Nitrogen-containing heterocyclic derivative inhibitor, preparation method therefor and use thereof

Patent metadata

Field	Value
Publication number	US-12497366-B2
Application number	US-202519177721-A
Country	US
Kind code	B2
Filing date	Apr 14, 2025
Priority date	Oct 14, 2022
Publication date	Dec 16, 2025
Grant date	Dec 16, 2025

Abstract

A nitrogen-containing heterocyclic derivative inhibitor, a preparation method therefor and the use thereof. Specifically disclosed are a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as an inhibitor in treating diseases such as cardiovascular and cerebrovascular diseases, wherein the definition of each substituent in the general formula (I) are the same as those defined in the description.

First claim

The invention claimed is:

1 . A compound represented by general formula (I-1′), or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein
ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;
M 5 is selected from N or CR 5 ;
R 5 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, or C 1-6 hydroxyalkyl;
R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, or C 3-8 cycloalkyl;
R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl;
R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, or C 1-6 hydroxyalkyl;
R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, thio, C 1-6 alkylthio, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, or C 3-8 cycloalkyl;
x is 0, 1, 2, or 3;
y is 0, 1, 2, or 3;
z is 0, 1, 2, or 3; and
e is 0, 1, 2, or 3.

2 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; further wherein
the cycloalkyl contains 3 to 6 carbon atoms; the heterocyclyl consists of 3 to 12 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m , wherein m is an integer from 0 to 2, but excluding ring moieties of —O—O—, —O—S— or —S—S—, and the remaining ring atoms are carbon; the aryl is a 6- to 14-membered all-carbon monocyclic or fused polycyclic group having a conjugated π electron system; and the heteroaryl consists of 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.

3 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from C 3-6 cycloalkyl, phenyl, 3- to 8-membered heterocyclyl, 7- to 10-membered bicyclic heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered fused 5-membered bicyclic heteroaryl, 5-membered fused 6-membered bicyclic heteroaryl, 5-membered fused 6-membered bicyclic heterocyclyl, 6-membered fused 5-membered bicyclic heteroaryl, or 6-membered fused 6-membered bicyclic heteroaryl.

4 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from C, cycloalkyl, phenyl, 5-membered nitrogen-containing heterocyclyl, 6-membered nitrogen-containing heterocyclyl, 7- to 10-membered bicyclic heterocyclyl, 5-membered nitrogen-containing heteroaryl, 6-membered nitrogen-containing heteroaryl, 5-membered fused 5-membered bicyclic nitrogen-containing heteroaryl, 5-membered fused 6-membered bicyclic nitrogen-containing heteroaryl, 6-membered fused 5-membered bicyclic nitrogen-containing heteroaryl, or 6-membered fused 6-membered bicyclic nitrogen-containing heteroaryl.

5 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is further represented by general formula (I-1), or (I-2):

6 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from

7 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from pyridine, pyrimidine, benzene,

8 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from pyridine, pyrimidine, benzene,

9 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from

10 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is further represented by general formula (V):

wherein
M 1 is selected from N or CH; M 2 is selected from N or CH; M 3 is selected from N or CH; and M 4 is selected from N or CH.

11 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein R a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, or C 3-8 cycloalkyl;
R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, or cyano-substituted C 1-3 alkyl; R c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, or C 1-3 hydroxyalkyl; and R d is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, oxo, thio, C 1-3 alkylthio, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 alkyl, or C 3-8 cycloalkyl.

12 . The compound or the stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the following compounds:

Assignees

• Shanghai Hansoh Biomedical Co Ltd
• Jiangsu Hansoh Pharmaceutical Group Co Ltd

Inventors

• Dong Jiaqiang
• Deng Xinxian
• Yu Wensheng
• Jin Fangfang
• Gong Zhen

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title