Azaindoles useful as inhibitors of rock and other protein kinases

• US 7,514,448 B2
• Filed: 04/04/2005
• Issued: 04/07/2009
• Est. Priority Date: 04/02/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Marhefka, Craig, Jimenez, Juan-Miguel, Court, John, Gao, Huai, Miller, Andrew, Green, Jeremy, Bandarage, Upul, Cao, Jingrong, Nanthakumar, Suganthini
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US11/098,751
• Publication Number:
  US 20060003968A1
• Time in Patent Office: 1,464 Days
• Field of Search: 546/113, 514/300
• US Class Current: 514/300
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• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

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:

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

4. 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;

5. The compound according to claim 4, wherein Q¹ is —

CO—

.

6. The compound according to claim 5, wherein R² is H, —

C_1-4 aliphatic, —

cyclopropyl or

7. The compound according to claim 4, wherein R⁴ is H or —

C_1-4 aliphatic.

8. The compound according to claim 4, wherein x is 1 and said compound has a formula selected from formulae VII-B-i or VII-B-ii:

9. The compound according to claim 8, wherein R¹ is H or F, R² is H and R⁴ is H, and the compound has a structure of formula V-B-iii:

10. The compound according to claim 9, 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)_1-4COR′

, 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.

11. The compound according to claim 9, wherein Ar¹ is

12. The compound according to claim 11, wherein t is 0, 1 or 2, and each TR⁷ is independently selected from halogen, —

CN, —

R′

, —

O(CH₂)_0-5R′

, —

NRR′

, —

OSO₂(CH₂)_0-4R′

, —

NRSO₂(CH₂)_0-5R′

, —

NRSO₂NR(CH₂)_0-5R′

, —

SO₂NR(CH₂)_0-5R′

, —

CONRR′

, —

COR′

, —

COOR′

, —

NRCOR′

or —

SO₂(CH₂)_0-5R′

.

13. The compound according to claim 9, wherein Ar¹ is a C_1-6 optionally substituted aliphatic.

14. The compound according to claim 1, wherein said compound is selected from:

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

16. A method of inhibiting ROCK, kinase activity in vitro in a biological sample selected from cell culture, saliva, urine, feces, semen, tears, or extracts thereof;

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

17. A method of treating or lessening the severity of glaucoma in a patient, said method comprising the step of administering to said patient a compound of claim 1 or a composition comprising said compound.