INHIBITORS OF BRUTON'S TYROSINE KINASE

• US 20110086866A1
• Filed: 10/12/2010
• Published: 04/14/2011
• Est. Priority Date: 10/12/2009
• Status: Active Grant

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated)
• Inventors: Smyth, Mark Stephen, Loury, David J., Luo, Wenchen, Mody, Tarak D., Verner, Erik, Chen, Wei
• Granted Patent: US 9,012,463 B2
• Time in Patent Office: Days
• US Class Current: 514/262.1
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.

Claims

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

2. The compound of claim 1 wherein Y and Z together with the carbon atom to which they are attached form a C₃-C₁₀cycloalkyl or C₂-C₁₀heterocycloalkyl.

3. The compound of claim 2 wherein Y and Z together with the carbon atom to which they are attached form a C₂-C₁₀heterocycloalkyl.

4. The compound of claim 1 wherein W is C(═

O)J.

5. The compound of claim 4 wherein J is —

C₁-C₆alkyl or —

C₂-C₆alkene.

6. The compound of claim 5 wherein J is substituted with at least one R₁.

7. The compound of claim 6 wherein R₁ is selected from F, Cl, Br, I, —

CN, —

NO₂, —

SR₂, —

OR₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, —

OC₁-C₆haloalkyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, heteroaryl, or phenyl.

8. The compound of claim 3 wherein C₂-C₁₀heterocycloalkyl is selected from:

9. The compound of claim 8 wherein C₂-C₁₀heterocycloalkyl is

10. The compound of claim 5 wherein C₁-C₆alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

11. The compound of claim 10 wherein C₁-C₆alkyl is substituted with one R₁.

12. The compound of claim 10 wherein C₁-C₆alkyl is substituted with two R₁.

13. The compound of claim 11 wherein R₁ is selected from F, Cl, Br, I, —

CN, NO₂, —

OR₃, and at least one amino acid fragment.

14. The compound of claim 5 wherein J is C₂-C₆alkene.

15. The compound of claim 14 wherein C₂-C₆alkene is C₂H₃.

16. The compound of claim 15 wherein C₂-C₆alkene is substituted with at least one R₁ selected from F, Cl, Br, I, —

CN, NO₂, OH, and —

OSO₃H.

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

18. The compound of claim 1 wherein the compound forms a covalent bond with a Cys 481 residue of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase.

19. A method for treating an autoimmune disease or inflammatory disease or condition comprising administering to a patient in need the compound of claim 1.

20. A method for treating a cancer comprising administering to a patient in need the compound of claim 1.

21. A method for treating an inflammatory disease or condition comprising administering to a patient in need the compound of claim 1.