Pyrimidinyl tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2016304494-A1
Application number	US-201615196389-A
Country	US
Kind code	A1
Filing date	Jun 29, 2016
Priority date	Jun 8, 2012
Publication date	Oct 20, 2016
Grant date	—

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 an is 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 any one of claims 1 - 20 or a composition thereof.

22 . A method of treating a disorder responsive to inhibition of Bruton's tyrosine kinase comprising administering to a subject an effective amount of a compound of any one of claims 1 - 20 or a composition thereof.

23 . A method of treating a disorder selected from the group consisting of autoimmune disorders, inflammatory disorders, and cancers comprising administering to a subject an effective amount of a compound of any one of claims 1 - 20 of a composition thereof.

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

25 . The method of claim 23 , wherein the disorder is systemic lupus erythematosus.

26 . The method of claim 23 , wherein the disorder is atopic dermatitis.

27 . The method of claim 23 , wherein the disorder is leukemia or lymphoma.

Assignees

• Biogen Ma Inc
• Sunesis Pharmaceuticals Inc

Inventors

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

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P37/06

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

• A61P9/06

  Antiarrhythmics · CPC title