Use of bi-aryl meta-pyrimidine inhibitors of kinases

• US 8,133,900 B2
• Filed: 10/14/2008
• Issued: 03/13/2012
• Est. Priority Date: 11/01/2005
• Status: Active Grant

• Current Assignee: Impact Biomedicines, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: TargeGen, Inc. (Sanofi )
• Inventors: Hood, John D., Noronha, Glenn
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Murray, Jeffrey
• Application Number:
  US12/251,061
• Publication Number:
  US 20090286789A1
• Time in Patent Office: 1,246 Days
• Field of Search: None
• US Class Current: 514/275
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention provides methods of treating a disease selected from systemic sclerosis, rheumatoid arthritis, mastocytosis, and chronic eosinophilic leukemia comprising administering biaryl meta-pyrimidine compounds having the general structure (A) to a subject in need thereof. The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the JAK kinase family, and various other specific receptor and non-receptor kinases.

Claims

1. A method for inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of at least one compound represented by structure (A):

2. The method of claim 1, wherein A is NH.

3. The method of claim 2, wherein at least one R⁷ is SO₂NH(t-butyl).

4. The method of claim 2, wherein G₀ is N, and R³ and R⁴ are taken together with G₀ to form a heterocyclic ring.

5. The method of claim 4, wherein R³ and R⁴ are taken together with G₀ to form a non-aromatic heterocyclic ring.

6. The method of claim 4, wherein X and Y taken together is a bond, p, q, and n are each 0, and the heterocyclic ring is a piperazinyl substituted with methyl.

7. The method of claim 5, wherein the compound, or a pharmaceutically acceptable salt thereof, administered is of the structure:

8. The method of claim 4, wherein X is O, Y is a bond, p is 0, q and n are each 1, and the heterocyclic ring is an unsubstituted pyrrolidinyl.

9. The method of claim 8, wherein the compound, or a pharmaceutically acceptable salt thereof, administered is of the structure:

10. The method of claim 1, wherein R⁶, R⁷ and R⁸ are each independently selected from the group consisting of —

CF₃, —

OCF₃, —

S(O₂)—

NH-t-butyl, and —

NH—

C(O)—

CH₃.

12. The method of claim 1, wherein the at least one compound of structure (A), or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition which comprises at least one compound of structure (A) and a pharmaceutically acceptable carrier.

15. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of compounds having the formulae:

16. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

17. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

18. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

19. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

20. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

21. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

22. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

23. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

24. The method of claim 1, wherein the at least one compound of structure (A) is selected from the group consisting of:

26. The method of claim 12, wherein the pharmaceutical composition is administered orally.

11. A method for inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of at least one compound comprising a first moiety chemically connected to a second moiety, or a pharmaceutically acceptable salt thereof, wherein the first moiety is selected from the group consisting of:

13. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis, comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of a compound represented by:

14. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis, comprising administering to the subject with rheumatoid arthritis a therapeutically effective amount of a compound represented by:

25. A method of inhibiting JAK2 kinase activity in a subject wherein the subject has rheumatoid arthritis, comprising administering to the subject with rheumatoid arthritis a compound selected from the group consisting of compounds having the formulae: