Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-10426760-B2
Application number	US-201816109199-A
Country	US
Kind code	B2
Filing date	Aug 22, 2018
Priority date	Jul 17, 2007
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

First claim

What is claimed is:

1. A method for treating a subject with melanoma, thyroid cancer, or colorectal cancer, said method comprising administering to the subject:
an effective amount of a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein:
L 1 is a bond or —N(H)C(O)—;
each R 1 is —N(R 5 )—C(X)—R 7 , lower alkyl, or optionally substituted heteroaryl;
R 2 is hydrogen or halogen;
R 4 is hydrogen;
R 3 is optionally substituted lower alkyl or optionally substituted aryl;
m is 0, 1, 2, or 3;
Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen;
R 5 is hydrogen;
X is O; and
R 7 is lower alkyl.

2. The method of claim 1 , wherein R 2 is hydrogen.

3. The method of claim 1 , wherein R 2 is halogen.

4. The method of claim 1 , wherein R 3 is optionally substituted phenyl.

5. The method of claim 1 , wherein R 3 is phenyl substituted with one or more substituents selected from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio.

6. The method of claim 1 , wherein R 3 is phenyl substituted with one or more fluoro.

7. The method of claim 1 , wherein one of the R 1 substituents is lower alkyl containing 1-4 carbon atoms.

8. The method of claim 1 , wherein one of the R 1 substituents is optionally substituted heteroaryl.

9. The method of claim 1 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia).

10. The method of claim 6 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

11. The method of claim 7 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

12. The method of claim 8 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

13. The method of claim 10 , wherein the subject has melanoma.

14. The method of claim 10 , wherein the melanoma is melanoma having a B-Raf V600E mutation.

15. A method for treating a subject with melanoma, thyroid cancer, or colorectal cancer, said method comprising administering to the subject:
an effective amount of a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein:
L 1 is a bond;
each R 1 is —N(R 5 )—C(X)—R 7 , lower alkyl, or optionally substituted heteroaryl;
R 2 is hydrogen or halogen;
R 4 is hydrogen;
R 3 is optionally substituted lower alkyl or optionally substituted aryl;
m is 0, 1, 2, or 3;
Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen;
R 5 is hydrogen;
X is O; and
R 7 is lower alkyl.

16. The method of claim 15 , wherein R 2 is hydrogen.

17. The method of claim 15 , wherein R 2 is halogen.

18. The method of claim 15 , wherein R 3 is optionally substituted phenyl.

19. The method of claim 15 , wherein R 3 is phenyl substituted with one or more substituents selected from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio.

20. The method of claim 15 , wherein R 3 is phenyl substituted with one or more fluoro.

21. The method of claim 15 , wherein one of the R 1 substituents is lower alkyl containing 1-4 carbon atoms.

22. The method of claim 15 , wherein one of the R 1 substituents is optionally substituted heteroaryl.

23. The method of claim 15 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia).

24. The method of claim 20 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

25. The method of claim 21 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

26. The method of claim 22 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

27. The method of claim 24 , wherein the subject has melanoma.

28. The method of claim 24 , wherein the melanoma is melanoma having a B-Raf V600E mutation.

29. A method for treating a subject with non-small cell lung cancer, said method comprising administering to the subject:
an effective amount of a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein:
L 1 is a bond or —N(H)C(O)—;
each R 1 is —N(R 5 )—C(X)—R 7 , lower alkyl, or optionally substituted heteroaryl;
R 2 is hydrogen or halogen;
R 4 is hydrogen;
R 3 is optionally substituted lower alkyl or optionally substituted aryl;
m is 0, 1, 2, or 3;
Ar is a monocyclic heteroaryl containing 5 to 6 atoms wherein at least one atom is nitrogen;
R 5 is hydrogen;
X is O; and
R 7 is lower alkyl.

30. The method of claim 29 , wherein R 2 is hydrogen.

31. The method of claim 29 , wherein R 2 is halogen.

32. The method of claim 29 , wherein R 3 is optionally substituted phenyl.

33. The method of claim 29 , wherein R 3 is phenyl substituted with one or more substituents selected from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio.

34. The method of claim 29 , wherein R 3 is phenyl substituted with one or more fluoro.

35. The method of claim 29 , wherein one of the R 1 substituents is lower alkyl containing 1-4 carbon atoms.

36. The method of claim 29 , wherein one of the R 1 substituents is optionally substituted heteroaryl.

37. The method of claim 29 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia).

38. The method of claim 34 , further comprising administering a chemotherapeutic agent in combination with the compound of formula (Ia), and wherein the chemotherapeutic agent is a kinase inhibitor.

39. The method of

Assignees

• Plexxikon Inc

Inventors

• Wu Guoxian
• Zhang Jiazhong
• Zhu Yong-Liang
• Zhang Chao
• Ibrahim Prabha N
• Shi Songyuan
• Spevak Wayne
• Artis Dean R
• Tsai James

Classifications

• A61P43/00

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

• A61P37/08

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

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title