Pyrimidinyl tyrosine kinase inhibitors
View Patent ↗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.
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.