Nitrogen-containing benzoheterocycle compound comprising carboxylic acid group, preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-11292785-B2
Application number	US-201916959691-A
Country	US
Kind code	B2
Filing date	Jan 18, 2019
Priority date	Feb 2, 2018
Publication date	Apr 5, 2022
Grant date	Apr 5, 2022

Abstract

Related is a nitrogen-containing benzoheterocycle compound containing a carboxylic acid group as shown in general formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. The compound has excellent pharmacokinetic properties and extremely remarkable liver targeting properties, and a pharmaceutical composition comprising the same may be used as a CCR antagonist, in particular a CCR2 and/or CCR5 antagonist and can be used in mediated disease, including, but not limited to, nonalcoholic fatty liver disease (NAFLD) or the like.

First claim

The invention claimed is:

1. A compound of general formula I or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned:

wherein R 1 is selected from C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with R 2 ; R 2 is selected from C 1-4 alkoxy;
L 1 is selected from C 1-3 alkylene and C 3-5 cycloalkylene;
L 2 is absent or selected from —NH—, —N(CH 3 )—, —C(CH 3 ) 2 —, —CH═CH—, —(C 1-3 alkyleneoxy) y1 -(C 1-3 alkyleneoxy) y2 -, C 3-6 cycloalkylene, C 6-8 arylene, C 5-8 heteroarylene, and 3- to 6-membered heterocyclylene, wherein y 1 and y 2 are each independently selected from 0, 1, or 2;
L 3 absent or selected from C 1-6 alkylene and C 2-6 alkenylene;
A is

wherein R 4 is selected from hydrogen, deuterium, or C 1-6 alkyl and C 3-6 cycloalkyl that are optionally substituted with R 6 , R 6 is selected from deuterium, hydroxyl, —CN, C 1-4 alkoxy and C 3-6 cycloalkoxy;
each R 5 is selected from hydrogen, deuterium, halogen, —CN, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylene-CN, C 1-6 alkylene-OH, C 1-6 alkylene-C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl and C 5-12 heteroaryl;
X is selected from N and C—R 5 , each R 5 is identical or different;

n is selected from 0, 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein, R 1 is

3. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein, L 1 is selected from —CH 2 — or —CH 2 —CH 2 —.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned,
wherein, L 2 is absent or selected from —NH—, —N(CH 3 )— and —C(CH 3 ) 2 —.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein,
L 3 is absent or selected from —C(CH 3 ) 2 —, —CH 2 —, and —CH═CH—.

6. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned,
R 4 is C 1-6 alkyl optionally substituted with R 6 ,
R 5 is independently selected from hydrogen, methyl, trifluoromethyl and cyclopropyl;
R 6 is selected from deuterium, hydroxyl, —CN, and C 1-4 alkoxy.

7. The compound according to claim 6 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein
X is selected from N and C—R 5 , R 5 is selected from hydrogen, methyl, trifluoromethyl, and cyclopropyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein A is selected from

9. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein L 1 is selected from methylene and ethylene;
L 2 is absent or selected from —NH—, —N(CH 3 )— and —C(CH 3 ) 2 —;
L 3 is absent or —CH 2 .

10. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein the compound has a structure shown by formula II a or formula II a′ :

wherein R 1 , R 4 , R 5 , X, L 1 , L 2 , L 3 and n are as defined in claim 1 .

11. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein the compound has a structure as shown by formula II b or formula II b′ :

wherein R 1 , R 4 , R 5 , X, L 1 , L 2 , L 3 or n are as defined in claim 1 .

12. The compound according to claim 10 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein n is selected from 1 or 2.

13. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or crystalline form, or a mixture of the aforementioned, wherein the compound is selected from:

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Song Shuai
• Tian Qiang
• Wu Yongyong
• Zhao Mingliang
• Wang Chaolei
• Cai Jiaqiang
• Wang Lichun
• Wang Jingyi

Classifications

• A61P1/16 Primary

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title