PYRROLOPYRAZINES AND PYRAZOLOPYRAZINES USEFUL AS INHIBITORS OF PROTEIN KINASES

• US 20130096302A1
• Filed: 10/12/2012
• Published: 04/18/2013
• Est. Priority Date: 11/22/2005
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Binch, Hayley, Robinson, Daniel, Fraysse, Damien, Miller, Andrew
• Application Number:
  US13/650,586
• Publication Number:
  US 20130096302A1
• Time in Patent Office: Days
• US Class Current: 544/117
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of Aurora protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Claims

1. A compound of formula I:

2. The compound according to claim 1 wherein X is CH.

3. The compound according to claim 1 wherein X is N.

4. The compound according to claim 2 or claim 3, wherein R¹ is a 5-6 membered aryl or heteroaryl.

5. The compound according to claim 4, wherein R¹ is a 5-6 membered heteroaryl.

6. The compound according to claim 4, represented by Formula II:

7. The compound according to claim 6 wherein one, two, or three G groups are N.

8. The compound according to claim 6 wherein at least G² is nitrogen.

9. The compound according any one of claims 6-8 wherein any two G groups selected from G², G³, G⁴, G⁵, and G⁶ are N.

10. The compound according claim 9 wherein only one G group is N.

11. The compound according to claim 4, wherein R¹ is phenyl optionally substituted with up to 5 J.

12. The compound according to any one of claims 1-11, wherein J is —

U—

(R⁶)_n wherein

each R⁶ is independently H or optionally substituted C_1-12 aliphatic, C_3-10 cycloaliphatic, C_7-12 benzofused cycloaliphatic, C_6-10aryl, 5-14 membered heterocyclyl, 5-14 membered heteroaryl, OR⁵, N(R⁴)₂, or SR⁵;

U is a bond or C_1-6 aliphatic wherein up to two methylene units are optionally replaced by Y in a chemically stable arrangement;

Y is a group selected from —

O—

, —

NR⁵—

, —

S—

, —

NR⁵C(O)—

, —

N(SO₂)—

, —

NR⁵C(O)NR⁵—

, —

C(O)NR⁵—

, —

C(O)—

, —

OC(O)NR⁵—

, —

NR⁵C(O)O—

, —

C(O)O—

, or —

OC(O)—

;

n is 1 or 2.

13. The compound according to claim 12, wherein Y is —

O—

, —

NR⁵—

, or —

S—

.

14. The compound according to claim 12, wherein Y—

NR⁵(C═

O)—

or —

(C═

O)NR⁵—

;

15. The compound according to claim 12, wherein Y is —

NR⁵—

.

16. The compound according to any one of claims 12-15, wherein one methylene unit of U is replaced by Y.

17. The compound according to claim 16, wherein U is —

Y—

(C_1-5aliphatic).

18. The compound according to any one of claims 6-17, wherein G³ is C and J is substituted in the 3-position as shown in formula III:

19. The compound according to claim 18, wherein J is —

U—

(R⁶)_n.

20. The compound according to any one of claims 12-19, wherein R⁶ is optionally substituted C_3-10 cycloaliphatic or C_7-12 benzofused cycloaliphatic.

21. The compound according to any one of claim 12-19, wherein R⁶ is an optionally substituted 5-6 membered aryl or heteroaryl.

22. The compound according to any one of claims 12-19, wherein R⁶ is optionally substituted phenyl.

23. The compound according to any one of claims 12-19, wherein R⁶ is an optionally substituted 5-6 membered heterocyclyl.

24. The compound according to any one of claims 1-12, and 18-23, wherein U is a bond.

26. The compound according to any one of claims 1-12, and 18-23, wherein U is —

NRCH(CH₃)—

wherein the methyl group is in the S conformation.

27. The compound according to any one of claim 18-26, wherein R⁶ is substituted with halogen, C_1-6aliphatic, C_1-6alkoxy, —

CN, —

N(R⁵)₂, —

C(O)R⁵, —

NC(O)R⁵, —

C(O)NR⁵, —

C(O)OR⁵, —

SOR⁵, or —

SO₂R⁵.

28. The compound according to any one of claims 1-27, wherein R² and R³ are each independently V—

R.

29. The compound according to any one of claims 1-27, wherein R² and R³ are each independently V—

R^a.

30. The compound according to any one of claims 1-27, wherein R² and R³ are each independently V—

R^b.

31. The compound according to any one of claims 1-27, wherein R² and R³ are each independently hydrogen, halogen, CN, or V—

R wherein V is —

C(O)O—

, —

NH—

, —

N(CH₃)—

, —

N(CH₂CH₃)—

, —

N(CH(CH₃)₂)—

, —

O(CH₂)₂O—

, —

C(O)NH—

, —

C(O)O—

, —

O—

, —

CH₂O—

, —

NHC(O)—

, —

SO₂NH—

, or —

SO₂N(CH₃)—

.

32. The compound according to claim 31, wherein V—

R is —

C(O)OH, —

C(O)OR⁵, —

O(CH₂)₂OCH₃, —

C(O)OCH₃, —

OH, —

CH₂OH, —

NHC(O)CH₃, —

SO₂NH₂, or —

SO₂N(Me)₂.

33. The compound according to any one of claims 1-27, wherein R² and R³ are each independently H, halogen, CN,

V—

R^b wherein V is a bond and R^b is N(R⁴)₂, or

V—

R^a wherein V is a bond and R^a is 5-6 membered aryl or 5-6 membered heteroaryl.

34. The compound according to any one of claims 1-27, wherein R² and R³ are each independently halogen.

35. The compound according to claim 34, wherein R² and R³ are each independently chlorine.

36. The compound according to any one of claims 28-33, wherein R² and R³ are each independently substituted with up to three occurrences of R⁷.

37. The compound according to claim any one of claims 28-36, wherein at least one of R² and R³ is H.

38. The compound according to claim 37, wherein R³ is H.

40. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

41. A method of inhibiting Aurora protein kinase activity in a patient comprising administering to said patient a composition of claim 40 or a compound of any one of claims 1-39.

42. A method of inhibiting Aurora protein kinase activity in a biological sample comprising or contacting said biological sample with a composition of claim 40 or a compound of any one of claims 1-39.

43. A method of treating or lessening the severity of a proliferative disorder in a patient, comprising the step of administering to said patient:

a) a compound of any one of claims 1-39;

or

b) a composition of claim 40.

44. The method according to claim 43, wherein the proliferative disorder is cancer.

45. A method of treating, or lessening the severity of, melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof wherein said method comprises administering to said patient a compound according to any one of claims 1-39 or a composition according to claim 40.

46. A method of treating or lessening the severity of a cancer in a patient in need thereof comprising the step of disrupting mitosis of the cancer cells by inhibiting one or more of Aurora-A, Aurora-B, and Aurora-C with:

a) a compound according to any one of claims 1-39;

or

b) a composition according to claim 40.

25. The compound according to any one 1-12, and 18-23, wherein U is C_1-3 aliphatic wherein zero methylene units are replaced.

39. A compound selected from the following compounds: