Pyrazolopyridines

• US 8,541,445 B2
• Filed: 11/04/2011
• Issued: 09/24/2013
• Est. Priority Date: 05/06/2009
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Collier, Philip
• Primary Examiner(s): Zarek, Paul
• Assistant Examiner(s): Kosturko, George W
• Application Number:
  US13/289,320
• Publication Number:
  US 20120178778A1
• Time in Patent Office: 690 Days
• Field of Search: 514/303, 548/360.1, 548/360.5
• US Class Current: 514/303
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of 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 represented by structural formula I or IA:

2. The compound of claim 1 wherein the structural formula is represented by Formula I.

3. The compounds of claim 1 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nC(O)N(R*)₂, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen.

4. The compound of claim 3 wherein:

each R₃ and R₄ independently is —

H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —

CN, —

NO₂, —

N(R*)₂, and —

OR*;

or

R₃ and R₄ taken together with the carbon to which they are attached form C═

O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

5. The compound of claim 4 wherein:

each R₃ and R₄ independently is —

H, C1-10 aliphatic, cycloalkylalkyl, wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —

CN, —

NO₂, —

N(R*)₂, and —

OR*;

or

R₃ and R₄ taken together with the carbon to which they are attached form C═

O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

6. The compounds of claim 2 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen.

7. The compound of claim 6 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a 3-8 membered saturated, or partially saturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

8. The compound of claim 7 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

9. The compound of claim 8 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

10. The compound of claim 8 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

11. The compounds of claim 8 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

each R₃ and R₄ independently is —

H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —

CN, —

NO₂, —

N(R*)₂, and —

OR*.

12. The compounds of claim 1 wherein

R₅ is —

H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and

R₆ is —

H or C1-4 alkyl.

13. The compounds of claim 12 wherein

R₅ is —

H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and

R₆ is —

H.

14. The compounds of claim 13 wherein

R₅ is trifluoromethyl;

and

R₆ is —

H.

15. The compound of claim 14 wherein:

each R₇ is independently C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R**)₂, or —

OR**;

or two R₇ groups together with the carbon to which they are attached form C═

O.

17. A composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

16. A compound represented by a structural formula selected from the group consisting of: