Azaindoles useful as inhibitors of rock and other protein kinases

• US 20060003968A1
• Filed: 04/04/2005
• Published: 01/05/2006
• Est. Priority Date: 04/02/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Court, John, Gao, Huai, Miller, Andrew, Green, Jeremy, Bandarage, Upul, Cao, Jingrong, Marhefka, Craig, Nanthakumar, Suganthini
• Granted Patent: US 7,514,448 B2
• Time in Patent Office: Days
• US Class Current: 514/81
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Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. 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.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein:

Q¹ is —

CO—

, —

SO₂—

, —

NR², —

NR²CO—

, CONR²—

, —

SO₂NR²—

; and

Ar¹ and Ar² are each independently a 5-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein Ar¹ and Ar² are each optionally substituted with 0-5 independent occurrences of TR⁷;

wherein T is a bond or is a C₁-C₆ alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —

NR—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR—

, —

NRCO—

, —

NRCO₂—

, —

SO₂NR—

, —

NRSO₂—

, —

CONRNR—

, —

NRCONR—

, —

OCONR—

, —

NRNR—

, —

NRSO₂NR—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR—

; and

each occurrence of R⁷ is independently —

R′

, halogen, —

NO₂ or —

CN.

3. The compound according to claim 2, wherein

7. The compound according to claim 3, wherein X₁ is CR⁴, X₂ is N and G is NR², to provide a compound of formula VII-A:

8. The compound according to claim 7, wherein Q¹ is —

CO—

.

9. The compound according to claim 8, wherein R² is H, —

C_1-4 aliphatic, -cyclopropyl or

11. The compound according to claim 7, wherein R⁴ is H or —

C_1-4 aliphatic.

13. The compound according to claim 7, wherein x is 1 and said compound has a formula selected from formulae VII-B-i or VII-B-ii:

18. The compound according to claim 13, wherein R¹ is H or F, R² is H and R⁴ is H, Q¹ is C═

O and the compound has a structure of formula V-B-iii;

19. The compound according to claim 18, wherein Q² is —

(CHR⁶)_q—

, —

(CHR⁶)_qO—

, —

(CHR⁶)_qS—

, —

(CHR⁶)_qS(O)₂—

, —

(CHR⁶)_qS(O)—

, —

(CHR⁶)_qNR—

, or —

(CHR⁶)_qC(O)—

, wherein q is 0, 1, 2, or 3, and each R⁶ is R′

, —

N(R)(R′

), —

(CH₂)₁ 4N(R)(R′

), —

(CH₂)_1-4C(CH₃)₂N(R)(R′

), —

(CH₂)_1-4CH(CH₃)N(R)(R′

), —

OR′

, —

(CH₂)_1-4OR′

, —

NR(CH₂)_1-4N(R)(R′

), —

NR(CH₂)_1-4SO₂R′

, —

NR(CH₂)_1-4COOR′

, or —

NR(CH₂)_1-4COR′

, or two occurrences of R⁶, taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or fully unsaturated ring.

23. The compound according to claim 18, wherein Ar¹ is

25. The compound according to claim 23, wherein t is 0, 1 or 2, and each TR⁷ is independently selected from halogen, —

CN, —

R′

, —

O(CH₂)_0-5R′

, —

NRR′

, —

OSO₂(CH₂)₀—

OR′

, —

NRSO₂(CH₂)_0-5R′

, —

NRSO₂NR(CH₂)_0-5R′

, —

SO₂NR(CH₂)_0-5R′

, —

CONRR′

, —

COR′

, —

COOR′

, —

NRCOR′

or —

SO₂(CH₂)_0-5R′

.

31. The compound according to claim 18, wherein Ar¹ is a C_1-6 optionally substituted aliphatic.

40. The compound according to claim 1, wherein said compound has a structure depicted in Table 1 or Table 2.

41. A composition comprising an effective amount of compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

42. The composition of claim 41, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

43. A method of inhibiting ROCK, ERK, GSK, AGC or Itk kinase activity in a biological sample;

which method contacting said biological sample with a compound of claim 1 or a composition comprising said compound.

45. A method of treating or lessening the severity of a disease condition or disorder selected from a proliferative disorder, a hyperproliferative disease, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient a compound of claim 1 or a composition comprising said compound.

46. The method of claim 45, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an anti-psychotic agent, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

4-6. -6. (canceled)

10. (canceled)

12. (canceled)

14-17. -17. (canceled)

20-22. -22. (canceled)

24. (canceled)

26-30. -30. (canceled)

32-39. -39. (canceled)

44. (canceled)

47-52. -52. (canceled)