阅读说明：本技术 Ssao抑制剂 (SSAO inhibitors ) 是由 罗志 李小林 杨亚讯 杨乐乐 李鹏 贺海鹰 黎健 陈曙辉 于 2018-06-20 设计创作，主要内容包括：本发公开了一类SSAO抑制剂,及其在制备治疗与SSAO关疾病的药物中的应用。具体公开了式(Ⅳ)所示化合物及其药学上可接受的盐。<Image he="344" wi="641" file="DDA0002304570060000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses an SSAO inhibitor and application thereof in preparing a medicament for treating SSAO related diseases. Specifically disclosed are a compound represented by the formula (IV) and a pharmaceutically acceptable salt thereof.)

A compound represented by the formula (IV) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R₄、R₅one of them is selected from H and the other is selected from F, Cl, Br, I;

ring a is selected from optionally substituted with R: 5-6 membered heterocycloalkyl, phenyl or 5-9 membered heteroaryl;

R₁selected from H, halogen, OH, NH₂、CN、COOH、-C(＝O)NH₂Or selected from optionally substituted with 1,2 or 3R: c_1-6Alkyl radical, C_1-6Heteroalkyl group, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl;

L₁selected from single bonds、-(CRR)_1-3-、

n is selected from 0,1, 2 or 3;

r is selected from H, F, Cl, Br, I, OH and NH₂、C(＝O)NH₂Or selected from optionally substituted with 1,2 or 3R': c_1-6Alkyl radical, C_{1- 6}Heteroalkyl group, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-NH-;

r' is selected from H, F, Cl, Br, I, OH, CN, NH₂、COOH、Me、Et、CF₃、CHF₂、CH₂F、NHCH₃、N(CH₃)₂(ii) a The 5-to 9-membered heteroaryl group, the 5-to 10-membered heterocycloalkyl group, C_1-6The "hetero" of heteroalkyl, 5-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl represents a heteroatom or a heteroatom group selected from-C (═ O) NH-, -C (═ NH) -, -S (═ O)₂NH-, -S (═ O) NH-, -O-, -S-, N, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -S (═ O) -and-S (═ O)₂-；

In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2 or 3, respectively.

The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from:

wherein the content of the first and second substances,

n is selected from 0,1, 2 or 3;

m is selected from 0 or 1;

T₁is selected from N or CH;

T₂is selected from N or CH;

T₃is selected from N or CH;

d is selected from O, S or NH;

R₁selected from H, halogen, OH, NH₂、CN、COOH、-C(＝O)NH₂Or selected from optionally substituted with 1,2 or 3R: c_1-6Alkyl radical, C_1-6Heteroalkyl group, C_3-6Cycloalkyl, 5-6 membered heterocycloalkyl, phenyl;

L₁selected from single bonds, - (CRR)_1-3-、

R₄、R₅One of them is selected from H and the other is selected from F, Cl, Br, I;

r is selected from H, F, Cl, Br, I, OH and NH₂、C(＝O)NH₂Or selected from optionally substituted with 1,2 or 3R': c_1-6Alkyl radical, C_{1- 6}Heteroalkyl group, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-NH-;

r' is selected from H, F, Cl, Br, I, OH, CN, NH₂、COOH、Me、Et、CF₃、CHF₂、CH₂F、NHCH₃、N(CH₃)₂(ii) a The 5-to 9-membered heteroaryl group, the 5-to 10-membered heterocycloalkyl group, C_1-6The "hetero" of heteroalkyl, 5-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl represents a heteroatom or a heteroatom group selected from-C (═ O) NH-, -C (═ NH) -, -S (═ O)₂NH-, -S (═ O) NH-, -O-, -S-, N, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -S (═ O) -and-S (═ O)₂-；

In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2 or 3, respectively.

A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, F, Cl, Br, I, OH, NH₂、C(＝O)NH₂Or selected from optionally substituted with 1,2 or 3R': me, Et,

A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R is selected from: H. f, Cl, Br, I, OH, NH₂、Me、Et、CF₃、C(＝O)NH₂、

The compound of any one of claims 1,3 or 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of optionally substituted with R: 1,3, 4-oxadiazolyl, 1,2, 4-oxadiazolyl, 1H-1,2, 4-triazolyl, thiazolyl, isothiazolyl, 1,2, 4-thiadiazolyl, oxazolyl, isoxazolyl, 1H-tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, benzoxazolyl, benzisoxazolyl, 4,5,6, 7-tetrahydro-1H-benzimidazolyl, 2H-1,2, 3-triazolyl, benzo [ d ] thiazolyl, 2H-benzo [ d ] imidazolyl, indolin-2, 3-diketo, 4, 5-dihydro-1H-imidazolyl, 1, 3-dihydro-1H-pyrrole.

A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of:

the compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from:

a compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein the structural unit

the compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from:

a compound according to any one of claims 1to 4, or a pharmaceutically acceptable salt thereof, wherein R₁Selected from H, halogen, OH, NH₂、 CN、COOH、-C(＝O)NH₂Or selected from optionally substituted with 1,2 or 3R: c_1-3Alkyl radical, C_1-3Heteroalkyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, cyclobutyl, tetrahydro-2H-pyranyl.

A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R₁Selected from: H.F、Cl、Br、I、OH、NH₂、CN、COOH、-C(＝O)NH₂、Me、CF₃、Et、

a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L₁Selected from: single bond, -CH₂-、-CH₂CH₂-、

A compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the building blockSelected from: H. NH (NH)₂、COOH、-C(＝O)NH₂、Me、CF₃、Et、

A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the building blockSelected from:

a compound according to claim 9 or 13, or a pharmaceutically acceptable salt thereof, wherein the building blockSelected from:

a compound according to any one of claims 1to 4, 10 to 13, or a pharmaceutically acceptable salt thereof, selected from:

wherein the content of the first and second substances,

R₁、L₁wherein R is as defined in claims 1-4 and 10-13.

A compound of the formula or a pharmaceutically acceptable salt thereof selected from:

the compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from:

use of a compound according to any one of claims 1to 18, pharmaceutically acceptable salts thereof and tautomers thereof for the manufacture of a medicament for treating a disease associated with SSAO.

The use according to claim 19, wherein the SSAO-related disease is nonalcoholic steatohepatitis.