Inhibitors of bruton's tyrosine kinase

• US 9,139,591 B2
• Filed: 07/06/2012
• Issued: 09/22/2015
• Est. Priority Date: 03/28/2007
• Status: Active Grant

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Inventors: Honigberg, Lee, Verner, Erik J., Buggy, Joseph J., Loury, David J., Chen, Wei
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US13/543,394
• Publication Number:
  US 20120277255A1
• Time in Patent Office: 1,173 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• 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: C07D 487/04 Ortho-condensed systems

Abstract

Described herein are irreversible kinase inhibitor compounds exemplified by the following structure Formula (A2):

methods for synthesizing such irreversible inhibitors, and methods for using such irreversible inhibitors in the treatment of a B cell proliferative disorder or a mast cell proliferative disorder.

Claims

1. A compound of Formula (A5) having the structure:

2. The compound of claim 1, wherein R₂ and R₃ are H.

3. The compound of claim 2, wherein R₁ is L₂-(substituted or unsubstituted heteroaryl), or L₂-(substituted or unsubstituted aryl).

4. The compound of claim 3 having the structure

5. The compound of claim 4, wherein L₃, X and L₄ taken together form a nitrogen containing heterocyclic ring.

6. The compound of claim 5, wherein G is

7. The compound of claim 6, wherein R₆, R₇, and R₈ are H.

8. The compound of claim 6, wherein

R₇ and R₈ are H;

and

R₆ is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.

9. The compound of claim 8, wherein R₆ is substituted lower alkyl.

10. The compound of claim 9, wherein lower alkyl is substituted with a disubstituted amino group.

11. The compound of claim 6, wherein

R₆ and R₈ are H;

and

R₇ is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.

12. The compound of claim 11, wherein R₇ is substituted lower alkyl.

13. The compound of claim 12, wherein lower alkyl is substituted with a disubstituted amino group.

14. The compound of claim 5, wherein G is

15. The compound of claim 14, wherein R₆ is H.

16. The compound of claim 14, wherein R₆ is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.

17. The compound of claim 16, wherein R₆ is substituted lower alkyl.

18. The compound of claim 17, wherein lower alkyl is substituted with a disubstituted amino group.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 19 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.