PCTCN2018088561-appb-000225

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(10mL)，加入EDC(153mg,0.796mmol)，加入HOBt(107mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入1-(m-苯甲基)丙胺(118mg,0.79mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2.5)，得到白色固体100mg，产率65.7％。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (10 mL), EDC (153 mg, 0.796 mmol) was added, HOBt (107 mg, 0.796 mmol) and DIEA (0.21) mL, 1.19 mmol), 1-(m-phenylmethyl)propylamine (118 mg, 0.79 mmol) was added, and stirred at room temperature overnight, and the mixture was poured into water, with a mixture of ethyl acetate:methanol = 10:1 (30 mL) The mixture was combined and washed with aq. EtOAc (EtOAc) (EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):8.46(d,J＝8.0Hz,1H),8.23(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.73(s,1H),7.22(t,J＝7.6Hz,1H),7.11-7.13(m,2H),7.06(d,J＝7.6Hz,1H),6.93(d,J＝8.8Hz,1H),5.07(q,J＝7.6Hz,1H),4.12-4.22(m,2H),2.46-2.49(m,1H),2.34(s,3H),1.87-1.93(m,2H),1.47(t,J＝7.2Hz,3H),1.18(dd,J 1＝6.8Hz,J 2＝4.0Hz,6H),0.93(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.46 (d, J = 8.0Hz, 1H), 8.23 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.11 - 7.13 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.93 ( d, J = 8.8 Hz, 1H), 5.07 (q, J = 7.6 Hz, 1H), 4.12-4.22 (m, 2H), 2.46-2.49 (m, 1H), 2.34 (s, 3H), 1.87-1.93 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.18 (dd, J 1 = 6.8 Hz, J 2 = 4.0 Hz, 6H), 0.93 (t, J = 7.2 Hz, 3H).

实施例(化合物)166Example (compound) 166

2-乙氧基-5-异丁酰氨基-N-(2-(6-甲氧基吡啶-2-基)丙烷-2-基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(2-(6-methoxypyridin-2-yl)propan-2-yl)benzamide

Figure PCTCN2018088561-appb-000226
Figure PCTCN2018088561-appb-000226

a)2-(6-甲氧基吡啶-2-基)丙烷-2-胺a) 2-(6-Methoxypyridin-2-yl)propan-2-amine

将三氯化铈(1.86g,7.5mmol)加入干燥THF(25mL)，在-66℃下氩气保护下将1.6M甲基锂溶液(4.7mL,7.5mmol)滴加入反应瓶中，滴毕继续在-66℃下反应1.5h，后将间甲基苯腈(335mg,2.5mmol)的THF(5mL)溶液滴加入反应瓶中，滴毕在-66℃下反应0.5h后逐渐升至室温反应，1h后加入氨水，过滤。滤液浓缩，加入乙酸和水，用乙醚萃取，水层用氨水调PH值至9左右，用DCM:MeOH＝10:1的混合液萃取，合并有机层，用无水硫酸镁干燥，浓缩，得到棕色油状物153mg，产率36.8％。Add ruthenium trichloride (1.86 g, 7.5 mmol) to dry THF (25 mL), and add 1.6 M methyllithium solution (4.7 mL, 7.5 mmol) to the reaction flask under argon at -66 ° C. After continuing to react at -66 ° C for 1.5 h, a solution of m-methylbenzonitrile (335 mg, 2.5 mmol) in THF (5 mL) was added dropwise to the reaction flask, and the reaction was allowed to react at -66 ° C for 0.5 h and then gradually warmed to room temperature. After the reaction, 1 hour later, aqueous ammonia was added and filtered. The filtrate was concentrated, and the mixture was combined with EtOAc EtOAc (EtOAc m. Brown oil 153 mg, yield 36.8%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.52(t,J＝7.6Hz,1H),6.95(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),6.58(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),3.94(s,3H),2.20(brs,2H),1.49(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.52 (t, J = 7.6 Hz, 1H), 6.95 (dd, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H), 6.58 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 3.94 (s, 3H), 2.20 (brs, 2H), 1.49 (s, 6H).

b)2-乙氧基-5-异丁酰氨基-N-(2-(6-甲氧基吡啶-2-基)丙烷-2-基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(2-(6-methoxypyridin-2-yl)propan-2-yl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(15mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入2-(6-甲氧基吡啶-2-基)丙烷-2-胺(110mg,0.66mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体130mg，产率74.7％。2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (15 mL). E.sub.2 (168 mg, &lt;RTI ID=0.0&gt; mL, 1.314 mmol), 2-(6-methoxypyridin-2-yl)propan-2-amine (110 mg, 0.66 mmol) was added and stirred at room temperature overnight. The mixture was extracted with a mixture of 10:1 (30 mL×2), and the combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=90:1) The white solid was 130 mg, and the yield was 74.7%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.82(s,1H),8.16(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.72(d,J＝2.8Hz,1H),7.54(t,J＝7.6Hz,1H),7.31(brs,1H),7.00(d,J＝7.6Hz,1H),6.94(d,J＝9.2Hz,1H),6.59(d,J＝8.4Hz,1H),4.19(q,J＝7.2Hz,2H),3.90(s,3H),2.43-2.50(m,1H),1.86(s,6H),1.46(t,J＝7.2Hz,3H),1.19-1.22(m,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.82 (s, 1H), 8.16 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.31 (brs, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.90 (s, 3H), 2.43-2.50 (m, 1H), 1.86 (s, 6H), 1.46 (t, J = 7.2) Hz, 3H), 1.19-1.22 (m, 6H).

实施例(化合物)167Example (compound) 167

2-乙氧基-5-异丁酰氨基-4-甲基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺2-ethoxy-5-isobutyrylamino-4-methyl-N-(3-(thiazol-2-yl)benzyl)benzamide

Figure PCTCN2018088561-appb-000227
Figure PCTCN2018088561-appb-000227

a)2-乙氧基-4-甲基-5-硝基苯甲酸甲酯a) Methyl 2-ethoxy-4-methyl-5-nitrobenzoate

将2-羟基-4-甲基-5-硝基苯甲酸甲酯(200mg,0.95mmol)溶于无水DMF(10mL)中，依次加入K 2CO 3(262mg,1.90mmol)、C 2H 5I(445mg，2.85mmol)加热至60℃反应10h，冷却，加水析出白色固体，过滤，水(20mL)洗涤滤饼，得白色固体210mg，收率为92.9％，熔点：103-104℃。 2-hydroxy-4-methyl-5-nitrobenzoate (200mg, 0.95mmol) was dissolved in anhydrous DMF (10mL) added sequentially K 2 CO 3 (262mg, 1.90mmol ), C 2 H 5 I (445 mg, 2.85 mmol) was heated to 60 ° C for 10 h, cooled, water was added to precipitate a white solid, filtered, water (20mL) washed filter cake to give a white solid 210mg, yield: 92.9%, melting point: 103-104 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.62(s,1H),6.83(s,1H),4.21(q,J＝7.2Hz,2H),3.91(s,3H),2.69(s,3H),1.51(t,J＝7.2Hz,3H)；ESI-MS m/z:240.09[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.62 (s, 1H), 6.83 (s, 1H), 4.21 (q, J = 7.2Hz, 2H), 3.91 (s, 3H), 2.69 ( s, 3H), 1.51 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 240.09 [M+H] + .

b)2-乙氧基-4-甲基-5-硝基苯甲酸b) 2-ethoxy-4-methyl-5-nitrobenzoic acid

将2-乙氧基-4-甲基-5-硝基苯甲酸甲酯(200mg,0.84mmol)溶于THF(20mL)/水(10mL)中，搅拌下加入NaOH(168mg,4.20mmol)室温反应6h，浓缩，加入乙醚(20mL)洗涤水层，水层用盐酸调pH＝3，析出固体174mg，收率为92.6％，熔点：163-164℃。 1H-NMR(400MHz,DMSO)δ(ppm):13.03(s,1H),8.34(s,1H), 7.21(s,1H),4.22(q,J＝6.8Hz,2H),2.60(s,3H),1.34(t,J＝6.8Hz,3H)；ESI-MS m/z:224.06[M-H] -。 Methyl 2-ethoxy-4-methyl-5-nitrobenzoate (200 mg, 0.84 mmol) was dissolved in THF (20 mL) / water (10 mL). After reacting for 6 hours, the mixture was concentrated. EtOAc (EtOAc) (EtOAc)EtOAc. 1 H-NMR (400MHz, DMSO ) δ (ppm): 13.03 (s, 1H), 8.34 (s, 1H), 7.21 (s, 1H), 4.22 (q, J = 6.8Hz, 2H), 2.60 (s , 3H), 1.34 (t, J = 6.8 Hz, 3H); ESI-MS m/z: 224.06 [MH] - .

c)2-乙氧基-4-甲基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺c) 2-ethoxy-4-methyl-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-4-甲基-5-硝基苯甲酸(150mg,0.67mmol)溶于DCM(15mL)中，依次加入DIEA(173mg,1.34mmol)、HATU(357mg,0.94mmol)，室温反应30min后，加入(3-(噻唑-2-基)苯基)甲胺(152mg,0.80mmol)，室温反应8h，原料消失。加入DCM(20mL)稀释，HCl(0.5N)(20mL)洗，饱和NaHCO 3(20mL)洗，水洗(20mL)，饱和食盐水洗(20mL)，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体232mg，收率为87.5％，熔点：172-173℃。 2-Ethoxy-4-methyl-5-nitrobenzoic acid (150 mg, 0.67 mmol) was dissolved in DCM (15 mL). After reacting for 30 min at room temperature, (3-(thiazol-2-yl)phenyl)methanamine (152 mg, 0.80 mmol) was added, and the mixture was reacted at room temperature for 8 h. Was added DCM (20mL) was diluted, HCl (0.5N) (20mL) wash with saturated NaHCO 3 (20mL) wash, water (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4, column chromatography (ethyl acetate The ester-petroleum ether (volume ratio: 1:1) was purified to give 232 mg of a white solid, yield: 87.5%, m.p.: 172-173.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.96(s,1H),8.12(brs,1H),7.99(s,1H),7.89–7.86(m,2H),7.44(d,J＝4.8Hz,2H),7.35(d,J＝3.2Hz,1H),6.82(s,1H),4.73(d,J＝5.2Hz,2H),4.23(q,J＝7.2Hz,2H),2.66(s,3H),1.38(t,J＝7.2Hz,3H)；ESI-MS m/z:398.12[M+H] +。 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.96 (s, 1H), 8.12 (brs, 1H), 7.99 (s, 1H), 7.89 - 7.86 (m, 2H), 7.44 (d, J) = 4.8 Hz, 2H), 7.35 (d, J = 3.2 Hz, 1H), 6.82 (s, 1H), 4.73 (d, J = 5.2 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 2.66 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); ESI-MS m/z: 398.12 [M+H] + .

d)5-氨基-2-乙氧基-4-甲基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺d) 5-Amino-2-ethoxy-4-methyl-N-(3-(thiazol-2-yl)benzyl)benzamide

将2-乙氧基-4-甲基-5-硝基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(210mg,0.53mmol)溶于THF(15mL)中，加入Pd/C(110mg)，室温下通入氢气反应过夜，过滤，浓缩，得无色油状物182mg，收率为93.8％。2-Ethoxy-4-methyl-5-nitro-N-(3-(thiazol-2-yl)benzyl)benzamide (210 mg, 0.53 mmol) was dissolved in THF (15 mL) Pd/C (110 mg) was added, and hydrogen was added to the mixture at room temperature overnight, filtered, and concentrated to give 182 mg (yield:

1H-NMR(400MHz,CDCl 3)δ(ppm):8.53(brs,1H),7.96(s,1H),7.90-7.82(m,2H),7.60(s,1H),7.46-7.38(m,2H),7.33(d,J＝3.2Hz,1H),6.68(s,1H),4.70(d,J＝5.2Hz,2H),4.05(q,J＝7.2Hz,2H),3.26(s,2H),2.19(s,3H),1.26(t,J＝6.8Hz,3H)；ESI-MS m/z:368.14[M+H] +。 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.53 (brs, 1H), 7.96 (s, 1H), 7.90-7.82 (m, 2H), 7.60 (s, 1H), 7.46-7.38 (m , 2H), 7.33 (d, J = 3.2 Hz, 1H), 6.68 (s, 1H), 4.70 (d, J = 5.2 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.26 (s , 2H), 2.19 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H); ESI-MS m/z: 368.14 [M+H] + .

e)2-乙氧基-5-异丁酰氨基-4-甲基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺e) 2-ethoxy-5-isobutyrylamino-4-methyl-N-(3-(thiazol-2-yl)benzyl)benzamide

将5-氨基-2-乙氧基-4-甲基-N-(3-(噻唑-2-基)苯甲基)苯甲酰胺(160mg,0.44mmol)溶于无水THF(10mL)中，冰浴下依次加入DIEA(114mg,0.88mmol)，异丁酰氯(70mg,0.66mmol)，继续反应1h，过滤，滤液浓缩，加入乙酸乙酯(20mL)稀释，HCl(0.5N)水溶液(10mL)洗，饱和NaHCO 3(10mL)洗,水(10mL)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，柱色谱(乙酸乙酯-石油醚，体积比1:1)纯化得白色固体127mg，收率为66.8％，熔点：146-147℃。 5-Amino-2-ethoxy-4-methyl-N-(3-(thiazol-2-yl)benzyl)benzamide (160 mg, 0.44 mmol) was dissolved in anhydrous THF (10 mL) DIEA (114 mg, 0.88 mmol), isobutyryl chloride (70 mg, 0.66 mmol) was added, and the reaction was stirred for 1 h, filtered, and the filtrate was concentrated, diluted with ethyl acetate (20 mL), HCl (0.5N) Washed, washed with saturated NaHCO 3 (10 mL), washed with water (10 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and purified by column chromatography (ethyl acetate- petroleum ether, volume ratio 1:1) A white solid 127 mg was obtained in a yield of 66.8%, m.p.: 146-147.

1H-NMR(400MHz,DMSO)δ(ppm):9.21(s,1H),8.61(brs,1H),7.94(s,1H),7.92(d,J＝3.2Hz,1H),7.83(d,J＝5.6Hz,1H),7.78(d,J＝3.2Hz,1H),7.65(s,1H),7.49-7.46(m,2H),7.01(s,1H),4.58(d,J＝5.6Hz,2H),4.16(q,J＝6.8Hz,2H),2.60 (m,1H),2.19(s,3H),1.31(t,J＝6.8Hz,3H),1.11(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C 24H 27O 3N 3S 438.1846[M+H] +,Found:438.1838。 1 H-NMR (400 MHz, DMSO) δ (ppm): 9.21 (s, 1H), 8.61 (brs, 1H), 7.94 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.83 (d) , J = 5.6 Hz, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.65 (s, 1H), 7.49-7.46 (m, 2H), 7.01 (s, 1H), 4.58 (d, J = 5.6 Hz, 2H), 4.16 (q, J = 6.8 Hz, 2H), 2.60 (m, 1H), 2.19 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8Hz, 6H); HR-MS (ESI): m / z, calcd.For C 24 H 27 O 3 N 3 S 438.1846 [m + H] +, Found: 438.1838.

实施例(化合物)168Example (compound) 168

2-乙氧基-5-异丁酰胺基-N-(1-(3-甲基苯基)乙基)烟酰胺2-ethoxy-5-isobutyramido-N-(1-(3-methylphenyl)ethyl)nicotinamide

Figure PCTCN2018088561-appb-000228
Figure PCTCN2018088561-appb-000228

a)2-羟基-5-硝基-烟酸a) 2-hydroxy-5-nitro-nicotinic acid

浓硫酸冷却至0℃，分批加入烟酸(1g，7.19mmol)，完全溶解后，加入发烟硝酸1mL，加热至50℃反应2.5h。原料消失后，加入冰水，得微黄色固体1.048g，收率79％。熔点：185-187℃.The concentrated sulfuric acid was cooled to 0 ° C, and nicotinic acid (1 g, 7.19 mmol) was added in portions. After completely dissolved, 1 mL of fuming nitric acid was added, and the mixture was heated to 50 ° C for 2.5 h. After the disappearance of the starting material, ice water was added to obtain 1.048 g of a pale yellow solid, yield 79%. Melting point: 185-187 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):9.00(d,J＝2.8Hz,1H),8.71(t,J＝3.2Hz,1H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 9.00 (d, J = 2.8 Hz, 1H), 8.71 (t, J = 3.2 Hz, 1H).

b)2-羟基-5-硝基烟酸甲酯b) 2-hydroxy-5-nitronicotinate methyl ester

2-羟基-5-硝基烟酸(1g，5.43mmol)溶于无水甲醇(20mL)，搅拌下缓慢加入SOCl 2溶液，50℃反应7h，冷却，过滤，冰甲醇洗涤滤饼，得白色固体738mg，收率69％。熔点：90-92℃. 2-Hydroxy-5-nitronicotinic acid (1g, 5.43mmol) was dissolved in anhydrous methanol (20mL), slowly added to SOCl 2 solution with stirring, reacted at 50 ° C for 7h, cooled, filtered, washed with ice methanol, white The solid was 738 mg, and the yield was 69%. Melting point: 90-92 ° C.

1H NMR(500MHZ,DMSO-d 6)δ(ppm):13.19(brs,1H),8.87(d,J＝3.2Hz,1H),8.62(d,J＝3.2Hz,1H),3.79(s,3H). 1 H NMR (500 MHZ, DMSO-d 6 ) δ (ppm): 13.19 (brs, 1H), 8.87 (d, J = 3.2 Hz, 1H), 8.62 (d, J = 3.2 Hz, 1H), 3.79 (s) , 3H).

c)2-乙氧基-5-硝基烟酸甲酯c) 2-ethoxy-5-nitronicotinate methyl ester

将2-羟基-5-硝基烟酸甲酯(700mg，3.53mmol)溶于无水DMF(8mL)，加入K 2CO 3(975mg，7.06mmol)，加入碘乙烷(0.85mL，10.59mmol)，加热至60℃反应10h。原料消失后，冷却，EA萃取，水洗，干燥，柱层析(P:E＝1:1)，得白色固体500mg，收率63％。熔点：113-115℃. Methyl 2-hydroxy-5-nitronicotinate (700 mg, 3.53 mmol) was dissolved in anhydrous DMF (8 mL), K 2 CO 3 (975 mg, 7.06 mmol) was added, and ethyl iodide (0.85 mL, 10.59 mmol) was added. ), heated to 60 ° C for 10 h. After the disappearance of the starting material, cooling, EA extraction, water washing, drying, and column chromatography (P: E = 1:1) gave a white solid, 500 mg, yield 63%. Melting point: 113-115 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):8.87(d,J＝3.2Hz,1H),8.80(d,J＝3.2Hz,1H),4.16(q,J＝7.2Hz,2H),3.94(s,3H),1.48(t,J＝7.2Hz,3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 8.87 (d, J = 3.2 Hz, 1H), 8.80 (d, J = 3.2 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).

d)2-乙氧基-5-硝基烟酸d) 2-ethoxy-5-nitronicotinic acid

2-乙氧基-5-硝基烟酸甲酯(400mg，1.77mmol)溶于THF(10mL)/(10mL)，搅拌下加入NaOH(354mg，8.84mmol)，室温下反应过夜，浓缩，浓盐酸调节至 pH＝2，EA萃取，干燥，浓缩，加入乙醚和少量的乙酸乙酯，得到白色固体311mg，收率83％。熔点：160-162℃.Methyl 2-ethoxy-5-nitronicotinate (400 mg, 1.77 mmol) was dissolved in THF (10 mL) / (10 mL). Hydrochloric acid was adjusted to pH = 2, extracted with EA, dried, concentrated, ethyl ether and ethyl acetate. Melting point: 160-162 ° C.

1H NMR(500MHZ,CDCl 3)δ(ppm):9.24(d,J＝2.8Hz,1H),8.86(d,J＝2.8Hz,1H),4.28(q,J＝7.2Hz,2H),1.55(t,J＝7.2Hz,3H). 1 H NMR (500 MHZ, CDCl 3 ) δ (ppm): 9.24 (d, J = 2.8 Hz, 1H), 8.86 (d, J = 2.8 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H).

e)2-乙氧基-5-硝基-N-(1-(3-甲基苯基)乙基)烟酰胺e) 2-ethoxy-5-nitro-N-(1-(3-methylphenyl)ethyl)nicotinamide

2-乙氧基-5-硝基烟酸(100mg，0.47mmol)溶于DCM(5mL)，加入HATU(214mg，0.56mmol)，DIEA(121mg，0.94mmol)，室温反应5min，加入1-(3-甲基苯基)乙基-1-胺(76mg，0.56mmol)，室温反应5h。水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝3:2)，得黄色油状物135mg，收率87％。直接投入下一步。2-Ethoxy-5-nitronicotinic acid (100 mg, 0.47 mmol) was dissolved in DCM (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) 3-Methylphenyl)ethyl-1-amine (76 mg, 0.56 mmol). Water (20 mL × 2) was washed and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 3:2) gave 135 mg of a yellow oil. Go directly to the next step.

f)2-乙氧基-5-氨基-N-(1-(3-甲基苯基)乙基)烟酰胺f) 2-ethoxy-5-amino-N-(1-(3-methylphenyl)ethyl)nicotinamide

2-乙氧基-5-硝基-N-(1-(3-甲基苯基)乙基)烟酰胺(130mg，0.39mmol)溶于DCM(2mL)/EtOH(6mL)/H 2O(1mL)，加入Fe粉(132mg，2.36mmol)，NH 4Cl(21mg，0.39mmol)，50℃回流反应2h。原料消失。过滤，浓缩，加入EA(10mL)稀释，水洗(10mL×2),无水硫酸镁干燥，浓缩，加入乙醚，得到淡绿色固体95mg，收率94％。 2-ethoxy-5-nitro -N- (1- (3- methylphenyl) ethyl) nicotinamide (130mg, 0.39mmol) was dissolved in DCM (2mL) / EtOH (6mL ) / H 2 O (1mL), was added Fe powder (132mg, 2.36mmol), NH 4 Cl (21mg, 0.39mmol), 50 ℃ reaction was refluxed for 2h. The raw materials disappeared. Filtration, concentration, EA (10 mL), EtOAc (EtOAc)EtOAc.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):10.69(d,J＝8.0Hz,1H),8.00(d,J＝2.8Hz,1H),7.25-7.21(m,2H),7.15-7.12(m,2H),7.06(d,J＝7.2Hz,1H),5.09-5.09(m,1H),4.66(brs,2H),4.01-3.91(m,2H),2.30(s,3H),1.43(d,J＝7.2Hz,3H),1.23(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 10.69 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.15 -7.12 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 5.09-5.09 (m, 1H), 4.66 (brs, 2H), 4.01-3.91 (m, 2H), 2.30 (s, 3H) ), 1.43 (d, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H).

g)2-乙氧基-5-异丁酰胺基-N-(1-(3-甲基苯基)乙基)烟酰胺g) 2-ethoxy-5-isobutyryl-N-(1-(3-methylphenyl)ethyl)nicotinamide

2-乙氧基-5-氨基-N-(1-(3-甲基苯基)乙基)烟酰胺(60mg，0.20mmol)溶于THF(6mL)，冰浴下加入TEA(70mg，0.69mmol)，搅拌下逐滴加入异丁酰氯(30mg，0.28mmol)，室温下搅拌反应20min。浓缩，加入EA(10mL)稀释，蒸馏水(10mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(P:E＝1:1)，得白色固体48mg，收率65％。熔点：157-159℃.2-Ethoxy-5-amino-N-(1-(3-methylphenyl)ethyl)nicotinamide (60 mg, 0.20 mmol) was dissolved in THF (6 mL). (mmol), isobutyryl chloride (30 mg, 0.28 mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 20 min. After concentration, it was diluted with EA (10 mL), washed with distilled water (10 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (P: E = 1:1) to give a white solid, 48 mg, yield 65%. Melting point: 157-159 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):10.59(d,J＝8.0Hz,1H),8.76(d,J＝3.2Hz,1H),8.47(d,J＝3.2Hz,2H),7.21(d,J＝7.2Hz,2H),7.16(d,J＝7.2Hz,1H),7.05(d,J＝7.2Hz,1H),5.29-5.22(m,1H),4.15-4.05(m,2H),2.57-2.50(m,1H),2.34(s,3H),1.57(d,J＝7.2Hz,3H),1.42(t,J＝7.2Hz,3H),1.16(dd,J 1＝2.0Hz,J 2＝6.8Hz,1H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 10.59 (d, J = 8.0 Hz, 1H), 8.76 (d, J = 3.2 Hz, 1H), 8.47 (d, J = 3.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 5.29 - 5.22 (m, 1H), 4.15 - 4.05 (m) , 2H), 2.57-2.50 (m, 1H), 2.34 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.16 (dd, J 1 =2.0 Hz, J 2 = 6.8 Hz, 1H).

实施例(化合物)169Example (compound) 169

2-乙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)烟酰胺2-ethoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)nicotinamide

Figure PCTCN2018088561-appb-000229
Figure PCTCN2018088561-appb-000229

a)2-乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)烟酰胺a) 2-ethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)nicotinamide

2-乙氧基-5-硝基烟酸(184mg，0.86mmol)溶于DCM(10mL)，加入HATU(494mg，1.30mmol)，DIEA(336mg，2.60mmol)，室温反应8min，加入S2(266mg，1.30mmol)，室温反应8h。浓缩，加入EA(15mL)稀释，水(10mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得淡黄色油状物333mg，收率97％。2-Ethoxy-5-nitronicotinic acid (184 mg, 0.86 mmol) was dissolved in DCM (10 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc , 1.30 mmol), reacted at room temperature for 8 h. Concentrated, diluted with EA (15 mL), water (10 mL×2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave 333 mg of pale yellow oil, yield 97%.

1H NMR(400MHZ,CDCl 3)δ(ppm):9.70(d,J＝6.8Hz,1H),9.22(d,J＝2.8Hz,1H),8.74(d,J＝2.8Hz,1H),8.01(s,1H),7.83-7.87(m,2H),7.41-7.48(m,2H),7.33(d,J＝2.8Hz,1H),5.30-5.37(m,1H),4.19(q,J＝7.2Hz,2H),1.65(d,J＝6.8Hz,3H),1.50(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 9.70 (d, J = 6.8 Hz, 1H), 9.22 (d, J = 2.8 Hz, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.01(s,1H),7.83-7.87(m,2H), 7.41-7.48(m,2H),7.33(d,J=2.8Hz,1H),5.30-5.37(m,1H),4.19(q, J = 7.2 Hz, 2H), 1.65 (d, J = 6.8 Hz, 3H), 1.50 (t, J = 7.2 Hz, 3H).

b)2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)烟酰胺b) 2-ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)nicotinamide

(330mg，0.82mmol)溶于DCM(2mL)/EtOH(8mL)/H 2O(1mL)，加入Fe粉(275mg，4.92mmol)，NH 4Cl(44mg，0.82mmol)，60℃回流反应2h。原料消失。过滤，浓缩，加入EA(20mL)稀释，水洗(20mL×2),无水硫酸镁干燥，浓缩，加入石油醚，冷冻得淡绿色固体220mg，收率73％。 (330mg, 0.82mmol) was dissolved in DCM (2mL) / EtOH (8mL ) / H 2 O (1mL), was added Fe powder (275mg, 4.92mmol), NH 4 Cl (44mg, 0.82mmol), 60 ℃ reflux 2h . The raw materials disappeared. Filtration, concentration, EA (20 mL), EtOAc (EtOAc)EtOAc.

1HNMR(400MHZ,DMSO-d 6)δ(ppm):10.80(d,J＝7.6Hz,1H),8.00(d,J＝3.2Hz,1H),7.93(d,J＝2.8Hz,2H),7.81-7.79(m,2H),7.51-7.45(m,2H),7.26(d,J＝2.8Hz,1H),5.21-5.14(m,1H),4.65(s,1H),4.01-3.91(m,2H),1.50(d,J＝6.8Hz,3H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 10.80 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 3.2 Hz, 1H), 7.93 (d, J = 2.8 Hz, 2H) , 7.81-7.79 (m, 2H), 7.51-7.45 (m, 2H), 7.26 (d, J = 2.8 Hz, 1H), 5.21-5.14 (m, 1H), 4.65 (s, 1H), 4.01-3.91 (m, 2H), 1.50 (d, J = 6.8 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H).

c)2-乙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)烟酰胺c) 2-ethoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)nicotinamide

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)烟酰胺(80mg，0.22mmol)溶于THF(6mL)，冰浴下加入TEA(66mg，0.65mmol)，搅拌下逐滴加入异丁酰氯(28mg，0.26mmol)，冰浴下搅拌反应30min。加入EA(10mL)稀释，蒸馏水(10mL×2)洗，无水硫酸镁干燥，浓缩，得类白色固体92mg，收率97％。熔点：195-197℃2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)nicotinamide (80 mg, 0.22 mmol) was dissolved in THF (6 mL). TEA (66 mg, 0.65 mmol) was added dropwise with isobutyryl chloride (28 mg, 0.26 mmol), and the mixture was stirred for 30 min. It was diluted with EA (10 mL), washed with distilled water (10 mL×2), dried over anhydrous magnesium sulfate, and evaporated to give a white solid. Melting point: 195-197 ° C

1H NMR(400MHZ,CDCl 3)δ(ppm):10.61(d,J＝8.0Hz,1H),8.71(d,J＝2.8Hz,1H),8.39(d,J＝2.8Hz,1H),7.97(s,1H),7.88-7.84(m,2H),7.45-7.40(m,2H),7.33 (d,J＝3.2Hz,1H),5.37-5.30(m,1H),4.13-4.04(m,2H),2.56-2.49(m,1H),1.64(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.17(dd,J 1＝1.2Hz,J 2＝6.8Hz,6H).. 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 10.61 (d, J = 8.0 Hz, 1H), 8.71 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.88-7.84 (m, 2H), 7.45-7.40 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 5.37-5.30 (m, 1H), 4.13-4.04 ( m, 2H), 2.56-2.49 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.17 (dd, J 1 = 1.2 Hz, J 2 =6.8Hz, 6H)..

实施例(化合物)170Example (compound) 170

2-乙氧基-5-异丁酰胺基-N-(1-(3-甲基苯基)乙基)异烟酰胺2-ethoxy-5-isobutyramido-N-(1-(3-methylphenyl)ethyl)isonicotinamide

Figure PCTCN2018088561-appb-000230
Figure PCTCN2018088561-appb-000230

a)2-羟基-5-硝基异烟酸a) 2-hydroxy-5-nitroisonicotinic acid

浓硫酸冷却至0℃，分批加入异烟酸(1g，7.19mmol)，完全溶解后，加入发烟硝酸1mL，加热至50℃反应6h。原料消失后，加入冰水，得微黄色固体650mg，收率45％。熔点：212-214℃。The concentrated sulfuric acid was cooled to 0 ° C, and isonicotinic acid (1 g, 7.19 mmol) was added in portions. After completely dissolved, 1 mL of fuming nitric acid was added, and the mixture was heated to 50 ° C for 6 h. After the disappearance of the starting material, ice water was added to obtain a yellowish solid 650 mg, yield 45%. Melting point: 212-214 ° C.

b)2-羟基-5-硝基异烟酸甲酯b) 2-hydroxy-5-nitroisonicotinate methyl ester

2-羟基-5-硝基异烟酸(630mg，3.42mmol)溶于无水甲醇(12mL)，搅拌下缓慢加入SOCl 2溶液，60℃反应5h，冷却，过滤，冰甲醇洗涤滤饼，得类白色固体300mg，收率44％熔点：123-125℃. 2-Hydroxy-5-nitroisonicotinic acid (630 mg, 3.42 mmol) was dissolved in anhydrous methanol (12 mL), and the SOCl 2 solution was slowly added with stirring, and reacted at 60 ° C for 5 h, cooled, filtered, and washed with ice methanol. White solid 300mg, yield 44% melting point: 123-125 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):11.04(s,1H),8.70(s,1H),8.45(s,1H),4.10(s,3H). 1H NMR (400MHZ, CDCl 3) δ (ppm): 11.04 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 4.10 (s, 3H).

c)2-乙氧基-5-硝基异烟酸甲酯c) 2-ethoxy-5-nitroisonicotinate methyl ester

2-羟基-5-硝基异烟酸甲酯(290mg，1.46mmol)溶于无水DMF(8mL)，加入K 2CO 3(404mg，2.93mmol)，加入碘乙烷(0.35mL，4.38mmol)，加热至70℃反应10h。原料消失后，冷却，EA萃取，水洗，干燥，柱层析(P:E＝4:1)，得白色固体130mg，收率39％。熔点：90-92℃. Methyl 2-hydroxy-5-nitroisonicotinate (290 mg, 1.46 mmol) was dissolved in anhydrous DMF (8 mL), K 2 CO 3 (404 mg, 2.93 mmol), and ethyl iodoethane (0.35 mL, 4.38 mmol) ), heated to 70 ° C for 10 h. After the disappearance of the starting material, the mixture was cooled, extracted with EA, washed with water, dried, and purified by column chromatography (P: E = 4:1) to give a white solid, 130 mg, yield 39%. Melting point: 90-92 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.60(s,1H),8.34(s,1H),4.42-4.37(m,2H),3.98(s,3H),4.10(s,3H),1.56(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.60 (s, 1H), 8.34 (s, 1H), 4.42-4.37 (m, 2H), 3.98 (s, 3H), 4.10 (s, 3H) , 1.56 (t, J = 7.2 Hz, 3H).

d)2-乙氧基-5-硝基异烟酸d) 2-ethoxy-5-nitroisonicotinic acid

将2-乙氧基-5-硝基异烟酸甲酯(125mg，0.55mmol)溶于THF(6mL)，0.5N NaOH5.5mL，室温下反应3h，浓缩，浓盐酸调节至pH＝2，EA萃取，干燥，浓缩，得到白色固体90mg，收率77％。熔点：214-216℃.Methyl 2-ethoxy-5-nitroisonicotinate (125 mg, 0.55 mmol) was dissolved in THF (6 mL), 0.5N NaOH 5.5 mL, and the mixture was reacted for 3h at room temperature, concentrated, and concentrated to pH=2 with concentrated hydrochloric acid. Extraction with EA, drying and concentration gave a white solid (yield: Melting point: 214-216 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):13.88(s,1H),8.57(s,3H),8.43(s,1H),4.43(q, J＝6.8Hz,2H),1.39(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 13.88 (s, 1H), 8.57 (s, 3H), 8.43 (s, 1H), 4.43 (q, J = 6.8 Hz, 2H), 1.39 (t) , J = 6.8 Hz, 3H).

e)2-乙氧基-5-硝基-N-(1-(3-甲基苯基)乙基)异烟酰胺e) 2-ethoxy-5-nitro-N-(1-(3-methylphenyl)ethyl)isonicotinamide

2-乙氧基-5-硝基异烟酸(90mg，0.42mmol)溶于DCM(12mL)，加入HATU(240mg，0.63mmol)，DIEA(163mg，1.26mmol)，室温反应5min，加入1-(3-甲基苯基)乙基-1-胺(114mg，0.84mmol)，室温反应10h。水(10mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体85mg，收率62％。熔点：133-135℃.2-Ethoxy-5-nitroisonicotinonic acid (90 mg, 0.42 mmol) was dissolved in DCM (12 mL), EtOAc (EtOAc, EtOAc (EtOAc) (3-Methylphenyl)ethyl-1-amine (114 mg, 0.84 mmol) was reacted for 10 h at room temperature. Water (10 mL × 2) was washed and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid, mp. Melting point: 133-135 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):9.00(s,1H),8.33(s,1H),8.03(d,J＝7.2Hz,1H),7.17(d,J＝7.6Hz,2H),7.12(d,J＝7.2Hz,1H),5.29-5.22(m,1H),4.49-4.40(m,2H),2.37(s,3H),1.60(d,J＝6.8Hz,3H),1.53(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 9.00 (s, 1H), 8.33 (s, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H) ), 7.12 (d, J = 7.2 Hz, 1H), 5.29 - 5.22 (m, 1H), 4.49 - 4.40 (m, 2H), 2.37 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H) , 1.53 (t, J = 6.8 Hz, 3H).

f)2-乙氧基-5-氨基-N-(1-(3-甲基苯基)乙基)异烟酰胺f) 2-ethoxy-5-amino-N-(1-(3-methylphenyl)ethyl)isonicotinamide

2-乙氧基-5-硝基-N-(1-(3-甲基苯基)乙基)异烟酰胺(75mg，0.22mmol)溶于DCM(1mL)/EtOH(4mL)/H 2O(0.5mL)，加入Fe粉(76mg，1.36mmol)，NH 4Cl(12mg，0.22mmol)，50℃回流反应1.5h。原料消失。过滤，浓缩，加入EA(10mL)稀释，水洗(10mL×2),无水硫酸镁干燥，浓缩，得到黄色固体60mg，收率92％。熔点：146-149℃. 2-ethoxy-5-nitro -N- (1- (3- methylphenyl) ethyl) isonicotinamide (75mg, 0.22mmol) was dissolved in DCM (1mL) / EtOH (4mL ) / H 2 O (0.5 mL), Fe powder (76 mg, 1.36 mmol), NH 4 Cl (12 mg, 0.22 mmol). The raw materials disappeared. Filtration, concentration, EA (10 mL), EtOAc (EtOAc)EtOAc. Melting point: 146-149 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.58(d,J＝8.0Hz,1H),7.80(s,1H),7.24-7.16(m,3H),7.06(d,J＝7.2Hz,1H),6.69(s,1H),5.72(s,2H),5.08-5.01(m,1H),4.05-3.99(m,2H),2.30(s,3H),1.42(d,J＝7.2Hz,3H),1.27(t,J＝7.2Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.58 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.24 - 7.16 (m, 3H), 7.06 (d, J = 7.2 Hz, 1H), 6.69 (s, 1H), 5.72 (s, 2H), 5.08-5.01 (m, 1H), 4.05-3.99 (m, 2H), 2.30 (s, 3H), 1.42 (d, J) =7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).

g)2-乙氧基-5-异丁酰胺基-N-(1-(3-甲基苯基)乙基)异烟酰胺g) 2-ethoxy-5-isobutyramido-N-(1-(3-methylphenyl)ethyl)isonicotinamide

2-乙氧基-5-氨基-N-(1-(3-甲基苯基)乙基)异烟酰胺(50mg，0.18mmol)溶于THF(7mL)，冰浴下加入TEA(55mg，0.54mmol)，搅拌下逐滴加入异丁酰氯(22mg，0.22mmol)，冰浴下搅拌反应10min。加入EA(10mL)稀释，蒸馏水(10mL)洗，无水硫酸镁干燥，柱层析(P:E＝2:1)，得微黄色油状物45mg，收率67％。2-Ethoxy-5-amino-N-(1-(3-methylphenyl)ethyl)isonicotinamide (50 mg, 0.18 mmol) was dissolved in THF (7 mL). 0.54 mmol), isobutyryl chloride (22 mg, 0.22 mmol) was added dropwise with stirring, and the reaction was stirred for 10 min. It was diluted with EA (10 mL), washed with distilled water (10 mL), dried over anhydrous magnesium sulfate.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.80(s,1H),7.99(s,2H),7.89(brs,1H),7.23(d,J＝7.6Hz,1H),7.17(d,J＝8.8Hz,1H),7.09(d,J＝7.2Hz,1H),5.31-7.24(m,1H),4.24-4.16(m,2H),2.57-2.50(m,1H),2.36(s,3H),1.57(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.25(d,J＝6.8Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.80 (s, 1H), 7.99 (s, 2H), 7.89 (brs, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 (d) , J = 8.8 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 5.31 - 7.24 (m, 1H), 4.24 - 4.16 (m, 2H), 2.57 - 2.50 (m, 1H), 2.36 ( s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 6H).

实施例(化合物)171Example (compound) 171

2-乙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)异烟酰胺2-ethoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)isonicotinamide

Figure PCTCN2018088561-appb-000231
Figure PCTCN2018088561-appb-000231

a)2-乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)异烟酰胺a) 2-ethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)isonicotinamide

2-乙氧基-5-硝基异烟酸(100mg，0.47mmol)溶于DCM(12mL)，加入HATU(357mg，0.94mmol)，DIEA(182mg，1.41mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(192mg，0.94mmol)，室温反应10h。水(10mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体85mg，收率45％。熔点：115-117℃.2-Ethoxy-5-nitroisonicotinonic acid (100 mg, 0.47 mmol) was dissolved in DCM (12 mL), EtOAc (EtOAc, EtOAc, EtOAc (3-thiazol-2-yl)phenyl)ethyl-1-amine (192 mg, 0.94 mmol). Water (10 mL × 2) was washed and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid, 85 mg, yield 45%. Melting point: 115-117 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.99(s,1H),8.35(s,1H),8.13(d,J＝6.8Hz,1H),8.09(s,1H),7.88(d,J＝3.6Hz,2H),7.46(d,J＝5.2Hz,1H),7.37(d,J＝3.2Hz,1H),5.40-5.33(m,1H),4.51-4.44(m,1H),1.67(d,J＝6.8Hz,3H),1.54(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.99 (s, 1H), 8.35 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 8.09 (s, 1H), 7.88 (d) , J = 3.6 Hz, 2H), 7.46 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 5.40 - 5.33 (m, 1H), 4.51-4.44 (m, 1H) , 1.67 (d, J = 6.8 Hz, 3H), 1.54 (t, J = 6.8 Hz, 3H).

b)2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)异烟酰胺b) 2-ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)isonicotinamide

2-乙氧基-5-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)异烟酰胺(80mg，0.20mmol)溶于DCM(1mL)/EtOH(6mL)/H 2O(1mL)，加入Fe粉(89mg，1.60mmol)，NH 4Cl(32mg，0.60mmol)，50℃回流反应2h。原料消失。过滤，浓缩，加入EA(10mL)稀释，水洗(10mL×2),无水硫酸镁干燥，浓缩，得到黄色固体60mg，收率92％。熔点：164-166℃. 2-Ethoxy-5-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)isonicotinamide (80 mg, 0.20 mmol) was dissolved in DCM (1 mL) /EtOAc. 6mL) / H 2 O (1mL ), was added Fe powder (89mg, 1.60mmol), NH 4 Cl (32mg, 0.60mmol), 50 ℃ reaction was refluxed for 2h. The raw materials disappeared. Filtration, concentration, EA (10 mL), EtOAc (EtOAc)EtOAc. Melting point: 164-166 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.71(d,J＝8.0Hz,1H),7.97(s,1H),7.93(d,J＝3.2Hz,1H),7.84-7.79(m,3H),7.52-7.45(m,2H),6.65(s,1H),5.71(s,2H),5.20-5.13(m,1H),4.04-3.99(m,2H),1.48(d,J＝6.8Hz,3H),1.24(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.71 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.84 - 7.79 (m, 3H), 7.52-7.45 (m, 2H), 6.65 (s, 1H), 5.71 (s, 2H), 5.20-5.13 (m, 1H), 4.04-3.99 (m, 2H), 1.48 (d) , J = 6.8 Hz, 3H), 1.24 (t, J = 6.8 Hz, 3H).

c)2-乙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)异烟酰胺c) 2-ethoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)isonicotinamide

2-乙氧基-5-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)异烟酰胺(32mg，0.08mmol)溶于THF(5mL)，冰浴下加入TEA(24mg，0.24mmol)，搅拌下逐滴加入异丁酰氯(17mg，0.16mmol)，冰浴下搅拌反应30min。加入EA(10mL)稀释，蒸馏水(10mL)洗，无水硫酸镁干燥，柱层析(P:E＝1:1)，得类白色固体15mg，收率43％。熔点：166-168℃.2-Ethoxy-5-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)isonicotinamide (32 mg, 0.08 mmol) dissolved in THF (5 mL) TEA (24 mg, 0.24 mmol) was added, and isobutyryl chloride (17 mg, 0.16 mmol) was added dropwise with stirring, and the mixture was stirred for 30 min. It was diluted with EA (10 mL), washed with distilled water (10 mL), dried over anhydrous magnesium sulfate. Melting point: 166-168 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.80(s,1H),8.06(d,J＝7.6Hz,1H),8.00(d,J＝7.6Hz,1H),7.94(s,1H),7.87-7.84(m,2H),7.47-7.41(m,2H),7.34(d,J＝3.2Hz,1H),5.41-5.30(m,1H),4.25-4.18(m,2H),2.58-2.51(m,2H),1.63(d,J＝6.8Hz,3H), 1.41(t,J＝6.8Hz,3H),1.25(d,J＝6.4Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.80 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H) ), 7.87-7.84 (m, 2H), 7.47-7.41 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 5.41-5.30 (m, 1H), 4.25-4.18 (m, 2H), 2.58-2.51 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 6.8 Hz, 3H), 1.25 (d, J = 6.4 Hz, 6H).

