Inhibitors of bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9802920-B2
Application number	US-201415102043-A
Country	US
Kind code	B2
Filing date	Dec 10, 2014
Priority date	Dec 13, 2013
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

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 caused by aberrant B-cell activation. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

First claim

The invention claimed is:

1. A compound of Formula I,

wherein:
R 1 is lower alkyl, phenyl, cycloalkyl, or pyridyl, optionally substituted with one or more R 1′ ;
each R 1′ is independently lower alkyl, halo, —C(═O)NH 2 , or cyano;

R 2 is hydrogen, halo, lower alkoxy, hydroxy, or lower alkyl;
R 3 is hydrogen, halo, lower alkoxy, hydroxy, or lower alkyl;
R 4 is hydrogen or heterocycloalkyl lower alkylenyl;
X is CH or N; and
Y is CH or N;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Y is CH.

3. The compound of claim 1 , wherein X is N.

4. The compound of claim 1 , wherein X is CH.

5. The compound of claim 1 , wherein R 4 morpholinyl methylene.

6. The compound of claim 1 , wherein R 4 is hydrogen.

7. The compound of claim 1 , wherein R 2 is hydrogen.

8. The compound of claim 1 , wherein R 2 is halo.

9. The compound of claim 1 , wherein R 2 is lower alkyl.

10. The compound of claim 1 , wherein R 2 is lower alkoxy.

11. The compound of claim 1 , wherein R 2 is hydroxy.

12. The compound of claim 1 , wherein R 3 is halo, lower alkoxy, or hydroxy.

13. The compound of claim 1 , wherein R 1 is phenyl, optionally substituted with one or more R 1′ .

14. The compound of claim 1 , wherein R 1 is lower alkyl, cycloalkyl, or heteroaryl, optionally substituted with one or more R 1′ .

15. A compound, selected from the group consisting of:
[5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
[5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
[5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
[5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
[5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
[5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
[5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
[5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
2-{(4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile;
3-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile;
3-{4-[5-Amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide;
{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone;
[5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone; and
3-{4-[5-Amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile,
or a pharmaceutically acceptable salt thereof.

16. A method for treating an inflammatory condition mediated by Bruton's tyrosine kinase, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

17. A method for treating rheumatoid arthritis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

18. A method for treating asthma, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

19. A pharmaceutical composition, comprising the compound of claim 1 , admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

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

21. A method for treating an inflammatory condition mediated by Bruton's tyrosine kinase, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 15 .

22. A method for treating rheumatoid arthritis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 15 .

23. A method for treating asthma, comprising the step of administering to a patient in need thereof a therapeutically effective amount of the compound of claim 15 .

Assignees

• Hoffmann La Roche
• Chugai Pharmaceutical Co Ltd
• Hoffman-La Roche Inc
• Chugai Pharamceutical Co

Inventors

• Dominique Romyr
• Kong Norman
• Lou Yan
• Lopez-Tapia Francisco Javier
• So Sung-Sau

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · 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