Furo[3,4-b]pyrrole-containing BTK inhibitor

Patent metadata

Field	Value
Publication number	US-11891405-B2
Application number	US-201917276025-A
Country	US
Kind code	B2
Filing date	Sep 12, 2019
Priority date	Sep 14, 2018
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to a furo[3,4-b]pyrrole-containing BTK inhibitor, and in particular, to a compound of formula (I), a stereisomer or pharmacologically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof in treating BTK-related diseases.

First claim

The invention claimed is:

1. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

wherein,
ring B is selected from the group consisting of 5-10 membered heteroaryl and C 6-10 aryl;
R 1 is independently selected from the group consisting of halogen, —OH, —NH 2 , cyano, C 1-6 alkyl and C 1-6 alkoxy, wherein C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with halogen;
m is 0, 1, 2, 3 or 4;
L is selected from the group consisting of —C(O)NH—, —NHC(O)—, —O—, —NH—, —S—, —C(O)O—, —OC(O)—, —S(O) 2 O— and —OS(O) 2 —;
R 2 is independently selected from the group consisting of halogen, —OH, —NH 2 , cyano, C 1-6 alkyl and C 1-6 alkoxy, wherein C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with halogen;
n is 0, 1, 2, 3 or 4;
R 3 is selected from the group consisting of H, R a C(O)—, R a S(O) 2 — and R a —;
R 5 is independently selected from the group consisting of halogen, —OH, —NH 2 , cyano, C 1-6 alkyl and C 1-6 alkoxy;
p is 0, 1, 2 or 3;
R 4 is selected from the group consisting of hydrogen, R a S(O) 2 —, (R a O) 2 P(O)— and R a C(O)—;
wherein R a is independently selected from the group consisting of C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, C 3-6 cycloalkyl, (C 1-6 alkyl)NH—, (C 1-6 alkyl) 2 N—, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl and C 6-10 aryl, wherein R a is optionally substituted with (C 1-6 alkyl) 2 N—, (C 1-6 alkyl)NH—, hydroxy, amino, halogen or cyano.

2. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is selected from the group consisting of 5- to 6-membered heteroaryl and phenyl.

3. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is independently selected from the group consisting of halogen, C 1-3 alkyl and C 1-3 alkoxy, wherein C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with halogen.

4. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein m is 0, 1 or 2.

5. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein L is selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(O)O— and —OC(O)—.

6. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is independently selected from the group consisting of halogen, —OH, —NH 2 , C 1-3 alkyl and C 1-3 alkoxy.

7. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 0, 1 or 2.

8. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is selected from the group consisting of H, R a C(O)— and R a S(O) 2 —.

9. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according claim 1 , wherein R a is independently selected from the group consisting of C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, C 3-6 cycloalkyl, (C 1-6 alkyl)NH—, (C 1-6 alkyl) 2 N—, 3- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl and C 6-10 aryl, wherein R a is optionally substituted with (C 1-3 alkyl) 2 N—, (C 1-3 alkyl)NH—, hydroxy or amino.

10. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 is independently selected from the group consisting of F, —OH, —NH 2 , methyl and methoxy, and p is 0, 1 or 2.

11. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is selected from the group consisting of hydrogen, C 3-6 cycloalkyl-S(O) 2 — and (C 1-6 alkyl-O) 2 P(O)—.

12. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of a compound of formula (II) and a compound of formula (III),

13. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , selected from the following compounds, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 .

15. A method for treating a BTK-related disease in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 .

16. The method according to claim 15 , wherein the BTK-related disease is selected from the group consisting of autoimmune diseases, inflammatory diseases and cancer; or the BTK-related disease is diffuse large B-cell lymphoma.

17. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 2 , wherein ring B is pyridinyl.

18. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 3 , wherein R 1 is trifluoromethyl.

19. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 9 , wherein R a is independently selected from the group consisting of propynyl, C 2-3 alkenyl, methyl, cyclopropyl, cyclobutyl, CH 3 NH—, (CH 3 ) 2 CHNH— and (CH 3 ) 2 N—, wherein methyl, C 2-3 alkenyl and cyclopropyl are optionally substituted with (CH 3 ) 2 N—, hydroxy or amino.

20. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is selected from the group consisting of hydrogen, cyclopropyl-S(O) 2 — and (CH 3 O) 2 —P(O)—.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Zhang Yinsheng
• Xu Hongjiang
• Ren Jing
• Wang Qinglin
• Wu Zheyang
• Jin Chao
• Shi Wei
• Wang Xiaojin
• He Xiangyi
• Chang Xiayun
• Wang Jie
• Zhao Tianxiao

Classifications

• C07D519/00 Primary

  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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title