实施例(化合物)172Example (compound) 172

2-乙氧基-5-异丁酰胺基-N-(1-(6-甲氧吡啶基-2-基)乙基)异烟酰胺2-ethoxy-5-isobutyramido-N-(1-(6-methoxypyridin-2-yl)ethyl)isonicotinamide

Figure PCTCN2018088561-appb-000232
Figure PCTCN2018088561-appb-000232

a)2-乙氧基-5-硝基-N-(1-(6-甲氧吡啶基-2-基)乙基)异烟酰胺a) 2-Ethoxy-5-nitro-N-(1-(6-methoxypyridin-2-yl)ethyl)isonicotinamide

2-乙氧基-5-硝基异烟酸(100mg，0.47mmol)溶于DCM(15mL)，加入HATU(270mg，0.71mmol)，DIEA(183mg，1.42mmol)，室温反应20min，加入1-(6-甲氧基吡啶-2-基)乙基-1-胺(107mg，0.71mmol)，室温反应10h。水(10mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝2:1)，得白色固体70mg，收率43％。熔点：129-131℃.2-Ethoxy-5-nitroisonicotinonic acid (100 mg, 0.47 mmol) was dissolved in DCM (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) (6-Methoxypyridin-2-yl)ethyl-1-amine (107 mg, 0.71 mmol). Water (10 mL × 2) was washed and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 2: 1) gave a white solid, 70 mg, yield 43%. Melting point: 129-131 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.99(s,1H),8.35(s,1H),8.13(d,J＝6.8Hz,1H),8.09(s,1H),7.88(d,J＝3.6Hz,2H),7.46(d,J＝5.2Hz,1H),7.37(d,J＝3.2Hz,1H),5.40-5.33(m,1H),4.51-4.44(m,1H),1.67(d,J＝6.8Hz,3H),1.54(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.99 (s, 1H), 8.35 (s, 1H), 8.13 (d, J = 6.8 Hz, 1H), 8.09 (s, 1H), 7.88 (d) , J = 3.6 Hz, 2H), 7.46 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 5.40 - 5.33 (m, 1H), 4.51-4.44 (m, 1H) , 1.67 (d, J = 6.8 Hz, 3H), 1.54 (t, J = 6.8 Hz, 3H).

b)2-乙氧基-5-氨基-N-(1-(6-甲氧吡啶基-2-基)乙基)异烟酰胺b) 2-ethoxy-5-amino-N-(1-(6-methoxypyridin-2-yl)ethyl)isonicotinamide

2-乙氧基-5-硝基-N-(1-(6-甲氧吡啶基-2-基)乙基)异烟酰胺(60mg，0.17mmol)溶于DCM(1mL)/EtOH(4mL)/H 2O(1mL)，加入Fe粉(58mg，1.04mmol)，NH 4Cl(27mg，0.51mmol)，50℃回流反应2h。原料消失。过滤，浓缩，加入EA(10mL)稀释，水洗(10mL×2),无水硫酸镁干燥，浓缩，得淡黄色固体50mg，收率94％。熔点：133-134℃. 2-Ethoxy-5-nitro-N-(1-(6-methoxypyridin-2-yl)ethyl)isonicotinamide (60 mg, 0.17 mmol) dissolved in DCM (1 mL) /EtOAc /H 2 O (1 mL), Fe powder (58 mg, 1.04 mmol), NH 4 Cl (27 mg, 0.51 mmol), and refluxed at 50 ° C for 2 h. The raw materials disappeared. Filtration, concentration, EA (10 mL), EtOAc (EtOAc)EtOAc. Melting point: 133-134 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):8.74(d,J＝7.6Hz,1H),7.84(s,1H),7.67(d,J＝7.6Hz,1H),7.02(d,J＝7.2Hz,1H),6.80(s,1H),6.71(d,J＝8.4Hz,1H),5.74(s,2H),5.12-5.05(m,1H),4.09-4.03(m,2H),3.88(s,2H),1.45(d,J＝6.8Hz,3H),1.28(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 8.74 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.02 (d) , J = 7.2 Hz, 1H), 6.80 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.74 (s, 2H), 5.12 - 5.05 (m, 1H), 4.09 - 4.03 (m, 2H), 3.88 (s, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H).

c)2-乙氧基-5-异丁酰胺基-N-(1-(6-甲氧吡啶基-2-基)乙基)异烟酰胺c) 2-ethoxy-5-isobutyramido-N-(1-(6-methoxypyridin-2-yl)ethyl)isonicotinamide

2-乙氧基-5-氨基-N-(1-(6-甲氧吡啶基-2-基)乙基)异烟酰胺(48mg，0.15mmol)溶于THF(6mL)，冰浴下加入TEA(45mg，0.45mmol)，搅拌下逐滴加入异丁酰氯(24mg，0.22mmol)，冰浴下搅拌反应30min。加入EA(10mL)稀释，蒸馏 水(15mL)洗，无水硫酸镁干燥，柱层析(P:E＝1:1)，得白色固体47mg，收率81％。熔点：103-104℃.2-Ethoxy-5-amino-N-(1-(6-methoxypyridin-2-yl)ethyl)isonicotinamide (48 mg, 0.15 mmol) was dissolved in THF (6 mL). TEA (45 mg, 0.45 mmol) was added dropwise with isobutyryl chloride (24 mg, 0.22 mmol), and stirred for 30 min. It was diluted with EA (10 mL), washed with distilled water (15 mL), dried over anhydrous magnesium sulfate. Melting point: 103-104 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.77(s,1H),8.37(d,J＝7.6Hz,1H),8.01(s,1H),7.92(brs,1H),7.55(t,J＝7.6Hz,1H),6.88(d,J＝7.2Hz,1H),6.64(d,J＝8.4Hz,1H),5.36-5.29(m,1H),4.24-4.18(m,2H),3.95(s,1H),2.58-2.49(m,1H),1.56(d,J＝6.4Hz,3H),1.43(t,J＝6.8Hz,3H),1.26(d,J＝6.8Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.77 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.1 (s, 1H), 7.92 (brs, 1H), 7.55 (t , J = 7.6 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.36-5.29 (m, 1H), 4.24 - 4.18 (m, 2H) , 3.95 (s, 1H), 2.58-2.49 (m, 1H), 1.56 (d, J = 6.4 Hz, 3H), 1.43 (t, J = 6.8 Hz, 3H), 1.26 (d, J = 6.8 Hz, 6H).

实施例(化合物)173Example (compound) 173

2-乙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)吡啶酰胺2-ethoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)pyridine amide

Figure PCTCN2018088561-appb-000233
Figure PCTCN2018088561-appb-000233

a)3-羟基吡啶甲酸甲酯a) Methyl 3-hydroxypicolinate

3-羟基吡啶甲酸(1g,，7.19mmol)溶于无水甲醇(20mL)，室温搅拌条件下滴加浓硫酸(2mL)，然后升温至80℃反应24h。加入EA(20mL)、水(20mL)萃取，DCM萃取水层(20mL×2)，合并有机层，无水硫酸镁干燥，浓缩，得类白色固体750mg，收率68％。熔点：68-69℃.3-Hydroxypicolinic acid (1 g, 7.19 mmol) was dissolved in anhydrous methanol (20 mL), and concentrated sulfuric acid (2 mL) was added dropwise under stirring at room temperature, and then warmed to 80 ° C for 24 h. After EA (20 mL) and water (20 mL), EtOAc (EtOAc) Melting point: 68-69 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):10.64(s,1H),8.30(d,J＝3.2Hz,1H),7.44(dd,J 1＝4.0Hz,J 2＝8.4Hz,1H),7.39(dd,J 1＝1.2Hz,J 2＝8.4Hz,1H),4.07(s,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 10.64 (s, 1H), 8.30 (d, J = 3.2 Hz, 1H), 7.44 (dd, J 1 = 4.0 Hz, J 2 = 8.4 Hz, 1H ), 7.39 (dd, J 1 = 1.2 Hz, J 2 = 8.4 Hz, 1H), 4.07 (s, 3H).

b)3-羟基-5-溴吡啶甲酸甲酯b) Methyl 3-hydroxy-5-bromopyridinecarboxylate

3-羟基吡啶甲酸甲酯(1g,6.49mmol)溶于乙腈(20mL)，将NBS(1.270g,7.14mmol)溶于乙腈(20mL)，缓慢滴入反应体系，室温条件下反应8h。旋除溶剂，加入EA(20mL)稀释，水洗(20mL)，NaCl洗(20mL)，干燥有机层，浓缩，得淡黄色固体1.2g，收率79％。熔点：>250℃.Methyl 3-hydroxypicolinate (1 g, 6.49 mmol) was dissolved in acetonitrile (20 mL). NBS (1. The solvent was evaporated, diluted with EtOAc EtOAc EtOAc EtOAc. Melting point: >250 °C.

1H NMR(400MHZ,CDCl 3)δ(ppm):10.69(s,1H),7.56(d,J＝8.8Hz,1H),7.27(d,J＝7.6Hz,1H),4.05(s,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 10.69 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H) ).

c)3-乙氧基-5-溴吡啶甲酸甲酯c) Methyl 3-ethoxy-5-bromopyridinecarboxylate

3-羟基-5-溴吡啶甲酸甲酯溶于DMF(8mL)，加入K 2CO 3(1.534g，11.12mmol)，加入碘乙烷(1.039g，6.66mmol)，加热至40℃反应1h。原料消失后，冷却，EA稀释(20mL)，水洗(15mL×3)，EA(20mL×2)萃取，无水硫酸镁干燥，柱层 析(P:E＝10:1)，得微黄色蜡状固体480mg，收率83％。 3-hydroxy-5-bromopyridine-carboxylate was dissolved in DMF (8mL), was added K 2 CO 3 (1.534g, 11.12mmol ), iodoethane (1.039g, 6.66mmol), the reaction was heated to 40 ℃ 1h. After the disappearance of the raw material, it was cooled, diluted with EA (20 mL), washed with water (15 mL×3), extracted with EA (20 mL×2), dried over anhydrous magnesium sulfate, column chromatography (P:E=10:1) to obtain slightly yellow wax The solid was 480 mg, and the yield was 83%.

1H NMR(400MHZ,CDCl 3)δ(ppm):7.53(d,J＝8.8Hz,1H),7.23(d,J＝8.8Hz,1H),4.22(q,J＝6.8Hz,2H),3.95(s,3H),1.47(t,J＝6.8Hz,3H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 7.53 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.22 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 1.47 (t, J = 6.8 Hz, 3H).

d)2-乙氧基-5-异丁酰胺基吡啶甲酸甲酯d) Methyl 2-ethoxy-5-isobutyrylpicolinate

3-乙氧基-5-溴吡啶甲酸甲酯(460mg，1.77mmol)、异丁酰胺(462mg，5.30mmol)、CsCO 3(1.727g，5.30mmol)、Pd 2(dba) 3(324mg，0.35mmol)、X-phos(338mg，0.71mmol)溶于二氧六环(3mL)，氩气保护下微波(100℃)反应30min。水洗(20mL)，柱层析(P:E＝2:1)，得类白色固体420mg，收率89％。熔点：45-146℃. Methyl 3-ethoxy-5-bromopyridinecarboxylate (460 mg, 1.77 mmol), isobutyramide (462 mg, 5.30 mmol), CsCO 3 (1.727 g, 5.30 mmol), Pd 2 (dba) 3 (324 mg, 0.35 Methyl), X-phos (338 mg, 0.71 mmol) was dissolved in dioxane (3 mL), and was subjected to microwave (100 ° C) for 30 min under argon. The mixture was washed with water (20 mL), EtOAc (EtOAc: EtOAc) Melting point: 45-146 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.37(d,J＝9.2Hz,1H),7.88(brs,1H),7.41(d,J＝9.2Hz,1H),4.13(q,J＝7.2Hz,2H),3.98(s,3H),1.45(t,J＝7.2Hz,3H),1.25(d,J＝6.8Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.37 (d, J = 9.2 Hz, 1H), 7.88 (brs, 1H), 7.41 (d, J = 9.2 Hz, 1H), 4.13 (q, J) = 7.2 Hz, 2H), 3.98 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H), 1.25 (d, J = 6.8 Hz, 6H).

e)2-乙氧基-5-异丁酰胺基吡啶甲酸e) 2-ethoxy-5-isobutyryl picolinic acid

将2-乙氧基-5-异丁酰胺基吡啶甲酸甲酯(300mg，1.13mmol)溶于THF(15mL)/0.5M NaOH(11mL)，室温下反应2h，浓缩，加入乙醚洗涤水层，浓盐酸调节至pH＝2，析出白色固体205mg，收率72％。熔点：134-135℃.Methyl 2-ethoxy-5-isobutyryl pyridinecarboxylate (300 mg, 1.13 mmol) was dissolved in THF (15 mL) / 0.5M EtOAc (11 mL). Concentrated hydrochloric acid was adjusted to pH = 2, and 205 mg of a white solid was precipitated, yield 72%. Melting point: 134-135 ° C.

1H NMR(400MHZ,DMSO-d 6)δ(ppm):13.16(s,3H),10.46(s,1H),8.14(d,J＝9.2Hz,1H),7.63(d,J＝9.2Hz,1H),4.08(q,J＝6.8Hz,2H),1.30(t,J＝7.2Hz,3H),1.07(d,J＝6.8Hz,6H). 1 H NMR (400 MHZ, DMSO-d 6 ) δ (ppm): 13.16 (s, 3H), 10.46 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 9.2 Hz) , 1H), 4.08 (q, J = 6.8 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.07 (d, J = 6.8 Hz, 6H).

f)2-乙氧基-5-异丁酰胺基-N-(1-(3-(噻唑-2-基)苯基)乙基)吡啶酰胺f) 2-ethoxy-5-isobutyramido-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)pyridine amide

2-乙氧基-5-异丁酰胺基吡啶甲酸(80mg，0.32mmol)溶于DCM(5mL)，加入HATU(243mg，0.64mmol)，DIEA(124mg，0.96mmol)，室温反应20min，加入1-(3-噻唑-2-基)苯基)乙基-1-胺(65mg，0.48mmol)，室温反应10h。水(20mL×2)洗，无水硫酸镁干燥。柱层析(P:E＝1:1)，得白色固体81mg，收率69％。熔点：75-76℃.2-Ethoxy-5-isobutyrylpyridinic acid (80 mg, 0.32 mmol) was dissolved in DCM (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) -(3-thiazol-2-yl)phenyl)ethyl-1-amine (65 mg, 0.48 mmol). Water (20 mL × 2) was washed and dried over anhydrous magnesium sulfate. Column chromatography (P: E = 1:1) gave a white solid, 81 mg, yield 69%. Melting point: 75-76 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.34(d,J＝7.2Hz,1H),8.06(d,J＝8.0Hz,1H),7.40(d,J＝8.8Hz,1H),7.24(d,J＝7.2Hz,1H),7.20(d,J＝9.2Hz,2H),7.09(d,J＝7.2Hz,2H),5.37-5.29(m,1H),4.18-4.10(m,2H),2.36(s,3H),1.60(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.25(d,J＝6.8Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.34 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 9.2 Hz, 2H), 7.09 (d, J = 7.2 Hz, 2H), 5.37-5.29 (m, 1H), 4.18-4.10 (m) , 2H), 2.36 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 6H).

实施例(化合物)174Example (compound) 174

2-乙氧基-5-异丁酰胺基-N-(1-(3-甲基苯基)乙基)吡啶酰胺2-ethoxy-5-isobutyramido-N-(1-(3-methylphenyl)ethyl)pyridine amide

Figure PCTCN2018088561-appb-000234
Figure PCTCN2018088561-appb-000234

2-乙氧基-5-异丁酰胺基吡啶甲酸(80mg，0.32mmol)溶于DCM(5mL)，加入HATU(243mg，0.64mmol)，DIEA(98mg，0.48mmol)，室温反应20min，加入1-(3-甲基苯基)乙基-1-胺(65mg，0.48mmol)，室温反应10h。水(15mL×2)洗，无水硫酸镁干燥，柱层析(P:E＝1:1)，得白色固体75mg，收率54％。熔点：92-94℃.2-Ethoxy-5-isobutyrylpyridinic acid (80 mg, 0.32 mmol) was dissolved in DCM (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) -(3-Methylphenyl)ethyl-1-amine (65 mg, 0.48 mmol). The mixture was washed with water (15 mL × 2), dried over anhydrous magnesium sulfate Melting point: 92-94 ° C.

1H NMR(400MHZ,CDCl 3)δ(ppm):8.29(d,J＝8.8Hz,2H),8.02(brs,1H),7.86(d,J＝3.2Hz,1H),7.83(d,J＝7.2Hz,1H),7.46-7.40(m,3H),7.34(d,J＝3.2Hz,1H),5.40-5.36(m,1H),4.16(q,J＝2.8Hz,2H),2.55-2.46(m,1H),1.64(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.20(d,J＝7.0Hz,6H). 1 H NMR (400 MHZ, CDCl 3 ) δ (ppm): 8.29 (d, J = 8.8 Hz, 2H), 8.02 (brs, 1H), 7.86 (d, J = 3.2 Hz, 1H), 7.83 (d, J) = 7.2 Hz, 1H), 7.46-7.40 (m, 3H), 7.34 (d, J = 3.2 Hz, 1H), 5.40-5.36 (m, 1H), 4.16 (q, J = 2.8 Hz, 2H), 2.55 -2.46 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.20 (d, J = 7.0 Hz, 6H).

实施例(化合物)175Example (compound) 175

5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)-2-(2,2,2-三氟乙氧基)苯甲酰胺5-isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)-2-(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000235
Figure PCTCN2018088561-appb-000235

a)2-氟-5-硝基苯甲酸甲酯a) Methyl 2-fluoro-5-nitrobenzoate

将化合物2-氟-5-硝基苯甲酸(1.5g)加入甲醇(40mL)，滴加入氯化亚砜(1mL)，加热回流反应，次日，停止反应，浓缩至干，加入乙酸乙酯，用饱和NaCl溶液30mL×2洗，无水硫酸镁干燥，浓缩，得到淡黄色固体1.3g产率81.2％。The compound 2-fluoro-5-nitrobenzoic acid (1.5 g) was added to methanol (40 mL), thionyl chloride (1 mL) was added dropwise, and the reaction was refluxed with heating. The next day, the reaction was stopped, concentrated to dryness and ethyl acetate was added. It was washed with a saturated NaCl solution (30 mL × 2), dried over anhydrous magnesium sulfate and evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.84-8.87(m,1H),8.41-8.44(m,1H),7.33(t,J＝9.2Hz,1H),4.00(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.84 - 8.87 (m, 1H), 8.41 - 8.44 (m, 1H), 7.33 (t, J = 9.2 Hz, 1H), 4.00 (s, 3H) ).

b)5-硝基-2-(2,2,2-三氟乙氧基)苯甲酸甲酯b) Methyl 5-nitro-2-(2,2,2-trifluoroethoxy)benzoate

将三氟乙醇(0.18mL,2.4mmol)，加入干燥的THF(15mL)，氩气保护下加入叔丁醇钾(246mg,2.2mmol)，室温搅拌10min后移至冰浴下，将化合物甲基2-氟-5-硝基苯酸酯(398mg,2mmol)的THF(15mL)溶液滴加至反应瓶中，滴毕，继续在冰浴下反应，1.5h后停止反应，加入水，用乙酸乙酯30mL×2萃取，合并有机层，用饱和NaCl溶液20mL×2洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:12，E:P＝1:10)，得到白色固体340mg，产率60.9％。Trifluoroethanol (0.18 mL, 2.4 mmol) was added to dry THF (15 mL). EtOAc (t. A solution of 2-fluoro-5-nitrobenzoate (398 mg, 2 mmol) in THF (15 mL) was added dropwise to the reaction flask, and the reaction was continued in an ice bath. After 1.5 h, the reaction was stopped and water was added. Ethyl acetate 30 mL × 2 was extracted, and the organic layer was combined, washed with a saturated NaCI solution (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:12, E:P=1:10) White solid 340 mg, yield 60.9%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.76(d,J＝2.4Hz,1H),8.39(dd,J 1＝9.2Hz,J 2＝2.4Hz,1H),7.08(d,J＝9.2Hz,1H),4.54(q,J＝8.0Hz,2H),3.96(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.76 (d, J = 2.4 Hz, 1H), 8.39 (dd, J 1 = 9.2 Hz, J 2 = 2.4 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.54 (q, J = 8.0 Hz, 2H), 3.96 (s, 3H).

c)5-氨基-2-(2,2,2-三氟乙氧基)苯甲酸甲酯c) Methyl 5-amino-2-(2,2,2-trifluoroethoxy)benzoate

将甲基5-硝基-2-(2,2,2-三氟乙氧基)苯酸酯(300mg)，加入EtOH(20mL)，加入10％Pd/C(90mg)，常温常压下氢化反应，4h后停止反应，过滤，浓缩，得到淡黄色油状物260mg，产率97.3％。Methyl 5-nitro-2-(2,2,2-trifluoroethoxy)benzoate (300 mg) was added to EtOH (20 mL), and 10% Pd/C (90 mg) was added at normal temperature and pressure. After hydrogenation, the reaction was quenched after 4 h.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.14(s,1H),6.90(d,J＝8.8Hz,1H),6.78(d,J＝8.4Hz,1H),4.32(q,J＝8.4Hz,2H),3.89(s,3H),3.66(brs,2H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.14 (s, 1H), 6.90 (d, J = 8.8Hz, 1H), 6.78 (d, J = 8.4Hz, 1H), 4.32 (q, J = 8.4 Hz, 2H), 3.89 (s, 3H), 3.66 (brs, 2H).

d)5-异丁酰氨基-2-(2,2,2-三氟乙氧基)苯甲酸甲酯d) methyl 5-isobutyrylamino-2-(2,2,2-trifluoroethoxy)benzoate

将甲基5-氨基-2-(2,2,2-三氟乙氧基)苯酸酯(226mg,0.907mmol)，加入DMF(15mL)，EDC(348mg,1.8mmol)，HOBt(243mg,1.8mmol)，DIEA(0.3mL,1.8mmol)以及异丁酸(0.084mL,0.907mmol)，室温搅拌反应，次日停止反应，加水，用乙酸乙酯30mL×2，合并有机层用饱和NaCl溶液20mL×2洗，无水硫酸镁干燥，柱层析(E:P＝1:5)得到白色固体210mg，产率72.6％。Methyl 5-amino-2-(2,2,2-trifluoroethoxy)benzoate (226 mg, 0.907 mmol) was added to DMF (15 mL), EtOAc (EtOAc, EtOAc 1.8 mmol), DIEA (0.3 mL, 1.8 mmol) and isobutyric acid (0.084 mL, 0.907 mmol), the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, ethyl acetate 30mL × 2, and the organic layer was combined with saturated NaCl solution It was washed with 20 mL × 2 and dried over anhydrous magnesium sulfate.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.84-7.86(m,2H),7.33(s,1H),6.99(d,J＝9.2Hz,1H),4.32(q,J＝8.4Hz,2H),3.89(s,3H),2.49-2.54(m,1H),1.25(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.84-7.86 (m, 2H), 7.33 (s, 1H), 6.99 (d, J = 9.2Hz, 1H), 4.32 (q, J = 8.4 Hz, 2H), 3.89 (s, 3H), 2.49-2.54 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H).

e)5-异丁酰氨基-2-(2,2,2-三氟乙氧基)苯甲酸e) 5-Isobutyrylamino-2-(2,2,2-trifluoroethoxy)benzoic acid

将甲基5-异丁酰氨基-2-(2,2,2-三氟乙氧基)苯酸酯(181mg,0.567mmol)置于反应瓶中，加入THF(3mL)，MeOH(3mL)，将氢氧化锂(18mg,0.737mmol)溶于水(2mL)中，滴加入反应瓶中，滴毕，室温搅拌反应，次日，停止反应，浓缩，加水，用乙醚10mL萃取，水层用稀盐酸溶液调PH值至3左右，有固体析出，抽滤，滤饼水洗，得到白色固体140mg，产率81.4％。Methyl 5-isobutyrylamino-2-(2,2,2-trifluoroethoxy)benzoate (181 mg, 0.567 mmol) was placed in a reaction flask, THF (3 mL), MeOH (3 mL) Lithium hydroxide (18mg, 0.737mmol) was dissolved in water (2mL), added dropwise to the reaction flask, dripped, stirred at room temperature, the next day, the reaction was stopped, concentrated, water, extracted with 10mL of ether, water layer The diluted hydrochloric acid solution was adjusted to a pH of about 3, and a solid precipitated, suction filtration, and the filter cake was washed with water to obtain a white solid (140 mg, yield: 81.4%).

1H-NMR(400MHz,CDCl 3)δ(ppm):12.83(s,1H),9.87(s,1H),7.95(s,1H),7.73(d,J＝8.8Hz,1H),7.15(d,J＝8.8Hz,1H),4.69(q,J＝8.8Hz,2H),2.49-2.58(m,1H),1.05(d,J＝6.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 12.83 (s, 1H), 9.87 (s, 1H), 7.95 (s, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.15 ( d, J = 8.8 Hz, 1H), 4.69 (q, J = 8.8 Hz, 2H), 2.49-2.58 (m, 1H), 1.05 (d, J = 6.4 Hz, 6H).

f)5-异丁酰氨基-N-(3-(噻唑-2-基)苯甲基)-2-(2,2,2-三氟乙氧基)苯甲酰胺f) 5-Isobutyrylamino-N-(3-(thiazol-2-yl)benzyl)-2-(2,2,2-trifluoroethoxy)benzamide

将5-异丁酰氨基-2-(2,2,2-三氟乙氧基)苯甲酸(120mg,0.39mmol)加入无水DMF(15mL)，加入EDC(150mg,0.78mmol)，加入HOBt(105mg,0.78mmol)和DIEA(0.17mL,0.975mmol)，加入(3-(噻唑-2-基)苯基)甲胺(186mg,0.98mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯30mL×2萃取，合并有机层用饱和NaCl 30mL×2洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝75:1)，得到白色固体55mg，产率26.8％。熔点：182-184℃5-Isobutyrylamino-2-(2,2,2-trifluoroethoxy)benzoic acid (120 mg, 0.39 mmol) was added to dry DMF (15 mL), EDC (150 mg, 0.78 mmol) (105 mg, 0.78 mmol) and DIEA (0.17 mL, 0.975 mmol), (3-(thiazol-2-yl)phenyl)methanamine (186 mg, 0.98 mmol). The mixture was extracted with ethyl acetate (30 mL), EtOAc (EtOAc m. . Melting point: 182-184 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.28(d,J＝6.8Hz,1H),7.95(s,1H),7.86-7.90(m,4H),7.68(s,1H),7.40-7.45(m,2H),7.34(s,1H),6.87(d,J＝8.8Hz,1H),4.71(d,J＝5.2Hz,2H),4.42(q,J＝8.0Hz,2H),2.50-2.54(m,1H),1.22(d,J＝6.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.28 (d, J = 6.8Hz, 1H), 7.95 (s, 1H), 7.86-7.90 (m, 4H), 7.68 (s, 1H), 7.40-7.45 (m, 2H), 7.34 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.71 (d, J = 5.2 Hz, 2H), 4.42 (q, J = 8.0 Hz, 2H) ), 2.50-2.54 (m, 1H), 1.22 (d, J = 6.4 Hz, 6H).

实施例(化合物)176Example (compound) 176

5-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)-2-(2,2,2-三氟乙氧基)苯甲酰胺5-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-2-(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000236
Figure PCTCN2018088561-appb-000236

将5-异丁酰氨基-2-(2,2,2-三氟乙氧基)苯甲酸(120mg，0.39mmol)加入无水DMF(15mL)，加入EDC(150mg,0.78mmol)，加入HOBt(105mg,0.78mmol)和DIEA(0.17mL,0.975mmol)，加入1-(3-(噻唑-2-基)苯基)乙胺(96mg,0.47mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯30mL×2萃取，合并有机层用饱和NaCl30mL×2洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2,E:P＝1:1.5)，得到白色固体155mg，产率80.7％。熔点：178-180℃5-Isobutyrylamino-2-(2,2,2-trifluoroethoxy)benzoic acid (120 mg, 0.39 mmol) was added to dry DMF (15 mL), EDC (150 mg, 0.78 mmol) (105 mg, 0.78 mmol) and DIEA (0.17 mL, 0.975 mmol), 1-(3-(thiazol-2-yl)phenyl)ethylamine (96 mg, 0.47 mmol). The mixture was extracted with EtOAc (EtOAc) (EtOAc) A white solid 155 mg was obtained in a yield of 80.7%. Melting point: 178-180 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.27(d,J＝8.8Hz,1H),7.97(s,1H),7.81-7.89(m,4H),7.66(s,1H),7.40-7.46(m,2H),7.33(s,1H),6.85(d,J＝8.8Hz,1H),5.32-5.36(m,1H),4.44-4.53(m,2H),2.45-2.50(m,1H),1.60(d,J＝7.2Hz,3H),1.19(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.27 (d, J = 8.8Hz, 1H), 7.97 (s, 1H), 7.81-7.89 (m, 4H), 7.66 (s, 1H), 7.40-7.46 (m, 2H), 7.33 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.32 - 5.36 (m, 1H), 4.44 - 4.53 (m, 2H), 2.45 - 2.50 ( m, 1H), 1.60 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 6.8 Hz, 6H).

实施例(化合物)177Example (compound) 177

2-硝基-N-(3-(噻唑-2-基)苯甲基)-5-(2,2,2-三氟乙氧基)苯甲酰胺2-nitro-N-(3-(thiazol-2-yl)benzyl)-5-(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000237
Figure PCTCN2018088561-appb-000237

a)5-氟-2-硝基-苯甲酸甲酯a) 5-fluoro-2-nitro-benzoic acid methyl ester

将2-硝基-5-氟苯甲酸(1.5g)加入40mL甲醇，滴加入1mL氯化亚砜，加热回流反应，次日，停止反应，浓缩至干，加入乙酸乙酯，用饱和NaCl溶液30mL×2洗，无水硫酸镁干燥，浓缩，得到淡黄色固体1.3g产率80.7％。2-Nitro-5-fluorobenzoic acid (1.5 g) was added to 40 mL of methanol, 1 mL of thionyl chloride was added dropwise, and the reaction was heated to reflux. The next day, the reaction was stopped, concentrated to dryness, ethyl acetate was added, and saturated NaCl solution was used. After washing with 30 mL × 2, dried over anhydrous magnesium sulfate, and evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.84～8.86(m,1H),8.41～8.44(m,1H),7.34(t,J＝9.2Hz,1H),4.00(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.84 to 8.86 (m, 1H), 8.41 to 8.44 (m, 1H), 7.34 (t, J = 9.2 Hz, 1H), 4.00 (s, 3H) ).

b)2-硝基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯b) Methyl 2-nitro-5-(2,2,2-trifluoroethoxy)benzoate

将三氟乙醇(0.36mL,4.8mmol)，加入干燥的THF(20mL)，氩气保护下加入叔丁醇钾(493mg,4.4mmol)，室温搅拌10min后移至冰浴下，将5-氟-2-硝基-苯甲酸甲酯(796mg,4mmol)的THF(15mL)溶液滴加至反应瓶中，滴毕，继续在冰浴下反应，1h后停止反应，加入水，用乙酸乙酯50mL×2萃取，合并有机层，用饱和NaCl溶液40mL×2洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:12，E:P＝1:10)，得到白色固体900mg，产率80.6％。Trifluoroethanol (0.36 mL, 4.8 mmol) was added to dry THF (20 mL). EtOAc. A solution of -2-nitro-benzoic acid methyl ester (796 mg, 4 mmol) in THF (15 mL) was added dropwise to the reaction flask, and the mixture was poured over and the reaction was continued in an ice bath. After 1 h, the reaction was stopped and water was added. The mixture was extracted with 50 mL×2, and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated 900 mg, yield 80.6%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.76(d,J＝2.4Hz,1H),8.39(dd,J 1＝9.2Hz,J 2＝2.4Hz,1H),7.08(d,J＝9.2Hz,1H),4.54(q,J＝8.0Hz,2H),3.96(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.76 (d, J = 2.4 Hz, 1H), 8.39 (dd, J 1 = 9.2 Hz, J 2 = 2.4 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.54 (q, J = 8.0 Hz, 2H), 3.96 (s, 3H).

c)2-硝基-5-(2,2,2-三氟乙氧基)苯甲酸c) 2-nitro-5-(2,2,2-trifluoroethoxy)benzoic acid

将2-硝基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯(200mg,0.716mmol)置于反应瓶中，加入THF(3mL)，MeOH(3mL)，将氢氧化锂(22.3mg,0.93mmol)溶于水(2mL)中，滴加入反应瓶中，滴毕，室温搅拌反应，2h后停止反应，浓缩，加水，用乙醚(10mL)萃取，水层用稀盐酸溶液调PH值至3左右，有固体析出，抽滤，滤饼水洗，得到白色固体150mg，产率78.9％。Methyl 2-nitro-5-(2,2,2-trifluoroethoxy)benzoate (200 mg, 0.716 mmol) was placed in a reaction flask and THF (3 mL), MeOH (3 mL) Lithium oxide (22.3mg, 0.93mmol) was dissolved in water (2mL), added dropwise to the reaction flask, dripped, stirred at room temperature, the reaction was stopped after 2h, concentrated, added water, extracted with ether (10mL), the water layer was diluted The hydrochloric acid solution was adjusted to a pH of about 3, and a solid was precipitated, suction filtered, and the filter cake was washed with water to give a white solid, 150 mg, yield 78.9%.

1H-NMR(400MHz,DMSO-d 6)δPPm:13.45(s,1H),8.49(s,1H),8.43(d,J＝9.2Hz,1H),7.46(d,J＝9.2Hz,1H),5.03(q,J＝8.4Hz,2H). 1 H-NMR δPPm (400MHz, DMSO-d 6): 13.45 (s, 1H), 8.49 (s, 1H), 8.43 (d, J = 9.2Hz, 1H), 7.46 (d, J = 9.2Hz, 1H ), 5.03 (q, J = 8.4 Hz, 2H).

d)2-硝基-N-(3-(噻唑-2-基)苯甲基)-5-(2,2,2-三氟乙氧基)苯甲酰胺d) 2-Nitro-N-(3-(thiazol-2-yl)benzyl)-5-(2,2,2-trifluoroethoxy)benzamide

将2-硝基-5-三氟乙氧基苯甲酸(80mg,0.3mmol)加入无水DMF(15mL)，加入EDC(115mg,0.6mmol)，加入HOBt(81mg,0.6mmol)和DIEA(0.13mL,0.75mmol)，加入(3-(噻唑-2-基)苯基)甲胺(171mg,0.9mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2.5)，得到白色固体90mg，产率68.7％。熔点：120-122℃Add 2-nitro-5-trifluoroethoxybenzoic acid (80 mg, 0.3 mmol) to dry DMF (15 mL), EtOAc (EtOAc) (3,5,5 mmol), and added (3-(thiazol-2-yl)phenyl)methanamine (171 mg, 0.9 mmol), and stirred at room temperature overnight. The combined organic layer was washed with EtOAc EtOAc EtOAc (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 68.7%. Melting point: 120-122 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):9.11(d,J＝3.2Hz,1H),8.35(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.98(s,1H),7.59(brs,1H),7.43-7.47(m,2H),7.35(d,J＝3.2Hz,1H),7.01(d,J＝9.2Hz,1H),4.73(d,J＝5.6Hz,2H),4.58(q,J＝7.6Hz,2H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 9.11 (d, J = 3.2 Hz, 1H), 8.35 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.98 (s, 1H), 7.59 (brs, 1H), 7.43-7.47 (m, 2H), 7.35 (d, J = 3.2 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 4.73 (d, J = 5.6) Hz, 2H), 4.58 (q, J = 7.6 Hz, 2H).

实施例(化合物)178Example (compound) 178

2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)-5-(2,2,2-三氟乙氧基)苯甲酰胺2-(Dimethylamino)-N-(3-(thiazol-2-yl)benzyl)-5-(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000238
Figure PCTCN2018088561-appb-000238

a)2-氨基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯a) Methyl 2-amino-5-(2,2,2-trifluoroethoxy)benzoate

将2-氨基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯(750mg)，加入EtOH(25mL)，加入10％Pd/C(225mg)，常温常压下氢化反应，16h后停止反应，过滤，浓缩，得到黄色油状物650mg，产率97.1％。Methyl 2-amino-5-(2,2,2-trifluoroethoxy)benzoate (750 mg) was added to EtOH (25 mL), and 10% Pd/C (225 mg) was added and hydrogenated at normal temperature and pressure. After 16 h, the reaction was quenched, filtered and concentrated to give 650 g, m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.15(s,1H),6.91(d,J＝8.8Hz,1H),6.79(d,J＝8.4Hz,1H),4.32(q,J＝8.4Hz,2H),3.89(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.15 (s, 1H), 6.91 (d, J = 8.8Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 4.32 (q, J=8.4Hz, 2H), 3.89(s, 3H).

b)2-二甲氨基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯b) Methyl 2-dimethylamino-5-(2,2,2-trifluoroethoxy)benzoate

将2-氨基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯(105mg,0.42mmol)置于反应瓶中，加入乙腈(8mL)，加入碳酸钾(174mg,1.26mmol)，加入碘甲烷(0.06mL,0.93mmol)，加热回流反应，4h后仍有大量原料剩余，补加碘甲烷(0.03mL,0.465mmol)，继续加热回流反应，3h后停止反应，过滤，浓缩，柱层析(E:P＝1:15，E:P＝1:8)，得到目标化合物40mg，产率34.4％。Methyl 2-amino-5-(2,2,2-trifluoroethoxy)benzoate (105 mg, 0.42 mmol) was placed in a reaction flask, acetonitrile (8 mL) was added, and potassium carbonate (174 mg, 1.26 mmol) was added. ), adding methyl iodide (0.06mL, 0.93mmol), heating and refluxing reaction, after 4h, there is still a large amount of raw materials remaining, supplemented with iodomethane (0.03mL, 0.465mmol), continue to heat reflux reaction, stop reaction after 3h, filter, concentrate Column chromatography (E: P = 1:15, E: P = 1:8) gave the title compound 40 mg (yield: 34.4%).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.17(s,1H),6.99(d,J＝8.8Hz,1H),6.84(d,J＝8.0Hz,1H),4.32(q,J＝8.4Hz,2H),3.91(s,3H),2.94(s,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.17 (s, 1H), 6.99 (d, J = 8.8Hz, 1H), 6.84 (d, J = 8.0Hz, 1H), 4.32 (q, J = 8.4 Hz, 2H), 3.91 (s, 3H), 2.94 (s, 6H).

c)2-二甲氨基-5-(2,2,2-三氟乙氧基)苯甲酸c) 2-dimethylamino-5-(2,2,2-trifluoroethoxy)benzoic acid

将2-二甲氨基-5-(2,2,2-三氟乙氧基)苯甲酸甲酯(180mg,0.65mmol)置于反应瓶中，加入THF(3mL)，MeOH(3mL)，将氢氧化锂(24mg,0.97mmol)溶于水(2mL)中，滴加入反应瓶中，滴毕，室温搅拌反应，6h后停止反应，浓缩，加水，用乙醚(10mL)萃取，水层用稀盐酸溶液调PH值至3左右，无固体析出，用DCM:MeOH＝10:1的混合液萃取，有机层用无水硫酸镁干燥，浓缩，得到淡黄色固体145mg，产率85.2％。Methyl 2-dimethylamino-5-(2,2,2-trifluoroethoxy)benzoate (180 mg, 0.65 mmol) was placed in a reaction flask, THF (3 mL), MeOH (3 mL) Lithium hydroxide (24mg, 0.97mmol) was dissolved in water (2mL), added dropwise to the reaction flask, dripped, stirred at room temperature, the reaction was stopped after 6h, concentrated, water was added, extracted with ether (10mL), the water layer was diluted The pH of the hydrochloric acid solution was adjusted to about 3, and no solid was precipitated. The mixture was extracted with DCM: MeOH = 10:1.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):12.75(s,1H),7.06(d,J＝8.8Hz,1H),6.98(s,1H),6.88(d,J＝9.2Hz,1H),4.57(q,J＝9.2Hz,2H),2.85(s,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 12.75 (s, 1H), 7.06 (d, J = 8.8Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.57 (q, J = 9.2 Hz, 2H), 2.85 (s, 6H).

d)2-(二甲氨基)-N-(3-(噻唑-2-基)苯甲基)-5-(2,2,2-三氟乙氧基)苯甲酰胺d) 2-(Dimethylamino)-N-(3-(thiazol-2-yl)benzyl)-5-(2,2,2-trifluoroethoxy)benzamide

将2-二甲氨基-5-(2,2,2-三氟乙氧基)苯甲酸(80mg,0.3mmol)加入无水DMF(15 mL)，加入EDC(115mg,0.6mmol)，加入HOBt(81mg,0.6mmol)和DIEA(0.13mL,0.75mmol)，加入(3-(噻唑-2-基)苯基)甲胺(171mg,0.9mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×)2洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2.5)，得到白色固体80mg，产率61％。熔点：122-124℃Add 2-dimethylamino-5-(2,2,2-trifluoroethoxy)benzoic acid (80 mg, 0.3 mmol) to dry DMF (15 mL). (81 mg, 0.6 mmol) and DIEA (0.13 mL, 0.75 mmol), (3-(thiazol-2-yl)phenyl)methanamine (171 mg, 0.9 mmol). The mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) 2.5), 80 mg of a white solid was obtained with a yield of 61%. Melting point: 122-124 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.95(s,1H),7.85～7.95(m,3H),7.62(brs,1H),7.42-7.45(m,2H),7.32(d,J＝3.2Hz,1H),6.82-6.85(m,2H),4.71(d,J＝5.6Hz,2H),4.36(q,J＝8.0Hz,2H),2.96(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.95 (s, 1H), 7.85 - 7.95 (m, 3H), 7.62 (brs, 1H), 7.42 - 7.45 (m, 2H), 7.32 (d) , J = 3.2 Hz, 1H), 6.82 - 6.85 (m, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.36 (q, J = 8.0 Hz, 2H), 2.96 (s, 6H).

