Inhibitors of bruton's tyrosine kinase

• US 9,012,463 B2
• Filed: 10/12/2010
• Issued: 04/21/2015
• Est. Priority Date: 10/12/2009
• Status: Active Grant

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated)
• Inventors: Chen, Wei, Loury, David J., Mody, Tarak D., Verner, Erik, Smyth, Mark Stephen, Luo, Wenchen
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US12/903,101
• Publication Number:
  US 20110086866A1
• Time in Patent Office: 1,652 Days
• Field of Search: 544/262, 514/262.1
• 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 of Formula IV:

• • wherein R_b, R₆, T, Y, and Z are defined herein. Also described herein are 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):

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

O)J.

3. The compound of claim 2 wherein J is substituted with at least one R₁.

4. The compound of claim 3 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.

5. The compound of claim 2 wherein Y and Z together with the carbon atom to which they are attached form a nitrogen atom-containing C₂-C₁₀heterocycloalkyl selected from:

6. The compound of claim 5 wherein C₂-C₁₀heterocycloalkyl is

7. The compound of claim 1 wherein J is substituted with one R₁.

8. The compound of claim 1 wherein J is substituted with two R₁.

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

CN, and —

OR₃.

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

11. The compound of claim 6 wherein C₂-C₁₀heterocycloalkyl is

12. The compound of claim 11 wherein J is ethyl optionally substituted with at least one R₁;

and R₁ is selected from F, Cl, Br, I, —

CN, —

SR₂, and —

OR₃.

13. The compound of claim 12 wherein J is unsubstituted ethyl.

14. The compound of claim 12 wherein J is —

CH(OH)CH₂(OH).