Inhibitors of bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-2020207741-A1
Application number	US-202016815443-A
Country	US
Kind code	A1
Filing date	Mar 11, 2020
Priority date	Dec 13, 2013
Publication date	Jul 2, 2020
Grant date	—

Abstract

This application discloses compounds according to generic Formula (I): wherein all variables are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are useful for the treatment of oncological, auto-immune, and inflammatory diseases onused by aberrant B-cell activation. Also disclosed are compositions containing compounds of Formula (I) and at least one carrier, diluent or excipient.

First claim

1 . A compound of Formula I,

wherein:
R 1 is H or halo;
R 2 is H, halo, or cyano;
R 3 is R 4 or R 5 ;
R 4 is halo or cyano;
R 5 is phenyl, heteroaryl, —C(═O)R 5′ , lower alkyl, or benzyl, optionally substituted with one or more R 5′ ;
R 5′ is lower alkyl, cyano, hydroxyl, heterocycloalkyl, phenyl, amino, alkyl amino, dialkyl amino, or lower alkoxy; and

X is lower alkyl or halo;
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein X is methyl and R 5 is heteroaryl, optionally substituted with one or more R 5′ .

3 . The compound of claim 1 or 2 , where in R 5 is thiophenyl, optionally substituted with one or more R 5′ .

4 . The compound of claim 1 or 2 , wherein R 5 is pyridyl, optionally substituted with one or more R 5′ .

5 . The compound of any one of claims 1 - 4 , wherein R 1 is F and R 2 is F.

6 . The compound of any one of claims 1 - 4 , wherein R 1 is H and R 2 is cyano.

7 . The compound of claim 1 , wherein R 5 is —C(═O)R 5′ .

8 . The compound of claim 7 , wherein R 5′ is morpholinyl, piperidinyl, loweralyl piperidinyl, or lower alkoxy.

9 . The compound of claim 8 , wherein R 1 is F and R 2 is F.

10 . The compound of claim 8 , wherein R 1 is H and R 2 is cyano.

11 . The compound of claim 1 or 2 , wherein R 5 is phenyl or benzyl, optionally substituted with one or more R 5′ .

12 . The compound of claim 1 or 2 , wherein R 5 is lower alkylene, optionally substituted with one or more R 5′ .

13 . The compound of either one of claims 11 or 12 , wherein R 1 is F and R 2 is F.

14 . The compound of either one of claims 11 or 12 , wherein R 1 is H and R 2 is cyano.

15 . The compound of any one of claims 1 - 14 selected from the group consisting of.
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-bromo-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-phenyl-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-thiophen-3-yl-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-pyrazol-1-yl-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-thiophen-2-yl-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(morpholine-4-carbonyl)-1H-indol-2-yl]-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl]-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-pyridin-2-yl-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-benzyl-1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(1H-indol-2-yl]-methanone;
3-(2-{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H-indol-4-yl)-benzonitrile;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[4-(3-chloro-phenyl)-1H-indol-2-yl]-methanone;
3-(2-{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H-indol-4-ylmethyl)-benzonitrile;
3-(4-{5-Amino-4-[4-(1H-pyrazol-4-yl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile;
3-(4-{5-Amino-4-[4-(morpholine-4-carbonyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile;
3-(4-{5-Amino-4-[4-(4-methyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile;
3-(4-{5-Amino-4-[4-(3-methoxy-benzyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile;
2-{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H-indole-4-carboxylic acid methyl ester;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(4-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone;
3-{4-[5-Amino-4-(4-cyanomethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile; and
2-{5-Amino-1-[4-(3-cyano-phenoxy)-2-methyl-phenyl]-1H-pyrazole-4-carbonyl}-1H-indole-4-carboxylic acid methylamide.

16 . A method for treating an inflammatory and/or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1 - 15 .

17 . A method for treating an inflammatory condition comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1 - 15 .

18 . A method for treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1 - 15 .

19 . A method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1 - 15 .

20 . A pharmaceutical composition comprising the compound of any one of claims 1 - 15 , admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

21 . The use of the compound of any one of claims 1 - 15 as therapeutically active substance.

22 . The use of the compound of any one of claims 1 - 15 for the treatment of an inflammatory and/or autoimmune condition.

23 . The compound of any one of claims 1 - 15 for use in the treatment of an inflammatory and/or autoimmune condition.

24 . The use of a compound of any one of claims 1 - 15 in the manufacture of a medicament for the treatment of an inflammatory and/or autoimmune condition.

25 . The invention as hereinbefore described.

Assignees

• Hoffmann La Roche
• Chugai Pharmaceutical Inc

Inventors

• Lopez-Tapia Francisco Javier
• So Sung-Sau
• Qiao Qi
• Dominique Romyr

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title