实施例(化合物)179Example (compound) 179

2-(二甲氨基)-N-(1-(3-(噻唑-2-基)苯基)乙基)-5-(2,2,2-三氟乙氧基)苯甲酰胺2-(Dimethylamino)-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-5-(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000239
Figure PCTCN2018088561-appb-000239

取化合物2-二甲氨基-5-(2,2,2-三氟乙氧基)苯甲酸(110mg,0.418mmol)加入无水DMF(15mL)，加入EDC(160mg,0.836mmol)，加入HOBt(113mg,0.836mmol)和DIEA(0.18mL,1.05mmol)，加入1-(3-(噻唑-2-基)苯基)乙胺(102mg,0.50mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2.5)，得到白色固体130mg，产率69.1％。熔点：126-127℃The compound 2-dimethylamino-5-(2,2,2-trifluoroethoxy)benzoic acid (110 mg, 0.418 mmol) was added to dry DMF (15 mL), EDC (160 mg, (113 mg, 0.836 mmol) and DIEA (0.18 mL, 1.05 mmol), 1-(3-(thiazol-2-yl)phenyl)ethylamine (102 mg, 0.50 mmol). The mixture was extracted with EtOAc (3 mL, EtOAc) (EtOAc) 1:2.5), 130 mg of a white solid was obtained with a yield of 69.1%. Melting point: 126-127 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.95-7.98(m,2H),7.83-7.85(m,2H),7.58(brs,1H),7.38-7.46(m,2H),7.31(d,J＝2.8Hz,1H),6.78-6.86(m,2H),5.32-5.36(m,1H),4.38-4.46(m,2H),2.93(s,6H),1.60(d,J＝7.2Hz,3H),. 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.95-7.98 (m, 2H), 7.83-7.85 (m, 2H), 7.58 (brs, 1H), 7.38-7.46 (m, 2H), 7.31 (d, J = 2.8 Hz, 1H), 6.78-6.86 (m, 2H), 5.32 - 5.36 (m, 1H), 4.38 - 4.46 (m, 2H), 2.93 (s, 6H), 1.60 (d, J =7.2Hz, 3H),.

实施例(化合物)180Example (compound) 180

2-氟-N-(1-(3-(噻唑-2-基)苯基)乙基)-5-(三氟甲基)苯甲酰胺2-fluoro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-5-(trifluoromethyl)benzamide

Figure PCTCN2018088561-appb-000240
Figure PCTCN2018088561-appb-000240

将2-氟-5-三氟甲基苯甲酸(120mg,0.577mmol)加入无水DMF(15mL)，加入EDC(221mg,1.15mmol)，加入HOBt(156mg,1.15mmol)和DIEA(0.4mL,2.3mmol)， 加入1-(3-(噻唑-2-基)苯基)乙胺(141mg,0.69mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2)，得到白色固体160mg，产率70.4％。熔点：118-119℃2-Fluoro-5-trifluoromethylbenzoic acid (120 mg, 0.577 mmol) was added to dry DMF (15 mL), EtOAc (EtOAc, EtOAc, 2.3 mmol), 1-(3-(thiazol-2-yl)phenyl)ethylamine (141 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water and extracted with ethyl acetate (30 mL×2) The combined organic layer was washed with EtOAc EtOAc EtOAc (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 70.4%. Melting point: 118-119 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.41(d,J＝6.8Hz,1H),8.03(s,1H),7.84-7.88(m,2H),7.70-7.78(m,1H),7.42-7.46(m,2H),7.34(d,J＝3.2Hz,1H),7.23-7.28(m,1H),6.96-7.04(m,1H),5.39-5.44(m,1H),1.67(d,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 8.41 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.84-7.88 (m, 2H), 7.70-7.78 (m, 1H) ), 7.42 - 7.46 (m, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.23 - 7.28 (m, 1H), 6.96 - 7.04 (m, 1H), 5.39 - 5.44 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H).

实施例(化合物)181Example (compound) 181

2-(二甲氨基)-N-(1-(3-(噻唑-2-基)苯基)乙基)-5-(三氟甲基)苯甲酰胺2-(Dimethylamino)-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-5-(trifluoromethyl)benzamide

Figure PCTCN2018088561-appb-000241
Figure PCTCN2018088561-appb-000241

a)2-(二甲氨基)-5-(三氟甲基)苯甲酸a) 2-(Dimethylamino)-5-(trifluoromethyl)benzoic acid

将2-氟-5-三氟甲基苯甲酸(624mg,3mmol)置于反应瓶中，加入乙腈(25mL)，加入二甲胺盐酸盐(316mg,3.9mmol)，加入DIEA(1.05mL,6mmol)，室温搅拌反应，次日补加二甲胺盐酸盐(316mg,3.9mmol)，加入DIEA(1.05mL,6mmol)，加热回流反应，20h后停止反应，浓缩，加入乙酸乙酯(60mL)，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝70:1)，得到白色固体350mg，产率50％。2-Fluoro-5-trifluoromethylbenzoic acid (624 mg, 3 mmol) was placed in a reaction flask, acetonitrile (25 mL) was added, dimethylamine hydrochloride (316 mg, 3.9 mmol) was added, and DIEA (1.05 mL, 6 mmol), the reaction was stirred at room temperature, dimethylamine hydrochloride (316 mg, 3.9 mmol) was added in the next day, and DIEA (1.05 mL, 6 mmol) was added, and the reaction was heated to reflux. After 20 h, the reaction was stopped, concentrated, ethyl acetate (60 mL) It was washed with a saturated NaCl solution (20 mL × 2), dried over anhydrous magnesium sulfate, and evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.59(s,1H),7.87(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,1H),2.88(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.59 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 2.88 (s, 6H).

b)2-(二甲氨基)-N-(1-(3-(噻唑-2-基)苯基)乙基)-5-(三氟甲基)苯酰胺b) 2-(Dimethylamino)-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-5-(trifluoromethyl)benzamide

将2-(二甲氨基)-5-(三氟甲基)苯甲酸(120mg,0.51mmol)加入无水DMF(15mL)，加入EDC(196mg,1.02mmol)，加入HOBt(138mg,1.02mmol)和DIEA(0.22mL,1.275mmol)，加入1-(3-(噻唑-2-基)苯基)乙胺(126mg,0.62mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2)，得到白色固体180mg，产率84.1％。熔点：128-129℃Add 2-(dimethylamino)-5-(trifluoromethyl)benzoic acid (120 mg, 0.51 mmol) to dry DMF (15 mL). And DIEA (0.22 mL, 1.275 mmol), 1-(3-(thiazol-2-yl)phenyl)ethylamine (126 mg, 0.62 mmol). (30 mL × 2), the organic layer was washed with saturated NaCI (30 mL × 2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (E: P = 1:4, E:P = 1:2) The white solid was 180 mg in a yield of 84.1%. Melting point: 128-129 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):9.25(d,J＝7.2Hz,1H),8.30(s,1H),8.05(s,1H),7.84-7.88(m,2H),7.62(d,J＝8.0Hz,1H),7.41-7.47(m,2H),7.35(t,J＝2.8Hz, 1H),7.22(d,J＝8.8Hz,1H),5.40-5.45(m,1H),2.75(s,6H),1.64(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 9.25 (d, J = 7.2 Hz, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.84-7.88 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.41 - 7.47 (m, 2H), 7.35 (t, J = 2.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.40 - 5.45 (m) , 1H), 2.75 (s, 6H), 1.64 (d, J = 6.8 Hz, 3H).

实施例(化合物)182Example (compound) 182

3-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺3-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000242
Figure PCTCN2018088561-appb-000242

a)3-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺a) 3-nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将3-硝基苯甲酸(125mg,0.748mmol)加入无水DMF(15mL)，加入EDC(287mg,1.5mmol)，加入HOBt(202mg,1.5mmol)和DIEA(0.32mL,1.87mmol)，加入1-(3-(噻唑-2-基)苯基)乙胺(168mg,0.82mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2)，得到白色固体250mg，产率94.6％。Add 3-nitrobenzoic acid (125 mg, 0.748 mmol) to dry DMF (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) -(3-(thiazol-2-yl)phenyl)ethylamine (168 mg, 0.82 mmol), EtOAc (EtOAc, m. The mixture was washed with EtOAc (3 mL, EtOAc).

1H-NMR(400MHz,CDCl 3)δ(ppm):8.60(s,1H),8.35(d,J＝8.4Hz,1H),8.16(d,J＝8.0Hz,1H),7.83-7.87(m,2H),7.63(t,J＝8.0Hz,1H),7.42-7.49(m,2H),7.35(d,J＝2.8Hz,1H),6.63(d,J＝6.8Hz,1H),5.38-5.42(m,1H),1.69(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.60 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.83-7.87 ( m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.42 - 7.49 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 6.8 Hz, 1H), 5.38-5.42 (m, 1H), 1.69 (d, J = 6.8 Hz, 3H).

b)3-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺b) 3-amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将3-硝基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯酰胺(200mg)，加入EtOH(15mL)，加入10％Pd/C(60mg)，常温常压下氢化反应，次日停止反应，过滤，浓缩，得到类白色固体170mg，产率92.8％。3-Nitro-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (200 mg), added to EtOH (15 mL), 10% Pd/C (60 mg), room temperature The hydrogenation reaction was carried out under normal pressure, and the reaction was stopped the next day, filtered, and concentrated to give a white solid (yield: 170 mg).

1H-NMR(400MHz,CDCl 3)δ(ppm):8.01(s,1H),7.86(s,1H),7.83(d,J＝7.2Hz,1H),7.39-7.46(m,2H),7.33(s,1H),7.13-7.20(m,2H),7.07(d,J＝6.4Hz,1H),6.78(d,J＝8.0Hz,1H),6.37(d,J＝6.8Hz,1H),5.34-5.39(m,1H),1.63(d,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.01 (s, 1H), 7.86 (s, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.39-7.46 (m, 2H), 7.33(s,1H), 7.13-7.20(m,2H),7.07(d,J=6.4Hz,1H),6.78(d,J=8.0Hz,1H),6.37(d,J=6.8Hz,1H ), 5.34 - 5.39 (m, 1H), 1.63 (d, J = 6.8 Hz, 3H).

c)3-异丁酰氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯甲酰胺c) 3-isobutyrylamino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide

将异丁酸(0.04mL,0.41mmol)加入无水DMF(15mL)，加入EDC(157mg,0.82mmol)，加入HOBt(111mg,0.82mmol)和DIEA(0.18mL,1.025mmol)，随后加入3-氨基-N-(1-(3-(噻唑-2-基)苯基)乙基)苯酰胺(132mg,0.41mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2,E:P＝1:1.5)，得到白色固体50mg，产率37.3％。熔点：184-186℃Add isobutyric acid (0.04 mL, 0.41 mmol) to dry DMF (15 mL), EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) Amino-N-(1-(3-(thiazol-2-yl)phenyl)ethyl)benzamide (132 mg, 0.41 mmol), mp. 2) The organic layer was washed with saturated NaCl (30 mL×2), dried over anhydrous magnesium sulfate. The yield was 37.3%. Melting point: 184-186 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):8.01(s,1H),7.86-7.89(m,2H),7.81(d,J＝6.8Hz,2H),7.71(s,1H),7.31-7.49(m,5H),6.57(d,J＝6.8Hz,1H),5.34-5.38(m,1H),2.47-2.53(m,1H),1.62(d,J＝6.8Hz,3H),1.21(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.01 (s, 1H), 7.86-7.89 (m, 2H), 7.81 (d, J = 6.8Hz, 2H), 7.71 (s, 1H), 7.31-7.49 (m, 5H), 6.57 (d, J = 6.8 Hz, 1H), 5.34 - 5.38 (m, 1H), 2.47 - 2.53 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H) , 1.21 (d, J = 6.8 Hz, 6H).

实施例(化合物)183Example (compound) 183

N-(3-(噻唑-2-基)苯甲基)-2,5-二(2,2,2-三氟乙氧基)苯甲酰胺N-(3-(thiazol-2-yl)benzyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000243
Figure PCTCN2018088561-appb-000243

将2,5-双三氟乙氧基苯甲酸(120mg,0.38mmol)加入无水DMF(15mL)，加入EDC(146mg,0.76mmol)，加入HOBt(103mg,0.76mmol)和DIEA(0.17mL,0.95mmol)，加入(3-(噻唑-2-基)苯基)甲胺(179mg,0.94mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4，E:P＝1:3)，得到白色固体60mg，产率32.2％。熔点：124-126℃Add 2,5-bistrifluoroethoxybenzoic acid (120 mg, 0.38 mmol) to dry DMF (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) (5,5 mmol), (3-(thiazol-2-yl)phenyl)methanamine (179 mg, 0.94 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water and extracted with ethyl acetate (30 mL×2) The organic layer was washed with saturated aqueous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH . Melting point: 124-126 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.96(s,1H),7.85-7.90(m,3H),7.80(d,J＝3.2Hz,1H),7.44(d,J＝4.4Hz,2H),7.34(d,J＝3.2Hz,1H),7.10(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),6.88(d,J＝9.2Hz,1H),4.71(d,J＝5.6Hz,2H),4.35-4.45(m,4H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.96 (s, 1H), 7.85-7.90 (m, 3H), 7.80 (d, J = 3.2Hz, 1H), 7.44 (d, J = 4.4 Hz, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.10 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.71 ( d, J = 5.6 Hz, 2H), 4.35 - 4.45 (m, 4H).

实施例(化合物)184Example (compound) 184

N-(1-(3-(噻唑-2-基)苯基)乙基)-2,5-二(2,2,2-三氟乙氧基)苯甲酰胺N-(1-(3-(thiazol-2-yl)phenyl)ethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide

Figure PCTCN2018088561-appb-000244
Figure PCTCN2018088561-appb-000244

将2,5-双三氟乙氧基苯甲酸(120mg,0.38mmol)加入无水DMF(15mL)，加入EDC(146mg,0.76mmol)，加入HOBt(103mg,0.76mmol)和DIEA(0.17mL,0.95mmol)，加入1-(3-(噻唑-2-基)苯基)乙胺(92mg,0.45mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4，E:P＝1:3)，得到无色油状物160mg，产率80.8％。Add 2,5-bistrifluoroethoxybenzoic acid (120 mg, 0.38 mmol) to dry DMF (15 mL), EtOAc (EtOAc, EtOAc (EtOAc) Addition of 1-(3-(thiazol-2-yl)phenyl)ethylamine (92 mg, 0.45 mmol), EtOAc. The combined organic layer was washed with EtOAc (3 mL, dryness. The yield was 80.8%.

1H-NMR(400MHz,CDCl 3)δPPm:7.99(s,1H),7.91(d,J＝6.4Hz,1H),7.82-7.86(m,2H),7.75(d,J＝2.8Hz,1H),7.40-7.46(m,2H),7.33(d,J＝2.8Hz,1H),7.09(dd, J 1＝8.8Hz,J 2＝2.8Hz,1H),6.87(d,J＝9.2Hz,1H),5.30-5.35(m,1H),4.40～4.55(m,2H),4.34(q,J＝8.0Hz,1H),1.61(d,J＝6.8Hz,3H). 1 H-NMR δPPm (400MHz, CDCl 3): 7.99 (s, 1H), 7.91 (d, J = 6.4Hz, 1H), 7.82-7.86 (m, 2H), 7.75 (d, J = 2.8Hz, 1H ), 7.40-7.46 (m, 2H), 7.33 (d, J = 2.8 Hz, 1H), 7.09 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 6.87 (d, J = 9.2 Hz) , 1H), 5.30-5.35 (m, 1H), 4.40 to 4.55 (m, 2H), 4.34 (q, J = 8.0 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H).

实施例(化合物)185Example (compound) 185

N-(1-(6-(苄氧基)吡啶-2-基)乙基)-2-乙氧基-5-异丁酰胺基苯甲酰胺N-(1-(6-(Benzyloxy)pyridin-2-yl)ethyl)-2-ethoxy-5-isobutyramidobenzamide

Figure PCTCN2018088561-appb-000245
Figure PCTCN2018088561-appb-000245

a)6-苄氧基-吡啶-2-甲酸a) 6-benzyloxy-pyridine-2-carboxylic acid

将化合物苄醇(0.83mL,8mmol)加入干燥THF(40mL)，氩气保护下室温下加入NaH(480mg,12mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(630mg,4mmol)加入反应瓶中，加毕，升温至回流反应，6h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至3左右，用DCM:MeOH＝10:1的混合液(60mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，用乙酸乙酯和石油醚重结晶，得到白色固体620mg，产率67.7％；m.p.119-121℃。1H-NMR(400MHz,CDCl3)δ(ppm):7.81-7.86(m,2H),7.37-7.47(m,5H),7.09-7.14(m,1H),5.41(s,2H).The compound benzyl alcohol (0.83 mL, 8 mmol) was added to dry THF (40 mL), EtOAc (EtOAc, EtOAc. Adding to the reaction flask, adding, heating to reflux reaction, stopping the reaction after 6h, adding water, washing with diethyl ether (20mL), adjusting the pH of the aqueous layer with dilute HCl to about 3, using a mixture of DCM: MeOH = 10:1 (60 mL × 2), EtOAc (3 mL, EtOAc) 119-121 ° C. 1H-NMR (400MHz, CDCl3) δ (ppm): 7.81-7.86 (m, 2H), 7.37-7.47 (m, 5H), 7.09-7.14 (m, 1H), 5.41 (s, 2H).

b)6-(苄氧基)-N-甲氧基-N-甲基吡啶-2-甲酰胺b) 6-(Benzyloxy)-N-methoxy-N-methylpyridine-2-carboxamide

将化合物6-苄氧基-吡啶-2-甲酸(573mg,2.5mmol)加入无水DMF(30mL)，加入HBTU(1.89g,5.0mmol)，HOBt(675mg,5.0mmol)和DIEA(2.6mL,15.0mmol)，加入N,O-二甲基羟胺(485mg,5.0mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4)，得到无色油状物630mg，产率92.6％。The compound 6-benzyloxy-pyridine-2-carboxylic acid (573 mg, 2.5 mmol) was taken in anhydrous DMF (30 mL). EtOAc (EtOAc, EtOAc, EtOAc 15.0 mmol), N,O-dimethylhydroxylamine (485 mg, 5.0 mmol) was added, and the mixture was stirred at room temperature overnight, and the mixture was poured into water and extracted with a mixture of ethyl acetate:methanol=10:1 (30 mL×2) The combined organic layer was washed with aq. EtOAc (EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.65-7.70(m,1H),7.31-7.45(m,6H),6.89(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),3.73(s,3H),3.36(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.65-7.70 (m, 1H), 7.31 - 7.45 (m, 6H), 6.89 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H ), 3.73 (s, 3H), 3.36 (s, 3H).

c)1-(6-(苄氧基)吡啶-2-基)乙酮c) 1-(6-(Benzyloxy)pyridin-2-yl)ethanone

将化合物6-(苄氧基)-N-甲氧基-N-甲基吡啶甲酰胺(590mg,2.17mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(2.82mL,2.82mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗， 无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20)，得到无色油状物420mg，产率85.2％。The compound 6-(benzyloxy)-N-methoxy-N-methylpyridinecarboxamide (590 mg, 2.17 mmol) was added to dry THF (20 mL) and 1M methylmagnesium bromide at 0 ° C under argon atmosphere. The THF solution (2.82 mL, 2.82 mmol) was added dropwise to the reaction flask. After the dropwise addition, the reaction was stirred at 0 ° C. After 2 h, the saturated ammonium chloride solution was added to the reaction flask, and extracted with EA (40 mL×2). The organic layer was washed with EtOAc EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.71(t,J＝7.2Hz,1H),7.63-7.65(m,1H),7.47-7.50(m,2H),7.32-7.41(m,3H),6.99(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),5.46(s,2H),2.67(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71 (t, J = 7.2 Hz, 1H), 7.63-7.65 (m, 1H), 7.47-7.50 (m, 2H), 7.32-7.41 (m) , 3H), 6.99 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 5.46 (s, 2H), 2.67 (s, 3H).

d)1-(6-(苄氧基)吡啶-2-基)乙酮肟d) 1-(6-(Benzyloxy)pyridin-2-yl)ethanone oxime

将1-(6-(苄氧基)吡啶-2-基)乙酮(380mg,1.67mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.29mL,5.02mmol)升温至60℃反应，3h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:10)得到白色固体314mg，产率77.7％；m.p.74-76℃。1-(6-(Benzyloxy)pyridin-2-yl)ethanone (380 mg, 1.67 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine solution (0.29 mL, 5.02 mmol) was added. The reaction was carried out at 60 ° C. After 3 h, the reaction was evaporated. EtOAc EtOAc m.

1H-NMR(500MHz,CDCl3)δ(ppm):7.58(t,J＝8.0Hz,1H),7.46-7.48(m,2H),7.35-7.39(m,3H),7.30-7.32(m,1H),6.79(d,J＝8.5Hz,1H),5.43(s,2H),2.35(s,3H). 1 H-NMR (500MHz, CDCl3 ) δ (ppm): 7.58 (t, J = 8.0Hz, 1H), 7.46-7.48 (m, 2H), 7.35-7.39 (m, 3H), 7.30-7.32 (m, 1H), 6.79 (d, J = 8.5 Hz, 1H), 5.43 (s, 2H), 2.35 (s, 3H).

e)1-(6-(苄氧基)吡啶-2-基)乙胺e) 1-(6-(Benzyloxy)pyridin-2-yl)ethylamine

将1-(6-(苄氧基)吡啶-2-基)乙酮肟(242mg,1.0mmol)置于反应瓶中，加入乙醇(8mL)，水(1.5mL)，加入锌粉(195mg,3.0mmol)以及2.5N HCl溶液(2.4mL,6.0mmol)，室温搅拌反应，4h后停止反应，过滤，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸氢钠溶液调PH值至8-9，用EA:MeOH＝10:1的混合液(20mL×3)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到无色油状物160mg，产率70.1％。1-(6-(Benzyloxy)pyridin-2-yl)ethanone oxime (242 mg, 1.0 mmol) was placed in a reaction flask, and ethanol (8 mL), water (1.5 mL) was added, and zinc powder (195 mg, 3.0 mmol) and 2.5N HCl solution (2.4 mL, 6.0 mmol), the reaction was stirred at room temperature, the reaction was stopped after 4 h, filtered, concentrated, water, extracted with ethyl ether 20mL, the aqueous layer was adjusted to a A mixture of EA: MeOH = 10:1 (20 mL, EtOAc). The yield was 70.1%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.49-7.54(m,1H),7.45-7.48(m,2H),7.29-7.38(m,3H),6.80(d,J＝7.2Hz,1H),6.65(d,J＝8.0Hz,1H),5.40(s,2H),4.04(q,J＝6.8Hz,1H),2.53(brs,2H),1.41(d,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.49-7.54 (m, 1H), 7.45-7.48 (m, 2H), 7.29-7.38 (m, 3H), 6.80 (d, J = 7.2 Hz) , 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.40 (s, 2H), 4.04 (q, J = 6.8 Hz, 1H), 2.53 (brs, 2H), 1.41 (d, J = 6.8 Hz) , 3H).

f)N-(1-(6-(苄氧基)吡啶-2-基)乙基)-2-乙氧基-5-异丁酰胺基苯甲酰胺f) N-(1-(6-(Benzyloxy)pyridin-2-yl)ethyl)-2-ethoxy-5-isobutyramidobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(15mL)，加入EDC(153mg,0.796mmol)，加入HOBt(108mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入化合物1-(6-(苄氧基)吡啶-2-基)乙胺(137mg,0.60mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2)，得到白色固体140mg，产率76.5％；m.p.157-159℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (15 mL). E.sub.2 (153 mg, 0.796 mmol) was added, and HOBt (108 mg, 0.796 mmol) and DIEA (0.21) The compound 1-(6-(benzyloxy)pyridin-2-yl)ethylamine (137 mg, 0.60 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was extracted with a mixture of 10:1 (30 mL×2), and the combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:4, E: P = 1:2) gave a white solid, 140 mg, yield 76.5%; mp 157-159.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.72(d,J＝7.6Hz,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.82(d,J＝2.0Hz,1H),7.53-7.58(m,2H),7.42-7.45(m,2H),7.27-7.34 (m,3H),6.89-6.93(m,2H),6.68(t,J＝9.2Hz,1H),5.40(s,2H),5.28-5.35(m,1H),4.10-4.17(m,2H),2.47-2.55(m,1H),1.57(d,J＝6.8Hz,3H),1.40(t,J＝6.8Hz,3H),1.21(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.72 (d, J = 7.6 Hz, 1H), 8.21. (dd, J 1 = 8.8 Hz, J 2 = 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.53-7.58 (m, 2H), 7.42-7.45 (m, 2H), 7.27-7.34 (m, 3H), 6.89-6.93 (m, 2H), 6.68 (t, J = 9.2 Hz, 1H), 5.40 (s, 2H), 5.28-5.35 (m, 1H), 4.10-4.17 (m, 2H), 2.47-2.55 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H) ), 1.40 (t, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 6H).

实施例(化合物)186Example (compound) 186

N-(1-(6-(2-(二甲氨基)乙氧基)吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(1-(6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000246
Figure PCTCN2018088561-appb-000246

a)6-(2-(二甲氨基)乙氧基)吡啶-2-甲酸a) 6-(2-(Dimethylamino)ethoxy)pyridine-2-carboxylic acid

将化合物2-N,N-二甲基乙醇(1mL,10mmol)加入干燥THF(40mL)，氩气保护下室温下加入NaH(480mg,12mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(630mg,4mmol)加入反应瓶中，加毕，升温至回流反应，8h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至4左右，用正丁醇(20mL×4)萃取，无水硫酸镁干燥，浓缩，得到类白色固体470mg，产率55.9％；m.p.60-62℃。The compound 2-N,N-dimethylethanol (1 mL, 10 mmol) was added to dry THF (40 mL), and then NaH (480 mg, 12 mmol) - Formic acid (630 mg, 4 mmol) was added to the reaction flask. After the addition, the mixture was heated to reflux. After 8 h, the reaction was stopped. Water was added and washed with diethyl ether (20 mL). The aqueous layer was adjusted to pH 4 with dilute HCl. (20 mL × 4) was extracted, dried over anhydrous magnesium sulfate and evaporated to afford 470 mg of white solid.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):7.91-7.95(m,1H),7.71(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),7.12(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),4.67-4.70(m,2H),3.49-3.52(m,2H),2.85(s,6H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 7.91 - 7.95 (m, 1H), 7.71 (dd, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H), 7.12 (dd, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H), 4.67 - 4.70 (m, 2H), 3.49 - 3.52 (m, 2H), 2.85 (s, 6H).

b)6-(2-(二甲氨基)乙氧基)-N-甲氧基-N-甲基吡啶-2-甲酰胺b) 6-(2-(Dimethylamino)ethoxy)-N-methoxy-N-methylpyridine-2-carboxamide

将6-(2-(二甲氨基)乙氧基)吡啶-2-甲酸(450mg,2.14mmol)加入无水DMF(30mL)，加入HBTU(1.62g,4.28mmol)，HOBt(578mg,4.28mmol)和DIEA(2.2mL,12.84mmol)，加入N,O-二甲基羟胺(416mg,4.28mmol)，室温搅拌过夜，次日停止反应，浓缩至干，柱层析(D:M:氨水＝40:1:0.005，D:M:氨水＝20:1:0.0075)，得到淡黄色油状物500mg，产率93.4％。6-(2-(Dimethylamino)ethoxy)pyridine-2-carboxylic acid (450 mg, 2.14 mmol) was added to dry DMF (30 mL), EtOAc (1. And DIEA (2.2 mL, 12.84 mmol), N,O-dimethylhydroxylamine (416 mg, 4.28 mmol) was added, stirred at room temperature overnight, the reaction was stopped the next day, concentrated to dryness, column chromatography (D:M: ammonia = 40:1:0.005, D:M: Ammonia = 20:1: 0.0075) gave a pale yellow oil, 500 mg, yield 93.4%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.61-7.66(m,1H),7.20-7.23(m,1H),6.88(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),4.62-4.65(m,2H),3.69(s,3H),3.33(s,3H),3.18-3.21(m,2H),2.68(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.61-7.66 (m, 1H), 7.20-7.23 (m, 1H), 6.88 (dd, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H ), 4.62-4.65 (m, 2H), 3.69 (s, 3H), 3.33 (s, 3H), 3.18-3.21 (m, 2H), 2.68 (s, 6H).

c)(6-(2-(二甲氨基)乙氧基)吡啶-2-基)乙酮c) (6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)ethanone

将6-(2-(二甲氨基)乙氧基)-N-甲氧基-N-甲基吡啶甲酰胺(530mg,2.09mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(5.22mL,5.22mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加 入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M:氨水＝500:10:2)，得到无色油状物178mg，产率41.2％。Add 6-(2-(dimethylamino)ethoxy)-N-methoxy-N-methylpyridinecarboxamide (530 mg, 2.09 mmol) to dry THF (20 mL). 1M methylmagnesium bromide in THF (5.22 mL, 5.22 mmol) was added dropwise to the reaction flask, and the reaction was continued at 0 ° C. After 2 h, saturated ammonium chloride solution was added to the reaction flask, using EA (40 mL) ×2) Extraction, the organic layer was combined, washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (D:M: ammonia = 500:10:2) to give a colorless oil. 178 mg, yield 41.2%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.70(t,J＝8.0Hz,1H),7.63(dd,J 1＝7.2Hz,J 2＝0.8Hz,1H),6.98(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),4.51(t,J＝4.8Hz,2H),2.77(t,J＝5.2Hz,2H),2.67(s,3H),2.37(s,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.70 (t, J = 8.0 Hz, 1H), 7.63 (dd, J 1 = 7.2 Hz, J 2 = 0.8 Hz, 1H), 6.98 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 4.51 (t, J = 4.8 Hz, 2H), 2.77 (t, J = 5.2 Hz, 2H), 2.67 (s, 3H), 2.37 (s, 6H).

d)1-(6-(2-(二甲氨基)乙氧基)吡啶-2-基)乙酮肟d) 1-(6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)ethanone oxime

将(6-(2-(二甲氨基)乙氧基)吡啶-2-基)乙酮(150mg,0.72mmol)置于反应瓶中，加入EtOH(5mL)，加入50％羟胺水溶液(0.13mL,2.16mmol)升温至60℃反应，4h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，浓缩得到淡黄色固体145mg，产率90.6％；m.p.96-98℃。(6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)ethanone (150 mg, 0.72 mmol) was placed in a reaction flask, EtOH (5 mL) was added, and 50% aqueous hydroxylamine solution (0.13 mL) was added. , 2.16 mmol) was warmed to 60 ° C. The reaction was quenched after 4 h, then DCM (30 mL).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.48-7.53(m,1H),7.34(d,J＝8.4Hz,1H),6.71-6.74(m,1H),4.51(t,J＝5.2Hz,2H),2.79(t,J＝5.6Hz,2H),2.39(s,6H),2.29(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.48-7.53 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.71-6.74 (m, 1H), 4.51 (t, J) = 5.2 Hz, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.39 (s, 6H), 2.29 (s, 3H).

e)2-((6-(1-氨基乙基)吡啶-2-基)氧代)-N,N-二甲基乙胺e) 2-((6-(1-Aminoethyl)pyridin-2-yl)oxo)-N,N-dimethylethylamine

将1-(6-(2-(二甲氨基)乙氧基)吡啶-2-基)乙酮肟(145mg,0.65mmol)，加入甲醇(6mL)，加入10％Pd/C(145mg)，加热至回流，加入甲酸铵(410mg,6.5mmol)，继续回流反应，30min后停止反应，过滤，浓缩得到淡黄色油状物120mg，产率88.2％。1-(6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)ethanone oxime (145 mg, 0.65 mmol) was added to methanol (6 mL), and 10% Pd/C (145 mg) was added. After heating to reflux, ammonium formate (410 mg, 6.5 mmol) was added, and the reaction was refluxed. After 30 min, the reaction was quenched, filtered and concentrated to give a pale yellow oil.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.49(t,J＝7.6Hz,1H),679(d,J＝7.2Hz,1H),6.61(d,J＝8.4Hz,1H),4.50(t,J＝6.0Hz,2H),4.07(q,J＝6.8Hz,1H),2.74(t,J＝5.6Hz,2H),2.34(s,6H),1.43(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.49 (t, J = 7.6 Hz, 1H), 679 (d, J = 7.2 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H) , 4.50 (t, J = 6.0 Hz, 2H), 4.07 (q, J = 6.8 Hz, 1H), 2.74 (t, J = 5.6 Hz, 2H), 2.34 (s, 6H), 1.43 (d, J = 6.8Hz, 3H).

f)N-(1-(6-(2-(二甲氨基)乙氧基)吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯酰胺f) N-(1-(6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(80mg,0.319mmol)加入无水DMF(15mL)，加入EDC(122mg,0.638mmol)，HOBt(122mg,0.638mmol)和DIEA(0.17mL,0.957mmol)，加入化合物2-((6-(1-氨基乙基)吡啶-2-基)氧代)-N,N-二甲基乙胺(100mg,0.478mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝20:1,D:M＝17.5:1,D:M＝12.5:1)，得到白色固体74mg，产率52.5％；m.p.90-92℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (80 mg, 0.319 mmol) was added to dry DMF (15 mL). E.sub.2 (122 mg, 0.638 mmol), HOBt (122 mg, 0.638 mmol) and DIEA (0.17 mL) , the compound 2-((6-(1-aminoethyl)pyridin-2-yl)oxo)-N,N-dimethylethylamine (100 mg, 0.478 mmol). The reaction mixture was poured into water and extracted with a mixture of ethyl acetate:methanol = 10:1 (30 mL×2). The organic layer was washed with saturated NaCI (15 mL×2) Chromatography (D: M = 20:1, D: M = 17.5:1, D: M = 12.5:1).

1H-NMR(400MHz,CDCl 3)δ(ppm):8.64(d,J＝8.0Hz,1H),8.20(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.83(d,J＝2.8Hz,1H),7.50-7.54(m,2H),6.94(d,J＝9.2Hz,1H), 6.88(d,J＝7.6Hz,1H),6.66(d,J＝8.4Hz,1H),5.26-5.33(m,1H),4.46-4.53(m,2H),4.18(q,J＝6.8Hz,2H),2.78(brs,2H),2.48-2.56(m,1H),2.38(s,6H),1.56(d,J＝7.2Hz,3H),1.44(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.64 (d, J = 8.0 Hz, 1H), 8.20 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.50 - 7.54 (m, 2H), 6.94 (d, J = 9.2 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.26-5.33 (m, 1H), 4.46-4.53 (m, 2H), 4.18 (q, J = 6.8 Hz, 2H), 2.78 (brs, 2H), 2.48-2.56 (m, 1H), 2.38 (s, 6H), 1.56 (d, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)187Example (compound) 187

4-((6-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯4-((6-(1-(2-ethoxy-5-isobutyryl)benzoylamino)ethyl)pyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester

Figure PCTCN2018088561-appb-000247
Figure PCTCN2018088561-appb-000247

a)6-((1-(叔-丁氧基羰基)哌啶-4-基)氧代)吡啶-2-甲酸a) 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)oxo)pyridine-2-carboxylic acid

将化合物N-Boc-4-羟基哌啶(1.61g,8mmol)加入干燥THF(40mL)，氩气保护下室温下加入NaH(480mg,12mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(630mg,4mmol)加入反应瓶中，加毕，升温至回流反应，8h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至3左右，用乙酸乙酯(60mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，得到类白色固体1.1g，产率84.6％；m.p.117-119℃。The compound N-Boc-4-hydroxypiperidine (1.61 g, 8 mmol) was added to dry THF (40 mL), EtOAc (EtOAc) - Formic acid (630 mg, 4 mmol) was added to the reaction flask, and the mixture was warmed to reflux. After 8 h, the reaction was stopped. Water was added and washed with diethyl ether (20 mL). (60 mL × 2), the combined organic layer was washed with EtOAc EtOAc m.

1H-NMR(500MHz,CDCl 3)δ(ppm):7.80-7.84(m,2H),7.01-7.04(m,1H),5.21-5.26(m,1H),3.70-3.75(m,2H),3.36-3.42(m,2H),1.96-2.05(m,2H),1.76-1.83(m,2H),1.48(s,9H). 1 H-NMR (500MHz, CDCl 3 ) δ (ppm): 7.80-7.84 (m, 2H), 7.01-7.04 (m, 1H), 5.21-5.26 (m, 1H), 3.70-3.75 (m, 2H) , 3.36-3.42 (m, 2H), 1.96-2.05 (m, 2H), 1.76-1.83 (m, 2H), 1.48 (s, 9H).

b)4-((6-(甲氧基(甲基)氨基甲酰)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯b) 4-((6-(Methoxy(methyl)carbamoyl)pyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester

将6-((1-(叔-丁氧基羰基)哌啶-4-基)氧代)吡啶-2-甲酸(1.06g,3.29mmol)加入无水DMF(40mL)，加入HBTU(2.15g,6.58mmol)，HOBt(888mg,6.58mmol)和DIEA(3.44mL,19.74mmol)，加入N,O-二甲基羟胺(638mg,6.58mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(50mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4,E:P＝1:2,D:M＝70:1)，得到无色油状物600mg，产率50％。Add 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)oxo)pyridine-2-carboxylic acid (1.06 g, 3.29 mmol) to dry DMF (40 mL). , 6.58 mmol), HOBt (888 mg, 6.58 mmol) and DIEA (3.44 mL, 19.74 mmol), and then added N,O-dimethylhydroxylamine (638 mg, 6.58 mmol), stirred at room temperature overnight, and poured into water. Ethyl acetate: a mixture of methanol = 10:1 (50 mL × 2). The combined organic layer was washed with saturated NaCI (30 mL×2), dried over anhydrous magnesium sulfate : 4, E: P = 1: 2, D: M = 70: 1), yielded 600 mg of colorless oil, yield 50%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.63-7.67(m,1H),7.20(brs,1H),6.79(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),5.25-5.30(m,1H),3.70-3.76(m,5H),3.40(s,3H),3.28-3.34(m,2H),1.92-1.99(m,2H),1.70-1.78(m,2H),1.47(s,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.63-7.67 (m, 1H), 7.20 (brs, 1H), 6.79 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 5.25-5.30(m,1H), 3.70-3.76(m,5H), 3.40(s,3H), 3.28-3.34(m,2H),1.92-1.99(m,2H),1.70-1.78(m,2H) ), 1.47 (s, 9H).

c)4-((6-乙酰基吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯c) 4-((6-Acetylpyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester

将化合物4-((6-(甲氧基(甲基)氨基甲酰)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯(550mg,1.50mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(1.96mL,1.96mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:15,E:P＝1:10)，得到无色油状物410mg，产率85.4％。The compound 4-((6-(methoxy(methyl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (550 mg, 1.50 mmol) was added to dry THF (20 mL) Under a argon atmosphere, 1 M methylmagnesium bromide in THF (1.96 mL, 1.96 mmol) was added dropwise to the reaction flask at 0 ° C. After completion, the reaction was stirred at 0 ° C, and saturated ammonium chloride was added after 2 h. The solution was added to a reaction flask, and extracted with EA (40 mL×2). The organic layer was combined, washed with a saturated NaCI solution (15mL×2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (E:P=1:15, E: P = 1: 10) gave 410 mg of colorless oil (yield: 85.4%).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.68(t,J＝5.6Hz,1H),7.59(dd,J 1＝7.6Hz,J 2＝1.2Hz,1H),6.88(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),5.24-5.30(m,1H),3.71-3.78(m,2H),3.29-3.36(m,2H),2.62(s,3H),1.98-2.03(m,2H),1.73-1.82(m,2H),1.46(s,9H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.68 (t, J = 5.6Hz, 1H), 7.59 (dd, J 1 = 7.6Hz, J 2 = 1.2Hz, 1H), 6.88 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 5.24-5.30 (m, 1H), 3.71-3.78 (m, 2H), 3.29-3.36 (m, 2H), 2.62 (s, 3H), 1.98 -2.03 (m, 2H), 1.73-1.82 (m, 2H), 1.46 (s, 9H).

d)4-((6-(1-(肟基)乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯d) 4-((6-(1-(indolyl)ethyl)pyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester

将化合物4-((6-乙酰基吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯(380mg,1.19mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.21mL,3.57mmol)升温至60℃反应，3h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:6)得到白色固体320mg，产率80.4％；m.p.142-144℃。The compound 4-((6-acetylpyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester (380 mg, 1.19 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% was added. The aqueous solution of hydroxylamine (0.21 mL, 3.57 mmol) was heated to 60 ° C, and the reaction was stopped after 3 h, then DCM (30 mL) was evaporated. The rate was 80.4%; mp142-144 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.57(t,J＝8.0Hz,1H),7.34(d,J＝8.4Hz,1H),6.70(d,J＝8.0Hz,1H),5.26-5.31(m,1H),3.71-3.81(m,2H),3.28-3.35(m,2H),2.32(s,3H),1.99-2.04(m,2H),1.73-1.79(m,2H),1.48(s,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.57 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H) , 5.26-5.31 (m, 1H), 3.71-3.81 (m, 2H), 3.28-3.35 (m, 2H), 2.32 (s, 3H), 1.99-2.04 (m, 2H), 1.73-1.79 (m, 2H), 1.48 (s, 9H).

e)4-((6-(1-氨基乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯e) 4-((6-(1-Aminoethyl)pyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester

将化合物4-((6-(1-(肟基)乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯(300mg,0.89mmol)，加入甲醇(8mL)，加入10％Pd/C(300mg)，加热至回流，加入甲酸铵(561mg,8.9mmol)，继续回流反应，20min后停止反应，过滤，浓缩得到无色油状物260mg，产率90.9％。The compound 4-((6-(1-(indolyl)ethyl)pyridin-2-yl)oxanylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.89 mmol) was added to methanol (8 mL). 10% Pd/C (300 mg) was added, and the mixture was evaporated to EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.50-7.55(m,1H),6.81(d,J＝9.6Hz,1H),6.59(d,J＝8.4Hz,1H),5.27-5.30(m,1H),4.06-4.13(m,3H),3.70-3.75(m,2H),3.30-3.36(m,2H),1.93-1.97(m,2H),1.68-1.77(m,2H),1.45-1.47(m,12H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.50-7.55 (m, 1H), 6.81 (d, J = 9.6 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.27- 5.30 (m, 1H), 4.06-4.13 (m, 3H), 3.70-3.75 (m, 2H), 3.30-3.36 (m, 2H), 1.93-1.97 (m, 2H), 1.68-1.77 (m, 2H) ), 1.45-1.47 (m, 12H).

f)4-((6-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯f) 4-((6-(1-(2-ethoxy-5-isobutyrylaminobenzoylamino)ethyl)pyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl ester

将2-乙氧基-5-异丁酰氨基苯甲酸(120mg,0.498mmol)加入无水DMF(15mL)，加入EDC(191mg,0.996mmol)，加入HOBt(134mg,0.996mmol)和DIEA(0.26mL, 1.494mmol)，加入化合物4-((6-(1-氨基乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯(240mg,0.747mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:2)，得到白色固体250mg，产率90.6％；m.p.81-83℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (120 mg, 0.498 mmol) was added to dry DMF (15 mL). E.sub.2 (191 mg, 0.996 mmol). The compound 4-((6-(1-aminoethyl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.747 mmol) The reaction mixture was poured into water and extracted with a mixture of ethyl acetate:methanol = 10:1 (30 mL×2). Column chromatography (E: P = 1:2) gave a white solid (yield: 250 mg, mp.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.63(d,J＝8.0Hz,1H),8.20(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.85-7.87(m,1.5H),7.65(brs,0.5H),7.50-7.56(m,1H),6.94(d,J＝9.2Hz,1H),6.87-6.89(m,1H),6.60(t,J＝8.4Hz,1H),5.22-5.34(m,1H),4.17(q,J＝7.2Hz,2H),3.68-3.73(m,2H),3.25-3.34(m,2H),2.48-2.55(m,1H),1.90-1.98(m,2H),1.70-1.78(m,2H),1.54-1.57(m,3H),1.47(s,9H),1.41-1.46(m,3H),1.19-1.22(m,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.63 (d, J = 8.0 Hz, 1H), 8.20 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.85-7.87 ( m, 1.5H), 7.65 (brs, 0.5H), 7.50-7.56 (m, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.87-6.89 (m, 1H), 6.60 (t, J = 8.4 Hz, 1H), 5.22-5.34 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.68-3.73 (m, 2H), 3.25-3.34 (m, 2H), 2.48-2.55 (m , 1H), 1.90-1.98 (m, 2H), 1.70-1.78 (m, 2H), 1.54-1.57 (m, 3H), 1.47 (s, 9H), 1.41-1.46 (m, 3H), 1.19-1.22 (m, 6H).

