Pyrazolopyridine kinase inhibitors

• US 9,067,932 B2
• Filed: 01/26/2011
• Issued: 06/30/2015
• Est. Priority Date: 01/27/2010
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Boyall, Dean, Brenchley, Guy, Davis, Chris, Fraysse, Damien, Golec, Julian, Jimenez, Juan-Miguel, Miller, Andrew, Settimo, Luca, Twin, Heather, Young, Stephen
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US13/014,505
• Publication Number:
  US 20120071494A1
• Time in Patent Office: 1,616 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• 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 17/06 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 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 of pyrazolopyridine derivatives useful as inhibitors of protein kinase. In one embodiment the compounds of the present invention are represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

Claims

1. A compound represented by the following structural formula:

2. The compound of claim 1, wherein U₁ is Z and U₃ is J_b.

3. The compound of claim 2, wherein U₁ and U₂ are Z and U₃ is J_b.

4. The compound of claim 1, wherein

Y2 is C1-C3 alkyl optionally and independently substituted with one or more J_d;

Q2 is absent or C3-C6 alkyl optionally and independently substituted with one or more J_e; and

each J_d is independently —

OR, or F.

5. The compound of claim 4, wherein J_b is —

OH or —

NH₂.

6. The compound of claim 5, wherein J_b is —

OH.

7. The compound of claim 1, wherein each J_c1 and J_c2 is independently —

CF₃, —

CN, —

F, or —

Cl.

8. The compound of claim 7, wherein each J_c1 and J_c2 is independently —

F, or —

Cl.

9. The compound of claim 8, wherein each J_c1 and J_c2 is —

F.

10. The compound of claim 8, wherein J_c1 is F and J_c2 is Cl;

or J_c1 is Cl and J_c2 is F.

29. A composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claim 1, 11, or 28, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

11. A compound represented by the following structural formula:

12. A process for making a compound represented by structural formula I:

13. The process of claim 12, wherein step a) is conducted in the presence of lithium diisopropylamide (LDA).

14. The process of claim 12, wherein the amine in step c) is protected.

15. The process of claim 12, wherein step c) is conducted in the presence of suitable base, selected from the group comprising potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, selected from the group comprising dimethylformamide, dimethylsulfoxide (DMSO), or n-butanol (n-Bu-OH).

16. The process of claim 12, wherein step c) is conducted between 70°

C. and 110°

C.

17. The process of claim 12, wherein step c) is conducted using Pd as a catalyst.

18. A process for making a compound represented by structural formula I:

19. The process of claim 18, wherein L is combined with M in the presence of Pd catalyst.

20. The process of claim 18, wherein in step b) the amine is protected.

21. The process of claim 18, wherein step b) is conducted in the presence of suitable base, selected from the group comprising potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, selected from the group comprising dimethylformamide, dimethylsulfoxide (DMSO), n-butanol (n-Bu-OH), or N-methylpyrrolidinone (NMP).

22. The process of claim 18, wherein step b) is conducted between 70°

C. and 110°

C.

23. The process of claim 18, wherein step b) is conducted using Pd as a catalyst.

24. A process for making a compound represented by structural formula I:

25. The process of claim 24, wherein step a) is conducted in the presence of a suitable base selected from the group comprising potassium carbonate, diisopropylethylamine (DIPEA), triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, selected from the group comprising dimethylformamide, dimethylsulfoxide (DMSO), n-butanol (n-Bu-OH), or N-methylpyrrolidinone (NMP).

26. The process of claim 24, wherein step a) is conducted between 100°

C. and 130°

C.

27. The process of claim 24, wherein step b) is conducted in the presence of Pd as a catalyst.

28. A compound selected from the following: