Protein Kinase Inhibitors

• US 20090099165A1
• Filed: 04/13/2007
• Published: 04/16/2009
• 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: Montigen Pharmaceuticals, Inc. (Otsuka Holdings Company Limited), Arizona Board of Regents (University of Arizona)
• Inventors: Mahadevan, Daruka, Von Hoff, Daniel D., Della Croce, Kimiko, Hurley, Laurence H., Grand, Cory L., Warner, Steven L., Bearss, David J., Bashyam, Sridevi, Welsh, James, Vankayalapati, Hariprasad, Han, Haiyong, Munoz, Ruben M.
• Application Number:
  US11/735,344
• Publication Number:
  US 20090099165A1
• Time in Patent Office: Days
• US Class Current: 514/232.8
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/00 Radiation therapy ultrasound therapy A61N7/00; devices or apparatus applicable to both therapy and diagnosis A61B6/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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.