实施例(化合物)188Example (compound) 188

2-乙氧基-5-异丁酰氨基-N-(1-(6-(哌啶-4-氧基)吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-(piperidin-4-oxy)pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000248
Figure PCTCN2018088561-appb-000248

将化合物4-((6-(1-(2-乙氧基-5-异丁酰氨基苯甲酰氨基)乙基)吡啶-2-基)氧代)哌啶-1-羧酸叔丁酯(180mg,0.325mmol)加入DCM(6mL)，加入TFA(0.24mL,3.25mmol)室温搅拌反应，6h后停止反应，加入乙醚，没有固体析出，浓缩至干，加入水，加入氨水调PH值至9左右，振荡片刻后用EA(20mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，用DCM和石油醚重结晶得到类白色固体物83mg，产率56.4％；m.p.167-169℃。The compound 4-((6-(1-(2-ethoxy-5-isobutyrylbenzoylamino)ethyl)pyridin-2-yl)oxo)piperidine-1-carboxylic acid tert-butyl The ester (180 mg, 0.325 mmol) was added to DCM (6 mL), and the mixture was stirred at room temperature with TFA (0.24 mL, 3.25 mmol). The reaction was stirred at room temperature. After 6h, the reaction was stopped, ether was added, no solids were precipitated, concentrated to dryness, water was added, and ammonia was added to adjust the pH. After vortexing, it was extracted with EA (20 mL×2). The organic layer was evaporated. 83 mg, yield 56.4%; mp 167-169 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.68(d,J＝8.0Hz,1H),8.22-8.27(m,1H),7.79-7.91(m,2H),7.49-7.54(m,1H),6.94(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),6.83-6.87(m,1H),6.59(dd,J 1＝8.0Hz,J 2＝1.2Hz,1H),5.26-5.32(m,1H),5.13-5.19(m,1H),4.14-4.21(m,2H),3.08-3.15(m,2H),2.68-2.79(m,2H),2.50-2.58(m,1H),1.98-2.08(m,2H),1.63-1.71(m,2H),1.55(dd,J 1＝6.8Hz,J 2＝1.6Hz,3H),1.42-1.47(m,3H),1.18-1.23(m,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.68 (d, J = 8.0 Hz, 1H), 8.22 - 8.27 (m, 1H), 7.79 - 7.91 (m, 2H), 7.49 - 7.54 (m) , 1H), 6.94 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 6.83 - 6.87 (m, 1H), 6.59 (dd, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H) , 5.26-5.32 (m, 1H), 5.13-5.19 (m, 1H), 4.14 - 4.21 (m, 2H), 3.08-3.15 (m, 2H), 2.68-2.79 (m, 2H), 2.50-2.58 ( m,1H), 1.98-2.08 (m, 2H), 1.63-1.71 (m, 2H), 1.55 (dd, J 1 = 6.8 Hz, J 2 = 1.6 Hz, 3H), 1.42-1.47 (m, 3H) , 1.18-1.23 (m, 6H).

实施例(化合物)189Example (compound) 189

2-乙氧基-5-异丁酰氨基-N-(1-(3-苯甲基)环丙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-phenylmethyl)cyclopropyl)benzamide

Figure PCTCN2018088561-appb-000249
Figure PCTCN2018088561-appb-000249

a)1-(3-甲基苯基)环丙基-1-胺a) 1-(3-methylphenyl)cyclopropyl-1-amine

将异丙醇锂的1M正己烷溶液(5mL,5mmol)置于氩气保护的三颈瓶中，加入THF(10mL)，碘化锂(670mg,5mmol)，然后小心滴加MeTi(O-iPr) 3的1M溶液(2.5mL,2.5mmol)和化合物3-甲基苯腈(234mg,2mmol)；然后缓慢滴加1M二乙基锌溶液(2.5mL,2.5mmol)，滴毕，室温搅拌反应，次日，停止反应，加水，室温搅拌30min后，过滤，滤液水洗，浓缩，加入1N的稀盐酸后用无水乙醚萃取，水层用氨水调PH值至8左右，用EA(30mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到棕黄色油状物110mg。 A 1 M solution of n-hexane (5 mL, 5 mmol) was placed in an argon-protected three-necked flask, THF (10 mL), lithium iodide (670 mg, 5 mmol) was added, and then MeTi (O-iPr) was carefully added dropwise. ) 1M solution of 3 (2.5mL, 2.5mmol) and the compound 3-methyl-benzonitrile (234mg, 2mmol); then slowly added dropwise 1M diethylzinc solution (2.5mL, 2.5mmol), dropwise, the reaction was stirred at room temperature On the next day, the reaction was stopped, water was added, and the mixture was stirred at room temperature for 30 min. After filtration, the filtrate was washed with water and concentrated, then 1N diluted hydrochloric acid was added and then extracted with anhydrous diethyl ether. The aqueous layer was adjusted to pH of about 8 with ammonia water, using EA (30 mL×2) The organic layer was combined, washed with aq. EtOAc (EtOAc)

b)2-乙氧基-5-异丁酰氨基-N-(1-(3-苯甲基)环丙基)苯甲酰胺b) 2-ethoxy-5-isobutyrylamino-N-(1-(3-phenylmethyl)cyclopropyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(80mg,0.318mmol)加入无水DMF(10mL)，加入EDC(122mg,0.636mmol)，加入HOBt(86mg,0.636mmol)和DIEA(0.17mL,0.954mmol)，加入化合物1-(3-甲基苯基)环丙基-1-胺(131mg,0.597mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:5)，得到白色固体130mg，产率72％；m.p.145-147℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (80 mg, 0.318 mmol) was added to dry DMF (10 mL). E.sub.2 (122 mg, 0.636 mmol) was added, and HOBt (86 mg, 0.636 mmol) and DIEA (0.17) were added. The compound 1-(3-methylphenyl)cyclopropyl-1-amine (131 mg, 0.597 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was extracted with a 10:1 mixture (30 mL×2), and the combined organic layer was washed with saturated NaCI (15mL×2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (E:P=1:5) Solid 130 mg, yield 72%; mp 145-147 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.64(s,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.83-7.90(m,2H),7.17(t,J＝8.4Hz,1H),7.04-7.06(m,2H),6.99(d,J＝7.6Hz,1H),6.94(d,J＝9.2Hz,1H),4.19(q,J＝7.2Hz,2H),2.36-2.44(m,1H),2.30(s,3H),1.50(t,J＝7.2Hz,3H),1.34(s,4H),1.10-1.14(m,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.64 (s, 1H), 8.21. (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1H), 7.83-7.90 (m, 2H), 7.17 (t, J = 8.4 Hz, 1H), 7.04-7.06 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 4.19 (q, J) = 7.2 Hz, 2H), 2.36-2.44 (m, 1H), 2.30 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H), 1.34 (s, 4H), 1.10-1.14 (m, 6H) .

实施例(化合物)190Example (compound) 190

2-乙氧基-5-异丁酰氨基-N-(1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000250
Figure PCTCN2018088561-appb-000250

a)6-(2,2,2-三氟乙氧基)吡啶-2-甲酸a) 6-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid

将化合物三氟乙醇(0.58mL,8mmol)加入DMA(20mL)，氩气保护下室温下加入 NaH(480mg,12mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(630mg,4mmol)加入反应瓶中，加毕，升温至90℃反应，20h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至3左右，用乙酸乙酯(60mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，得到类白色固体500mg，产率56.5％；m.p.128-130℃。The compound trifluoroethanol (0.58 mL, 8 mmol) was added to MeOH (20 mL), EtOAc (EtOAc) Adding to the reaction flask, adding, heating to 90 ° C reaction, stopping the reaction after 20 h, adding water, washing with diethyl ether (20 mL), the aqueous layer was adjusted to pH 3 with dilute HCl, extracted with ethyl acetate (60 mL × 2) The combined organic layers were washed with aq. EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.16(s,1H),7.99(t,J＝8.0Hz,1H),7.79(d,J＝7.2Hz,1H),7.25(d,J＝8.4Hz,1H),5.11(q,J＝8.8Hz,2H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 13.16 (s, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.25 ( d, J = 8.4 Hz, 1H), 5.11 (q, J = 8.8 Hz, 2H).

b)N-甲氧基-N-甲基-6-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺b) N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide

将化合物6-(2,2,2-三氟乙氧基)吡啶-2-甲酸(480mg,2.17mmol)加入无水DMF(20mL)，加入HBTU(1.64g,4.34mmol)，HOBt(585mg,4.34mmol)和DIEA(2.3mL,13.02mmol)，加入N,O-二甲基羟胺(421mg,4.34mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:7.5,E:P＝1:6)，得到无色油状物460mg，产率80.2％。The compound 6-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (480 mg, 2.17 mmol) was added to dry DMF (20 mL), EtOAc (EtOAc, EtOAc, 4.34mmol) and DIEA (2.3mL, 13.02mmol), N,O-dimethylhydroxylamine (421mg, 4.34mmol) was added, stirred at room temperature overnight, the reaction was poured into water, ethyl acetate: methanol = 10:1 The mixture was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI (20mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:7.5, E:P=1: 6), 460 mg of a colorless oil was obtained, yield 80.2%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.75(t,J＝8.0Hz,1H),7.33(brs,1H),6.96(d,J＝9.2Hz,1H),4.79(q,J＝8.4Hz,2H),3.74(s,3H),3.39(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.75 (t, J = 8.0 Hz, 1H), 7.33 (brs, 1H), 6.96 (d, J = 9.2 Hz, 1H), 4.79 (q, J = 8.4 Hz, 2H), 3.74 (s, 3H), 3.39 (s, 3H).

c)1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙酮c) 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone

将化合物N-甲氧基-N-甲基-6-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺(400mg,1.51mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(2.57mL,2.57mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20)，得到白色固体240mg，产率72.5％；m.p.51-52℃。The compound N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (400 mg, 1.51 mmol) was added to dry THF (20 mL) 1M methylmagnesium bromide in THF (2.57mL, 2.57mmol) was added dropwise to the reaction flask at 0 ° C, and the reaction was stirred at 0 ° C. After 2 h, the saturated ammonium chloride solution was added to the reaction flask. The extract was extracted with EtOAc (40 mL×2), EtOAcjjjjjjjjjjjjj , yield 72.5%; mp 51-52 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.80(t,J＝7.6Hz,1H),7.74(dd,J 1＝7.2Hz,J 2＝0.4Hz,1H),7.07(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),4.83(q,J＝8.8Hz,2H),2.67(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.80 (t, J = 7.6 Hz, 1H), 7.74 (dd, J 1 = 7.2 Hz, J 2 = 0.4 Hz, 1H), 7.07 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 4.83 (q, J = 8.8 Hz, 2H), 2.67 (s, 3H).

d)1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙酮肟d) 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone oxime

将化合物1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙酮(210mg,0.96mmol)置于反应瓶中，加入EtOH(5mL)，加入50％羟胺水溶液(0.17mL,2.87mmol)升温至60℃反应，3h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:10)得到白色固体200mg，产率89.2％；m.p.108-110℃。The compound 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone (210 mg, 0.96 mmol) was placed in a reaction flask, EtOH (5 mL) was added, and 50% hydroxylamine was added. The aqueous solution (0.17 mL, 2.87 mmol) was heated to 60 ° C, and the reaction was stopped after 3 h, then DCM (30 mL) was evaporated. 89.2%; mp 108-110 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.66(t,J＝7.6Hz,1H),7.49(t,J＝7.6Hz,1H),6.87(d,J＝8.4Hz,1H),4.81(q,J＝8.4Hz,2H),2.34(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.66 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H) , 4.81 (q, J = 8.4 Hz, 2H), 2.34 (s, 3H).

e)1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙胺e) 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethylamine

将化合物1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙酮肟(190mg,0.81mmol)，加入甲醇(5mL)，加入10％Pd/C(190mg)，加热至回流，加入甲酸铵(510mg,8.1mmol)，继续回流反应，15min后停止反应，过滤，浓缩得到淡黄色油状物150mg，产率84.2％。The compound 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone oxime (190 mg, 0.81 mmol) was added to methanol (5 mL) and 10% Pd/C (190 mg) After heating to reflux, ammonium formate (510 mg, 8.1 mmol) was added, and the reaction was refluxed. After 15 min, the reaction was quenched, filtered and concentrated to give a pale yellow oil 150 mg (yield: 84.2%).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.57-7.61(m,1H),6.93(d,J＝8.4Hz,1H),4.79(q,J＝8.4Hz,2H),4.04(q,J＝6.8Hz,1H),1.97(brs,2H),1.41(d,J＝6.8Hz,3H).f)2-乙氧基-5-异丁酰氨基-N-(1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙基)苯甲酰胺 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.57-7.61 (m, 1H), 6.93 (d, J = 8.4Hz, 1H), 4.79 (q, J = 8.4Hz, 2H), 4.04 ( q, J = 6.8 Hz, 1H), 1.97 (brs, 2H), 1.41 (d, J = 6.8 Hz, 3H). f) 2-ethoxy-5-isobutyrylamino-N-(1-( 6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)benzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(15mL)，加入EDC(153mg,0.796mmol)，加入HOBt(108mg,0.796mmol)和DIEA(0.209mL,1.19mmol)，加入化合物1-(6-(2,2,2-三氟乙氧基)吡啶-2-基)乙胺(131mg,0.597mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体130mg，产率72％；m.p.129-131℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (15 mL). E.sub.2 (153 mg, 0.796 mmol) was added, and HOBt (108 mg, 0.796 mmol) and DIEA (0.209) were added. mL, 1.19 mmol), the compound 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethylamine (131 mg, 0.597 mmol) was added and stirred at room temperature overnight. The mixture was extracted with a mixture of ethyl acetate:methanol = 10:1 (30 mL×2). M = 90: 1) gave a white solid, 130 mg, yield 72%; mp 129-131.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.65(d,J＝8.0Hz,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.81(d,J＝2.8Hz,1H),7.61(t,J＝8.0Hz,1H),7.44(brs,1H),7.01(d,J＝7.2Hz,1H),6.96(d,J＝8.8Hz,1H),6.75(d,J＝8.4Hz,1H),5.28-5.32(m,1H),4.79(q,J＝8.4Hz,2H),4.19(q,J＝8.0Hz,2H),2.47-2.55(m,1H),1.56(d,J＝6.8Hz,3H),1.46(t,J＝6.8Hz,3H),1.23(d,J＝6.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.65 (d, J = 8.0Hz, 1H), 8.21 (dd, J 1 = 8.8Hz, J 2 = 2.4Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.44 (brs, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H) , 6.75 (d, J = 8.4 Hz, 1H), 5.28-5.32 (m, 1H), 4.79 (q, J = 8.4 Hz, 2H), 4.19 (q, J = 8.0 Hz, 2H), 2.47-2.55 ( m, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.46 (t, J = 6.8 Hz, 3H), 1.23 (d, J = 6.4 Hz, 6H).

实施例(化合物)191Example (compound) 191

2-乙氧基-N-(1-(6-乙氧基吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺2-ethoxy-N-(1-(6-ethoxypyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000251
Figure PCTCN2018088561-appb-000251

a)6-乙氧基吡啶-2-甲酸a) 6-ethoxypyridine-2-carboxylic acid

将化合物乙醇(0.58mL,10mmol)加入DMA(30mL)，氩气保护下室温下加入NaH(600mg,15mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(788mg,5mmol)加入反应瓶中，加毕，升温至90℃反应，10h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至3左右，用乙酸乙酯(60mL×2)萃取，合并有机层用饱和NaCl 溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，得到类白色固体580mg，产率69.4％；m.p.116-117℃。The compound ethanol (0.58 mL, 10 mmol) was added to DMA (30 mL), and NaH (600 mg, 15 mmol) was stirred at room temperature under argon atmosphere for 1 h, then 6-chloro-pyridine-2-carboxylic acid (788 mg, 5 mmol) was added to the reaction. In the bottle, after the addition, the temperature was raised to 90 ° C, the reaction was stopped after 10 h, water was added, and the mixture was washed with diethyl ether (20 mL). The aqueous layer was adjusted to pH 3 with dilute HCl, and extracted with ethyl acetate (60 mL×2). The organic layer was washed with aq. EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.02(s,1H),7.84(td,J 1＝7.6Hz,J 2＝0.8Hz,1H),7.64(dd,J 1＝7.2Hz,J 2＝0.8Hz,1H),7.02(dt,J 1＝8.0Hz,J 2＝0.8Hz,1H),4.37(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 13.02 (s, 1H), 7.84 (td, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H), 7.64 (dd, J 1 = 7.2 Hz, J 2 = 0.8 Hz, 1H), 7.02 (dt, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2) Hz, 3H).

b)6-乙氧基-N-甲氧基-N-甲基吡啶甲酰胺b) 6-ethoxy-N-methoxy-N-methylpyridinecarboxamide

将化合物6-乙氧基吡啶-2-甲酸(500mg,2.99mmol)加入无水DMF(20mL)，加入HBTU(2.27g,5.98mmol)，HOBt(807mg,5.98mmol)和DIEA(3.1mL,17.94mmol)，加入N,O-二甲基羟胺(580mg,5.98mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:6,E:P＝1:5)，得到无色油状物600mg，产率95.6％。The compound 6-ethoxypyridine-2-carboxylic acid (500 mg, 2.99 mmol) was added to anhydrous DMF (20 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc To a solution of the mixture of ethyl acetate:methanol = 10:1 (30 mL×2), The combined organic layer was washed with aq. EtOAc (EtOAc (EtOAc) The yield was 95.6%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.64(t,J＝7.6Hz,1H),7.24(brs,1H),6.79(d,J＝8.4Hz,1H),4.38(q,J＝7.6Hz,2H),3.79(s,3H),3.41(s,3H),1.39(t,J＝7.2Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64 (t, J = 7.6 Hz, 1H), 7.24 (brs, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.38 (q, J = 7.6 Hz, 2H), 3.79 (s, 3H), 3.41 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).

c)1-(6-乙氧基吡啶-2-基)乙酮c) 1-(6-ethoxypyridin-2-yl)ethanone

将化合物6-乙氧基-N-甲氧基-N-甲基吡啶甲酰胺(510mg,2.43mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(4.37mL,4.37mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(30mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:45)，得到白色固体230mg，产率57.5％；m.p.45-47℃。The compound 6-ethoxy-N-methoxy-N-methylpyridinecarboxamide (510 mg, 2.43 mmol) was added to dry THF (20 mL), and 1 M methyl bromide in THF at 0 ° C under argon. The solution (4.37 mL, 4.37 mmol) was added dropwise to the reaction flask, and the reaction was continued at 0 ° C. After 2 h, the saturated ammonium chloride solution was added to the reaction flask, and extracted with EA (30 mL×2), and the organic layer was combined. It was washed with a saturated NaCl solution (15 mL × 2), dried over anhydrous magnesium sulfate.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.68(t,J＝8.0Hz,1H),7.61(d,J＝7.2Hz,1H),6.90(d,J＝8.0Hz,1H),4.44(q,J＝6.8Hz,2H),2.66(s,3H),1.43(t,J＝6.8Hz,3H).d)1-(6-乙氧基吡啶-2-基)乙酮肟 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.68 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H) , 4.44 (q, J = 6.8 Hz, 2H), 2.66 (s, 3H), 1.43 (t, J = 6.8 Hz, 3H). d) 1-(6-ethoxypyridin-2-yl)ethanone肟

将化合物1-(6-乙氧基吡啶-2-基)乙酮(200mg,1.21mmol)置于反应瓶中，加入EtOH(5mL)，加入50％羟胺水溶液(0.21mL,3.63mmol)升温至60℃反应，2h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:20)得到白色固体190mg，产率87.1％；m.p.70-72℃。The compound 1-(6-ethoxypyridin-2-yl)ethanone (200 mg, 1.21 mmol) was placed in a reaction flask, EtOH (5 mL) was added, and 50% aqueous hydroxylamine (0.21 mL, 3. The reaction was carried out at 60 ° C, and the reaction was quenched with EtOAc EtOAc EtOAc EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.57(t,J＝8.4Hz,1H),7.35(d,J＝7.6Hz,1H),6.71(d,J＝8.4Hz,1H),4.21(q,J＝7.2Hz,2H),2.35(s,3H),1.41(t,J＝7.2Hz,3H). e)1-(6-乙氧基吡啶-2-基)乙胺 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.57 (t, J = 8.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H) , 4.21 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). e) 1-(6-ethoxypyridin-2-yl)ethylamine

将化合物1-(6-乙氧基吡啶-2-基)乙酮肟(168mg,0.93mmol)，加入甲醇(5mL)，加入10％Pd/C(168mg)，加热至回流，加入甲酸铵(586mg,9.3mmol)，继续回流反应，15min后停止反应，过滤，浓缩得到淡黄色油状物150mg，产率97.4％。 1H-NMR(400MHz,CDCl 3)δ(ppm):7.93(brs,2H),7.54(t,J＝7.6Hz,1H),6.83(d,J＝7.2Hz,1H),6.64(d,J＝8.4Hz,1H),4.33-4.38(m,3H),1.58(d,J＝6.8Hz,3H),1.35(t,J＝7.2Hz,3H). The compound 1-(6-ethoxypyridin-2-yl)ethanone oxime (168 mg, 0.93 mmol) was added to methanol (5 mL), then 10% Pd / C (168 mg) 586 mg, 9.3 mmol), the reaction was refluxed, and the reaction was quenched after 15 min, filtered and concentrated to give a pale yellow oil, 150 mg, yield 97.4%. 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.93 (brs, 2H), 7.54 (t, J = 7.6Hz, 1H), 6.83 (d, J = 7.2Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.33-4.38 (m, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H).

f)2-乙氧基-N-(1-(6-乙氧基吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺f) 2-Ethoxy-N-(1-(6-ethoxypyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(15mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.31mmol)，加入化合物1-(6-乙氧基吡啶-2-基)乙胺(130mg,0.788mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体108mg，产率61.7％。m.p.144-145℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (15 mL). E.sub.2 (168 mg, &lt;RTI ID=0.0&gt; The compound 1-(6-ethoxypyridin-2-yl)ethylamine (130 mg, 0.788 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was extracted with a mixture of EtOAc (1 mL, EtOAc (EtOAc) (EtOAc) 108 mg, yield 61.7%. M.p. 144-145 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.65(d,J＝8.0Hz,1H),8.21(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.83(d,J＝2.8Hz,1H),7.60(brs,1H),7.56(t,J＝8.0Hz,1H),6.94(d,J＝8.8Hz,1H),6.89(d,J＝7.2Hz,1H),6.62(d,J＝8.0Hz,1H),5.28-5.36(m,1H),4.36-4.42(m,2H),4.15-4.21(m,2H),2.48-2.56(m,1H),1.58(d,J＝6.8Hz,3H),1.45(t,J＝7.2Hz,3H),1.40(t,J＝6.8Hz,3H),1.22(dd,J 1＝6.8Hz,J 2＝1.2Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.65 (d, J = 8.0 Hz, 1H), 8.21. (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.60 (brs, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H) , 6.62 (d, J = 8.0 Hz, 1H), 5.28-5.36 (m, 1H), 4.36-4.42 (m, 2H), 4.15-4.21 (m, 2H), 2.48-2.56 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.45 (t, J = 7.2 Hz, 3H), 1.40 (t, J = 6.8 Hz, 3H), 1.22 (dd, J 1 = 6.8 Hz, J 2 = 1.2 Hz , 6H).

实施例(化合物)192Example (compound) 192

2-乙氧基-N-(1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺2-ethoxy-N-(1-(6-((4-fluorobenzyl)oxy)pyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000252
Figure PCTCN2018088561-appb-000252

a)6-((4-氟苯甲基)氧代)吡啶-2-甲酸a) 6-((4-fluorobenzyl)oxo)pyridine-2-carboxylic acid

将化合物4-氟苄醇(1.01g,8mmol)加入THF(40mL)，氩气保护下室温下加入NaH(480mg,12mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(630mg,4mmol)加入反应瓶中，加毕，升温至回流反应，10h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至2左右，有固体析出，抽滤，滤饼水洗，得到类白色固体980mg，产率99.1％；m.p.140-142℃。The compound 4-fluorobenzyl alcohol (1.01 g, 8 mmol) was added to THF (40 mL), EtOAc (EtOAc, EtOAc. 4mmol) was added to the reaction flask, added, heated to reflux reaction, 10h, the reaction was stopped, water was added, washed with ether (20mL), the water layer was adjusted to pH 2 with dilute HCl, solid precipitation, suction filtration, filter cake After washing with water, 980 mg of an off-white solid was obtained, yield: 99.1%; mp 140-142 ° C.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.08(brs,1H),7.89(t,J＝7.2Hz,1H),7.68(d,J＝8.0Hz,1H),7.55-7.59(m,2H),7.18-7.23(m,2H),7.01(d,J＝8.4Hz,1H),5.40(s,2H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 13.08 (brs, 1H), 7.89 (t, J = 7.2Hz, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.55- 7.59 (m, 2H), 7.18-7.23 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H).

b)6-((4-氟苯甲基)氧代)-N-甲氧基-N-甲基吡啶甲酰胺b) 6-((4-fluorobenzyl)oxo-N-methoxy-N-methylpyridinecarboxamide

将化合物6-((4-氟苯甲基)氧代)吡啶-2-甲酸(741mg,3.0mmol)加入无水DMF(25mL)，加入HBTU(2.27g,6.0mmol)，加入HOBt(810mg,6.0mmol)和DIEA(3.14mL,18.0mmol)，加入N,O-二甲基羟胺(582mg,6.0mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4.5,E:P＝1:4)，得到无色油状物790mg，产率90.8％。The compound 6-((4-fluorobenzyl)oxo)pyridin-2-carboxylic acid (741 mg, 3.0 mmol) was added to anhydrous DMF (25 mL), EtOAc (2. 6.0 mmol) and DIEA (3.14 mL, 18.0 mmol), N,O-dimethylhydroxylamine (582 mg, 6.0 mmol) was added and stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate:methanol = 10:1 The mixture was extracted (40 mL×2), and the combined organic layer was washed with saturated NaCI (20mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:4.5, E:P=1: 4), 790 mg of a colorless oil was obtained with a yield of 90.8%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.65-7.70(m,1H),7.39-7.43(m,2H),7.25(brs,1H),7.02-7.07(m,2H),6.87(td,J 1＝8.4Hz,J 2＝0.8,1H),5.36(s,2H),3.73(s,3H),3.37(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.65-7.70 (m, 1H), 7.39-7.43 (m, 2H), 7.25 (brs, 1H), 7.02-7.07 (m, 2H), 6.87 (td, J 1 = 8.4 Hz, J 2 = 0.8, 1H), 5.36 (s, 2H), 3.73 (s, 3H), 3.37 (s, 3H).

c)1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙酮c) 1-(6-((4-fluorobenzyl)oxo)pyridin-2-yl)ethanone

将化合物6-((4-氟苯甲基)氧代)-N-甲氧基-N-甲基吡啶甲酰胺(660mg,2.27mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(4.09mL,4.09mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20)，得到白色固体400mg，产率71.9％；m.p.69-71℃。The compound 6-((4-fluorobenzyl)oxo-n-methoxy-N-methylpyridinecarboxamide (660 mg, 2.27 mmol) was added to dry THF (20 mL) 1 M methylmagnesium bromide in THF (4.09 mL, 4.09 mmol) was added dropwise to the reaction flask, and the reaction was continued at 0 ° C. After 2 h, a saturated ammonium chloride solution was added to the reaction flask, and EA was used. 40 mL × 2), the organic layer was combined, washed with EtOAc EtOAc EtOAcjjjjjjjjj %; mp69-71 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.69-7.74(m,1H),7.65(dd,J 1＝7.2Hz,J 2＝0.8Hz,1H),7.43-7.47(m,2H),7.04-7.09(m,2H),6.98(dd,J 1＝8.4Hz,J 2＝0.8Hz,1H),5.42(s,2H),2.67(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.69-7.74 (m, 1H), 7.65 (dd, J 1 = 7.2 Hz, J 2 = 0.8 Hz, 1H), 7.43-7.47 (m, 2H) ), 7.04-7.09 (m, 2H), 6.98 (dd, J 1 = 8.4 Hz, J 2 = 0.8 Hz, 1H), 5.42 (s, 2H), 2.67 (s, 3H).

d)1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙酮肟d) 1-(6-((4-fluorobenzyl)oxo)pyridin-2-yl)ethanone oxime

将化合物1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙酮(370mg,1.51mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.27mL,4.53mmol)升温至60℃反应，3h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:15)得到白色固体370mg，产率94.3％；m.p.96-98℃。The compound 1-(6-((4-fluorobenzyl)oxy)pyridin-2-yl)ethanone (370 mg, 1.51 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and a 50% aqueous solution of hydroxylamine was added. (0.27 mL, 4.53 mmol) was heated to 60 ° C, and the reaction was stopped after 3 h, then DCM (30 mL) was evaporated. %; mp96-98 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.57-7.62(m,1H),7.42-7.46(m,2H),7.39(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),7.03-7.08(m,2H),6.78(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),5.40(s,2H),2.35(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.57-7.62 (m, 1H), 7.42-7.46 (m, 2H), 7.39 (dd, J 1 = 7.6Hz, J 2 = 0.8Hz, 1H ), 7.03-7.08 (m, 2H), 6.78 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 5.40 (s, 2H), 2.35 (s, 3H).

e)1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙胺e) 1-(6-((4-fluorobenzyl)oxo)pyridin-2-yl)ethylamine

将化合物1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙酮肟(325mg,1.25mmol)置于反应瓶中，加入乙醇(10mL)，水(2mL)，加入锌粉(244mg,3.75mmol)以及2.5N HCl溶液(3.0mL,7.5mmol)，室温搅拌反应，4h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸氢钠溶液调PH值至7-8，用乙酸乙酯：甲醇＝10:1的混合液(40mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物200mg，产率64.9％。The compound 1-(6-((4-fluorobenzyl)oxy)pyridin-2-yl)ethanone oxime (325 mg, 1.25 mmol) was placed in a reaction flask, and ethanol (10 mL) was added, water (2 mL) Add zinc powder (244mg, 3.75mmol) and 2.5N HCl solution (3.0mL, 7.5mmol), stir the reaction at room temperature, stop the reaction after 4h, concentrate, add water, extract with ether 20mL, the water layer is adjusted with saturated sodium bicarbonate solution The mixture was extracted with a mixture of ethyl acetate:methanol = 10:1 (40 mL×2). A pale yellow oil of 200 mg was obtained in a yield of 64.9%.

f)2-乙氧基-N-(1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺f) 2-Ethoxy-N-(1-(6-((4-fluorobenzyl)oxy)pyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(110mg,0.438mmol)加入无水DMF(15mL)，加入EDC(168mg,0.876mmol)，加入HOBt(118mg,0.876mmol)和DIEA(0.23mL,1.314mmol)，加入化合物1-(6-((4-氟苯甲基)氧代)吡啶-2-基)乙胺(130mg,0.828mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝100:1)，得到白色固体150mg，产率71.4％；m.p.161-163℃； 1H-NMR(400MHz,CDCl 3)δ(ppm):8.70(d,J＝7.6Hz,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.82(d,J＝2.8Hz,1H),7.57(t,J＝8.0Hz,1H),7.52(brs,1H),7.40-7.44(m,2H),6.98-7.03(m,2H),6.92-6.96(m,2H),6.68(d,J＝8.4Hz,1H),5.38(s,2H),5.31-5.35(m,1H),4.12-4.19(m,2H),2.48-2.55(m,1H),1.58(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.23(d,J＝6.8Hz,6H). 2-Ethoxy-5-isobutyrylaminobenzoic acid (110 mg, 0.438 mmol) was added to dry DMF (15 mL). E.sub.2 (168 mg, &lt;RTI ID=0.0&gt; mL, 1.314 mmol), the compound 1-(6-((4-fluorobenzyl)oxy)pyridin-2-yl)ethylamine (130 mg, 0.828 mmol) was added and stirred at room temperature overnight. It was extracted with a mixture of ethyl acetate:methanol = 10:1 (30 mL×2). The combined organic layer was washed with saturated NaCI (15 mL×2), dried over anhydrous magnesium sulfate =100:1), 150 mg of white solid, yield 71.4%; mp 161-163 ° C; 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.70 (d, J = 7.6 Hz, 1H), 8.21. Dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.52 (brs, 1H), 7.40- 7.44 (m, 2H), 6.98-7.03 (m, 2H), 6.92-6.96 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 5.31-5.35 (m, 1H), 4.12-4.19 (m, 2H), 2.48-2.55 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.23 (d, J) =6.8Hz, 6H).

实施例(化合物)193Example (compound) 193

N-(1-(2-氯嘧啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(2-chloropyrimidin-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000253
Figure PCTCN2018088561-appb-000253

a)2-氯-N-甲氧基-N-甲基嘧啶-4-甲酰胺a) 2-Chloro-N-methoxy-N-methylpyrimidine-4-carboxamide

将化合物2-氯-嘧啶-5-甲酸(850mg,5.38mmol)加入无水DMF(50mL)，加入HATU(4.09g,10.76mmol)和DIEA(5.6mL,32.28mmol)，加入N,O-二甲基羟胺(1.04g,10.76mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(50mL×2)萃取，合并有机层用饱和NaCl溶液(30mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:4)，得到无色油状物800mg，产率74％。The compound 2-chloro-pyrimidine-5-carboxylic acid (850 mg, 5.38 mmol) was added to dry DMF (50 mL). EtOAc (EtOAc: EtOAc, EtOAc Methylhydroxylamine (1.04 g, 10.76 mmol), stirred at room temperature overnight, the reaction mixture was poured into water, and extracted with a mixture of ethyl acetate:methanol=10:1 (50 mL×2) After washing with 30 mL × 2), dried over anhydrous magnesium sulfate, and evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.77(d,J＝4.8Hz,1H),7.49(d,J＝4.4Hz,1H),3.78(s,3H),3.36(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.77 (d, J = 4.8Hz, 1H), 7.49 (d, J = 4.4Hz, 1H), 3.78 (s, 3H), 3.36 (s, 3H).

b)1-(2-氯嘧啶-4-基)乙酮b) 1-(2-chloropyrimidin-4-yl)ethanone

将化合物2-氯-N-甲氧基-N-甲基嘧啶-4-甲酰胺(402mg,2.0mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(4.0mL,4.0mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，1h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:25,E:P＝1:10)，得到无色油状物400mg，产率65.9％。The compound 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (402 mg, 2.0 mmol) was added to dry THF (20 mL), and 1M methylmagnesium bromide was obtained at 0 ° C under argon atmosphere. The THF solution (4.0 mL, 4.0 mmol) was added dropwise to the reaction flask. After the dropwise addition, the reaction was stirred at 0 ° C. After 1 h, a saturated ammonium chloride solution was added to the reaction flask, and extracted with EA (40 mL×2). The layer was washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and then purified by column chromatography (E: P = 1:25, E:P = 1:10) to give 400 mg of colorless oil. The rate is 65.9%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.85(d,J＝4.8Hz,1H),7.83(d,J＝4.8Hz,1H),2.71(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.85 (d, J = 4.8Hz, 1H), 7.83 (d, J = 4.8Hz, 1H), 2.71 (s, 3H).

c)1-(2-氯嘧啶-4-基)乙酮肟c) 1-(2-chloropyrimidin-4-yl)ethanone oxime

将化合物1-(2-氯嘧啶-4-基)乙酮(370mg,2.37mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.42mL,7.11mmol)升温至60℃反应，3h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:6)得到白色固体320mg，产率79％；m.p.166-168℃。The compound 1-(2-chloropyrimidin-4-yl)ethanone (370 mg, 2.37 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine solution (0.42 mL, 7.11 mmol) was added to warm to 60 ° C. The reaction was quenched after 3 h, EtOAc EtOAc EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.58(d,J＝5.2Hz,1H),7.77(d,J＝5.2Hz,1H),2.33(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.58 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 5.2 Hz, 1H), 2.33 (s, 3H).

d)1-(2-氯嘧啶-4-基)乙胺d) 1-(2-chloropyrimidin-4-yl)ethylamine

将化合物1-(2-氯嘧啶-4-基)乙酮肟(300mg,1.75mmol)置于反应瓶中，加入乙醇(10mL)，水(2mL)，加入锌粉(342mg,5.25mmol)以及2.5N HCl溶液(4.2mL,10.5mmol)，室温搅拌反应，2h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯：甲醇＝10:1的混合液(30mL×10)萃取，水层仍然有产品点。合并有机层，无水硫酸镁干燥，浓缩，得到棕色油状物130mg，产率47.2％。The compound 1-(2-chloropyrimidin-4-yl)ethanone oxime (300 mg, 1.75 mmol) was placed in a reaction flask, and ethanol (10 mL), water (2 mL) was added, and zinc powder (342 mg, 5.25 mmol) was added and 2.5N HCl solution (4.2 mL, 10.5 mmol), the reaction was stirred at room temperature, the reaction was stopped after 2 h, concentrated, water was added, extracted with diethyl ether 20 mL, the aqueous layer was adjusted to a pH of about 9 with saturated sodium carbonate solution, with ethyl acetate: methanol The mixture of =10:1 (30mL×10) was extracted, and the water layer still had product points. The organic layer was combined, dried over anhydrous magnesium sulfate

e)N-(1-(2-氯嘧啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺e) N-(1-(2-chloropyrimidin-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(125mg,0.50mmol)加入无水DMF(15mL)，加入EDC(192mg,1.0mmol)，加入HOBt(135mg,1.0mmol)和DIEA(0.26mL,1.5mmol)，加入化合物1-(2-氯嘧啶-4-基)乙胺(120mg,0.76mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯:甲醇＝10:1的混合液(30mL×2)萃取，合并有机 层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体135mg，产率69.2％。2-Ethoxy-5-isobutyrylaminobenzoic acid (125 mg, 0.50 mmol) was added to dry DMF (15 mL). E.sub.2 (192 mg, 1.0 mmol) was added to HOBt (135 mg, 1.0 mmol) and DIEA (0.26) The compound 1-(2-chloropyrimidin-4-yl)ethylamine (120 mg, 0.76 mmol) was added and the mixture was stirred at room temperature overnight, and the mixture was poured into water, ethyl acetate: methanol = 10:1 The mixture was extracted (30 mL×2). EtOAc (EtOAc m. The yield was 69.2%.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.97(d,J＝7.2Hz,1H),8.56(d,J＝4.8Hz,1H),8.18(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.80(d,J＝2.8Hz,1H),7.32(brs,1H),7.27(d,J＝5.2Hz,1H),6.97(d,J＝8.8Hz,1H),5.30-5.37(m,1H),4.25(q,J＝6.8Hz,2H),2.47-2.54(m,1H),1.57-1.62(m,6H),1.24(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.97 (d, J = 7.2Hz, 1H), 8.56 (d, J = 4.8Hz, 1H), 8.18 (dd, J 1 = 8.8Hz, J 2 = 2.8 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.32 (brs, 1H), 7.27 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H) , 5.30-5.37 (m, 1H), 4.25 (q, J = 6.8 Hz, 2H), 2.47-2.54 (m, 1H), 1.57-1.62 (m, 6H), 1.24 (d, J = 6.8 Hz, 6H) ).

实施例(化合物)194Example (compound) 194

2-乙氧基-5-异丁酰氨基-N-(1-(2-(甲基氨基)嘧啶-4-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(2-(methylamino)pyrimidin-4-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000254
Figure PCTCN2018088561-appb-000254

将化合物N-(1-(2-氯嘧啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(55mg,0.14mmol)加入乙腈(8mL)，加入甲胺盐酸盐(19mg,0.28mmol)以及DIEA(0.08mL,0.42mmol)，室温搅拌反应，6h后TLC显示仅有微弱新点生成，升温至60℃反应，2d后TLC显示原料仍然大量剩余，将反应液转移至封管中，补加甲胺氧酸盐(38mg,0.56mmol)，DIEA(0.16mL,0.82)封管120℃反应，2h后原料消失，加入乙酸乙酯(40mL)，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝50:1,D:M＝30:1)，得到白色固体27mg，产率50％；m.p.135-137℃。The compound N-(1-(2-chloropyrimidin-4-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (55 mg, 0.14 mmol) was added to acetonitrile (8 mL). The amine hydrochloride (19mg, 0.28mmol) and DIEA (0.08mL, 0.42mmol) were stirred at room temperature. After 6h, TLC showed only weak new point formation, and the temperature was raised to 60 ° C. After 2 days, TLC showed that the raw material remained in a large amount. The reaction solution was transferred to a sealed tube, and the methylamine hydrochloride (38 mg, 0.56 mmol) was added, and DIEA (0.16 mL, 0.82) was sealed at 120 ° C. After 2 h, the starting material disappeared and ethyl acetate (40 mL) was added. The mixture was washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate. 135-137 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.82(d,J＝6.8Hz,1H),8.20-8.22(m,2H),7.87(brs,1H),7.64(brs,1H),6.94(d,J＝8.8Hz,1H),6.52(d,J＝4.4Hz,1H),5.28(brs,1H),4.20(q,J＝6.8Hz,2H),3.00(d,J＝4.8Hz,3H),2.50-2.58(m,1H),1.48-1.52(m,6H),1.22(dd,J 1＝6.8Hz,J 2＝3.2Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.82 (d, J = 6.8Hz, 1H), 8.20-8.22 (m, 2H), 7.87 (brs, 1H), 7.64 (brs, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 4.4 Hz, 1H), 5.28 (brs, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.00 (d, J = 4.8) Hz, 3H), 2.50-2.58 (m, 1H), 1.48-1.52 (m, 6H), 1.22 (dd, J 1 = 6.8 Hz, J 2 = 3.2 Hz, 6H).

