Pyrimidinyl tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9394277-B2
Application number	US-201314406315-A
Country	US
Kind code	B2
Filing date	Jun 7, 2013
Priority date	Jun 8, 2012
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
each R 1 is independently hydrogen, an optionally substituted C 1-6 aliphatic group, an optionally substituted 3-7 membered monocyclic heterocyclic group, or an optionally substituted heterocyclylalkyl group having 3-7 carbon atoms and 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two R 1 groups are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein optionally substituted groups may be substituted with halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —N(R)C(O)OR, —C(O)N(R) 2 , —OC(O)R, —N(R)C(O)R, —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
each R is independently hydrogen or C 1-6 aliphatic;
or two R groups attached to the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms, in which any second heteroatom is independently selected from nitrogen, oxygen, or sulfur;

Ring A is

R 2 is —Cl or —F; and
R 3 is —CF 3 , —OCF 3 , or —F.

2. The compound of claim 1 , wherein the compound is of formula II-a:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of formula II-b:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of formula III:

5. The compound of claim 1 , wherein the compound is formula IV:

6. The compound of claim 5 , wherein R 3 is —CF 3 .

7. The compound of claim 5 , wherein R 3 is —F.

8. The compound of claim 5 , wherein both R 1 are hydrogen.

9. The compound of claim 5 , wherein one R 1 is hydrogen and the other R 1 is an optionally substituted C 1-6 aliphatic.

10. The compound of claim 9 , wherein one R 1 is hydrogen and the other R 1 is methyl.

11. The compound of claim 5 , wherein both R 1 are optionally substituted C 1-6 aliphatic groups.

12. The compound of claim 1 , wherein one R 1 is hydrogen and the other R 1 is an optionally substituted C 1-6 aliphatic.

13. The compound of claim 1 , wherein both R 1 are optionally substituted C 1-6 aliphatic groups.

14. The compound of claim 1 , wherein both R 1 are hydrogen.

15. The compound of claim 1 , wherein R 2 is —Cl.

16. The compound of claim 1 , wherein R 2 is —F.

17. The compound of claim 1 , wherein R 3 is —CF 3 .

18. The compound of claim 1 , wherein R 3 is —OCF 3 .

19. The compound of claim 1 , wherein R 3 is —F.

20. A compound selected from the group consisting of:

21. A method of decreasing the enzymatic activity of Bruton's tyrosine kinase comprising contacting Bruton's tyrosine kinase with an effective amount of a compound of claim 1 or a composition thereof.

22. A method of treating a disorder selected from the group consisting of rheumatoid arthritis, lupus, atopic dermatitis, leukemia, or lymphoma, comprising administering to a human subject an effective amount of a compound of claim 1 or a composition thereof.

23. The method of claim 22 , wherein the disorder is rheumatoid arthritis.

24. The method of claim 22 , wherein the disorder is systemic lupus erythematosus.

25. The method of claim 22 , wherein the disorder is atopic dermatitis.

26. The method of claim 22 , wherein the disorder is leukemia or lymphoma.

Assignees

• Biogen Idec Inc
• Sunesis Pharmaceuticals Inc
• Biogen Ma Inc

Inventors

• Hopkins Brian T
• Conlon Patrick
• Chan Timothy R
• Jenkins Tracy J
• Cai Xiongwei
• Humora Michael
• Shi Xianglin
• Miller Ross A
• Thompson Andrew

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title