Protein Kinase Inhibitors

• US 20090143399A1
• Filed: 08/20/2007
• Published: 06/04/2009
• Est. Priority Date: 10/14/2003
• Status: Abandoned Application

• Current Assignee: Supergen Incorporated (Otsuka Holdings Company Limited), Arizona Board of Regents (University of Arizona)
• Original Assignee: Supergen Incorporated (Otsuka Holdings Company Limited), Arizona Board of Regents (University of Arizona)
• Inventors: Warner, Steven L., Croce, Kimiko Della, Mahadevan, Daruka, Von Hoff, Daniel D., Hurley, Laurence H., Grand, Cory L., Bearss, David J., Bashyam, Sridevi, Welsh, James, Vankayalapati, Hariprasad, Han, Haiyong, Munoz, Ruben M.
• Application Number:
  US11/841,574
• Publication Number:
  US 20090143399A1
• Time in Patent Office: Days
• US Class Current: 514/252.160
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/14 Ortho-condensed systems

Abstract

Protein kinase inhibitors are disclosed having utility in the treatment of protein kinase-mediated diseases and conditions, such as cancer. The compounds of this invention have the following structure:

including steroisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein A is a ring moiety selected from:

and wherein R1, R2, R3, X, Z, L1, Cycl1, L2 and Cycl2 are as defined herein. Also disclosed are compositions containing a compound of this invention, as well as methods relating to the use thereof.

Claims

1. A compound having the following structure (I):

2. The compound of claim 1, wherein ring moiety A is (I-A).

3. The compound of claim 2 wherein L₁ is a direct bond.

4. The compound of claim 3 wherein X is NH and Z is CH.

5. The compound of claim 3 wherein R₁ and R₂ are selected from —

OCH₃, —

OH, —

Cl, —

CF₃ or —

OC(═

O)CH₃, and R₃ is hydrogen or —

NH2.

6. The compound of claim 3 wherein Cycl₁ is selected from:

7. The compound of claim 3 wherein L₂ is selected from —

C(═

S)NH—

, —

C(═

S)NHCH₂—

, —

NHC(═

S)NH—

, —

NHC(═

O)—

, and —

NHC(═

O)NH—

.

8. The compound of claim 3 wherein Cycl₂ is selected from:

9. The compound of claim 2, wherein L₁ is —

NH—

or —

OC(═

S)NH—

.

10. The compound of claim 9, wherein X is NH and Z is CH.

11. The compound of claim 9, wherein R₁ and R₂ are methoxy, and R₃ is hydrogen or —

NH2.

12. The compound of claim 9, wherein Cycl₁ is selected from:

13. The compound of claim 9, wherein L₂ is selected from —

NHCH₂—

, —

NH—

, —

C(═

S)NH—

, —

NHC(═

S)—

, —

C(═

S)NHCH₂—

, —

NHC(═

S)NH—

, —

NHC(═

O)—

, —

NHC(═

O)NH—

;

—

S(═

O)₂—

; and

14. The compound of claim 9, wherein Cycl₂ is selected from:

15. The compound of claim 9 having the following structure (II-2-6):

16. The compound of claim 9 having the following structure (II-2-7):

17. The compound of claim 1, wherein ring moiety A is (I-B).

18. The compound of claim 17 wherein L₁ is a direct bond.

19. The compound of claim 18 wherein R₁, R₂ and R₃ are hydrogen.

20. The compound of claim 18 wherein Cycl₁ is:

21. The compound of claim 18 wherein L₂ is selected from —

C(═

S)NH—

, —

C(═

S)—

, —

C(═

S)NHCH₂—

or —

CH₂—

.

22. The compound of claim 18 wherein Cycl₂ is selected from:

23. The compound of claim 17 wherein L₁ is —

NH—

or —

OC(═

S)NH—

.

24. The compound of claim 23 wherein R₁, R₂ and R₃ are hydrogen.

25. The compound of claim 23 wherein Cycl₁ is selected from:

26. The compound of claim 23 wherein L₂ is selected from —

NHC(═

S)NH—

, —

NHC(═

O)—

, —

NH—

or —

NHCH₂—

.

27. The compound of claim 23 wherein Cycl₂ is selected from:

28. The compound of claim 23 having the following structure (III-1-3):

29. The compound of claim 23 having the following structure (III-1-4):

30. The compound of claim 23 having the following structure (III-1-5):

31. The compound of claim 1, wherein ring moiety A is (I-C).

32. The compound of claim 31 wherein L₁ is a direct bond.

33. The compound of claim 32 wherein R₁ and R₂ are methoxy and R₃ is hydrogen.

34. The compound of claim 32 wherein Cycl₁ is:

35. The compound of claim 32 wherein L₂ is —

C(═

S)NH—

.

36. The compound of claim 32 wherein Cycl₂ is:

37. The compound of claim 31 wherein L₁ is —

NH—

.

38. The compound of claim 37 wherein R₁ and R₂ are methoxy;

and R₃ is hydrogen.

39. The compound of claim 37 wherein Cycl₁ is:

40. The compound of claim 37 wherein L₂ is selected from —

NHC(═

S)NH—

, —

NH—

or —

NHCH₂—

.

41. The compound of claim 37 wherein Cycl₂ is selected from:

42. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

43. A method for treating a protein kinase-mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 42.

44. The method of claim 43, wherein the protein kinase-mediated disease is an aurora-2 kinase-mediated disease, a c-kit-mediated disease, a PDGFR-a-mediated disease, a c-ret-mediated disease or a c-met-mediated disease.

45. The method of claim 44 wherein the protein-kinase mediated disease is cancer.

46. The method of claim 45 wherein the cancer is a cancer of the pancreas, breast, ovary or colon.

47. The method of claim 43, further comprising administering to the patient a DNA-damaging anticancer agent.

48. The method of claim 43, further comprising administering radiation to the patient.