实施例(化合物)195Example (compound) 195

2-乙氧基-5-异丁酰氨基-N-(1-(2-甲氧基嘧啶-4-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(2-methoxypyrimidin-4-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000255
Figure PCTCN2018088561-appb-000255

将化合物Na(7mg,0.307mmol)加入甲醇(3mL)，搅拌至完全溶解后，加入化合物N-(1-(2-氯嘧啶-4-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(30mg,0.077mmol)升温至回流反应，30min后停止反应，加水，用乙酸乙酯(20mL×2)萃取，合并有 机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，用乙酸乙酯和石油醚重结晶，得到白色固体16mg，产率53.3％；m.p.180-182℃。The compound Na (7 mg, 0.307 mmol) was added to methanol (3 mL) and stirred until completely dissolved. Compound N-(1-(2-chloropyrimidin-4-yl)ethyl)-2-ethoxy-5- The isobutyrylaminobenzamide (30 mg, 0.077 mmol) was warmed to reflux. After 30 min, the reaction was quenched, water was added, and ethyl acetate (20 mL×2) was evaporated. The organic layer was combined and washed with saturated NaCI solution (15 mL×2) The residue was dried over anhydrous MgSO.sub.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.88(d,J＝7.2Hz,1H),8.45(d,J＝5.2Hz,1H),8.20(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.80(d,J＝2.8Hz,1H),7.39(brs,1H),6.94-6.97(m,2H),5.24-5.31(m,1H),4.22(q,J＝6.8Hz,2H),4.30(s,3H),2.47-2.54(m,1H),1.53-1.59(m,6H),1.23(d,J＝6.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.88 (d, J = 7.2 Hz, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.20 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.39 (brs, 1H), 6.94 - 6.97 (m, 2H), 5.24 - 5.31 (m, 1H), 4.22 (q, J) = 6.8 Hz, 2H), 4.30 (s, 3H), 2.47-2.54 (m, 1H), 1.53-1.59 (m, 6H), 1.23 (d, J = 6.8 Hz, 6H).

实施例(化合物)196Example (compound) 196

2-乙氧基-N-(1-(6-氟吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺2-ethoxy-N-(1-(6-fluoropyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000256
Figure PCTCN2018088561-appb-000256

a)6-氟-N-甲氧基-N-甲基吡啶甲酰胺a) 6-fluoro-N-methoxy-N-methylpyridinecarboxamide

将6-氟吡啶-2-甲酸(1.13g,8.0mmol)加入无水DMF(50mL)，加入HATU(6.08g,16.0mmol)和DIEA(6.97mL,40.0mmol)，加入N,O-二甲基羟胺(1.55g,16.0mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(50mL×2)萃取，合并有机层用饱和NaCl溶液(25mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:5,E:P＝1:4)，得到无色油状物1.25g，产率85％。Add 6-fluoropyridine-2-carboxylic acid (1.13 g, 8.0 mmol) to dry DMF (50 mL), add HATU (6.08 g, 16.0 mmol) and DIEA (6.97 mL, 40.0 mmol), and add N,O-dimethyl The hydroxylamine (1.55 g, 16.0 mmol) was stirred at room temperature overnight. The reaction mixture was poured into water and evaporated with ethyl acetate (50 mL×2), and the organic layer was washed with saturated NaCI solution (25 mL×2) Drying, concentration and column chromatography (EtOAc: EtOAc: EtOAc:

1H-NMR(400MHz,CDCl 3)δ(ppm):7.88-7.94(m,1H),7.57(brs,2H),7.04(dd,J 1＝8.0Hz,J 2＝2.8Hz,1H),3.80(s,3H),3.39(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.88-7.94 (m, 1H), 7.57 (brs, 2H), 7.04 (dd, J 1 = 8.0Hz, J 2 = 2.8Hz, 1H), 3.80(s,3H), 3.39(s,3H).

b)1-(6-氟吡啶-2-基)乙酮b) 1-(6-fluoropyridin-2-yl)ethanone

将6-氟-N-甲氧基-N-甲基甲基吡啶酰胺(830mg,4.5mmol)加入干燥THF(25mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(6.76mL,6.76mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，1h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:25)，得到无色油状物400mg，产率63.9％；m.p.42-43℃。6-Fluoro-N-methoxy-N-methylmethylpyridine amide (830 mg, 4.5 mmol) was added to dry THF (25 mL) and 1M methylmagnesium bromide in THF at 0 ° C under argon ( 6.76mL, 6.76mmol) was added dropwise to the reaction flask, and the reaction was stirred at 0 ° C. After 1 h, the saturated ammonium chloride solution was added to the reaction flask, extracted with EA (40 mL×2), and the organic layer was combined. The mixture was washed with aq. EtOAc (EtOAc) (EtOAc:EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.94-7.99(m,2H),7.14-7.18(m,1H),2.69(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.94 - 7.79 (m, 2H), 7.14 - 7.18 (m, 1H), 2.69 (s, 3H).

c)1-(6-氟吡啶-2-基)乙酮肟c) 1-(6-fluoropyridin-2-yl)ethanone oxime

将化合物1-(6-氟吡啶-2-基)乙酮(349mg,2.51mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.44mL,7.53mmol)升温至60℃反应，2h后停止反应， 加入DCM(20mL)，无水硫酸镁干燥，柱层析(E:P＝1:30，E:P＝1:10)得到白色固体350mg，产率90.6％；m.p.94-95℃。The compound 1-(6-fluoropyridin-2-yl)ethanone (349 mg, 2.51 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine solution (0.44 mL, 7.53 mmol) was added to warm to 60 ° C. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc:EtOAc. 94-95 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.76-7.82(m,1H),7.71-7.74(m,1H),6.90-9.94(m,1H),2.34(s,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.76-7.82 (m, 1H), 7.71-7.74 (m, 1H), 6.90-9.94 (m, 1H), 2.34 (s, 3H).

d)1-(6-氟吡啶-2-基)乙胺d) 1-(6-fluoropyridin-2-yl)ethylamine

将化合物1-(6-氟吡啶-2-基)乙酮肟(340mg,2.2mmol)置于反应瓶中，加入乙醇(10mL)，水(2mL)，加入锌粉(430mg,6.6mmol)以及2.5N HCl溶液(5.3mL,13.2mmol)，室温搅拌反应，2h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9，用EA:MeOH＝10:1的混合液(20mL×3)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物250mg，产率81.1％。The compound 1-(6-fluoropyridin-2-yl)ethanone oxime (340 mg, 2.2 mmol) was placed in a reaction flask, and ethanol (10 mL), water (2 mL) was added, and zinc powder (430 mg, 6.6 mmol) was added and 2.5N HCl solution (5.3 mL, 13.2 mmol), the reaction was stirred at room temperature. After 2 h, the reaction was stirred, concentrated, water was added, and extracted with 20 mL of ethyl ether. The aqueous layer was adjusted to pH 9 with saturated sodium carbonate solution, using EA: MeOH = 10: The mixture was extracted with EtOAc (EtOAc m.)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.76(q,J＝7.2Hz,1H),7.19(dd,J 1＝7.6Hz,J 2＝2.4Hz,1H),6.80(dd,J 1＝8.0Hz,J 2＝2.8Hz,1H),4.15(q,J＝6.8Hz,1H),2.42(brs,2H),1.44(d,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.76 (q, J = 7.2 Hz, 1H), 7.19 (dd, J 1 = 7.6 Hz, J 2 = 2.4 Hz, 1H), 6.80 (dd, J 1 = 8.0 Hz, J 2 = 2.8 Hz, 1H), 4.15 (q, J = 6.8 Hz, 1H), 2.42 (brs, 2H), 1.44 (d, J = 6.8 Hz, 3H).

e)2-乙氧基-N-(1-(6-氟吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺e) 2-Ethoxy-N-(1-(6-fluoropyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(210mg,0.837mmol)加入无水DMF(20mL)，加入EDC(321mg,1.674mmol)，加入HOBt(226mg,1.674mmol)和DIEA(0.44mL,2.51mmol)，加入1-(6-氟吡啶-2-基)乙胺(210mg,1.51mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1)，得到白色固体260mg，产率83.3％；m.p.146-148℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (210 mg, 0.837 mmol) was added to dry DMF (20 mL), EtOAc (EtOAc EtOAc EtOAc </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; The combined organic layers were washed with aq. EtOAc (EtOAc) (EtOAc (EtOAcjjjjjj .

1H-NMR(400MHz,CDCl 3)δ(ppm):9.07(d,J＝7.2Hz,1H),8.20(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.85(d,J＝2.8Hz,1H),7.75(q,J＝8.0Hz,1H),7.49(brs,1H),7.18(dd,J 1＝7.6Hz,J 2＝2.4Hz,1H),6.95(d,J＝8.8Hz,1H),6.82(dd,J 1＝8.0Hz,J 2＝2.4Hz,1H),5.34-5.41(m,1H),4.17-4.25(m,2H),2.48-2.55(m,1H),1.59(t,J＝7.2Hz,3H),1.55(d,J＝6.8Hz,3H),1.23(dd,J 1＝6.8Hz,J 2＝1.6Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 9.07 (d, J = 7.2 Hz, 1H), 8.20 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.75 (q, J = 8.0 Hz, 1H), 7.49 (brs, 1H), 7.18 (dd, J 1 = 7.6 Hz, J 2 = 2.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.82 (dd, J 1 = 8.0 Hz, J 2 = 2.4 Hz, 1H), 5.34 - 5.41 (m, 1H), 4.17 - 4.25 (m, 2H), 2.48 - 2.55 (m , 1H), 1.59 (t, J = 7.2 Hz, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.23 (dd, J 1 = 6.8 Hz, J 2 = 1.6 Hz, 6H).

实施例(化合物)197Example (compound) 197

2-乙氧基-5-异丁酰氨基-N-(1-(6-(甲基氨基)吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-(methylamino)pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000257
Figure PCTCN2018088561-appb-000257

将化合物2-乙氧基-N-(1-(6-氟吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺(10mg,0.0268mmol)置于微波反应管中，加入40％甲胺水溶液1mL，加入甲醇0.5mL，微波150℃反应，1h后停止反应，加入乙酸乙酯15mL，用饱和NaCl溶液(10mL×2)洗，无水硫酸镁干燥，浓缩。另将化合物2-乙氧基-N-(1-(6-氟吡啶-2-基)乙基)-5-异丁酰氨基苯甲酰胺(55mg,0.147mmol)置于微波反应管中，加入40％甲胺水溶液2mL，加入甲醇0.75mL，微波150℃反应，1h后停止反应，加入乙酸乙酯25mL，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，共同重结晶得到类白色固体47mg，产率67％；m.p.165-167℃。The compound 2-ethoxy-N-(1-(6-fluoropyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide (10 mg, 0.0268 mmol) was placed in a microwave reaction tube and added 1 mL of a 40% aqueous solution of methylamine, 0.5 mL of methanol was added, and the reaction was carried out in a microwave at 150 ° C. After 1 h, the reaction was stopped. 15 mL of ethyl acetate was added, washed with a saturated NaCI solution (10 mL×2), dried over anhydrous magnesium sulfate and evaporated. Further, the compound 2-ethoxy-N-(1-(6-fluoropyridin-2-yl)ethyl)-5-isobutyrylaminobenzamide (55 mg, 0.147 mmol) was placed in a microwave reaction tube. Add 2 mL of 40% aqueous solution of methylamine, add 0.75 mL of methanol, and react at 150 ° C in the microwave. After 1 h, stop the reaction. Add 25 mL of ethyl acetate, wash with saturated NaCl solution (15 mL×2), dry over anhydrous magnesium sulfate, and concentrate. Crystallization gave 47 mg as an off-white solid, yield 67%; mp 165-167.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):9.81(s,1H),8.72(d,J＝7.6Hz,1H),8.01(d,J＝2.8Hz,1H),7.80(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.35(t,J＝8.4Hz,1H),7.10(q,J＝9.2Hz,1H),6.51(d,J＝7.2Hz,1H),6.40-6.45(m,1H),6.32(d,J＝8.4Hz,1H),4.95-5.02(m,1H),4.12-4.19(m,2H),2.80(d,J＝4.8Hz,3H),2.53-2.58(m,1H),1.41(d,J＝6.8Hz,3H),1.34(t,J＝6.8Hz,3H),1.09(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 9.81 (s, 1H), 8.72 (d, J = 7.6Hz, 1H), 8.01 (d, J = 2.8Hz, 1H), 7.80 ( Dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.10 (q, J = 9.2 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 6.40-6.45 (m, 1H), 6.32 (d, J = 8.4 Hz, 1H), 4.95-5.02 (m, 1H), 4.12-4.19 (m, 2H), 2.80 (d, J = 4.8 Hz) , 3H), 2.53-2.58 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 6H).

实施例(化合物)198Example (compound) 198

(2-((6-(1-(2-乙氧基-5-异丁酰胺基苯基酰胺基)乙基)吡啶-2-基)氧代)乙基)(甲基)氨基甲酸叔丁酯ZJ8513(2-((6-(1-(2-ethoxy-5-isobutylamidophenyl)))))))))))))))))))) Butyl ester ZJ8513

Figure PCTCN2018088561-appb-000258
Figure PCTCN2018088561-appb-000258

a)6-(2-(甲基氨基)乙氧基)吡啶-2-甲酸a) 6-(2-(Methylamino)ethoxy)pyridine-2-carboxylic acid

将化合物2-胺甲基乙醇(600mg,8mmol)加入THF(40mL)，氩气保护下室温下加入NaH(480mg,12mmol)室温搅拌1h后，将6-氯-吡啶-2-甲酸(630mg,4mmol)加入反应瓶中，加毕，升温至回流反应，4h后停止反应，加水，用乙醚(20mL)洗，水层用稀HCl调PH值至2左右，用正丁醇萃取，水层仍有大量产物，浓缩水层至干，用DCM:MeOH＝10:1的混合液洗固体，抽滤，滤液浓缩，加入DCM，抽滤，得到白色固体200mg，产率25.5％；m.p.219-221℃。The compound 2-aminomethylethanol (600 mg, 8 mmol) was added to THF (40 mL), EtOAc (EtOAc, EtOAc. 4mmol) was added to the reaction flask, added, heated to reflux reaction, the reaction was stopped after 4h, water was added, washed with ether (20mL), the water layer was adjusted to pH 2 with dilute HCl, extracted with n-butanol, the water layer was still A large amount of product was obtained, the aqueous layer was concentrated to dryness, and the solid was washed with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc °C.

1H-NMR(400MHz,DMSO-d 6)δ(ppm):13.26(brs,1H),9.37(brs,1H),7.94(t,J＝ 7.2Hz,1H),7.72(d,J＝7.2Hz,1H),7.12(d,J＝8.0Hz,1H),4.60(s,2H),3.34(s,2H),2.61(s,3H). 1 H-NMR (400MHz, DMSO -d 6) δ (ppm): 13.26 (brs, 1H), 9.37 (brs, 1H), 7.94 (t, J = 7.2Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.60 (s, 2H), 3.34 (s, 2H), 2.61 (s, 3H).

b)6-(2-((叔-丁氧羰基)(甲基)氨基)乙氧基)吡啶-2-甲酸b) 6-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)pyridine-2-carboxylic acid

将化合物6-(2-(甲基氨基)乙氧基)吡啶-2-甲酸(158mg,0.806mmol)加入乙腈(10mL)，加入(Boc)2O(351mg,1.61mmol)以及三乙胺(0.35mL,2.418mmol)室温搅拌反应，1h后停止反应，浓缩至干，加入饱和碳酸钠溶液，用乙醚萃取，水层用稀盐酸调PH值至2左右，用乙酸乙酯(15mL×2)萃取，合并有机层用饱和NaCl溶液(10mL×2)洗，无水硫酸镁干燥，浓缩，得到白色固体149mg，产率62.6％；m.p.78-80℃。The compound 6-(2-(methylamino)ethoxy)pyridine-2-carboxylic acid (158 mg, 0.806 mmol) was added to acetonitrile (10 mL), (Boc)2O (351 mg, 1.61 mmol) and triethylamine (0.35) The reaction was stirred at room temperature. After 1 h, the reaction was dried. EtOAc was evaporated. The combined organic layer was washed with EtOAc EtOAc (EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.78-7.86(m,2H),6.99(d,J＝7.6Hz,1H),4.48(t,J＝6.4Hz,2H),3.63(t,J＝6.4Hz,2H),2.97(s,3H),1.47(s,9H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.78-7.86 (m, 2H), 6.99 (d, J = 7.6Hz, 1H), 4.48 (t, J = 6.4Hz, 2H), 3.63 ( t, J = 6.4 Hz, 2H), 2.97 (s, 3H), 1.47 (s, 9H).

c)(2-(6-(甲氧基(甲基)氨基甲酰基)吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯c) (2-(6-(Methoxy(methyl)carbamoyl)pyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester

将化合物6-(2-((叔-丁氧羰基)(甲基)氨基)乙氧基)吡啶-2-甲酸(750mg,2.79mmol)加入无水DMF(25mL)，加入HBTU(2.11g,5.58mmol)，HOBt(753mg,5.58mmol)和DIEA(2.9mL,16.74mmol)，加入N,O-二甲基羟胺(541mg,5.58mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:3,E:P＝1:2)，得到无色油状物850mg，产率94.3％。The compound 6-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)pyridine-2-carboxylic acid (750 mg, 2.79 mmol) was added to dry DMF (25 mL). </RTI> 5. Ethyl acetate (40 mL×2) was extracted, and the combined organic layer was washed with saturated NaCI (20 mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:3, E:P=1:2) ), 850 mg of a colorless oil was obtained, yield 94.3%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.64-7.68(m,1H),7.25(brs,1H),6.80(dd,J 1＝8.4Hz,J 2＝0.8,1H),4.45(t,J＝5.2Hz,2H),3.78(s,3H),3.61(t,J＝5.2Hz,2H),3.40(s,3H),2.96(s,3H),1.44(s,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.64 - 7.68 (m, 1H), 7.25 (brs, 1H), 6.80 (dd, J 1 = 8.4 Hz, J 2 = 0.8, 1H), 4.45 (t, J = 5.2 Hz, 2H), 3.78 (s, 3H), 3.61 (t, J = 5.2 Hz, 2H), 3.40 (s, 3H), 2.96 (s, 3H), 1.44 (s, 9H) .

d)(2-(6-乙酰基吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯d) (2-(6-Acetylpyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester

将化合物(2-(6-(甲氧基(甲基)氨基甲酰基)吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯(830mg,2.57mmol)加入干燥THF(30mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(4.62mL,4.62mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，1h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20,E:P＝1:10)，得到无色油状物450mg，产率62.9％。The compound (2-(6-(methoxy(methyl)carbamoyl)pyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester (830 mg, 2.57 mmol) was added to dry THF (30 mL) 1M methylmagnesium bromide in THF (4.62 mL, 4.62 mmol) was added dropwise to the reaction flask at 0 ° C under argon atmosphere. After the dropwise addition, the reaction was stirred at 0 ° C. After 1 h, the saturated ammonium chloride solution was added. It was added to a reaction flask, and extracted with EA (40 mL×2). The organic layer was combined, washed with a saturated NaCI solution (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (E:P=1:20, E :P = 1:10), 450 mg of a colorless oil was obtained, yield 62.9%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.71(t,J＝7.6Hz,2H),7.64(dd,J 1＝7.6Hz,J 2＝0.8,1H),6.92(dd,J 1＝8.0Hz,J 2＝0.8,1H),4.52(t,J＝5.6Hz,2H),3.66(t,J＝5.6Hz,2H),2.98(s,3H),2.67(s,3H),1.43(s,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.71 (t, J = 7.6 Hz, 2H), 7.64 (dd, J 1 = 7.6 Hz, J 2 = 0.8, 1H), 6.92 (dd, J 1 = 8.0 Hz, J 2 = 0.8, 1H), 4.52 (t, J = 5.6 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.98 (s, 3H), 2.67 (s, 3H) , 1.43 (s, 9H).

e)(2-(6-(1-(肟基)乙基)吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯e) (2-(6-(1-(indolyl)ethyl)pyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester

将化合物(2-(6-乙酰基吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯(430mg,1.54mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.27mL,4.62mmol)升温至60℃反应，1h后停止反应，加入DCM(20mL)，无水硫酸镁干燥，柱层析(E:P＝1:8，E:P＝1:7)得到白色固体430mg，产率95.3％。The compound (2-(6-acetylpyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester (430 mg, 1.54 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% hydroxylamine was added. The aqueous solution (0.27 mL, 4.62 mmol) was heated to 60 ° C, and the reaction was stopped after 1 h, then DCM (20 mL) was evaporated, dried over anhydrous magnesium sulfate, and column chromatography (E:P=1:8, E:P=1:7) 430 mg of a white solid were obtained in a yield of 95.3%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.58(t,J＝7.6Hz,1H),7.38-7.41(m,1H),6.72(d,J＝8.4Hz,1H),4.49(s,2H),3.63(s,2H),2.97(s,3H),2.34-2.35(m,3H),1.41-1.46(m,9H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.58 (t, J = 7.6 Hz, 1H), 7.38-7.41 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 4.49 ( s, 2H), 3.63 (s, 2H), 2.97 (s, 3H), 2.34 - 2.35 (m, 3H), 1.41-1.46 (m, 9H).

f)(2-(6-(1-氨基乙基)吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯f) (2-(6-(1-Aminoethyl)pyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester

将化合物(2-(6-(1-(肟基)乙基)吡啶-2-基)乙基)(甲基)氨基甲酸叔丁酯(400mg,1.365mmol)加入甲醇(5mL)，加入10％Pd/C(400mg)至回流后加入甲酸铵(860mg,13.65mmol)继续加热回流反应，30min后停止反应，过滤，浓缩，得到淡黄色油状物290mg，产率76.1％。The compound (2-(6-(1-(indolyl)ethyl)pyridin-2-yl)ethyl)(methyl)carbamic acid tert-butyl ester (400 mg, 1.365 mmol) was added to methanol (5 mL) After the addition of %Pd/C (400 mg) to EtOAc (EtOAc, EtOAc, EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.52(t,J＝7.6Hz,1H),6.82(d,J＝7.2Hz,1H),6.57(d,J＝8.4Hz,1H),4.43-4.47(m,1H),3.99-4.04(m,1H),3.61(brs,2H),2.96(s,3H),2.20(brs,2H),1.40-1.45(m,12H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.52 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H) , 4.43-4.47 (m, 1H), 3.99-4.04 (m, 1H), 3.61 (brs, 2H), 2.96 (s, 3H), 2.20 (brs, 2H), 1.40-1.45 (m, 12H).

g)(2-((6-(1-(2-乙氧基-5-异丁酰胺基苯基酰胺基)乙基)吡啶-2-基)氧代)乙基)(甲基)氨基甲酸叔丁酯g)(2-((6-(1-(2-ethoxy-5-isobutyrylphenyl))))))))))))))))) Tert-butyl formate

将2-乙氧基-5-异丁酰氨基苯甲酸(150mg,0.597mmol)加入无水DMF(20mL)，加入EDC(229mg,1.194mmol)，加入HOBt(161mg,1.194mmol)和DIEA(0.31mL,1.79mmol)，加入化合物(44)(250mg,0.896mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝80:1,D:M＝60:1)，得到白色固体260mg，产率83.3％；m.p.92-94℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (150 mg, 0.597 mmol) was added to dry DMF (20 mL). E.sub.2 (229 mg, 1.194 mmol) was added, HOBt (161 mg, 1.194 mmol) and DIEA (0.31) The compound (44) (250 mg, 0.896 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (40 mL×2). 2) Washing, drying over anhydrous magnesium sulfate, EtOAc (EtOAc: EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):8.69(brs,1H),8.22(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.85(s,1H),7.68(s,1H),7.55(t,J＝7.6Hz,1H),6.94(d,J＝9.2Hz,1H),6.90(d,J＝7.2Hz,1H),6.62(t,J＝7.2Hz,1H),5.27-5.35(m,1H),4.44-4.50(m,2H),4.18(q,J＝6.8Hz,2H),3.60(brs,2H),2.95(s,3H),2.48-2.56(m,1H),1.57(d,J＝6.8Hz,3H),1.40-1.46(m,12H),1.21(dd,J 1＝6.8Hz,J 2＝2.0Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.69 (brs, 1H), 8.22 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.85 (s, 1H), 7.68 ( s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 6.62 (t, J = 7.2 Hz, 1H), 5.27-5.35 (m, 1H), 4.44 - 4.50 (m, 2H), 4.18 (q, J = 6.8 Hz, 2H), 3.60 (brs, 2H), 2.95 (s, 3H), 2.48-2.56 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.40-1.46 (m, 12H), 1.21 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 6H).

实施例(化合物)199Example (compound) 199

2-乙氧基-5-异丁酰氨基-N-(1-(6-(2-(甲基氨基)乙氧基)吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-(2-(methylamino)ethoxy)pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000259
Figure PCTCN2018088561-appb-000259

取化合物(2-((6-(1-(2-乙氧基-5-异丁酰胺基苯基酰胺基)乙基)吡啶-2-基)氧代)乙基)(甲基)氨基甲酸叔丁酯(200mg,0.378mmol)，加入DCM(5mL)，加入TFA(0.28mL,3.78mmol)室温搅拌反应，5h后停止反应，浓缩至干，加入氨水，用DCM(20mL×3)萃取,合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，用DCM和石油醚重结晶，得到白色固体130mg,产率80.2％；m.p.83-85℃。Taking the compound (2-((6-(1-(2-ethoxy-5-isobutyrylphenyl))))pyridin-2-yl)oxo)ethyl)(methyl)amino Tert-butyl formate (200 mg, 0.378 mmol), EtOAc (EtOAc) (EtOAc) The organic layer was combined, washed with EtOAc EtOAc EtOAc EtOAc EtOAc

1H-NMR(400MHz,CDCl 3)δ(ppm):8.67(d,J＝8.0Hz,1H),8.22(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.84(brs,1H),7.50-7.54(m,1H),6.93(d,J＝9.2Hz,1H),6.87(d,J＝7.2Hz,1H),6.62(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),5.26-5.33(m,1H),4.39-4.50(m,2H),2.98(t,J＝5.6Hz,2H),2.51-2.57(m,1H),2.50(s,3H),2.12(brs,1H),1.56(d,J＝6.8Hz,3H),1.44(t,J＝7.2Hz,3H),1.21(dd,J 1＝6.8Hz,J 2＝1.2Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.67 (d, J = 8.0 Hz, 1H), 8.22 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.84 (brs, 1H), 7.50-7.54 (m, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.62 ( Dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 5.26 - 5.33 (m, 1H), 4.39 - 4.50 (m, 2H), 2.98 (t, J = 5.6 Hz, 2H), 2.51-2.57 (m, 1H), 2.50 (s, 3H), 2.12 (brs, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.21 (dd, J 1 = 6.8 Hz, J 2 = 1.2 Hz, 6H).

实施例(化合物)200Example (compound) 200

N-(1-(6-溴吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺N-(1-(6-bromopyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000260
Figure PCTCN2018088561-appb-000260

a)1-(6-溴吡啶-2-基)乙酮肟a) 1-(6-bromopyridin-2-yl)ethanone oxime

将化合物1-(6-溴吡啶-2-基)乙酮(1g,5mmol)置于反应瓶中，加入EtOH(15mL)，加入50％羟胺水溶液(0.88mL,15mmol)升温至60℃反应，1h后停止反应，加入DCM(20mL)，无水硫酸镁干燥，柱层析(E:P＝1:20，E:P＝1:15)得到白色固体950mg，产率88.8％；m.p.141-143℃。The compound 1-(6-bromopyridin-2-yl)ethanone (1 g, 5 mmol) was placed in a reaction flask, EtOH (15 mL) was added, and 50% aqueous hydroxylamine solution (0.88 mL, 15 mmol) was added and the mixture was warmed to 60 ° C. After 1 h, the reaction was quenched, EtOAc EtOAc (EtOAc m. 143 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.80(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),7.54(t,J＝8.0Hz,1H),7.46(dd,J 1＝8.0Hz,J 2＝0.8Hz,1H),2.36(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.80 (dd, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.46 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 2.36 (s, 3H).

b)1-(6-溴吡啶-2-基)乙胺b) 1-(6-bromopyridin-2-yl)ethylamine

将化合物1-(6-溴吡啶-2-基)乙酮肟(700mg,3.27mmol)置于反应瓶中，加入乙醇(10mL)，水(2mL)，加入锌粉(638mg,9.82mmol)以及2.5N HCl溶液(7.8mL,19.62 mmol)，室温搅拌反应，3h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9，用EA:MeOH＝10:1的混合液(20mL×3)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物500mg，产率76.4％。The compound 1-(6-bromopyridin-2-yl)ethanone oxime (700 mg, 3.27 mmol) was placed in a reaction flask, and ethanol (10 mL), water (2 mL) was added, and zinc powder (638 mg, 9.82 mmol) was added and 2.5N HCl solution (7.8 mL, 19.62 mmol). The reaction was stirred at room temperature. After 3 h, the reaction was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was extracted with EtOAc (EtOAc) (EtOAc)

c)N-(1-(6-溴吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺c) N-(1-(6-bromopyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(350mg,1.39mmol)加入无水DMF(25mL)，加入EDC(534mg,2.78mmol)，加入HOBt(375mg,2.78mmol)和DIEA(0.72mL,4.17mmol)，加入1-(6-溴吡啶-2-基)乙胺(500mg,2.50mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体450mg，产率74.7％；m.p.163-165℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (350 mg, 1.39 mmol) was added to dry DMF (25 mL). E.sub.2 (534 mg, 2.78 mmol). </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The combined organic layers were washed with aq. EtOAc (EtOAc) (EtOAcjjjjjjj .

1H-NMR(400MHz,CDCl3)δ(ppm):9.05(d,J＝7.2Hz,1H),8.19(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.83(d,J＝2.8Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(brs,1H),7.38(dd,J 1＝7.6Hz,J 2＝0.8Hz,1H),7.24-7.27(m,1H),6.96(d,J＝9.2Hz,1H),5.33-5.40(m,1H),4.25(q,J＝7.2Hz,2H),2.48-2.55(m,1H),1.55-1.61(m,6H),1.24(dd,J 1＝6.8Hz,J 2＝1.2Hz,6H). 1 H-NMR (400MHz, CDCl3 ) δ (ppm): 9.05 (d, J = 7.2Hz, 1H), 8.19 (dd, J 1 = 9.2Hz, J 2 = 2.8Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (brs, 1H), 7.38 (dd, J 1 = 7.6 Hz, J 2 = 0.8 Hz, 1H), 7.24 - 7.27 (m) , 1H), 6.96 (d, J = 9.2 Hz, 1H), 5.33-5.40 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 2.48-2.55 (m, 1H), 1.55-1.61 ( m, 6H), 1.24 (dd, J 1 = 6.8 Hz, J 2 = 1.2 Hz, 6H).

实施例(化合物)201Example (compound) 201

2-乙氧基-5-异丁酰氨基-N-(1-(6-(噻唑-2-基)吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-(thiazol-2-yl)pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000261
Figure PCTCN2018088561-appb-000261

将化合物N-(1-(6-溴吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(50mg,0.115mmol)加入甲苯(10mL)，氩气保护下加入Pd(PPh 3) 2Cl 2(16mg,0.023mmol)以及2-(三丁基锡基)噻唑(65mg,0.173mmol)升温至100℃反应，5h后停止反应，浓缩，柱层析(D:M＝90:1,D:M＝70:1,D:M＝50:1)得到类白色固体40mg，产率80％；m.p.142-144℃。 The compound N-(1-(6-bromopyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (50 mg, 0.115 mmol) was added toluene (10 mL), argon Under the protection, Pd(PPh 3 ) 2 Cl 2 (16 mg, 0.023 mmol) and 2-(tributyltinyl)thiazole (65 mg, 0.173 mmol) were added to raise the temperature to 100 ° C. After 5 h, the reaction was stopped, concentrated, and column chromatography (D) :M=90:1, D:M=70:1, D:M=50:1) Obtained 40 mg as an off white solid, yield 80%; mp 142-144 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.86(d,J＝8.0Hz,1H),8.21(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),8.07(d,J＝7.2Hz,1H),7.91(d,J＝3.2Hz,1H),7.87(d,J＝2.4Hz,1H),7.76(t,J＝7.6Hz,1H),7.60(brs,1H),7.43(d,J＝2.8Hz,1H),7.35(d,J＝7.6Hz,1H),6.95(d,J＝8.8Hz,1H),5.42-5.49(m,1H),4.19(q,J＝6.8Hz,2H),2.49-2.56 (m,1H),1.64(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.22(dd,J 1＝6.8Hz,J 2＝1.6Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.86 (d, J = 8.0 Hz, 1H), 8.21. (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.91 (d, J=3.2 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 7.60 (brs, 1H) , 7.43 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 5.42 - 5.49 (m, 1H), 4.19 (q, J=6.8 Hz, 2H), 2.49-2.56 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.22 (dd, J 1 = 6.8 Hz) , J 2 = 1.6 Hz, 6H).

实施例(化合物)202Example (compound) 202

2-乙氧基-5-异丁酰氨基-N-(1-(6-(嘧啶-2-基)吡啶-2-基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(6-(pyrimidin-2-yl)pyridin-2-yl)ethyl)benzamide

Figure PCTCN2018088561-appb-000262
Figure PCTCN2018088561-appb-000262

将化合物N-(1-(6-溴吡啶-2-基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(87mg,0.2mmol)加入甲苯(10mL)，氩气保护下加入Pd(PPh 3) 2Cl 2(28mg,0.04mmol)以及2-(三丁基锡基)嘧啶(111mg,0.3mmol)升温至100℃反应，5h后停止反应，浓缩，柱层析(D:M＝90:1,D:M＝80:1,D:M＝50:1,D:M＝40:1)得到类白色固体22mg，产率25.5％；m.p.238-240℃。 The compound N-(1-(6-bromopyridin-2-yl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide (87 mg, 0.2 mmol) was added toluene (10 mL), argon was added Pd (PPh 3) 2 Cl 2 (28mg, 0.04mmol) and 2- (tributylstannyl) pyrimidine (111mg, 0.3mmol) the reaction temperature was raised to 100 deg.] C, the reaction was stopped after 5h, concentrated, and column chromatographed (D protected :M=90:1, D:M=80:1, D:M=50:1, D:M=40:1) Obtained as an off-white solid 22mg, yield 25.5%; mp 238-240 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.02(d,J＝7.6Hz,1H),8.95(d,J＝4.8Hz,2H),8.37(d,J＝7.6Hz,1H),8.20(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.83-7.88(m,2H),7.62(s,1H),7.47(d,J＝7.6Hz,1H),7.35(t,J＝5.2Hz,1H),6.93(d,J＝8.8Hz,1H),5.51-5.59(m,1H),4.21(q,J＝6.8Hz,2H),2.47-2.55(m,1H),1.70(d,J＝6.8Hz,3H),1.39(t,J＝7.2Hz,3H),1.21(dd,J 1＝6.8Hz,J 2＝1.6Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.02 (d, J = 7.6Hz, 1H), 8.95 (d, J = 4.8Hz, 2H), 8.37 (d, J = 7.6Hz, 1H) , 8.20 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.83 - 7.88 (m, 2H), 7.62 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 ( t, J = 5.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.51-5.59 (m, 1H), 4.21 (q, J = 6.8 Hz, 2H), 2.47-2.55 (m, 1H) ), 1.70 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H), 1.21 (dd, J 1 = 6.8 Hz, J 2 = 1.6 Hz, 6H).

实施例(化合物)203Example (compound) 203

2-乙氧基-N-(1-(3-乙氧基-5-氟苯基)乙基)-5-异丁酰氨基苯酰胺2-ethoxy-N-(1-(3-ethoxy-5-fluorophenyl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000263
Figure PCTCN2018088561-appb-000263

a)3-乙氧基-5-氟苯甲酸乙酯a) 3-ethoxy-5-fluorobenzoic acid ethyl ester

将化合物3-羟基-5-氟苯甲酸(937mg,6mmol)置于反应瓶中，加入DMF(30mL)，室温搅拌下加入K2CO3(2.48g,18mmol)以及碘乙烷(0.96mL,12mmol)加热至40℃反应，4h后停止反应，将反应液倒入冰水中，用乙酸乙酯(30mL×3)萃取,合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到无色油状物1.1g,产率86.6％。The compound 3-hydroxy-5-fluorobenzoic acid (937 mg, 6 mmol) was placed in a reaction flask, and DMF (30 mL) was added, and K2CO3 (2.48 g, 18 mmol) and ethyl iodide (0.96 mL, 12 mmol) The reaction was carried out to a temperature of 40 ° C, and the reaction was stopped after 4 h. The reaction mixture was poured into EtOAc EtOAc (EtOAc) Concentration gave 1.1 g of a colorless oil, yield 86.6%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.28(s,1H),7.24(d,J＝8.8Hz,1H),7.13(d,J＝ 10.8Hz,1H),4.31(q,J＝7.2Hz,2H),4.10(q,J＝7.2Hz,2H),1.30-1.36(m,6H).b)3-乙氧基-5-苯甲酸 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.28 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 10.8 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 1.30-1.36 (m, 6H). b) 3-ethoxy-5-benzoic acid

将化合物3-乙氧基-5-氟苯甲酸乙酯(910mg,4.29mmol)，加入MeOH(10mmol)，THF(10mL),将LiOH(155mg,6.44mmol)溶于8mL水中，加入反应液中室温搅拌反应，3h后停止反应，浓缩，用无水乙醚萃取，水层用稀盐酸调PH值至2左右，用乙酸乙酯(30mL×3)萃取,合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到白色固体740mg,产率93.85％；m.p.126-128℃。The compound 3-ethoxy-5-fluorobenzoic acid ethyl ester (910 mg, 4.29 mmol) was added MeOH (10 mmol), THF (10 mL), LiOH (155 mg, 6.44 mmol) was dissolved in water The reaction was stirred at room temperature. After 3 h, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was washed with MgSO.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.39-7.43(m,1H),7.36-7.39(m,1H),6.87(t,J＝2.4Hz,0.5H),6.84(t,J＝2.4Hz,0.5H),4.08(q,J＝6.8Hz,2H),1.44(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.39-7.43 (m, 1H), 7.36-7.39 (m, 1H), 6.87 (t, J = 2.4Hz, 0.5H), 6.84 (t, J = 2.4 Hz, 0.5 H), 4.08 (q, J = 6.8 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H).

c)3-乙氧基-5-氟-N-甲氧基-N-甲基苯甲酰胺c) 3-ethoxy-5-fluoro-N-methoxy-N-methylbenzamide

将化合物3-乙氧基-5-苯甲酸(680mg,3.695mmol)加入无水DMF(25mL)，加入EDC(1.42g,7.39mmol)，加入HOBt(998mg,7.39mmol)和DIEA(3.86mL,22.17mmol)，加入N,O-二甲基羟胺(717mg,7.39mmol)，室温搅拌过夜，次日停止反应，加水用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:10,E:P＝1:6)，得到无色油状物750mg，产率89.5％。The compound 3-ethoxy-5-benzoic acid (680 mg, 3.695 mmol) was taken in anhydrous DMF (25 mL), EtOAc (EtOAc, EtOAc, EtOAc 22.17 mmol), N,O-dimethylhydroxylamine (717 mg, 7.39 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was stopped the next day, and water was extracted with ethyl acetate (40 mL×2). ×2) Washed, dried over anhydrous magnesium sulfate, EtOAc (EtOAc: EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):6.94-6.99(m,2H),6.67-6.71(m,1H),4.04(q,J＝6.8Hz,2H),3.57(s,3H),3.34(s,3H),1.39-1.44(m,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 6.94-6.99 (m, 2H), 6.67-6.71 (m, 1H), 4.04 (q, J = 6.8 Hz, 2H), 3.57 (s, 3H) ), 3.34 (s, 3H), 1.39-1.44 (m, 3H).

d)1-(3-乙氧基-5-氟苯基)乙酮d) 1-(3-ethoxy-5-fluorophenyl)ethanone

将化合物3-乙氧基-5-氟-N-甲氧基-N-甲基苯甲酰胺(600mg,2.64mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(3.96mL,3.96mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20)，得到淡黄色油状物375mg，产率78％。The compound 3-ethoxy-5-fluoro-N-methoxy-N-methylbenzamide (600 mg, 2.64 mmol) was added to dry THF (20 mL) and 1 M methyl bromide at 0 ° C under argon A solution of magnesium THF (3.96 mL, 3.96 mmol) was added dropwise to the reaction flask, and the reaction was continued at 0 ° C. After 2 h, a saturated ammonium chloride solution was added to the reaction flask and extracted with EA (40 mL×2). The organic layer was combined, washed with EtOAc EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.26-7.27(m,1H),7.21-7.22(m,0.5H),7.19-7.20(m,0.5H),6.81(t,J＝2.4Hz,0.5H),6.79(t,J＝2.4Hz,0.5H),4.07(q,J＝6.8Hz,2H),2.57(s,3H),1.43(t,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.26-7.27 (m, 1H), 7.21 - 7.22 (m, 0.5H), 7.19-7.20 (m, 0.5H), 6.81 (t, J = 2.4 Hz, 0.5 H), 6.79 (t, J = 2.4 Hz, 0.5 H), 4.07 (q, J = 6.8 Hz, 2H), 2.57 (s, 3H), 1.43 (t, J = 6.8 Hz, 3H) .

e)1-(3-乙氧基-5-氟苯基)乙酮肟e) 1-(3-Ethoxy-5-fluorophenyl)ethanone oxime

将化合物1-(3-乙氧基-5-氟苯基)乙酮(330mg,1.81mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.32mL,5.44mmol)升温至60℃反应，6h后停止反 应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:30,E:P＝1:25)得到白色固体290mg，产率81.2％；m.p.65-66℃。The compound 1-(3-ethoxy-5-fluorophenyl)ethanone (330 mg, 1.81 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine solution (0.32 mL, 5.44 mmol) was added. The reaction was stopped at 60 ° C, and the reaction was stopped after 6 h, then DCM (30 mL) was evaporated. %; mp65-66 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):6.95-6.97(m,1H),6.92-6.94(m,0.5H),6.90-6.91(m,0.5H),6.64(t,J＝2.4Hz,0.5H),6.61(t,J＝2.4Hz,0.5H),4.04(q,J＝6.8Hz,2H),2.25(s,3H),1.42(t,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 6.95-6.97 (m, 1H), 6.92-6.94 (m, 0.5H), 6.90-6.91 (m, 0.5H), 6.64 (t, J = 2.4 Hz, 0.5 H), 6.61 (t, J = 2.4 Hz, 0.5 H), 4.04 (q, J = 6.8 Hz, 2H), 2.25 (s, 3H), 1.42 (t, J = 6.8 Hz, 3H) .

f)1-(3-乙氧基-5-氟苯基)乙胺f) 1-(3-Ethoxy-5-fluorophenyl)ethylamine

将化合物1-(3-乙氧基-5-氟苯基)乙酮肟(200mg,1.015mmol)置于反应瓶中，加入乙醇(8mL)，水(1.5mL)，加入锌粉(198mg,3.04mmol)以及2.5N HCl溶液(2.4mL,6.09mmol)，室温搅拌反应，4h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯(40mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物165mg，产率88.7％。The compound 1-(3-ethoxy-5-fluorophenyl)ethanone oxime (200 mg, 1.015 mmol) was placed in a reaction flask, and ethanol (8 mL), water (1.5 mL) was added, and zinc powder (198 mg, 3.04mmol) and 2.5N HCl solution (2.4mL, 6.09mmol), the reaction was stirred at room temperature, the reaction was stopped after 4h, concentrated, water was added, extracted with 20mL of ether, the aqueous layer was adjusted to pH about 9 with saturated sodium carbonate solution, with acetic acid Ethyl acetate (40 mL × 2) was evaporated, evaporated, evaporated, evaporated, evaporated

1H-NMR(400MHz,CDCl 3)δ(ppm):6.69(t,J＝1.6Hz,1H),6.66(t,J＝1.6Hz,0.5H),6.64(t,J＝2.0Hz,0.5H),6.49(t,J＝2.4Hz,0.5H),6.46(t,J＝2.0Hz,0.5H),4.06(q,J＝6.4Hz,1H),4.01(q,J＝6.8Hz,2H),1.84(brs,2H),1.41(t,J＝6.8Hz,3H),1.36(d,J＝6.4Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 6.69 (t, J = 1.6 Hz, 1H), 6.66 (t, J = 1.6 Hz, 0.5H), 6.64 (t, J = 2.0 Hz, 0.5 H), 6.49 (t, J = 2.4 Hz, 0.5H), 6.46 (t, J = 2.0 Hz, 0.5H), 4.06 (q, J = 6.4 Hz, 1H), 4.01 (q, J = 6.8 Hz, 2H), 1.84 (brs, 2H), 1.41 (t, J = 6.8 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H).

g)2-乙氧基-N-(1-(3-乙氧基-5-氟苯基)乙基)-5-异丁酰氨基苯酰胺g) 2-Ethoxy-N-(1-(3-ethoxy-5-fluorophenyl)ethyl)-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(15mL)，加入EDC(153mg,0.796mmol)，加入HOBt(108mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入化合物1-(3-乙氧基-5-氟苯基)乙胺(109mg,0.597mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体150mg，产率90.9％；m.p.104-105℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (15 mL). E.sub.2 (153 mg, 0.796 mmol) was added, and HOBt (108 mg, 0.796 mmol) and DIEA (0.21) The compound 1-(3-ethoxy-5-fluorophenyl)ethylamine (109 mg, 0.597 mmol) was added, and the mixture was stirred at room temperature overnight. 2) Extraction, the combined organic layer was washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated and then purified by column chromatography (D:M=90:1) to give a white solid 150 mg, yield 90.9%; 104-105 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.44(d,J＝7.6Hz,1H),8.23(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.86(d,J＝2.4Hz,1H),7.78(s,1H),6.93(d,J＝9.2Hz,1H),6.70(t,J＝1.6Hz,1H),6.67(t,J＝1.6Hz,0.5H),6.64(t,J＝1.6Hz,0.5H),6.50(t,J＝2.0Hz,0.5H),6.48(t,J＝2.4Hz,0.5H),5.20-5.27(m,1H),4.17(q,J＝7.2Hz,2H),4.99(q,J＝6.8Hz,2H),2.45-2.52(m,1H),1.53(d,J＝6.8Hz,3H),1.45(t,J＝6.8Hz,3H),1.39(t,J＝6.8Hz,3H),1.20(dd,J 1＝6.8Hz,J 2＝2.0Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.44 (d, J = 7.6 Hz, 1H), 8.23 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.70 (t, J = 1.6 Hz, 1H), 6.67 (t, J = 1.6 Hz, 0.5H) ), 6.64 (t, J = 1.6 Hz, 0.5H), 6.50 (t, J = 2.0 Hz, 0.5H), 6.48 (t, J = 2.4 Hz, 0.5H), 5.20-5.27 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.99 (q, J = 6.8 Hz, 2H), 2.45-2.52 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.45 (t, J = 6.8 Hz, 3H), 1.39 (t, J = 6.8 Hz, 3H), 1.20 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 6H).

