INHIBITORS OF B LYMPHOCYTE KINASE

• US 20120165328A1
• Filed: 02/24/2012
• Published: 06/28/2012
• Est. Priority Date: 03/28/2007
• Status: Abandoned Application

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated)
• Inventors: Honigberg, Lee, Verner, Erik J., Buggy, Joseph J., Loury, David J., Chen, Wei
• Application Number:
  US13/404,422
• Publication Number:
  US 20120165328A1
• Time in Patent Office: Days
• US Class Current: 514/234.2
• 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, methods for synthesizing such irreversible inhibitors, and methods for using such irreversible inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate irreversible inhibitor of a protein, including a kinase.

Claims

1-100. -100. (canceled)

101. An inhibited tyrosine kinase comprising an irreversible BLK inhibitor having a covalent bond to a cysteine residue of a B lymphocyte kinase (BLK).

102. The inhibited tyrosine kinase of claim 101, wherein the covalent bond is formed between a portion of a Michael acceptor moiety on the inhibitor and a portion of a cysteine residue of the B lymphocyte kinase (BLK).

103. The inhibited tyrosine kinase of claim 102, wherein the Michael acceptor moiety is an acrylamide, vinyl sulfonamide or propargylamide.

104. The inhibited tyrosine kinase of claim 101, wherein the B lymphocyte kinase is activated.

105. The inhibited tyrosine kinase of claim 101, wherein the inhibited tyrosine kinase has

the structure:

106. The inhibited tyrosine kinase of claim 105, wherein the inhibitor has a covalent bond to a cysteine residue on the tyrosine kinase.

107. The inhibited tyrosine kinase of claim 101, wherein the inhibitor has a plasma half life of less than about 4 hours.

108. An inhibited tyrosine kinase comprising an irreversible BLK inhibitor having a covalent bond to a cysteine residue of a B lymphocyte kinase (BLK) wherein the irreversible BLK inhibitor comprises a Michael acceptor moiety.

109. An inhibited tyrosine kinase comprising an irreversible BLK inhibitor having a covalent bond to a cysteine residue of a B lymphocyte kinase (BLK) wherein the irreversible BLK inhibitor comprises an acrylamide, vinyl sulfonamide or propargylamide moiety.