实施例(化合物)204Example (compound) 204

2-乙氧基-N-(1-(5-乙氧基-2-氟苯基)乙基)-5-异丁酰氨基苯甲酰胺2-ethoxy-N-(1-(5-ethoxy-2-fluorophenyl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000264
Figure PCTCN2018088561-appb-000264

a)5-乙氧基-2-氟苯甲酸乙酯a) ethyl 5-ethoxy-2-fluorobenzoate

将化合物5-羟基-2-氟苯甲酸(937mg,6mmol)置于反应瓶中，加入DMF(30mL)，室温搅拌下加入K 2CO 3(2.48g,18mmol)以及碘乙烷(0.96mL,12mmol)加热至40℃反应，10h后停止反应，将反应液倒入冰水中，用乙酸乙酯(30mL×3)萃取,合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到无色油状物1.2g,产率94.5％。 The compound 5-hydroxy-2-fluorobenzoic acid (937 mg, 6 mmol) was placed in a reaction flask, and DMF (30 mL) was added, and K 2 CO 3 (2.48 g, 18 mmol) and ethyl iodide (0.96 mL, 12 mmol), the reaction was heated to 40 ° C, and the reaction was stopped after 10 h. The reaction solution was poured into ice water and extracted with ethyl acetate (30 mL×3). The organic layer was combined and washed with saturated NaCI solution (15 mL×2). The magnesium was dried and concentrated to give a colorless oil (yield: 1.2 g).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.37-7.40(m,1H),7.00-7.04(m,2H),4.39(q,J＝7.2Hz,2H),4.03(q,J＝7.2Hz,2H),1.37-1.43(m,6H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.37-7.40 (m, 1H), 7.00-7.04 (m, 2H), 4.39 (q, J = 7.2 Hz, 2H), 4.03 (q, J) =7.2 Hz, 2H), 1.37-1.43 (m, 6H).

b)5-乙氧基-2-氟苯甲酸b) 5-ethoxy-2-fluorobenzoic acid

将化合物5-乙氧基-2-氟苯甲酸乙酯(1.1g,5.19mmol)，加入MeOH(10mmol)，THF(10mL),将LiOH(187mg,7.78mmol)溶于8mL水中，加入反应液中室温搅拌反应，3h后停止反应，浓缩，用无水乙醚萃取，水层用稀盐酸调PH值至2左右，The compound 5-ethoxy-2-fluorobenzoic acid ethyl ester (1.1 g, 5.19 mmol) was added to MeOH (10 mmol), THF (10 mL), and LiOH (187 mg, 7.78 mmol) was dissolved in 8 mL of water. The reaction was stirred at room temperature, and the reaction was stopped after 3 h, concentrated, extracted with anhydrous diethyl ether, and the aqueous layer was adjusted to pH 2 with dilute hydrochloric acid.

用乙酸乙酯(30mL×3)萃取,合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到白色固体850mg,产率89％；m.p.137-139℃。The organic layer was combined with EtOAc (EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.47-7.49(m,1H),7.05-7.12(m,2H),4.05(q,J＝6.8Hz,2H),1.43(t,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.47-7.49 (m, 1H), 7.05-7.12 (m, 2H), 4.05 (q, J = 6.8 Hz, 2H), 1.43 (t, J =6.8Hz, 3H).

c)5-乙氧基-2-氟-N-甲氧基-N-甲基苯甲酰胺c) 5-ethoxy-2-fluoro-N-methoxy-N-methylbenzamide

将化合物5-乙氧基-2-氟苯甲酸(680mg,3.695mmol)加入无水DMF(25mL)，加入EDC(1.42g,7.39mmol)，加入HOBt(998mg,7.39mmol)和DIEA(3.86mL,22.17mmol)，加入N,O-二甲基羟胺(717mg,7.39mmol)，室温搅拌过夜，次日停止反应，The compound 5-ethoxy-2-fluorobenzoic acid (680 mg, 3.695 mmol) was added to dry DMF (25 mL), EtOAc (EtOAc, EtOAc, , 22.17 mmol), N,O-dimethylhydroxylamine (717 mg, 7.39 mmol) was added, stirred at room temperature overnight, and the reaction was stopped the next day.

加水用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，The water was extracted with ethyl acetate (40 mL×2), and the combined organic layer was washed with saturated NaCI (20mL×2).

无水硫酸镁干燥，浓缩，柱层析(E:P＝1:10,E:P＝1:6)，得到无色油状物770mg，产率91.8％。Drying over anhydrous magnesium sulfate, EtOAc (EtOAc:EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):6.97-7.03(m,12H),6.88-6.92(m,2H),4.00(q,J＝7.2Hz,2H),3.59(s,3H),3.34(s,3H),1.40(t,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 6.97-7.03 (m, 12H), 6.88-6.92 (m, 2H), 4.00 (q, J = 7.2Hz, 2H), 3.59 (s, 3H ), 3.34 (s, 3H), 1.40 (t, J = 6.8 Hz, 3H).

d)1-(5-乙氧基-2-氟苯基)乙酮d) 1-(5-ethoxy-2-fluorophenyl)ethanone

将化合物5-乙氧基-2-氟-N-甲氧基-N-甲基苯甲酰胺(670mg,2.95mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(4.4mL,4.4mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，1h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:20)，得到淡黄色油状物345mg，产率64.2％。The compound 5-ethoxy-2-fluoro-N-methoxy-N-methylbenzamide (670 mg, 2.95 mmol) was added to dry THF (20 mL) and 1 M methyl bromide at 0 ° C under argon A solution of magnesium THF (4.4 mL, 4.4 mmol) was added dropwise to the reaction flask, and the reaction was continued at 0 ° C. After 1 h, a saturated ammonium chloride solution was added to the reaction flask and extracted with EA (40 mL×2). The organic layer was combined, washed with EtOAc EtOAc (EtOAc m.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.26-7.34(m,1H),7.02-7.06(m,2H),4.03(q,J＝6.8Hz,2H),2.64(m,3H),1.41(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.26-7.34 (m, 1H), 7.02-7.06 (m, 2H), 4.03 (q, J = 6.8Hz, 2H), 2.64 (m, 3H ), 1.41 (t, J = 7.2 Hz, 3H).

e)1-(5-乙氧基-2-氟苯基)乙酮肟e) 1-(5-ethoxy-2-fluorophenyl)ethanone oxime

将化合物1-(5-乙氧基-2-氟苯基)乙酮(320mg,1.76mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.31mL,5.28mmol)升温至60℃反应，6h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:30,E:P＝1:20)得到白色固体290mg，产率83.6％；m.p.88-90℃。The compound 1-(5-ethoxy-2-fluorophenyl)ethanone (320 mg, 1.76 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine solution (0.31 mL, 5.28 mmol) was added. The reaction was stopped at 60 ° C, and the reaction was stopped after 6 h, then DCM (30 mL) was evaporated. %; mp88-90 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):6.97-7.03(m,1H),6.94-6.98(m,1H),6.83-6.88(m,1H),4.01(q,J＝7.2Hz,2H),2.28(m,3H),1.40(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 6.97-7.03 (m, 1H), 6.94-6.98 (m, 1H), 6.83-6.88 (m, 1H), 4.01 (q, J = 7.2Hz , 2H), 2.28 (m, 3H), 1.40 (t, J = 7.2 Hz, 3H).

f)1-(5-乙氧基-2-氟苯基)乙胺f) 1-(5-ethoxy-2-fluorophenyl)ethylamine

将化合物1-(5-乙氧基-2-氟苯基)乙酮肟(200mg,1.015mmol)置于反应瓶中，加入乙醇(8mL)，水(1.5mL)，加入锌粉(198mg,3.04mmol)以及2.5N HCl溶液(2.4mL,6.09mmol)，室温搅拌反应，4h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯(40mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物170mg，产率91.4％。The compound 1-(5-ethoxy-2-fluorophenyl)ethanone oxime (200 mg, 1.015 mmol) was placed in a reaction flask, and ethanol (8 mL), water (1.5 mL) was added, and zinc powder (198 mg, 3.04mmol) and 2.5N HCl solution (2.4mL, 6.09mmol), the reaction was stirred at room temperature, the reaction was stopped after 4h, concentrated, water was added, extracted with 20mL of ether, the aqueous layer was adjusted to pH about 9 with saturated sodium carbonate solution, with acetic acid Ethyl acetate (40 mL × 2) was evaporated, evaporated, evaporated, evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):6.89-6.95(m,2H),6.67-6.71(m,1H),4.34(q,J＝6.8Hz,1H),4.00(q,J＝6.8Hz,2H),1.77(brs,2H),1.38-1.42(m,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 6.89-6.95 (m, 2H), 6.67-6.71 (m, 1H), 4.34 (q, J = 6.8Hz, 1H), 4.00 (q, J = 6.8 Hz, 2H), 1.77 (brs, 2H), 1.38-1.42 (m, 6H).

g)2-乙氧基-N-(1-(5-乙氧基-2-氟苯基)乙基)-5-异丁酰氨基苯甲酰胺g) 2-Ethoxy-N-(1-(5-ethoxy-2-fluorophenyl)ethyl)-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(15mL)，加入EDC(153mg,0.796mmol)，加入HOBt(108mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入化合物1-(5-乙氧基-2-氟苯基)乙胺(109mg,0.597mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白 色固体140mg，产率84.8％；m.p.100-102℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (15 mL). E.sub.2 (153 mg, 0.796 mmol) was added, and HOBt (108 mg, 0.796 mmol) and DIEA (0.21) The compound 1-(5-ethoxy-2-fluorophenyl)ethylamine (109 mg, 0.597 mmol) was added, and the mixture was stirred at room temperature overnight. 2) Extraction, the combined organic layer was washed with a saturated NaCI solution (15 mL × 2), dried over anhydrous magnesium sulfate, and concentrated, and the column chromatography (D:M=90:1) to give a white solid (140 mg, yield 84.8%; 100-102 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.66(d,J＝8.0Hz,1H),8.22(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),7.86(d,J＝2.8Hz,1H),7.80(s,1H),6.91-6.98(m,2H),6.84-6.87(m,1H),6.69-6.73(m,1H),5.38-5.46(m,1H),4.15-4.21(m,2H),3.96(q,J＝7.2Hz,2H),2.46-2.54(m,1H),1.56(d,J＝7.2Hz,3H),1.49(t,J＝6.8Hz,3H),1.37(t,J＝6.8Hz,3H),1.20(dd,J 1＝6.8Hz,J 2＝2.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.66 (d, J = 8.0Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 2 = 2.4Hz, 1H), 7.86 (d, J=2.8 Hz, 1H), 7.80 (s, 1H), 6.91-6.98 (m, 2H), 6.84-6.87 (m, 1H), 6.69-6.73 (m, 1H), 5.38-5.46 (m, 1H) , 4.15-4.21 (m, 2H), 3.96 (q, J = 7.2 Hz, 2H), 2.46-2.54 (m, 1H), 1.56 (d, J = 7.2 Hz, 3H), 1.49 (t, J = 6.8) Hz, 3H), 1.37 (t, J = 6.8 Hz, 3H), 1.20 (dd, J 1 = 6.8 Hz, J 2 = 2.4 Hz, 6H).

实施例(化合物)205Example (compound) 205

2-乙氧基-N-(1-(3-乙氧基-4-氟苯基)乙基)-5-异丁酰氨基苯甲酰胺2-ethoxy-N-(1-(3-ethoxy-4-fluorophenyl)ethyl)-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000265
Figure PCTCN2018088561-appb-000265

a)3-乙氧基-4-氟苯酸乙酯a) 3-ethoxy-4-fluorobenzoic acid ethyl ester

将化合物2-羟基-4-氟苯甲酸(937mg,6mmol)置于反应瓶中，加入DMF(30mL)，室温搅拌下加入K 2CO 3(2.48g,18mmol)以及碘乙烷(0.96mL,12mmol)加热至40℃反应，4h后停止反应，将反应液倒入冰水中，用乙酸乙酯(30mL×3)萃取,合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，得到无色油状物1.2g,产率94.4％。 The compound 2-hydroxy-4-fluorobenzoic acid (937 mg, 6 mmol) was placed in a reaction flask, and DMF (30 mL) was added, and K 2 CO 3 (2.48 g, 18 mmol) and ethyl iodide (0.96 mL, 12 mmol), the reaction was heated to 40 ° C, and the reaction was stopped after 4 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (30 mL×3). The organic layer was combined and washed with saturated NaCl solution (15 mL×2) The magnesium was dried and concentrated to give a colorless oil (1.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.60-7.66(m,2H),7.07-7.12(m,1H),4.36(q,J＝7.2Hz,2H),4.10(q,J＝6.8Hz,2H),1.47(t,J＝6.8Hz,3H),1.39(t,J＝7.2Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60-7.66 (m, 2H), 7.07-7.12 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.10 (q, J) = 6.8 Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H).

b)4-氟-5-乙氧基苯甲酸b) 4-fluoro-5-ethoxybenzoic acid

将化合物3-乙氧基-4-氟苯甲酸乙酯(1.1g,5.19mmol)，加入MeOH(10mmol)，THF(10mL),将LiOH(187mg,7.78mmol)溶于8mL水中，加入反应液中室温搅拌反应，3h后停止反应，浓缩，用无水乙醚萃取，水层用稀盐酸调PH值至2左右，The compound 3-ethoxy-4-fluorobenzoic acid ethyl ester (1.1 g, 5.19 mmol) was added MeOH (10 mmol), THF (10 mL), LiOH (187 mg, 7.78 mmol) was dissolved in water The reaction was stirred at room temperature, and the reaction was stopped after 3 h, concentrated, extracted with anhydrous diethyl ether, and the aqueous layer was adjusted to pH 2 with dilute hydrochloric acid.

有固体析出，抽滤，滤饼水洗，得到白色固体920mg,产率96.3％；m.p.170-172℃。The solid was precipitated, suction filtered, and the filter cake was washed with water to give a white solid 920 mg, yield 96.3%; m.p. 170-172 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.69-7.74(m,2H),7.12-7.18(m,1H),4.18(q,J＝6.8Hz,2H),1.49(t,J＝7.2Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.69 - 7.74 (m, 2H), 7.12 - 7.18 (m, 1H), 4.18 (q, J = 6.8 Hz, 2H), 1.49 (t, J) =7.2Hz, 3H).

c)3-乙氧基-4-氟-N-甲氧基-N-甲基苯甲酰胺c) 3-ethoxy-4-fluoro-N-methoxy-N-methylbenzamide

将化合物4-氟-5-乙氧基苯甲酸(860mg,4.67mmol)加入无水DMF(25mL)，加入EDC(1.79g,9.34mmol)，加入HOBt(1.26g,9.34mmol)和DIEA(4.9mL,28.02 mmol)，加入N,O-二甲基羟胺(907mg,9.34mmol)，室温搅拌过夜，次日停止反应，加水用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:5,E:P＝1:4)，得到无色油状物920mg，产率86.8％。Compound 4-Fluoro-5-ethoxybenzoic acid (860 mg, 4.67 mmol) was added to dry DMF (25 mL) EtOAc (EtOAc: EtOAc, EtOAc </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> (20 mL × 2) washed, dried over anhydrous magnesium sulfate, EtOAc (EtOAc:EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.36(dd,J 1＝8.4Hz,J 2＝2.0Hz,1H),7.27-7.31(m,1H),7.05-7.11(m,1H),4.13(q,J＝7.2Hz,2H),3.56(s,3H),3.36(s,3H),1.46(t,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.36 (dd, J 1 = 8.4 Hz, J 2 = 2.0 Hz, 1H), 7.27-7.31 (m, 1H), 7.05-7.11 (m, 1H) ), 4.13 (q, J = 7.2 Hz, 2H), 3.56 (s, 3H), 3.36 (s, 3H), 1.46 (t, J = 6.8 Hz, 3H).

d)1-(3-乙氧基-4-氟苯基)乙酮d) 1-(3-Ethoxy-4-fluorophenyl)ethanone

将化合物3-乙氧基-4-氟-N-甲氧基-N-甲基苯甲酰胺(815mg,3.59mmol)加入干燥THF(20mL)，氩气保护下0℃下将1M甲基溴化镁的THF溶液(5.4mL,5.4mmol)滴加入反应瓶中，滴毕，继续在0℃下搅拌反应，2h后将饱和氯化铵溶液加入反应瓶中，用EA(40mL×2)萃取，合并有机层，用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(E:P＝1:25,E:P＝1:20)，得到白色固体500mg，产率76.5％；m.p.38-40℃。The compound 3-ethoxy-4-fluoro-N-methoxy-N-methylbenzamide (815 mg, 3.59 mmol) was added to dry THF (20 mL) and 1 M methyl bromide at 0 ° C under argon The magnesium THF solution (5.4 mL, 5.4 mmol) was added dropwise to the reaction flask, and the reaction was continued at 0 ° C. After 2 h, the saturated ammonium chloride solution was added to the reaction flask and extracted with EA (40 mL×2). The organic layer was combined, washed with aq. EtOAc EtOAc (EtOAc m. Yield 76.5%; mp 38-40 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.60(dd,J 1＝8.4Hz,J 2＝2.0Hz,1H),7.49-7.53(m,1H),7.10-7.15(m,1H),4.17(q,J＝6.8Hz,2H),2.58(s,3H),1.47(t,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.60 (dd, J 1 = 8.4 Hz, J 2 = 2.0 Hz, 1H), 7.49-7.53 (m, 1H), 7.10-7.15 (m, 1H) ), 4.17 (q, J = 6.8 Hz, 2H), 2.58 (s, 3H), 1.47 (t, J = 6.8 Hz, 3H).

e)1-(3-乙氧基-4-氟苯基)乙酮肟e) 1-(3-Ethoxy-4-fluorophenyl)ethanone oxime

将化合物1-(3-乙氧基-4-氟苯基)乙酮(380mg,2.09mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.37mL,6.26mmol)升温至60℃反应，4h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:30,E:P＝1:25)得到白色固体330mg，产率80.1％；m.p.74-75℃。The compound 1-(3-ethoxy-4-fluorophenyl)ethanone (380 mg, 2.09 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine solution (0.37 mL, 6.26 mmol) was added. The reaction was stopped at 60 ° C, and the reaction was stopped after 4 h, then DCM (30 mL) was evaporated. %; mp74-75 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.29(dd,J 1＝8.4Hz,J 2＝2.0Hz,1H),7.04-7.13(m,2H),4.14(q,J＝6.8Hz,2H),2.27(s,3H),1.46(t,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.29 (dd, J 1 = 8.4 Hz, J 2 = 2.0 Hz, 1H), 7.04-7.13 (m, 2H), 4.14 (q, J = 6.8) Hz, 2H), 2.27 (s, 3H), 1.46 (t, J = 6.8 Hz, 3H).

f)1-(3-乙氧基-4-氟苯基)乙胺f) 1-(3-Ethoxy-4-fluorophenyl)ethylamine

将化合物1-(3-乙氧基-4-氟苯基)乙酮肟(210mg,1.15mmol)置于反应瓶中，加入乙醇(8mL)，水(1.5mL)，加入锌粉(224mg,3.44mmol)以及2.5N HCl溶液2.8mL(6.9mmol)，室温搅拌反应，4h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯(40mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物175mg，产率83％。The compound 1-(3-ethoxy-4-fluorophenyl)ethanone oxime (210 mg, 1.15 mmol) was placed in a reaction flask, and ethanol (8 mL), water (1.5 mL) was added, and zinc powder (224 mg, 3.44mmol) and 2.8mL (6.9mmol) of 2.5N HCl solution, stir the reaction at room temperature, stop the reaction after 4h, concentrate, add water, extract with 20mL of ether, adjust the pH value to about 9 with saturated sodium carbonate solution, use acetic acid The ester was extracted with EtOAc (EtOAc)EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):6.98-7.03(m,2H),6.81-6.86(m,1H),4.06-4.15(m,3H),1.75(brs,2H),1.45(t,J＝6.8Hz,3H),1.36(d,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 6.98-7.03 (m, 2H), 6.81-6.86 (m, 1H), 4.06-4.15 (m, 3H), 1.75 (brs, 2H), 1.45 (t, J = 6.8 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H).

g)2-乙氧基-N-(1-(3-乙氧基-4-氟苯基)乙基)-5-异丁酰氨基苯甲酰胺g) 2-Ethoxy-N-(1-(3-ethoxy-4-fluorophenyl)ethyl)-5-isobutyrylaminobenzamide

将2-乙氧基-5-异丁酰氨基苯甲酸(100mg,0.398mmol)加入无水DMF(15mL)，加入EDC(153mg,0.796mmol)，加入HOBt(108mg,0.796mmol)和DIEA(0.21mL,1.19mmol)，加入化合物1-(3-乙氧基-4-氟苯基)乙胺(109mg,0.597mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体135mg，产率81.3％；m.p.67-69℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (100 mg, 0.398 mmol) was added to dry DMF (15 mL). E.sub.2 (153 mg, 0.796 mmol) was added, and HOBt (108 mg, 0.796 mmol) and DIEA (0.21) The compound 1-(3-ethoxy-4-fluorophenyl)ethylamine (109 mg, 0.597 mmol) was added and the mixture was stirred at room temperature overnight, and the mixture was poured into water with ethyl acetate (30 mL) 2) Extraction, the combined organic layer was washed with a saturated NaCI solution (15 mL×2), dried over anhydrous magnesium sulfate, and concentrated, and column chromatography (D:M=90:1) to give white solid 135 mg, yield 81.3%; 67-69 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.41(d,J＝7.2Hz,1H),8.19(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.83(d,J＝2.8Hz,1H),7.64(s,1H),6.99-7.04(m,1H),6.95(dd,J 1＝8.0Hz,J 2＝2.0Hz,1H),6.91(d,J＝8.8Hz,1H),6.85-6.89(m,1H),5.18-5.25(m,1H),4.12-4.16(m,2H),4.08(q,J＝7.2Hz,2H),2.45-2.52(m,1H),1.54(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.39(t,J＝6.8Hz,3H),1.20(dd,J 1＝6.8Hz,J 2＝0.8Hz,6H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 8.41 (d, J = 7.2 Hz, 1H), 8.19 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.83 (d, J=2.8 Hz, 1H), 7.64 (s, 1H), 6.99-7.04 (m, 1H), 6.95 (dd, J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H), 6.91 (d, J = 8.8) Hz, 1H), 6.85-6.89 (m, 1H), 5.18-5.25 (m, 1H), 4.12-4.16 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 2.45-2.52 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.39 (t, J = 6.8 Hz, 3H), 1.20 (dd, J 1 = 6.8 Hz, J 2 = 0.8Hz, 6H).

实施例(化合物)206Example (compound) 206

(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰基)乙基)苯基)(乙基)氨基甲酸苄酯(3-(1-(2-ethoxy-5-isobutyramidobenzoyl)ethyl)phenyl)(ethyl)carbamate

Figure PCTCN2018088561-appb-000266
Figure PCTCN2018088561-appb-000266

a)(3-乙酰基苯基)氨基甲酸苄酯a) Benzyl (3-acetylphenyl)carbamate

将化合物3-氨基苯乙酮(5.4g,40mmol)，加入乙酸乙酯(100mL)，水(50mL)，加入碳酸氢钠(10.08g,120mmol)，将CBZ-Cl(8.4mL,60mmol)滴加入反应瓶中，滴毕，继续室温搅拌反应，1h后停止反应，加入乙酸乙酯(80mL)，用饱和NaCl溶液(40mL×2)洗，无水硫酸镁干燥，用二氯甲烷和石油醚重结晶，得到白色固体9.0g，产率83.6％；m.p.108-109℃The compound 3-aminoacetophenone (5.4 g, 40 mmol) was added ethyl acetate (100 mL), water (50 mL), sodium hydrogen carbonate (10.08 g, 120 mmol), and CBZ-Cl (8.4 mL, 60 mmol) After adding to the reaction flask, the reaction was completed, and the reaction was stirred at room temperature. After 1 h, the reaction was stopped, ethyl acetate (80 mL) was added, washed with saturated NaCI solution (40 mL×2), dried over anhydrous magnesium sulfate Recrystallization, 9.0 g of a white solid, yield 83.6%; mp 108-109 ° C

1H-NMR(400MHz,CDCl 3)δ(ppm):7.94(brs,1H),7.67-7.70(m,1H),7.63-7.66(m,1H),7.34-7.42(m,6H),6.91(brs,1H),5.22(s,2H),2.53(s,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.94 (brs, 1H), 7.67-7.70 (m, 1H), 7.63-7.66 (m, 1H), 7.34-7.42 (m, 6H), 6.91 (brs, 1H), 5.22 (s, 2H), 2.53 (s, 3H).

b)(3-乙酰基苯基)(乙基)氨基甲酸苄酯b) Benzyl (3-acetylphenyl)(ethyl)carbamate

将化合物(3-乙酰基苯基)氨基甲酸苄酯(1g,3.72mmol)置于反应瓶中，加入DMF(20mL)，氩气保护下加入NaH(178mg,4.46mmol)室温搅拌反应1h后加入碘乙 烷(0.31mL,3.91mmol)升温至40℃反应，3h后停止反应，加水，用乙酸乙酯(30mL×2)，饱和NaCl溶液(15mL×2)洗，用无水硫酸镁干燥，浓缩至干，柱层析(E:P＝1:8)得到淡黄色油状物500mg，产率45.2％。The compound (3-acetylphenyl)carbamate (1 g, 3.72 mmol) was placed in a reaction flask, DMF (20 mL) was added, and NaH (178 mg, 4.46 mmol) was added under argon atmosphere. Ethyl iodide (0.31 mL, 3.91 mmol) was heated to 40 ° C, and the reaction was stopped after 3 h, water was added, washed with ethyl acetate (30 mL×2), saturated NaCI solution (15 mL×2) and dried over anhydrous magnesium sulfate. Concentration to dryness, EtOAc (EtOAc:EtOAc)

1H-NMR(400MHz,CDCl 3)δ(ppm):7.79-7.84(m,2H),7.25-7.47(m,7H),5.16(s,2H),3.77(q,J＝7.2Hz,2H),2.57(s,3H),1.17(t,J＝6.8Hz,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.79-7.84 (m, 2H), 7.25-7.47 (m, 7H), 5.16 (s, 2H), 3.77 (q, J = 7.2 Hz, 2H) ), 2.57 (s, 3H), 1.17 (t, J = 6.8 Hz, 3H).

c)乙基(3-(1-(肟基)乙基)苯基)氨基甲酸苄酯c) Ethyl (3-(1-(indolyl)ethyl)phenyl)carbamate

将化合物(3-乙酰基苯基)(乙基)氨基甲酸苄酯(450mg,1.51mmol)置于反应瓶中，加入EtOH(8mL)，加入50％羟胺水溶液(0.27mL,4.54mmol)升温至60℃反应，3h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:8,E:P＝1:7)得到白色粘稠状液体360mg，产率76.4％。The compound (3-acetylphenyl)(ethyl)carbamate (450 mg, 1.51 mmol) was placed in a reaction flask, EtOH (8 mL) was added, and 50% aqueous hydroxylamine (0.27 mL, 4.54 mmol) The reaction was stopped at 60 ° C, and the reaction was stopped after 3 h, and DCM (30 mL) was added, dried over anhydrous magnesium sulfate, and column chromatography (E:P=1:8, E:P=1:7) to obtain 360 mg of white viscous liquid. The rate is 76.4%.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.48-7.52(m,2H),7.21-7.40(m,7H),5.16(s,2H),3.75(q,J＝7.2Hz,2H),2.56(s,3H),1.65(t,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.48-7.52 (m, 2H), 7.21-7.40 (m, 7H), 5.16 (s, 2H), 3.75 (q, J = 7.2 Hz, 2H) ), 2.56 (s, 3H), 1.65 (t, J = 6.8 Hz, 3H).

d)(3-(1-氨基乙基)苯基)(乙基)氨基甲酸苄酯d) Benzyl (3-(1-aminoethyl)phenyl)(ethyl)carbamate

将化合物乙基(3-(1-(肟基)乙基)苯基)氨基甲酸苄酯(330mg,1.06mmol)置于反应瓶中，加入乙醇(8mL)，水(1.5mL)，加入锌粉(206mg,3.17mmol)以及2.5N HCl溶液(2.5mL,6.36mmol)，室温搅拌反应，5h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯(40mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物200mg，产率83％。The compound ethyl (3-(1-(indolyl)ethyl)phenyl)carbamate (330 mg, 1.06 mmol) was placed in a reaction flask, and ethanol (8 mL), water (1.5 mL) was added, and zinc was added. Powder (206 mg, 3.17 mmol) and 2.5N HCl solution (2.5 mL, 6.36 mmol). The reaction was stirred at room temperature. After 5h, the reaction was stopped, concentrated, water was added, extracted with diethyl ether 20mL, and the aqueous layer was adjusted to pH 9 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (40 mL, EtOAc).

e)(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰基)乙基)苯基)(乙基)氨基甲酸苄酯e) (3-(1-(2-ethoxy-5-isobutyramidobenzoyl)ethyl)phenyl)(ethyl)carbamate

将2-乙氧基-5-异丁酰氨基苯甲酸(120mg,0.478mmol)加入无水DMF(15mL)，加入EDC(183mg,0.956mmol)，加入HOBt(129mg,0.956mmol)和DIEA(0.25mL,1.434mmol)，加入化合物(3-(1-氨基乙基)苯基)(乙基)氨基甲酸苄酯(178mg,0.598mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(30mL×2)萃取，合并有机层用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝150:1，D:M＝90:1)，得到白色固体150mg，产率60％；m.p.48-50℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (120 mg, 0.478 mmol) was added to dry DMF (15 mL). EtOAc (EtOAc, EtOAc. Add benzyl (3-(1-aminoethyl)phenyl)(ethyl)carbamate (178 mg, 0.598 mmol), stir at room temperature overnight, then pour the mixture into water with ethyl acetate The ester was extracted (30 mL×2), and the combined organic layer was washed with saturated NaCI (15mL×2), dried over anhydrous magnesium sulfate, and concentrated, column chromatography (D:M=150:1, D:M=90:1) , 150 mg of a white solid was obtained, yield 60%; mp 48-50 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.44(d,J＝2.8Hz,1H),8.21(d,J＝8.4Hz,1H),7.84(s,1H),7.62(s,1H),7.09-7.37(m,8H),7.10(d,J＝7.6Hz,1H),6.91(d,J＝8.4Hz,1H),5.28-5.32(m,1H),5.13(s,2H),4.06-4.14(m,2H),3.72(q,J＝7.2Hz,2H),2.47-2.53(m,1H),1.55(d,J＝6.8Hz,3H),1.35(t,J＝6.8Hz,3H),1.21(d,J＝5.6Hz,6H),1.15(d,J＝6.8Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.44 (d, J = 2.8Hz, 1H), 8.21 (d, J = 8.4Hz, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.09-7.37 (m, 8H), 7.10 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.28-5.32 (m, 1H), 5.13 (s, 2H) ), 4.06-4.14 (m, 2H), 3.72 (q, J = 7.2 Hz, 2H), 2.47-2.53 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.35 (t, J = 6.8 Hz, 3H), 1.21 (d, J = 5.6 Hz, 6H), 1.15 (d, J = 6.8 Hz, 3H).

实施例(化合物)207Example (compound) 207

2-乙氧基-N-(1-(3-(乙胺基)苯基)乙基)-5-异丁酰氨基苯甲酰胺ZJ87082-Ethoxy-N-(1-(3-(ethylamino)phenyl)ethyl)-5-isobutyrylaminobenzamide ZJ8708

Figure PCTCN2018088561-appb-000267
Figure PCTCN2018088561-appb-000267

将化合物(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰基)乙基)苯基)(乙基)氨基甲酸苄酯(100mg)加入EtOH(8mL)加入10％Pd/C(30mg)常温常压下氢化反应，4h后停止反应，过滤，浓缩，柱层析(D:M＝80:1)得到白色固体50mg，产率67.5％；m.p.87-89℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.48(d,J＝7.6Hz,1H),8.23(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.76(brs,1H),7.17(t,J＝8.0Hz,1H),6.91(d,J＝9.2Hz,1H),6.75(d,J＝7.2Hz,1H),6.67(brs,1H),6.57(d,J＝7.6Hz,1H),5.16-5.30(m,1H),4.10-4.18(m,2H),3.14(q,J＝7.2Hz,2H),2.50-2.57(m,1H),1.55(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.20-1.25(m,9H). The compound (3-(1-(2-ethoxy-5-isobutyrylbenzoyl)ethyl)phenyl)(ethyl)carbamate (100 mg) was added to EtOH (8 mL), 10% Pd/C (30 mg) was hydrogenated at normal temperature and normal pressure, and the reaction was stopped after 4 h, filtered, concentrated, and purified by column chromatography (D:M=80:1) to yield 50 mg of white solid, yield 67.5%; mp 87-89 ° C. 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.48 (d, J = 7.6Hz, 1H), 8.23 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.76 (brs, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H) , 6.67 (brs, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.16-5.30 (m, 1H), 4.10-4.18 (m, 2H), 3.14 (q, J = 7.2 Hz, 2H), 2.50-2.57 (m, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.42 (t, J = 6.8 Hz, 3H), 1.20-1.25 (m, 9H).

实施例(化合物)208Example (compound) 208

(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰基)乙基)苯基)(丙基)氨基甲酸苄酯(3-(1-(2-ethoxy-5-isobutyramidobenzoyl)ethyl)phenyl)(propyl)carbamate

Figure PCTCN2018088561-appb-000268
Figure PCTCN2018088561-appb-000268

a)(3-乙酰基苯基)(丙基)氨基甲酸苄酯a) (3-Acetylphenyl) (propyl) carbamic acid benzyl ester

将化合物(3-乙酰基苯基)氨基甲酸苄酯(1g,3.72mmol)置于反应瓶中，加入DMF(20mL)，氩气保护下加入Cs 2CO 3(2.42g,7.44mmol)室温搅拌反应1h后加入溴代正丙烷(0.68mL,7.44mmol)升温至40℃反应，3d后停止反应，加水，用乙酸乙酯(30mL×2)，饱和NaCl溶液(15mL×2)洗，用无水硫酸镁干燥，浓缩至干，柱层析(E:P＝1:8)得到无色油状物860mg，产率74.4％。 The compound (3-acetylphenyl)carbamate (1 g, 3.72 mmol) was placed in a reaction flask, DMF (20 mL) was added, and Cs 2 CO 3 (2.42 g, 7.44 mmol) was stirred under argon atmosphere. After 1 h of reaction, bromo-n-propane (0.68 mL, 7.44 mmol) was added and the mixture was heated to 40 ° C. After 3 d, the reaction was stopped, water was added, and ethyl acetate (30 mL × 2), saturated NaCl solution (15 mL × 2) was washed with The residue was dried over MgSO.sub.4.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.79-7.83(m,2H),7.40-7.47(m,2H),7.24-7.34(m,5H),5.15(s,2H),3.66-3.70(m,2H),2.57(s,3H),1.52-1.62(m,2H),0.88(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.79-7.83 (m, 2H), 7.40-7.47 (m, 2H), 7.24-7.34 (m, 5H), 5.15 (s, 2H), 3.66 -3.70 (m, 2H), 2.57 (s, 3H), 1.52-1.62 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

b)(3-(1-(肟基)乙基)苯基)(丙基)氨基甲酸苄酯b) (3-(1-(indolyl)ethyl)phenyl)(propyl)carbamate

将化合物(3-乙酰基苯基)(丙基)氨基甲酸苄酯(840mg,2.7mmol)置于反应瓶中，加入EtOH(10mL)，加入50％羟胺水溶液(0.49mL,8.1mmol)升温至60℃反应，5h 后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:8)得到无色油状物800mg，产率90.9％。The compound (3-acetylphenyl) (propyl) carbamic acid benzyl ester (840 mg, 2.7 mmol) was placed in a reaction flask, EtOH (10 mL) was added, and 50% aqueous hydroxylamine solution (0.49 mL, 8.1 mmol) was added to warm The reaction was carried out at 60 ° C, and the reaction was stopped after 5 h, then DCM (30 mL) was evaporated.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.47-7.52(m,2H),7.36(t,J＝7.6Hz,1H),7.02-7.31(m,6H),5.15(s,2H),3.64-3.68(m,2H),2.25(s,3H),1.52-1.62(m,2H),0.88(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.47-7.52 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.02-7.31 (m, 6H), 5.15 (s, 2H) ), 3.64 - 3.68 (m, 2H), 2.25 (s, 3H), 1.52-1.62 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

c)(3-(1-氨基乙基)苯基)(丙基)氨基甲酸苄酯c) Benzyl (3-(1-aminoethyl)phenyl)(propyl)carbamate

将化合物(3-(1-(肟基)乙基)苯基)(丙基)氨基甲酸苄酯(730mg,2.24mmol)置于反应瓶中，加入乙醇(15mL)，水(3.0mL)，加入锌粉(437mg,6.72mmol)以及2.5N HCl溶液5.4mL(13.44mmol)，室温搅拌反应，5h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯(50mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物，含有产物，以及产物脱CBZ的化合物，分析可能是由于浓缩时过干，造成盐酸浓度升高将CBZ脱除。The compound (3-(1-(indolyl)ethyl)phenyl)(propyl)carbamate (730 mg, 2.24 mmol) was placed in a reaction flask, and ethanol (15 mL), water (3.0 mL), Add zinc powder (437mg, 6.72mmol) and 5.4mL (13.44mmol) of 2.5N HCl solution, stir the reaction at room temperature, stop the reaction after 5h, concentrate, add water, extract with 20mL of ether, adjust the pH value with saturated sodium carbonate solution to The mixture was extracted with ethyl acetate (50 mL×2). EtOAc (EtOAc m. For the compound, the analysis may be due to excessive drying during concentration, resulting in an increase in the concentration of hydrochloric acid to remove CBZ.

d)(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰基)乙基)苯基)(乙基)氨基甲酸苄酯d) (3-(1-(2-ethoxy-5-isobutyrylbenzoyl)ethyl)phenyl)(ethyl)carbamate

将2-乙氧基-5-异丁酰氨基苯甲酸(200mg,0.797mmol)加入无水DMF(20mL)，加入EDC(306mg,1.59mmol)，加入HOBt(215mg,1.59mmol)和DIEA(0.42mL,2.15mmol)，加入化合物(3-(1-氨基乙基)苯基)(丙基)氨基甲酸苄酯(380mg,1.22mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(25mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到产物100mg,产物与产物脱CBZ的混合物250mg；m.p.46-48。2-Ethoxy-5-isobutyrylaminobenzoic acid (200 mg, 0.797 mmol) was added to dry DMF (20 mL), EtOAc (EtOAc, EtOAc. Add benzyl (3-(1-aminoethyl)phenyl)(propyl)carbamate (380 mg, 1.22 mmol), stir at room temperature overnight, then pour the mixture into water with ethyl acetate The ester (40 mL × 2) was extracted, and the combined organic layer was washed with saturated NaCI (25mL×2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (D:M=90:1) The mixture of de-CBZ was 250 mg; mp 46-48.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.22(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.82(d,J＝2.8Hz,1H),7.54(brs,1H),7.20-7.35(m,8H),7.10(d,J＝7.6Hz,1H),6.91(d,J＝9.2Hz,1H),5.26-5.34(m,1H),5.12(s,2H),4.06-4.15(m,2H),3.60-3.64(m,2H),2.48-2.55(m,1H),1.51-1.59(m,5H),1.35(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H),0.86(t,J＝7.2Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.54 (brs, 1H), 7.20-7.35 (m, 8H), 7.10 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 5.26- 5.34 (m, 1H), 5.12 (s, 2H), 4.06-4.15 (m, 2H), 3.60-3.64 (m, 2H), 2.48-2.55 (m, 1H), 1.51-1.59 (m, 5H), 1.35 (t, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H).

实施例(化合物)209Example (compound) 209

2-乙氧基-5-异丁酰氨基-N-(1-(3-(丙基氨基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(propylamino)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000269
Figure PCTCN2018088561-appb-000269

将化合物(5含有原料和产物)(200mg)加入EtOH(10mL)加入10％Pd/C(40mg)常温常压下氢化反应，4h后停止反应，过滤，浓缩，用乙酸乙酯和石油醚将化合物固化，得到白色固体150mg；m.p.105-106℃。The compound (5 containing the starting material and the product) (200 mg) was added to EtOH (10 mL), and 10% Pd/C (40 mg) was hydrogenated at normal temperature and normal pressure. After 4 h, the reaction was stopped, filtered, and concentrated with ethyl acetate and petroleum ether. The compound was solidified to give a white solid, 150 mg; mp 105-106.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.47(d,J＝6.8Hz,1H),8.23(dd,J 1＝8.8Hz,J 2＝2.0Hz,1H),7.87(brs,1H),7.83(brs,1H),7.16(t,J＝8.0Hz,1H),6.91(d,J＝8.8Hz,1H),6.72(d,J＝7.2Hz,1H),6.63(brs,1H),6.53(d,J＝7.6Hz,1H),5.16-5.24(m,1H),4.09-4.17(m,2H),3.06(t,J＝7.2Hz,2H),2.49-2.56(m,1H),1.59-1.67(m,2H),1.55(d,J＝6.8Hz,3H),1.21(d,J＝6.4Hz,6H),0.98(t,J＝7.6Hz,3H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.47 (d, J = 6.8Hz, 1H), 8.23 (dd, J 1 = 8.8Hz, J 2 = 2.0Hz, 1H), 7.87 (brs, 1H), 7.83 (brs, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.63 (brs, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.16-5.24 (m, 1H), 4.09-4.17 (m, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.49-2.56 (m) , 1H), 1.59-1.67 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H), 0.98 (t, J = 7.6 Hz, 3H).

实施例(化合物)210Example (compound) 210

(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰胺基)乙基)苯基)(异丙基)氨基甲酸苄酯(3-(1-(2-ethoxy-5-isobutyramidobenzamide)ethyl)phenyl)(isopropyl)carbamate

Figure PCTCN2018088561-appb-000270
Figure PCTCN2018088561-appb-000270

a)(3-乙酰基苯基)(异丙基)氨基甲酸苄酯a) Benzyl (3-acetylphenyl)(isopropyl)carbamate

将化合物(3-乙酰基苯基)氨基甲酸苄酯(1g,3.72mmol)置于反应瓶中，加入DMF(20mL)，氩气保护下加入Cs 2CO 3(2.42mg,7.44mmol)室温搅拌反应1h后加入2-碘代丙烷(0.56mL,5.58mmol)升温至40℃反应，2d后停止反应，加水，用乙酸乙酯(30mL×2)，饱和NaCl溶液(15mL×2)洗，用无水硫酸镁干燥，浓缩至干，柱层析(E:P＝1:8)得到白色油状物800mg，产率69.1％。 The compound (3-acetylphenyl)carbamate (1 g, 3.72 mmol) was placed in a reaction flask, DMF (20 mL) was added, and Cs 2 CO 3 (2.42 mg, 7.44 mmol) was stirred under argon atmosphere. After 1 h of reaction, 2-iodopropane (0.56 mL, 5.58 mmol) was added and the mixture was heated to 40 ° C. After 2 d, the reaction was stopped, water was added, and ethyl acetate (30 mL × 2), saturated NaCl solution (15 mL × 2) was used for washing. The residue was dried over anhydrous MgSO.sub.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.90(dt,J 1＝8.0Hz,J 2＝1.2Hz,1H),7.70(t,J＝2.0Hz,2H),7.47(t,J＝8.0Hz,2H),7.18-7.41(m,6H),5.11(s,2H),4.58-4.65(m,1H),2.58(s,3H),1.14(s,3H),1.13(s,3H). 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.90 (dt, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H), 7.70 (t, J = 2.0 Hz, 2H), 7.47 (t, J=8.0 Hz, 2H), 7.18-7.41 (m, 6H), 5.11 (s, 2H), 4.58-4.65 (m, 1H), 2.58 (s, 3H), 1.14 (s, 3H), 1.13 (s) , 3H).

b)(3-(1-(肟基)乙基)苯基)(异丙基)氨基甲酸苄酯b) (3-(1-(indolyl)ethyl)phenyl)(isopropyl)carbamate

将化合物(3-乙酰基苯基)(异丙基)氨基甲酸苄酯(780mg,2.51mmol)置于反应瓶中，加入EtOH(10mL)，加入50％羟胺水溶液(0.45mL,7.52mmol)升温至60℃反应，4h后停止反应，加入DCM(30mL)，无水硫酸镁干燥，柱层析(E:P＝1:8)得到无色油状物600mg，产率73.3％。The compound (3-acetylphenyl)(isopropyl)carbamate (780 mg, 2.51 mmol) was placed in a reaction flask, EtOH (10 mL) was added, and 50% aqueous hydroxylamine solution (0.45 mL, 7.52 mmol) was added. The reaction was carried out at 60 ° C. After 4 h, the reaction was quenched, EtOAc (EtOAc)EtOAc.

1H-NMR(400MHz,CDCl 3)δ(ppm):7.58-7.61(m,1H),7.37-7.41(m,2H),7.12-7.31(m,6H),5.12(s,2H),4.58-4.63(m,1H),2.27(s,3H),1.13(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3 ) δ (ppm): 7.58-7.61 (m, 1H), 7.37-7.41 (m, 2H), 7.12-7.31 (m, 6H), 5.12 (s, 2H), 4.58 -4.63 (m, 1H), 2.27 (s, 3H), 1.13 (d, J = 6.8 Hz, 6H).

c)(3-(1-氨基乙基)苯基)(异丙基)氨基甲酸苄酯c) Benzyl (3-(1-aminoethyl)phenyl)(isopropyl)carbamate

将化合物(3-(1-(肟基)乙基)苯基)(异丙基)氨基甲酸苄酯(550mg,1.686mmol)置于反应瓶中，加入乙醇(10mL)，水(2.0mL)，加入锌粉(329mg,5.06mmol)以及2.5N HCl溶液4.05mL(10.1mmol)，室温搅拌反应，5h后停止反应，浓缩，加水，用乙醚20mL萃取，水层用饱和碳酸钠溶液调PH值至9左右，用乙酸乙酯(40mL×2)萃取，合并有机层，用饱和NaCl溶液(20mL×2)洗，无水硫酸镁干燥，浓缩，得到淡黄色油状物450mg，产率85.5％。The compound (3-(1-(indolyl)ethyl)phenyl)(isopropyl)carbamate (550 mg, 1.686 mmol) was placed in a reaction flask, and ethanol (10 mL), water (2.0 mL) Add zinc powder (329mg, 5.06mmol) and 2.5N HCl solution 4.05mL (10.1mmol), stir the reaction at room temperature, stop the reaction after 5h, concentrate, add water, extract with 20mL of ether, adjust the pH of the water layer with saturated sodium carbonate solution The mixture was extracted with ethyl acetate (40 mL×2).

1H-NMR(400MHz,CDCl 3)δ(ppm):7.17-7.34(m,7H),7.08(brs,1H),6.98(dt,J 1＝6.4Hz,J 2＝1.6Hz,1H),5.10(s,2H),4.55-4.62(m,1H),4.11(q,J＝6.4Hz,1H),1.74(brs,2H),1.37(d,J＝6.8Hz,3H),1.12(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 7.17-7.34 (m, 7H), 7.08 (brs, 1H), 6.98 (dt, J 1 = 6.4Hz, J 2 = 1.6Hz, 1H), 5.10(s, 2H), 4.55-4.62 (m, 1H), 4.11 (q, J = 6.4 Hz, 1H), 1.74 (brs, 2H), 1.37 (d, J = 6.8 Hz, 3H), 1.12 (d) , J = 6.8 Hz, 6H).

d)(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰胺基)乙基)苯基)(异丙基)氨基甲酸苄酯d) (3-(1-(2-ethoxy-5-isobutyramidobenzamide)ethyl)phenyl)(isopropyl)carbamate

将2-乙氧基-5-异丁酰氨基苯甲酸(180mg,0.717mmol)加入无水DMF(15mL)，加入EDC(275mg,1.434mmol)，加入HOBt(196mg,1.434mmol)和DIEA(0.37mL,2.15mmol)，加入化合物(3-(1-氨基乙基)苯基)(异丙基)氨基甲酸苄酯(380mg,1.22mmol)，室温搅拌过夜，将反应液倒入水中，用乙酸乙酯(40mL×2)萃取，合并有机层用饱和NaCl溶液(25mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝90:1)，得到白色固体330mg，产率84.6％；m.p.45-47℃。2-Ethoxy-5-isobutyrylaminobenzoic acid (180 mg, 0.717 mmol) was added to dry DMF (15 mL). E.sub.2 (275 mg, 1.434 mmol) was added, and HOBt (196 mg, 1.434 mmol) and DIEA (0.37) were added. Add benzyl (3-(1-aminoethyl)phenyl)(isopropyl)carbamate (380 mg, 1.22 mmol), stir at room temperature overnight, then pour the mixture into water with acetic acid Ethyl acetate (40 mL × 2) was extracted, and the combined organic layer was washed with saturated NaCI (25 mL×2), dried over anhydrous magnesium sulfate. The rate was 84.6%; mp 45-47 ° C.

1H-NMR(400MHz,CDCl 3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.22(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.66(brs,1H),7.33-7.35(m,2H),7.10-7.23(m,6H),7.02-7.04(m,1H),6.91(d,J＝9.2Hz,1H),5.28-5.36(m,1H),5.09(s,2H),4.54-4.61(m,1H),4.05-4.15(m,2H),2.48-2.55(m,1H),1.56(d,J＝6.8Hz,3H),1.34(t,J＝6.8Hz,3H),1.21(d,J＝6.8Hz,6H),1.10(t,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.45 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.84 (d, J=2.8 Hz, 1H), 7.66 (brs, 1H), 7.33-7.35 (m, 2H), 7.10-7.23 (m, 6H), 7.02-7.04 (m, 1H), 6.91 (d, J = 9.2 Hz) , 1H), 5.28-5.36 (m, 1H), 5.09 (s, 2H), 4.54-4.61 (m, 1H), 4.05-4.15 (m, 2H), 2.48-2.55 (m, 1H), 1.56 (d) , J = 6.8 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 6H), 1.10 (t, J = 6.8 Hz, 6H).

实施例(化合物)211Example (compound) 211

2-乙氧基-5-异丁酰氨基-N-(1-(3-(异丙基氨基)苯基)乙基)苯甲酰胺2-ethoxy-5-isobutyrylamino-N-(1-(3-(isopropylamino)phenyl)ethyl)benzamide

Figure PCTCN2018088561-appb-000271
Figure PCTCN2018088561-appb-000271

将化合物(3-(1-(2-乙氧基-5-异丁酰胺基苯甲酰胺基)乙基)苯基)(异丙基)氨基甲酸苄 酯(240mg)加入EtOH(10mL)加入10％Pd/C(72mg)常温常压下氢化反应，4h后停止反应，过滤，浓缩，用乙酸乙酯和石油醚将化合物固化，得到白色固体130mg，产率72.2％；m.p.119-120℃。The compound (3-(1-(2-ethoxy-5-isobutylamidobenzamide)ethyl)phenyl)(isopropyl)carbamate (240 mg) was added to EtOH (10 mL). 10% Pd/C (72 mg) was hydrogenated at normal temperature and normal pressure. After 4 h, the reaction was stopped, filtered, concentrated, and ethyl acetate and petroleum ether were evaporated to give a white solid (130 mg, yield: 72.2%; mp 119-120 ° C .

1H-NMR(400MHz,CDCl 3)δ(ppm):8.48(d,J＝7.6Hz,1H),8.22(dd,J 1＝8.8Hz,J 2＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.65(brs,1H),7.15(t,J＝7.6Hz,1H),6.91(d,J＝8.8Hz,1H),6.71(d,J＝7.6Hz,1H),6.61(brs,1H),6.53(brs,1H),5.15-5.23(m,1H),4.07-4.19(m,2H),3.58-3.64(m,1H),2.49-2.57(m,1H),1.55(d,J＝6.8Hz,3H),1.41(t,J＝7.2Hz,3H),1.22(dd,J 1＝6.8Hz,J 2＝1.2Hz,6H),1.20(d,J＝6.4Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 8.48 (d, J = 7.6Hz, 1H), 8.22 (dd, J 1 = 8.8Hz, J 2 = 2.8Hz, 1H), 7.84 (d, J = 2.8 Hz, 1H), 7.65 (brs, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H) , 6.61 (brs, 1H), 6.53 (brs, 1H), 5.15-5.23 (m, 1H), 4.07-4.19 (m, 2H), 3.58-3.64 (m, 1H), 2.49-2.57 (m, 1H) , 1.55 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.22 (dd, J 1 = 6.8 Hz, J 2 = 1.2 Hz, 6H), 1.20 (d, J = 6.4Hz, 6H).

实施例(化合物)214Example (compound) 214

N-(1-(3-乙酰氨基苯基)乙基)-2-乙氧基-5-异丁酰氨基苯酰胺N-(1-(3-acetamidophenyl)ethyl)-2-ethoxy-5-isobutyrylaminobenzamide

Figure PCTCN2018088561-appb-000272
Figure PCTCN2018088561-appb-000272

取化合物N-(1-(3-氨基苯基)乙基)-2-乙氧基-5-异丁酰氨基苯甲酰胺(56mg,0.152mmol)加入DCM(8mL)，加入Et 3N(0.044mL,0.304mmol)，冰浴下将乙酰氯(13mg,0.167mml)的DCM(2mL)溶液滴加入反应瓶中，滴毕继续在冰浴下反应，2h后仍有原料剩余，补加乙酰氯(6.7mg,0.08mml)的DCM(2mL)溶液继续反应，1h后停止反应，加入DCM(25mL)用饱和NaCl溶液(15mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(D:M＝50:1,D:M＝40:1)，得到白色固体50mg，产率80％。m.p.>250℃。 Of compound N- (1- (3- aminophenyl) ethyl) -2-ethoxy-5-isobutyramido-benzamide (56mg, 0.152mmol) was added DCM (8mL), was added Et 3 N ( 0.044mL, 0.304mmol), a solution of acetyl chloride (13mg, 0.167mml) in DCM (2mL) was added to the reaction flask under ice bath. After the dropwise addition, the reaction was continued in an ice bath. After 2 hours, the remaining material remained. A solution of the acid chloride (6.7 mg, 0.08 mm) in DCM (2 mL) was evaporated. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m D: M = 50:1, D: M = 40:1) afforded 50 mg as a white solid. Mp>250 °C.

1H-NMR(400MHz,CDCl 3)δ(ppm):9.92(s,1H),9.80(s,1H),8.52(d,J＝7.6Hz,1H),7.92(d,J＝2.8Hz,1H),7.78(dd,J 1＝9.2Hz,J 2＝2.8Hz,1H),7.57(s,1H),7.48(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),7.06-7.09(m,2H),5.02-5.114(m,1H),4.09-4.15(m,2H),2.52-2.58(m,1H),2.02(s,3H),1.44(d,J＝6.8Hz,3H),1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H). 1 H-NMR (400MHz, CDCl 3) δ (ppm): 9.92 (s, 1H), 9.80 (s, 1H), 8.52 (d, J = 7.6Hz, 1H), 7.92 (d, J = 2.8Hz, 1H), 7.78 (dd, J 1 = 9.2 Hz, J 2 = 2.8 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.06-7.09 (m, 2H), 5.02-5.114 (m, 1H), 4.09-4.15 (m, 2H), 2.52-2.58 (m, 1H), 2.02 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 6H).

药理实验：Pharmacological experiment:

试验例1 体外筛选实验结果Test Example 1 In vitro screening experiment results

1.化合物抑制Kv2.1钾电流的IC 50 1. IC 50 of compound inhibiting Kv2.1 potassium current

1.1 实验方法：1.1 Experimental method:

1.1.1 细胞培养1.1.1 Cell culture

转染了人Kv2.1钾离子通道亚型的HEK293细胞(HEK293/Kv2.1)培养于含0.2g/L G418、10％胎牛血清、1万U/L青霉素和链霉素的DMEM培养基中；当细胞生长融合达到80％时进行传代，接种于35mm培养皿中用于后续电生理记录。1.1.2电生理记录HEK293 cells (HEK293/Kv2.1) transfected with human Kv2.1 potassium channel subtype were cultured in DMEM containing 0.2 g/L G418, 10% fetal bovine serum, 10,000 U/L penicillin and streptomycin. Base; when the cell growth fusion reached 80%, passage was performed and inoculated in a 35 mm culture dish for subsequent electrophysiological recording. 1.1.2 Electrophysiological recording

记录Kv2.1钾通道电流的细胞外液成分(mmol·L -1):NaCl 140,KCl 5,MgCl 21,HEPES 10,glucose 10,pH 7.40；电极内液成分(mmol·L -1):KCl 140,MgCl 2 2,EGTA 10,HEPES 10,ATP-2Na 2,pH 7.20。将培养的HEK293/Kv2.1用细胞外液漂洗2次后置于倒置相差显微镜下。玻璃微电极(原料:GG17,外径:15mm,内径:7.5mm)由P-97型拉制仪拉制,充灌电极内液后电阻为3～5MΩ。在显微镜下选择边缘整齐、胞内无明显颗粒的细胞,移动电极并轻压细胞表面,用负压使电极尖端与细胞表面形成GΩ封接后,以较大负压破膜,对电容及电极串联阻抗进行补偿,形成全细胞记录方式。将细胞钳制在-70mV,从-50mV以20mV的阶跃去极化到+50mV,持续300ms,测量+50mV电位下的电流幅度即为Kv2.1钾电流。全细胞电流由EPC-10型膜片钳放大器记录,电流采用3kHz低通滤波,采样率为20kHz。应用Pulse 8.5软件进行刺激发放和信号采集。所有实验均在室温(23～25℃)下进行。 Record the extracellular liquid component of Kv2.1 potassium channel current (mmol·L -1 ): NaCl 140, KCl 5, MgCl 2 1, HEPES 10, glucose 10, pH 7.40; electrode internal liquid component (mmol·L -1 ) : KCl 140, MgCl 2 2, EGTA 10, HEPES 10, ATP-2Na 2, pH 7.20. The cultured HEK293/Kv2.1 was rinsed twice with the extracellular fluid and placed under an inverted phase contrast microscope. The glass microelectrode (raw material: GG17, outer diameter: 15 mm, inner diameter: 7.5 mm) was drawn by a P-97 type drawing apparatus, and the electric resistance after filling the electrode was 3 to 5 MΩ. Under the microscope, select cells with neat edges and no obvious particles in the cells, move the electrode and gently press the surface of the cell, and use a negative pressure to form a GΩ seal on the tip of the electrode and the cell surface, then break the membrane with a large negative pressure, and the capacitor and the electrode. The series impedance is compensated to form a whole cell recording mode. The cells were clamped at -70 mV, depolarized from -50 mV to a step of 20 mV to +50 mV for 300 ms, and the current amplitude at a potential of +50 mV was measured as Kv2.1 potassium current. The whole cell current was recorded by an EPC-10 patch clamp amplifier, and the current was filtered using 3 kHz low-pass with a sampling rate of 20 kHz. Use the Pulse 8.5 software for stimulus distribution and signal acquisition. All experiments were carried out at room temperature (23 to 25 ° C).

1.1.3 统计分析1.1.3 Statistical analysis

为了计算化合物抑制Kv2.1的IC 50，每个化合物选取至少3个浓度，每个浓度至少n＝3,采用Origin 7.5拟合出IC 50。 In order to calculate the compound inhibition of Kv2.1 IC 50, each of at least three compounds selected concentration, each concentration of at least n = 3, fitted using Origin 7.5 IC 50.

实验结果见表1The experimental results are shown in Table 1.

表1.部分化合物抑制Kv2.1的IC 50 Table 1. IC 50 of some compounds inhibiting Kv2.1

Figure PCTCN2018088561-appb-000273
Figure PCTCN2018088561-appb-000273

Figure PCTCN2018088561-appb-000274
Figure PCTCN2018088561-appb-000274

试验例2 体内整体动物药效学实验结果Test Example 2 In vivo overall animal pharmacodynamics test results

1.化合物61整体动物实验结果1. Compound 61 overall animal experiment results

1.1 化合物61腹腔注射对KKAy小鼠血脂的影响1.1 Effect of intraperitoneal injection of compound 61 on blood lipids in KKAy mice

1.1.1 实验方法1.1.1 Experimental method

给药剂量：3mg/kg腹腔给药，连续给药四天，末次禁食1小时后给药，药后1小时测定血脂。Dosage: 3 mg/kg intraperitoneal administration, continuous administration for 4 days, administration after 1 hour of fasting, and blood lipids 1 hour after drug administration.

药物配制：10％DMSO+30％PEG-400+生理盐水Drug preparation: 10% DMSO + 30% PEG-400 + saline

对照和模型均未给予溶剂。No solvent was given to either the control nor the model.

1.1.2 实验结果见表21.1.2 Experimental results are shown in Table 2.

化合物61对血脂有显著降低作用。Compound 61 has a significant effect on blood lipids.

表2.化合物61给药对KKay小鼠血脂的影响Table 2. Effect of Compound 61 Administration on Blood Lipid in KKay Mice

Figure PCTCN2018088561-appb-000275
Figure PCTCN2018088561-appb-000275

数据表示为：平均值±SD， ##p<0.01vs.C57, *p<0.05vs.模型组 Data are expressed as: mean ± SD, ## p<0.01 vs. C57, * p<0.05 vs. model group

1.2 化合物61口服给药对KKAy小鼠血脂的影响1.2 Effect of oral administration of compound 61 on blood lipids in KKAy mice

1.2.1 实验方法1.2.1 Experimental methods

给药剂量：10、20mg/kg口服给药，连续给药四天，末次禁食1小时后给药，药后1小时测定血脂。Dosage: 10, 20 mg/kg orally, continuous administration for four days, administration after 1 hour of fasting, and blood lipids 1 hour after drug administration.

药物配制：0.5％CMC-Na悬浮研磨Drug preparation: 0.5% CMC-Na suspension grinding

对照和模型均给予溶剂，禁食1小时后给药，药后1小时取血、测定血脂。The control and the model were administered with a solvent, and after 1 hour of fasting, blood was taken 1 hour after the drug, and blood lipid was measured.

1.2.2 实验结果见表3：1.2.2 The experimental results are shown in Table 3:

化合物61对甘油三酯均有一定的降低作用，且有剂量依赖效应关系。详见Compound 61 has a certain reduction effect on triglycerides and has a dose-dependent effect. See details

表2:Table 2:

表3.化合物61单次给药对KKay小鼠血糖、血脂的影响Table 3. Effect of single administration of compound 61 on blood glucose and blood lipids in KKay mice

Figure PCTCN2018088561-appb-000276
Figure PCTCN2018088561-appb-000276

数据表示为：平均值±SEM， ##p<0.01vs.C57, *p<0.05vs.模型组 Data are expressed as: mean ± SEM, ## p<0.01 vs. C57, * p<0.05 vs. model group

1.3 化合物61对东莨菪碱诱导的小鼠学习记忆缺失的改善作用的研究1.3 The effect of compound 61 on scopolamine-induced learning and memory loss in mice

1.3.1 实验方法：1.3.1 Experimental method:

化合物：化合物61白色粉末Compound: Compound 61 white powder

阳性药:安理申(多奈哌齐)片剂，购自药房网(京卫药房)Positive drug: Anritsu (Doneipezil) tablets, purchased from Pharmacy Network (Jingwei Pharmacy)

造模药物：东莨菪碱，货号A4559，购自SigmaModeling drug: scopolamine, item number A4559, purchased from Sigma

实验动物：雄性ICR小鼠112只(实际到货115只)，SPF级。实验时体重20-30克，购自北京维通利华实验动物技术有限公司。Experimental animals: 112 male ICR mice (actually arrived at 115), SPF grade. The weight of the experiment was 20-30 g, which was purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

实验分组：Experimental grouping:

小鼠随机分为7各组：空白组、溶剂组、模型组、阳性药组、治疗药物化合物61小剂量组(ip.0.3mg/kg小鼠体重)、治疗药物化合物61中剂量组(ip.1mg/kg小鼠体重)、治疗药物化合物61大剂量组(ip.3mg/kg小鼠体重)。阳性药组和治疗药物组分别连续给予多奈哌齐(ig.3mg/kg小鼠体重)和治疗药物化合物61，连续给予治疗药1天后，开始进行跳台实验，于每天行为学实验开始前1小时分别灌胃给予治疗药物和阳性药，行为学实验开始前30分钟腹腔给予东莨菪碱直至实验结束。模型组按10ml/kg小鼠体重的剂量腹腔注射东莨菪碱，溶剂组按10ml/kg小鼠体重的剂量腹腔注射溶剂(20％DMSO、10％PEG400和70％N.S.)。The mice were randomly divided into 7 groups: blank group, solvent group, model group, positive drug group, therapeutic drug compound 61 low dose group (ip. 0.3 mg/kg mouse body weight), therapeutic drug compound 61 medium dose group (ip) .1 mg/kg mouse body weight), therapeutic drug compound 61 high dose group (ip. 3 mg/kg mouse body weight). The positive drug group and the therapeutic drug group were continuously given donepezil (ig. 3 mg/kg mouse body weight) and the therapeutic drug compound 61, and after one day of continuous administration of the therapeutic drug, the platform test was started, and the experiment was performed one hour before the start of the daily behavioral experiment. The stomach was given a therapeutic drug and a positive drug, and scopolamine was administered intraperitoneally 30 minutes before the start of the behavioral experiment until the end of the experiment. The model group was intraperitoneally injected with scopolamine at a dose of 10 ml/kg of mouse body weight, and the solvent group was intraperitoneally injected with a solvent (20% DMSO, 10% PEG400, and 70% N.S.) at a dose of 10 ml/kg of mouse body weight.

1.3.2 实验结果见图1：1.3.2 Experimental results are shown in Figure 1:

化合物61 0.3、1和3mg/kg可显著减少东莨菪碱诱导的痴呆小鼠跳台错误次数，显示出改善学习和记忆的作用。Compounds 61, 0.3, 1 and 3 mg/kg significantly reduced the number of tripping errors in scopolamine-induced dementia mice, showing improved learning and memory.

1.4 化合物61的抗抑郁作用1.4 Antidepressant effect of Compound 61

1.4.2 实验方法1.4.2 Experimental methods

药品：化合物61，白色粉末，不溶于水。Drug: Compound 61, white powder, insoluble in water.

配制方法：0.5％羧甲基纤维素钠制成混悬溶液。Formulation method: 0.5% sodium carboxymethylcellulose was prepared as a suspension solution.

动物：ICR小鼠，雄性20-22g。Animal: ICR mice, male 20-22 g.

小鼠悬尾实验：Mouse tail suspension experiment:

小鼠每组一只依次给药，每轮间隔10min。给药60min后，用小夹子将小鼠尾尖1cm处固定于悬尾架上，使小鼠头朝下，距地面大于15cm。相邻小鼠用隔板隔开，间距为15cm。录像6min，计后4min内的小鼠不动时间。计算受试药与对照组相比小鼠悬尾不动时间的变化率并进行统计学分析。Each group of mice was administered sequentially, with a 10 minute interval between each round. After 60 minutes of administration, the mouse tip was fixed to the suspension frame 1 cm with a small clip so that the mouse head was facing down, which was larger than 15 cm from the ground. Adjacent mice were separated by a septum with a spacing of 15 cm. The video was recorded for 6 min, and the mice within 4 min did not move for a period of time. The rate of change of the suspension time of the test sample compared with the control group was calculated and statistical analysis was performed.

给药方式：腹腔注射，给药体积为10ml/kgMode of administration: intraperitoneal injection, the dosage volume is 10ml/kg

动物分组：随机分为4组，正常组，化合物61腹腔注射0.3、1、3mg/kg剂量组。Animal grouping: Randomly divided into 4 groups, the normal group, compound 61 was intraperitoneally injected into the 0.3, 1, 3 mg/kg dose group.

1.4.2 实验结果见图2：1.4.2 Experimental results are shown in Figure 2:

化合物61 1和3mg/kg可显著减少悬尾小鼠的不动时间，显示出抗抑郁作用。Compounds 61 1 and 3 mg/kg significantly reduced the immobility time of the tailed mice and showed an antidepressant effect.

1.5 化合物61抗急性缺氧(断头法)的作用研究1.5 The effect of Compound 61 against acute hypoxia (decapitation)

1.5.1 实验方法1.5.1 Experimental methods

取ICR小鼠26-30g，腹腔给予化合物61 1,3,10mg/kg 15min后，断头。观察小鼠张嘴呼吸时间。26-30 g of ICR mice were taken, and the compounds were decapitated after intraperitoneal administration of compound 61 1,3,10 mg/kg for 15 min. Observe the mouth breathing time of the mice.

1.5.2 实验结果见表4和图31.5.2 Experimental results are shown in Table 4 and Figure 3.

化合物61对ICR小鼠断头后的呼吸时间有明显的延长作用。Compound 61 significantly prolonged the respiratory time of ICR mice after decapitation.

表4.化合物61对急性缺氧(断头法)的作用Table 4. Effect of Compound 61 on Acute Hypoxia (Decapitation)

Figure PCTCN2018088561-appb-000277
Figure PCTCN2018088561-appb-000277

1.6 化合物61抗缺氧(闷罐法)的作用研究1.6 Study on the effect of Compound 61 against hypoxia (squeeze method)

1.6.1 实验方法1.6.1 Experimental method

取ICR小鼠22-26g，腹腔给予化合物61 1,3,10mg/kg 15min后，闷罐。观 察小鼠生存时间。22-26 g of ICR mice were taken and compounded with compound 61 1,3,10 mg/kg for 15 min. Observe the survival time of mice.

1.6.2 实验结果见表5和图41.6.2 Experimental results are shown in Table 5 and Figure 4.

化合物61对ICR小鼠缺氧后的生存时间有明显的延长作用。Compound 61 significantly prolonged the survival time of ICR mice after hypoxia.

表5.化合物61对脑缺氧(闷罐法)的作用Table 5. Effect of Compound 61 on cerebral hypoxia (squeeze method)

Figure PCTCN2018088561-appb-000278
Figure PCTCN2018088561-appb-000278

1.7 化合物61静脉注射对MCAO大鼠脑梗死体积的影响1.7 Effect of intravenous injection of compound 61 on cerebral infarction volume in MCAO rats

1.7.1 实验方法1.7.1 Experimental method

药品：化合物61，白色粉末，不溶于水。Drug: Compound 61, white powder, insoluble in water.

配制方法：20％DMSO现溶解，30％PEG400助溶，50％N.S.溶解。Preparation method: 20% DMSO is dissolved, 30% PEG400 is dissolved, 50% N.S. is dissolved.

实验动物：SD大鼠，雄性，280-300gExperimental animals: SD rats, male, 280-300g

给药方式：缺血手术后5min舌静脉注射，给药体积为1ml/kgMode of administration: 5 minutes after ischemic surgery, the tongue is injected intravenously at a dose of 1 ml/kg.

动物分组：随机分为4组，模型，化合物61静脉注射0.1、1、3mg/kg剂量组。Animal grouping: Randomly divided into 4 groups, the model, Compound 61 was intravenously injected into the 0.1, 1, 3 mg/kg dose group.

1.7.2 实验结果：见表6：1.7.2 Experimental results: See Table 6:

化合物61有显著的抗脑缺血作用。Compound 61 has a significant anti-ischemic effect.

表6.化合物61静脉注射对SD大鼠MCAO模型药效学研究Table 6. Pharmacodynamic study of compound 61 intravenous injection on SD rats MCAO model

Figure PCTCN2018088561-appb-000279
Figure PCTCN2018088561-appb-000279

数据表示为：平均值±SD， **p<0.01vs.模型组 Data are expressed as: mean ± SD, ** p < 0.01 vs. model group

2.化合物61光学异构体整体动物实验结果2. Compound 61 optical isomers overall animal experiment results

2.1 化合物61、化合物61-1(+)和化合物61-2(-)对KKAy小鼠血脂的影响2.1 Effects of Compound 61, Compound 61-1(+) and Compound 61-2(-) on Blood Lipid in KKAy Mice

2.1.1 实验方法2.1.1 Experimental methods

给药剂量：20mg/kg口服给药Dosage: Oral administration at 20 mg/kg

药物配制：10％DMSO 40％PEG-400 50％生理盐水Drug preparation: 10% DMSO 40% PEG-400 50% saline

受试物：化合物61-1(+),化合物61-2(-)和化合物61。Test substance: Compound 61-1 (+), Compound 61-2 (-) and Compound 61.

给药体积：0.1ml/10g bwDosing volume: 0.1ml/10g bw

给药周期：连续给药4天、每天一次；末次给药前禁食1小时，给药后再禁食1小时测定血液指标。Dosing cycle: continuous administration for 4 days, once a day; fasting for 1 hour before the last administration, and fasting for 1 hour after administration to determine the blood index.

对照和模型均给予溶剂。Both the control and the model were given a solvent.

2.1.2 实验结果见表7：2.1.2 The experimental results are shown in Table 7:

连续口服给予化合物61-1(+),化合物61-2(-)和化合物61，化合物61-1(+)和化合物61对甘油三酯TG有较为显著的降低作用。Compound 61-1 (+), compound 61-2 (-) and compound 61 were continuously administered orally, and compounds 61-1 (+) and compound 61 had a significant reduction in triglyceride TG.

表7.化合物61给药对KKay小鼠血脂的影响(Mean±SEM)Table 7. Effect of Compound 61 Administration on Blood Lipids in KKay Mice (Mean ± SEM)

Figure PCTCN2018088561-appb-000280
Figure PCTCN2018088561-appb-000280

数据表示为：平均值±SEM， ##p<0.01vs.C57, *p<0.05vs.模型组 Data are expressed as: mean ± SEM, ## p<0.01 vs. C57, * p<0.05 vs. model group

2.2 化合物61-1(+)和化合物61-2(-)对ICR小鼠断头实验的影响2.2 Effects of Compound 61-1(+) and Compound 61-2(-) on Decapitation of ICR Mice

2.2.1 实验方法2.2.1 Experimental methods

受试化合物：化合物61-1(+)、化合物61-2(-)Test compound: compound 61-1 (+), compound 61-2 (-)

阳性药：尼莫地平Positive drug: nimodipine

溶剂：5％DMSO+45％聚乙二醇400+50％生理盐水Solvent: 5% DMSO + 45% polyethylene glycol 400 + 50% saline

方法：取ICR小鼠22-26g，腹腔给予各化合物10mg/kg(10ml/kg)30min后，断头。观察ICR小鼠张口次数和存活时长；阳性工具药尼莫地平120mg/kg需要提前60min口服(10ml/kg),断头前30min，腹腔给予同样溶剂。观察ICR小鼠 张口次数和存活时长。METHODS: 22-26 g of ICR mice were taken and 10 mg/kg (10 ml/kg) of each compound was intraperitoneally administered for 30 min. The number of mouth opening and survival time of ICR mice were observed. The positive tool drug nimodipine 120 mg/kg needs to be taken orally (10 ml/kg) 60 minutes earlier, 30 minutes before decapitation, and the same solvent is given intraperitoneally. The number of mouth openings and the length of survival of ICR mice were observed.

2.2.2 实验结果：见表82.2.2 Experimental results: see Table 8

表8.化合物61-1(+)和化合物61-2(-)对ICR小鼠断头张口次数和存活时长的影响。Table 8. Effect of Compound 61-1 (+) and Compound 61-2 (-) on the number of broken mouth openings and duration of survival in ICR mice.

Figure PCTCN2018088561-appb-000281
Figure PCTCN2018088561-appb-000281

数据表示为：平均值±SD **P<0.01, ***P<0.001vs溶剂对照组 Data are expressed as: mean ± SD ** P < 0.01, *** P < 0.001 vs solvent control

化合物61-1(+)和化合物61-2(-)有显著的抗缺氧作用。Compound 61-1 (+) and compound 61-2 (-) have significant anti-hypoxia effects.

2.3 化合物61、化合物61-1(+)和化合物61-2(-)对ICR小鼠闷罐实验的影响2.3 Effect of Compound 61, Compound 61-1(+) and Compound 61-2(-) on ICR Mouse Stuffing Experiment

2.3.1 实验方法2.3.1 Experimental methods

受试化合物：化合物61、化合物61-1(+)、化合物61-2(-)Test compound: Compound 61, Compound 61-1 (+), Compound 61-2 (-)

阳性药：阿替洛尔Positive drug: atenolol

溶剂：5％DMSO+45％聚乙二醇400+50％生理盐水Solvent: 5% DMSO + 45% polyethylene glycol 400 + 50% saline

方法：取ICR小鼠22-26g，腹腔给予各化合物10mg/kg(10ml/kg)15min后，闷罐。观察ICR小鼠生存时间。阳性工具药阿替洛尔50mg/kg(10ml/kg)需提前30min口服，闷罐前15min，腹腔给予同样溶剂。METHODS: 22-26 g of ICR mice were taken and 10 mg/kg (10 ml/kg) of each compound was intraperitoneally administered for 15 min. Observe the survival time of ICR mice. The positive tool drug atenolol 50mg/kg (10ml/kg) should be taken orally 30min in advance, 15min before the stuffing can, the same solvent is given intraperitoneally.

2.3.2 实验结果：见表92.3.2 Experimental results: see Table 9

表9.化合物61、化合物61-1(+),化合物61-2(-)对ICR小鼠闷罐存活时间的影响Table 9. Effect of Compound 61, Compound 61-1 (+), Compound 61-2 (-) on the survival time of smoldering cans in ICR mice

Figure PCTCN2018088561-appb-000282
Figure PCTCN2018088561-appb-000282

Figure PCTCN2018088561-appb-000283
Figure PCTCN2018088561-appb-000283

数据表示为：平均值±SD, **P<0.01, ***P<0.001vs溶剂对照组 Data are expressed as: mean ± SD, ** P < 0.01, *** P < 0.001 vs solvent control

化合物61、化合物61-1(+)和化合物61-2(-)有显著的抗缺氧作用。Compound 61, compound 61-1 (+) and compound 61-2 (-) have significant anti-hypoxia effects.

3.化合物123的药效学评价3. Pharmacodynamic evaluation of compound 123

3.1 化合物123抗急性缺氧(断头法)的作用3.1 Compound 123 against acute hypoxia (decapitation)

3.1.1 实验方法3.1.1 Experimental methods

受试化合物：化合物123和尼莫地平Test compound: Compound 123 and Nimodipine

溶剂：5％DMSO+45％聚乙二醇400+50％生理盐水Solvent: 5% DMSO + 45% polyethylene glycol 400 + 50% saline

方法：取ICR小鼠22-26g，腹腔给予化合物123 3mg/kg和10mg/kg(10ml/kg)30min后，断头。观察ICR小鼠张口次数和存活时长；阳性工具药尼莫地平120mg/kg需要提前60min口服(10ml/kg)，断头前30min，腹腔给予同样溶剂。观察ICR小鼠张口次数和存活时长。Methods: 22-26 g of ICR mice were taken and the compounds 123 3 mg/kg and 10 mg/kg (10 ml/kg) were intraperitoneally administered for 30 min. The number of mouth opening and survival time of ICR mice were observed. The positive tool drug nimodipine 120 mg/kg needs to be taken orally (10 ml/kg) 60 minutes earlier, 30 minutes before decapitation, and the same solvent is given intraperitoneally. The number of mouth openings and the length of survival of ICR mice were observed.

3.1.2 实验结果：见表103.1.2 Experimental results: see Table 10

化合物123对ICR小鼠断头后的呼吸时间有明显的延长作用，有显著的抗缺氧作用。Compound 123 significantly prolonged the respiratory time of ICR mice after decapitation, and had significant anti-hypoxia effect.

表10.化合物123对急性缺氧(断头法)的作用Table 10. Effect of Compound 123 on Acute Hypoxia (Decapitation)

Figure PCTCN2018088561-appb-000284
Figure PCTCN2018088561-appb-000284

3.2 化合物123对MCAO模型大鼠脑梗死体积的作用3.2 Effect of Compound 123 on Cerebral Infarction Volume in MCAO Model Rats

3.2.1 实验方法3.2.1 Experimental methods

实验动物：雄性SD大鼠260-300g购自维通利华实验动物中心Experimental animals: Male SD rats 260-300g purchased from Vital River Laboratory Animal Center

方法：实验动物适应环境一天后随即分组，气麻后开始进行MCAO手术，缺血后5分钟内立刻口服给予化合物123 5mg/kg和dl-NBP 200mg/kg。各组动 物缺血2小时后再灌注，再灌注时间控制在2分钟左右。再灌注24小时分别记录行为学评分及死亡率，而后处死动物进行脑组织取材切片，4％TTC染色处理，拍照，Photoshop软件处理分析计算脑梗死体积。METHODS: Experimental animals were grouped one day after adaptation to the environment. MCAO was performed after air anesthesia. Compound 123 5 mg/kg and dl-NBP 200 mg/kg were orally administered within 5 minutes after ischemia. Each group of animals was reperfused after 2 hours of ischemia, and the reperfusion time was controlled to about 2 minutes. Behavioral scores and mortality were recorded at 24 hours after reperfusion, and then the animals were sacrificed for brain tissue sectioning, 4% TTC staining, photographing, and Photoshop software processing analysis to calculate cerebral infarction volume.

数据分析：应用Photoshop软件处理分析所有动物脑组织切片，计算脑梗死体积。Data analysis: All animal brain tissue sections were analyzed by Photoshop software to calculate the volume of cerebral infarction.

3.2.2 实验结果：3.2.2 Experimental results:

见表11，化合物123口服有抗脑缺血作用。See Table 11, Compound 123 has an anti-cerebral ischemia effect orally.

表11.化合物123口服对SD大鼠tMCAO模型行为学评价及脑梗死体积比较Table 11. Behavioral evaluation of compound 123 oral tMCAO model and comparison of cerebral infarction volume

Figure PCTCN2018088561-appb-000285
Figure PCTCN2018088561-appb-000285

*P<0.05、**P<0.01和***P<0.001与溶剂对照组比较*P<0.05, **P<0.01 and ***P<0.001 compared with the solvent control group

Claims (30)

如通式I所示化合物及其药用盐，a compound of the formula I and pharmaceutically acceptable salts thereof,
Figure PCTCN2018088561-appb-100001
Figure PCTCN2018088561-appb-100001
 在式I中，In formula I, X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其 中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms; R 1选自如下基团或结构片断： R 1 is selected from the group consisting of: (1)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) 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 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, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基；3-8元环的氧杂环烷基和3-8元环的氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and The 3-8 membered ring nitrogen a heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其 中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra '10 independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said benzene ring, nitrogen-containing six-membered aromatic heterocycle The five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of hetero atoms selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; R 2选自如下基团或结构片断： R 2 is selected from the group consisting of: (1)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6CONRf 4Rf 5、NRe 7SO 2Rf 6,其中所述的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独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁 基、环戊基； (1) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 CONRf 4 Rf 5 , NRe 7 SO 2 Rf 6 , wherein 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 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkane a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein said 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, ring Propylmethylene, cyclobutyl, cyclopentyl; 所述的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也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , 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, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time; 所述的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也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , 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 , Ra' 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain One N atom may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms, and the hetero atom is selected from O, N, S; n is selected from 1, 2, 3 Wherein the halogen includes F, Cl, Br; (2)CONRh 1Ri 1、COORh 2、SO 2Rh 3、SO 2NRh 4Ri 2，其中所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said 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 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C 1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、 NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Heterocycloalkyl, 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 , 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 a methylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring of an oxaheterocycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; 所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight a chain or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted. It may also be a polysubstituted one; 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; (3)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (3) a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, a substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 members) a cyclic lactam) 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments: (2)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(2) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of (a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br. R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl; (3)R 9、R 10可成环，环系大小为3-7元脂环。 (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 members of alicyclic ring. 根据权利要求1的化合物及其药用盐，其特征在于，所述的化合物如通式IA所示The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is as shown in Formula IA
Figure PCTCN2018088561-appb-100002
Figure PCTCN2018088561-appb-100002
 在式IA中，In formula IA, X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； Said Re 1, Re 2, Rf 1 , Re 3, Re 4, Rf 2, Re 5, Rf 3, Re 6, Rf 4 may be independently selected from substituted or unsubstituted C3-7 cycloalkyl, a 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 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight chain Or a branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring oxacycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom, Can contain multiple heteroatoms at the same time; R 2选自如下基团或结构片断： R 2 is selected from the group consisting of: (1)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6CONRf 4Rf 5、NRe 7SO 2Rf 6,其中所述的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独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 CONRf 4 Rf 5 , NRe 7 SO 2 Rf 6 , wherein 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 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkane a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein said 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, ring Propylmethylene, cyclobutyl, cyclopentyl; 所述的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也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , 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, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time; 所述的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也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、 CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , 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 , Ra' 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain One N atom may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms, and the hetero atom is selected from O, N, S; n is selected from 1, 2, 3 Wherein the halogen includes F, Cl, Br; (2)CONRh 1Ri 1、COORh 2、SO 2Rh 3、SO 2NRh 4Ri 2，其中所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said 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 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C 1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Heterocycloalkyl, 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 , 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 a methylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring of an oxaheterocycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; 所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是 多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight a chain or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted. It may also be a polysubstituted one; 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; (3)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (3) a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, a substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 members) a cyclic lactam) 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments: (1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of (a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br. R 4选自如下基团或结构片断： R 4 is selected from the group consisting of the following groups or structural fragments: (1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br; R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基， 环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl; (3)R 9、R 10可成环，环系大小为3-7元脂环。 (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 members of alicyclic ring. 根据权利要求2的化合物及其药用盐，其特征在于，所述的化合物如通式IA-1所示The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein said compound is as shown in Formula IA-1
Figure PCTCN2018088561-appb-100003
Figure PCTCN2018088561-appb-100003
 在式IA-1中，In formula IA-1, X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms; R 3选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments: (1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of (a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、 其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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, Rb 5 is independently selected from H, C1-4 straight-chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环 丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br. R 4选自如下基团或结构片断： R 4 is selected from the group consisting of the following groups or structural fragments: (1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br; R 7、R 8可独立地选自如下基团或结构片断： R 7 and R 8 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基；3-8元环的氧杂环烷基和3-8元环的氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and The 3-8 membered ring nitrogen a heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (3) CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 are independently selected From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkynyl 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, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子；所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直 链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, Cyclopropylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl may contain 1 hetero atom or may contain multiple heteroatoms; 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 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 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 , 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and 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、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl; (3)R 9、R 10可成环，环系大小为3-7元脂环。 (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 members of alicyclic ring. 根据权利要求3的化合物及其药用盐，其特征在于，所述的化合物如通式IA-1a所示The compound according to claim 3 and a pharmaceutically acceptable salt thereof, wherein said compound is as shown in Formula IA-1a
Figure PCTCN2018088561-appb-100004
Figure PCTCN2018088561-appb-100004
 在式IAa-1a中，In the formula IAa-1a, X、Y、Z、R 4、R 7、R 8、R 9、R 10的定义同权利要求3一致； X, Y, Z, R 4 , R 7 , R 8 , R 9 , R 10 are as defined in claim 3; R 11选自如下基团或结构片段： R 11 is selected from the group consisting of: (1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤 素包括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; A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、 Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Contains multiple heteroatoms. 根据权利要求4的化合物及其药用盐、溶剂化物或前药，其特征在于，所述的化合物如通式IA-1a-1所示A compound according to claim 4, and a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein said compound is represented by the formula IA-1a-1
Figure PCTCN2018088561-appb-100005
Figure PCTCN2018088561-appb-100005
 在式IA-1a-1中，In the formula IA-1a-1, R 4、R 7、R 8、R 9、R 10和R 11的定义同权利要求4一致； The definitions of R 4 , R 7 , R 8 , R 9 , R 10 and R 11 are in accordance with claim 4; A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N; R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; (3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6 元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, and cyclopropylene group; the 3-6 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms. 根据权利要求5的化合物及其药用盐，其特征在于，所述的化合物如通式IA-1a-1a所示The compound according to claim 5, wherein the compound is as shown in the formula IA-1a-1a, and a pharmaceutically acceptable salt thereof
Figure PCTCN2018088561-appb-100006
Figure PCTCN2018088561-appb-100006
 在式IA-1a-1a中，In the formula IA-1a-1a, R 4、R 9、R 10、A'、B'、C'、D'、X'、Y'、Z'的定义同权利要求5一致； The definitions of R 4 , R 9 , R 10 , A′, B′, C′, D′, X′, Y′, Z′ are in accordance with claim 5; R' 7、R' 8可独立地选自如下基团或结构片断： R '7, R' 8 may be independently selected from a group or structure fragments: 氢、甲基、乙基、丙基、CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的 Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-6直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； Hydrogen, methyl, ethyl, propyl, CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 is independently selected from H, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2- a straight or branched alkynyl group, wherein said 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 , R b 4 , Ra 8 , Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-3直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-3直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子；所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-3 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-3 straight or branched alkyl, cyclopropyl, Cyclopropylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl may contain 1 hetero atom or may contain multiple heteroatoms; 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 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 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 , 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and 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' 11选自如下基团或结构片段： R '11 group or a structural fragment selected from the following: (1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地 选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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. 根据权利要求5的化合物及其药用盐，其特征在于，所述的化合物如通式IA-1a-1b所示The compound according to claim 5, wherein the compound is as shown in the formula IA-1a-1b, and a pharmaceutically acceptable salt thereof
Figure PCTCN2018088561-appb-100007
Figure PCTCN2018088561-appb-100007
 在式IA-1a-1b中，In formula IA-1a-1b, R 4、R 9、R 10、A'、B'、C'、D'、X'、Y'、Z'的定义同权利要求5一致； The definitions of R 4 , R 9 , R 10 , A′, B′, C′, D′, X′, Y′, Z′ are in accordance with claim 5; R' 7、R' 8可独立地选自如下基团或结构片断： R '7, R' 8 may be independently selected from a group or structure fragments: 氢、甲基、乙基、丙基、CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-6直链或支链烷基、 取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； Hydrogen, methyl, ethyl, propyl, CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 is independently selected from H, substituted or unsubstituted C1-6 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched alkenyl, substituted or unsubstituted C2- a straight or branched alkynyl group, wherein said 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 , R b 4 , Ra 8 , Rb 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-3直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-3直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子；所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-6 membered ring azacycloalkyl, wherein said substituent is selected from C1-3 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-3 straight or branched alkyl, cyclopropyl, Cyclopropylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl may contain 1 hetero atom or may contain multiple heteroatoms; 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 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 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 , 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and 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; Ar' 2可独立地选自如下基团或结构片断： Ar' 2 may be independently selected from the group consisting of: (1)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (1) 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br. 根据权利要求5-7任一项的化合物及其药用盐，其特征在于，其中所述的X'、Y'、Z'、A'、B'、C'、D'选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 The compound according to any one of claims 5 to 7, wherein the X', Y', Z', A', B', C', D' are selected from CH, N, and pharmaceutically acceptable salts thereof. , CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 . 根据权利要求2的化合物及其药用盐，其特征在于，所述的化合物如通式IA-2所示The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein said compound is as shown in Formula IA-2
Figure PCTCN2018088561-appb-100008
Figure PCTCN2018088561-appb-100008
 在式IA-2中，In formula IA-2, X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms; Ar 1选自如下基团或结构片断： Ar 1 is selected from the group consisting of the following groups or structural fragments: 取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 membered ring lactam) 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 the group consisting of H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片断： R 3 is selected from the group consisting of the following groups or structural fragments: (1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of (a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br; R 4选自如下基团或结构片断： R 4 is selected from the group consisting of the following groups or structural fragments: (1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br; R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl; (3)R 9、R 10可成环，环系大小为3-7元脂环。 (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 members of alicyclic ring. 根据权利要求9的化合物及其药用盐，其特征在于，所述的化合物如通式IA-2a所示The compound according to claim 9 and a pharmaceutically acceptable salt thereof, wherein said compound is as shown in the formula IA-2a
Figure PCTCN2018088561-appb-100009
Figure PCTCN2018088561-appb-100009
 在式IA-2a中，In formula IA-2a, X、Y、Z、R 4、Ar 1、R 9、R 10的定义同权利要求9一致； The definitions of X, Y, Z, R 4 , Ar 1 , R 9 , and R 10 are the same as in claim 9; R 11选自如下基团或结构片段： R 11 is selected from the group consisting of: (1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代 或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、 SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Contains multiple heteroatoms. 根据权利要求10的化合物及其药用盐，其特征在于，所述的化合物如通式IA-2a-1a所示The compound according to claim 10, and a pharmaceutically acceptable salt thereof, wherein said compound is as shown in the formula IA-2a-1a
Figure PCTCN2018088561-appb-100010
Figure PCTCN2018088561-appb-100010
 在式IA-2a-1中，In formula IA-2a-1, R 4、Ar 1、R 9、R 10的定义同权利要求10一致； The definitions of R 4 , Ar 1 , R 9 , and R 10 are the same as in claim 10; R 11选自如下基团或结构片段： R 11 is selected from the group consisting of: (1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N; R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; (3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, and cyclopropylene group; the 3-6 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms. 根据权利要求11的化合物及药用盐，其特征在于，其中所述的X'、Y'、Z'、A'、B'、C'、D'选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 The compound according to claim 11 and a pharmaceutically acceptable salt, wherein said X', Y', Z', A', B', C', D' are selected from the group consisting of CH, N, CF, CCl, CCH 3, CC 2 H 5, COCH 3, COC 2 H 5, CNHCH 3, CNHC 2 H 5. 根据权利要求1的化合物及其药用盐，其特征在于，所述的化合物如通式IB所示The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is as shown in Formula IB
Figure PCTCN2018088561-appb-100011
Figure PCTCN2018088561-appb-100011
 在式IB中，In the formula IB, X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、 环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms; R 2选自如下基团或结构片断： R 2 is selected from the group consisting of: (1)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6CONRf 4Rf 5、NRe 7SO 2Rf 6,其中所述的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独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 CONRf 4 Rf 5 , NRe 7 SO 2 Rf 6 , wherein 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 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkane a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight or branched alkynyl group, wherein said 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, ring Propylmethylene, cyclobutyl, cyclopentyl; 所述的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也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链 烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； 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 , 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, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and azacycloalkyl It may contain one hetero atom or multiple hetero atoms at the same time; 所述的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也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； 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 , NRa' 8 CORb' 5 , (CH 2 ) nNRa' 9 Rb' 6 , (CH 2 ) nORa' 10 , 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 , Ra' 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; The ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain One N atom may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms, and the hetero atom is selected from O, N, S; n is selected from 1, 2, 3 Wherein the halogen includes F, Cl, Br; (2)CONRh 1Ri 1、COORh 2、SO 2Rh 3、SO 2NRh 4Ri 2，其中所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) CONRh 1 Ri 1 , COORh 2 , SO 2 Rh 3 , SO 2 NRh 4 Ri 2 , wherein said 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 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C 1 - 4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个 杂原子； The 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. Heterocycloalkyl, 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 , 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 a methylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring of an oxaheterocycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; 所述的Rh 1、Ri 1、Rh 2、Rh 3、Rh 4、Ri 2也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； The 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight a chain or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted. It may also be a polysubstituted one; 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; (3)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (3) a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, a substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 members) a cyclic lactam) 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片段： R 3 is selected from the group consisting of the following groups or structural fragments: (1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of (a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地 选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4 直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms. O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br. R 5、R 6可独立地选自如下基团或结构片段： R 5 and R 6 may be independently selected from the group consisting of: (1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳 杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br; R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl; (3)R 9、R 10可成环，环系大小为3-7元脂环. (3) R 9 and R 10 can form a ring, and the ring system is 3-7 yuan alicyclic. 根据权利要求13的化合物及其药用盐，其特征在于，所述的化合物如通式IB-1所示：The compound according to claim 13 and a pharmaceutically acceptable salt thereof, wherein the compound is as shown in the formula IB-1:
Figure PCTCN2018088561-appb-100012
Figure PCTCN2018088561-appb-100012
 在式IB-1中，In the formula IB-1, X、Y、Z、R3、R5、R6、R9、R10的定义同权利要求13；X, Y, Z, R3, R5, R6, R9, R10 are as defined in claim 13; R 7、R 8可独立地选自如下基团或结构片断： R 7 and R 8 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、 Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基；3-8元环的氧杂环烷基和3-8元环的氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, wherein The substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 is independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring oxacycloalkyl and The 3-8 membered ring nitrogen a heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)CORf′ 1、COORf′ 2、SO 2Rf′ 3、CONRf′ 4Rf′ 5，其中所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (3) CORf' 1 , COORf' 2 , SO 2 Rf' 3 , CONRf' 4 Rf' 5 , wherein Rf' 1 , Rf' 2 , Rf' 3 , Rf' 4 , Rf' 5 are independently selected From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkynyl 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, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； The 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. Oxheterocycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight or branched alkyl, F, Cl, Br, CN And 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, a cypromethylene group, a cyclobutyl group, a cyclopentyl group; a 3-8 membered ring oxacycloalkyl group and a nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; 所述的Rf′ 1、Rf′ 2、Rf′ 3、Rf′ 4、Rf′ 5也可独立地选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、 环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 The 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 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 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1 - a linear or branched alkyl group, a cyclopropyl group, a cyclopropylmethylene group, a cyclobutyl group, a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be a single The substitution may also be a multiple substitution; the six-membered aromatic heterocyclic ring may contain one N atom or may contain a plurality of nitrogen atoms; The five-membered aromatic heterocyclic ring may contain one hetero atom or a plurality of hetero atoms selected from O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br. 根据权利要求14的化合物及其药用盐，其特征在于，所述的化合物如通式IB-1a所示：The compound according to claim 14 and a pharmaceutically acceptable salt thereof, wherein the compound is as shown in the formula IB-1a:
Figure PCTCN2018088561-appb-100013
Figure PCTCN2018088561-appb-100013
 在式IB-1a中，In the formula IB-1a, X、Y、Z、R5、R6、R7、R8、R9、R10的定义同权利要求14；X, Y, Z, R5, R6, R7, R8, R9, R10 are as defined in claim 14; R 11选自如下基团或结构片段： R 11 is selected from the group consisting of: (1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、 F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Contains multiple heteroatoms. 根据权利要求15的化合物及其药用盐，其特征在于，所述的化合物如通式IB-1a-1所示：The compound according to claim 15 and a pharmaceutically acceptable salt thereof, wherein the compound is represented by the formula IB-1a-1:
Figure PCTCN2018088561-appb-100014
Figure PCTCN2018088561-appb-100014
 在式IB-1a-1中，In the formula IB-1a-1, R5、R6、R7、R8、R9、R10、R11的定义同权利要求15；R5, R6, R7, R8, R9, R10, R11 are as defined in claim 15; A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、 也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N; R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; (3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 And Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原 子。 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, and cyclopropylene group; the 3-6 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms. 根据权利要求16的化合物及药用盐，其特征在于，其中所述的X'、Y'、Z'、A'、B'、C'、D'选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 The compound according to claim 16 and a pharmaceutically acceptable salt, wherein said X', Y', Z', A', B', C', D' are selected from the group consisting of CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 . 根据权利要求13的化合物及其药用盐，其特征在于，所述的化合物如通式IB-2所示The compound according to claim 13 and a pharmaceutically acceptable salt thereof, wherein said compound is represented by the formula IB-2
Figure PCTCN2018088561-appb-100015
Figure PCTCN2018088561-appb-100015
 在式IB-2中，In the formula IB-2, X选自CR x、N；Y选自CR y、N；Z选自CR z、N；X、Y、Z可以单独为N、二个同时为N和/或三个同时为N； 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和R z独立选自如下原子或基团或结构片断，包括 R x , R y and R z are independently selected from the group consisting of the following atoms or groups or structural fragments, including (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, ring Propyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched olefin a substituted or unsubstituted C2-8 straight or branched alkynyl group wherein said 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 , 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 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 3-7 cycloalkyl, substituted or non-substituted a substituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, wherein said substituent is selected from C1-5 straight Chain 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 , NRa 8 CORb 5 Wherein 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 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 a hetero atom, which may also contain a plurality of heteroatoms; Ar 1选自如下基团或结构片断： Ar 1 is selected from the group consisting of the following groups or structural fragments: 取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、取代或未取代的4-8元杂环(包括4-8元环内酰胺)，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, substituted or unsubstituted 4-8 membered heterocyclic ring (including 4-8 membered ring lactam) 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 the group consisting of H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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选自如下基团或结构片段： R 3 is selected from the group consisting of the following groups or structural fragments: (1)取代或非取代的苯基，取代或非取代的含氮六元芳杂环，取代或非取代的五 元芳杂环，其中所述的取代基选自(1) a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of (a)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (a) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (b)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (b) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤 素包括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; (2)取代或非取代的芳香性的稠环或稠杂环、取代或非取代的非芳香性的稠环或稠杂环，包括取代或非取代的萘环、取代或非取代的苯并六元杂环、取代或非取代的苯并五元杂环，其中所述的取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基、环丁基、环戊基；其中所述的萘环、苯并六元杂环或苯并五元杂环上可以是单取代，也可以是多取代；苯并六元杂环或苯并五元杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br。 (2) a substituted or unsubstituted aromatic fused or fused heterocyclic ring, a substituted or unsubstituted non-aromatic fused or fused heterocyclic ring, including a substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo a six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered 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, ORs 1 , SRs 2 , NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7, Rt 4, Rs 8 , Rt 5, Rs 9, Rt 6, Rs 10 is independently selected from H, C1-4 straight-chain or branched alkyl, cyclopropyl, cyclopropylmethyl, methylene, cyclobutyl And a cyclopentyl group; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring may be monosubstituted or polysubstituted; a benzo six-membered heterocyclic ring or a benzo five-membered heterocyclic ring May contain a hetero atom or multiple heteroatoms selected from heteroatoms O, N, S; n is selected from 1, 2, 3; wherein the halogen includes F, Cl, Br. R 5、R 6可独立地选自如下基团或结构片段： R 5 and R 6 may be independently selected from the group consisting of: (1)选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基； (1) a C1-8 straight or branched alkyl group substituted or unsubstituted, a substituted or unsubstituted C2-8 straight or branched alkenyl group, a substituted or unsubstituted C2-8 straight chain or a branched alkynyl group, 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 independent Is selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; (2)可选自取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) 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, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-8 membered ring of oxalate The cycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms at the same time; (3)可选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自C1-4直链或支链烷基、卤素取代的C1-4直链 或支链烷基、F、Cl、Br、NO 2、CN、亚甲二氧基、ORa′ 1、SRa′ 2、NRa′ 3Rb′ 1、COORa′ 4、CONRa′ 5Rb′ 2、NRa′ 6COORb′ 3、SO 2NRa′ 7Rb′ 4、NRa′ 8CORb′ 5、(CH 2)nNRa′ 9Rb′ 6、(CH 2)nORa′ 10，其中所述的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、Ra′ 9、Rb′ 6、Ra′ 10独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括F、Cl、Br； (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 , Ra' 4 , Ra' 5 , Rb' 2 , Ra' 6 , Rb' 3 , Ra' 7 , Rb' 4 , Ra' 8 , Rb' 5 , Ra' 9 , Rb' 6 , Ra' 10 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl And a cyclopentyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring, and the five-membered aromatic heterocyclic ring may be monosubstituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain one N atom, or Containing a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain one hetero atom or may contain a plurality of impurities Promoter, hetero atoms selected from O, N, S; n is selected from 2, 3; wherein the halogens include F, Cl, Br; R 9、R 10可独立地选自如下基团或结构片断： R 9 and R 10 may be independently selected from the group consisting of: (1)氢、取代或非取代的C1-4直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、C1-4直链或支链烷基、环丙基，环丙亚甲基，环丁基，环戊基； (1) Hydrogen, substituted or unsubstituted C1-4 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched alkenyl, substituted or unsubstituted C2-4 straight or branched An alkynyl group, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , wherein Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from H, C1-4 straight or branched alkyl, cyclopropyl, cyclopropylene, cyclobutyl, cyclopentyl; (2)取代或非取代的C3-6环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORx 1、SRx 2、NRx 3Ry 1、NRx 4CORy 2、COORx 5、CONRx 6Ry 3、NRx 7COORy 4、SO 2NRx 8Ry 5，所述的Rx 1、Rx 2、Rx 3、Ry 1、Rx 4、Ry 2、Rx 5、Rx 6、Ry 3、Rx 7、Ry 4、Rx 8、Ry 5独立地选自H、甲基、乙基、丙基、异丙基、环丙基，环丙亚甲基，环丁基，环戊基； (2) a substituted or unsubstituted C3-6 cycloalkyl group, wherein the substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx 1 , SRx 2 , NRx 3 Ry 1 , NRx 4 CORy 2 , COORx 5 , CONRx 6 Ry 3 , NRx 7 COORy 4 , SO 2 NRx 8 Ry 5 , Rx 1 , Rx 2 , Rx 3 , Ry 1 , Rx 4 , Ry 2 , Rx 5 , Rx 6 , Ry 3 , Rx 7 , Ry 4 , Rx 8 , Ry 5 are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cypromethylene, Cyclobutyl, cyclopentyl; (3)R 9、R 10可成环，环系大小为3-7元脂环。 (3) R 9 and R 10 may form a ring, and the ring system has a size of 3-7 members of alicyclic ring. 根据权利要求18的化合物及其药用盐，其特征在于，所述的化合物如通式IB-2a所示The compound according to claim 18, wherein the compound is as shown in the formula IB-2a, and a pharmaceutically acceptable salt thereof
Figure PCTCN2018088561-appb-100016
Figure PCTCN2018088561-appb-100016
 在式IB-2a中，In the formula IB-2a, X、Y、Z、R 5、R 6、Ar 1、R 9、R 10的定义同权利要求18； X, Y, Z, R 5 , R 6 , Ar 1 , R 9 , R 10 are as defined in claim 18; R 11选自如下基团或结构片段： R 11 is selected from the group consisting of: (1)C1-8直链或支链烷基、卤素取代的C1-8直链或支链烷基、F、Cl、Br、NO 2、CN，亚甲二氧基、ORs 1、SRs 2、NRs 3Rt 1、NRs 4CORt 2、COORs 5、CONRs 6Rt 3、NRs 7COORt 4、SO 2NRs 8Rt 5、(CH 2)nNRs 9Rt 6、(CH 2)nORs 10，其中所述的Rs 1、Rs 2、Rs 3、Rt 1、Rs 4、Rt 2、Rs 5、Rs 6、Rt 3、Rs 7、Rt 4、Rs 8、Rt 5、Rs 9、Rt 6、Rs 10独立地选自H、取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基、取代或非取代的C2-8直链或支链炔基、取代或未取代的3-7元环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基、取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (1) a C1-8 linear or branched alkyl group, a halogen-substituted C1-8 straight or branched alkyl group, F, Cl, Br, NO 2 , CN, methylenedioxy, ORs 1 , SRs 2 NRs 3 Rt 1 , NRs 4 CORt 2 , COORs 5 , CONRs 6 Rt 3 , NRs 7 COORt 4 , SO 2 NRs 8 Rt 5 , (CH 2 )nNRs 9 Rt 6 , (CH 2 )nORs 10 , wherein Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rs 4 , Rt 2 , Rs 5 , Rs 6 , Rt 3 , Rs 7 , Rt 4 , Rs 8 , Rt 5 , Rs 9 , Rt 6 , Rs 10 independently From H, substituted or unsubstituted C1-8 straight or branched alkyl, substituted or unsubstituted C2-8 straight or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkyne a substituted, unsubstituted 3-7 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted Or an unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, 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 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 chain or Branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; 3-8 membered ring oxacycloalkyl or azacycloalkyl can contain 1 heteroatom , can also contain multiple heteroatoms at the same time; (2)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基或氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (2) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (c)取代或非取代的苯基、取代或非取代的六元芳杂环、取代或非取代的五元芳杂环，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、C1-4直链或支链烷基、环丙基、环丙亚甲基、环丁基、环戊基、环己基； (c) a substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring wherein said 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, cyclopentyl, cyclohexyl; 苯环、含氮六元芳杂环或五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个N原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S；n选自1,2,3；其中所述的卤素包括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; A选自CR a、N；B选自CR b、N；C选自CR c、N；D选自CR d、N；A、B、C、D可以单独为N、二个同时为N和/或三个同时为N； 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和R d独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基、环戊基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-8直链或支链烷基、取代或非取代的C2-8直链或支链烯基或炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (2) a substituted or unsubstituted C1-8 straight or branched alkyl group, a substituted or unsubstituted C2-8 straight or branched alkenyl or alkynyl group, 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 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, methyl, ethyl, propyl, cyclopropyl , propylene methylene, cyclobutyl, cyclopentyl; (3)取代或非取代的C3-7环烷基、取代或非取代的3-8元环的氧杂环烷基、取代或非取代的3-8元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-8元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-7 cycloalkyl group, a substituted or unsubstituted 3-8 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-8 membered ring azacycloalkyl group, 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 , NRa 8 CORb 5 , wherein 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 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; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-5直链或支链烷基、取代或非取代的C2-6直链或支链烯基、取代或非取代的C2-6直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-5 straight or branched alkyl, substituted or unsubstituted C2-6 straight or branched olefin a substituted or unsubstituted C2-6 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自C1-5直链或支链烷基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、 NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基、环丁基、环戊基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, ethyl , propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; 3-6 membered ring oxacycloalkyl and azacycloalkyl may contain 1 hetero atom, or both Contains multiple heteroatoms. 根据权利要求19的化合物及其药用盐，其特征在于，所述的化合物如通式IB-2a-1所示The compound according to claim 19 and a pharmaceutically acceptable salt thereof, wherein said compound is represented by the formula IB-2a-1
Figure PCTCN2018088561-appb-100017
Figure PCTCN2018088561-appb-100017
 在式IB-2a-1中，In the formula IB-2a-1, R 5、R 6、Ar 1、R 9、R 10、R 11的定义同权利要求19； R 5 , R 6 , Ar 1 , R 9 , R 10 , R 11 are as defined in claim 19; A'选自CR' a、N；B'选自CR' b、N；C'选自CR' c、N；D'选自CR' d、N；X'选自CR' x、N；Y'选自CR' y、N；Z'选自CR' z、N；A'、B'、C'、D'、X'、Y'、Z'可以单独为N、也可多个同时为N； 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; X 'is selected from CR' x, N; Y 'is selected from CR' y, N; Z 'is selected from CR' z, N; A ' , B', C ', D', X ', Y', Z ' may be used alone as N, may be a plurality of simultaneously Is N; R' a、R' b、R' c、R' d、R' x、R' y、R' z独立选自如下原子或基团或结构片断，包括 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 (1)H、F、Cl、Br、CN、NO 2、NH 2、CONRc 1Rd 1、COORc 2、SO 2Rc 3、SO 2NRc 4Rd 2,其中所述的Rc 1、Rc 2、Rc 3、Rc 4、Rd 1、Rd 2独立地选自H、甲基、乙基、丙基、异丙基、环丙基、环丙亚甲基、环丁基； (1) H, F, Cl, Br, CN, NO 2 , NH 2 , CONRc 1 Rd 1 , COORc 2 , SO 2 Rc 3 , SO 2 NRc 4 Rd 2 , wherein 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; (2)取代或非取代的C1-4直链或支链烷基、其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (2) a substituted or unsubstituted C1-4 straight or branched alkyl group, 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, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; (3)取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基；3-6 元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子； (3) a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted 3-6 membered ring oxacycloalkyl group, a substituted or unsubstituted 3-6 membered ring azacycloalkyl group, wherein The 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 and Rb 5 are independently selected from the group consisting of H, methyl, ethyl, propyl and cyclopropyl; and the 3-6 membered ring of oxacycloalkyl and azacycloalkyl can contain 1 hetero atom. It can also contain multiple heteroatoms at the same time; (4)ORe 1、NRe 2Rf 1、SRe 3、NRe 4CORf 2、NRe 5COORf 3、NRe 6SO 2Rf 4,其中所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4独立地选自H、取代或非取代的C1-3直链或支链烷基、取代或非取代的C2-4直链或支链烯基、取代或非取代的C2-4直链或支链炔基，其中所述的取代基选自F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基； (4) ORe 1 , NRe 2 Rf 1 , SRe 3 , NRe 4 CORf 2 , NRe 5 COORf 3 , NRe 6 SO 2 Rf 4 , wherein Re 1 , Re 2 , Rf 1 , Re 3 , Re 4 , Rf 2 , Re 5 , Rf 3 , Re 6 , Rf 4 are independently selected from H, substituted or unsubstituted C1-3 straight or branched alkyl, substituted or unsubstituted C2-4 straight or branched olefin a substituted or unsubstituted C2-4 straight or branched alkynyl group wherein said 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 , 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 the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; 所述的Re 1、Re 2、Rf 1、Re 3、Re 4、Rf 2、Re 5、Rf 3、Re 6、Rf 4也可独立地选自取代或非取代的C3-6环烷基、取代或非取代的3-6元环的氧杂环烷基、取代或非取代的3-6元环的氮杂环烷基，其中所述的取代基选自甲基、乙基、丙基、异丙基、F、Cl、Br、CN、ORa 1、SRa 2、NRa 3Rb 1、COORa 4、CONRa 5Rb 2、NRa 6COORb 3、SO 2NRa 7Rb 4、NRa 8CORb 5，其中所述的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独立地选自H、甲基、乙基、丙基、环丙基、环丙亚甲基；3-6元环的氧杂环烷基和氮杂环烷基中可以含有1个杂原子，也可以同时含有多个杂原子。 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 5 , Rb 2 , Ra 6 , Rb 3 , Ra 7 , Rb 4 , Ra 8 , Rb 5 are independently selected from H, methyl, Ethyl group, propyl group, cyclopropyl group, and cyclopropylene group; the 3-6 membered ring oxacycloalkyl group and the nitrogen heterocycloalkyl group may have one hetero atom or may contain a plurality of hetero atoms. 根据权利要求20的化合物及药用盐，其特征在于，其中所述的X'、Y'、Z'、A'、B'、C'、D'选自CH、N、CF、CCl、CCH 3、CC 2H 5、COCH 3、COC 2H 5、CNHCH 3、CNHC 2H 5。 The compound according to claim 20 and a pharmaceutically acceptable salt, wherein said X', Y', Z', A', B', C', D' are selected from the group consisting of CH, N, CF, CCl, CCH 3 , CC 2 H 5 , COCH 3 , COC 2 H 5 , CNHCH 3 , CNHC 2 H 5 . 根据权利要求1的化合物及其药用盐，其特征在于，所述的化合物选自：A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Figure PCTCN2018088561-appb-100018
Figure PCTCN2018088561-appb-100018
Figure PCTCN2018088561-appb-100019
Figure PCTCN2018088561-appb-100019
Figure PCTCN2018088561-appb-100020
Figure PCTCN2018088561-appb-100020
Figure PCTCN2018088561-appb-100021
Figure PCTCN2018088561-appb-100021
Figure PCTCN2018088561-appb-100022
Figure PCTCN2018088561-appb-100022
Figure PCTCN2018088561-appb-100023
Figure PCTCN2018088561-appb-100023
Figure PCTCN2018088561-appb-100024
Figure PCTCN2018088561-appb-100024
 根据权利要求1-22中任一项的化合物及其药用盐，其特征在于，所述化合物的药用盐选自与无机酸、有机酸、碱金属离子、碱土金属离子或能提供生理上可接受的阳离子的有机碱结合形成的盐以及铵盐。The compound according to any one of claims 1 to 22, and a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt of the compound is selected from the group consisting of inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or physiologically Acceptable cationic organic bases combine to form salts as well as ammonium salts. 根据权利要求23的化合物及其药用盐，其特征在于，所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、枸杞酸、马来酸、酒石酸、富马酸、柠檬酸或乳酸；所述的碱金属离子选自锂离子，钠离子，钾离子；所述的碱土金属离子包括钙离子，镁离子；所述的能提供生理上可接受的阳离子的有机碱选自甲胺、二甲胺、三甲胺、哌啶、吗啉或三(2-羟乙基)胺。The compound according to claim 23, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; and the organic acid is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, and the like. Fluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ion is selected from the group consisting of lithium ions, sodium ions, potassium ions; the alkaline earth metal ions include calcium ions, magnesium ions The organic base capable of providing a physiologically acceptable cation is selected from the group consisting of methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine. 制备权利要求1-22中任一项化合物的方法，其特征在于，包括如下步骤：A method of preparing a compound according to any one of claims 1 to 22, comprising the steps of: 芳甲酰胺类目标化合物(通式I所示)的合成是通过由2位和5位不同取代的酸和取代的伯胺发生缩合反应制备；其中关键酸中间体是由2-羟基-5-硝基芳(杂)酸、2-羟基-5-溴代芳(杂)酸在氯化亚砜的作用下发生酯化反应，然后进行取代反应和水解反应制备，或者是由2-氯-5-硝基芳(杂)酸与胺发生亲核取代反应得到。另一类关键中间体胺10是由溴代芳(杂)基酰基化合物7a出发，依次通过偶联反应，与羟胺缩合反应，还原反应制备；或者是由不同取代的芳(杂)基酰胺化合物7b依次通过加成消除反应，与羟胺反应，还原反应制备；或者是由不同取代的氰基化合物7c出发，依次发生加成消除反应，与羟胺反应，和还原反应制备。α位双取代的胺11是由不同取代的氰基化合物发生加成反应制备；将得到的酸与胺进行缩合反应，得到化合物12，15，17，20，23和26，然后化合物12、17、23和26通过还原反应、酰化反应或是还原氨化反应制备目标化合物；化合物15和20通过偶联反应制备目标化合物；The synthesis of the arylformamide target compound (shown in Formula I) 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- 5-Nitroaryl (hetero) acid is obtained by nucleophilic substitution reaction with an amine. Another key intermediate, amine 10, is prepared from a bromoaryl(hetero)yl acyl compound 7a, followed by a coupling reaction, a condensation reaction with hydroxylamine, a reduction reaction, or a differently substituted aryl(hetero)amide compound. 7b is sequentially prepared by addition reaction to eliminate the reaction, reacting with hydroxylamine, and reducing reaction; or starting from differently substituted cyano compound 7c, sequential addition elimination reaction, reaction with hydroxylamine, and reduction reaction are prepared. The α-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 to prepare a target compound by a reduction reaction, an acylation reaction or a reductive amination reaction; the compounds 15 and 20 are prepared by a coupling reaction to prepare a target compound;
Figure PCTCN2018088561-appb-100025
Figure PCTCN2018088561-appb-100025
Figure PCTCN2018088561-appb-100026
Figure PCTCN2018088561-appb-100026
 试剂及反应条件：(a)o-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)，1-羟基苯并三唑(HOBT),二异丙基乙胺(DIEA)，N,N-二甲基甲酰胺(DMF),室温；或者1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC),1-羟基苯并三唑,二异丙基乙胺，N,N-二甲基甲酰胺，室温；(b)氯化亚砜(SOCl 2)，无水甲醇(Anhydrous MeOH)，60℃；(c)R-I或者R-Br,碳酸钾(K 2CO 3)，无水N,N-二甲基甲酰胺(Anhydrous DMF)，60℃；(d)氢氧化钠(NaOH)，四氢呋喃/水(THF/H 2O)，室温；(e)四三苯基磷化钯(Pd(PPh 3) 4)，碳酸钠(Na 2CO 3)，R-Br，1,4-二氧六环(1,4-dioxane)，水，氩气，110℃；或者三(二亚苄基丙酮)二钯(Pd 2(dba) 3)，(±)-2,2'-双-(二苯膦基)-1,1'-联萘(BINAP)，叔丁醇钠，甲苯(Toluene)，氩气，100℃；(f)甲基溴化镁(CH 3MgBr)，无水四氢呋喃，氩气，0℃；(g)甲基锂(CH 3Li)，无水四氢呋喃，氩气，-66℃；(h)50％羟胺水溶液，乙醇(EtOH)，水，60℃；(i)锌粉(Zn)，盐酸，乙醇，水，室温；或者10％钯/碳(10％Pd/C)，甲酸铵，甲醇，回流；(j)三氯化铈(CeCl 3)，甲基锂，氩气，-66℃；(k)10％钯/碳，氢气(H 2)，乙醇，室温；或者铁粉(Fe)，氯化铵(NH 4Cl)，乙醇，水，回流；(l)R-COCl，三乙胺(Et 3N)，二氯甲烷(DCM)，0℃；或者RR’CO，三乙酰氧基硼氢化钠(NaBH(OAc) 3)，二氯甲烷，室温；(m)三(二亚苄基丙酮)二钯，(±)-2,2'-双-(二苯膦基)-1,1'-联萘，叔丁醇钠，甲苯，氩气，100℃；或者四三苯基磷化钯，碳酸钠，1,4-二氧六环，水，氩气，110℃或者1,10-邻菲啰啉，碳酸钾，碘化铜(CuI)，N,N-二甲基甲酰胺，氩气，120℃；或者乙酰丙酮铁(III)，碳酸铯(Cs 2CO 3)，氧化铜(CuO)，N,N-二甲基甲酰胺，120℃；(n)R 5R 6-NH，乙腈，二异丙基乙胺，65℃； 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 / H 2 O), room temperature; e) tetrakistriphenylphosphine palladium (Pd(PPh 3 ) 4 ), sodium carbonate (Na 2 CO 3 ), R-Br, 1,4-dioxane, water, argon Gas, 110 ° C; or tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (BINAP), sodium tert-butoxide, toluene, argon, 100 ° C; (f) methyl magnesium bromide (CH 3 MgBr), anhydrous tetrahydrofuran, argon, 0 ° C; (g) methyl lithium (CH 3 Li), anhydrous tetrahydrofuran, argon, -66 ° C; (h) 50% aqueous hydroxylamine solution, ethanol (EtOH), water, 60 ° C; (i) Zinc powder (Zn), hydrochloric acid, ethanol, water, room temperature; or 10% palladium/carbon (10% Pd/C), ammonium formate, methanol, reflux; (j) cesium trichloride (CeCl 3 ), methyl lithium , argon, -66 ° C; (k) 10% palladium / carbon, hydrogen (H 2 ), ethanol, room temperature; or iron powder (Fe), ammonium chloride (NH 4 Cl), ethanol, water, reflux; l) R-COCl, triethylamine (Et 3 N), dichloromethane (DCM), 0 ° C; or RR 'CO, sodium triacetoxyborohydride (NaBH (OAc) 3 ), dichloromethane, room temperature (m) tris(dibenzylideneacetone)dipalladium, (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, sodium tert-butoxide, toluene, argon , 100 ° C; or tetrakistriphenylphosphine palladium, sodium carbonate, 1,4-dioxane, water, argon, 110 ° C or 1,10-phenanthroline, potassium carbonate, copper iodide (CuI ), N,N-dimethylformamide, argon, 120 ° C; or iron (III) acetylacetonate, cesium carbonate (Cs 2 CO 3 ), copper oxide (CuO), N, N-dimethylformamide , 120 ° C; (n) R 5 R 6 -NH, acetonitrile, diisopropylethylamine, 65 ° C; 其中所述的X、Y、Z、A、B、C、D、Ar 1、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11的定义如权利要求1-22任一项所述。 Wherein X, Y, Z, A, B, C, D, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 And R 11 are as defined in any one of claims 1-22. 一种药物组合物，其特征在于，包括有效剂量的权利要求1-24中任一项的化合物和药效学上可接受的载体。A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier. 权利要求1-24中任一项的化合物及其药用盐在制备Kv2.1抑制剂中的应用。Use of a compound according to any one of claims 1 to 24, and a pharmaceutically acceptable salt thereof, for the preparation of a Kv2.1 inhibitor. 权利要求1-24中任一项的化合物及其药用盐在制备预防和\或治疗与Kv2.1有关的疾病的药物中的应用。Use of a compound according to any one of claims 1 to 24, and a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with Kv2.1. 根据权利要求28中的应用，其特征在于，与Kv2.1有关的疾病选自精神神经系统疾病、代谢性疾病或心脑血管疾病。The use according to claim 28, characterized in that the disease associated with Kv2.1 is selected from the group consisting of a mental nervous system disease, a metabolic disease or a cardiovascular and cerebrovascular disease. 根据权利要求29的应用，其特征在于，所述的与Kv2.1有关的疾病选自阿尔茨海默病、抑郁症、糖尿病、动脉粥样硬化症、脑卒中。The use according to claim 29, characterized in that the Kv2.1-related disease is selected from the group consisting of Alzheimer's disease, depression, diabetes, atherosclerosis, stroke.
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