Inhibitors of bruton's tyrosine kinase

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.

1 .- 100 . (canceled) 
     
     
         101 . A compound of Formula (A5) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is -L 2 -(substituted or unsubstituted aryl), wherein L 2  is a bond; 
 R 2  and R 3  are H; 
 R 4  is L 3 -X-L 4 -G, wherein, 
 L 3  is substituted or unsubstituted alkyl; 
 X is a bond; 
 L 4  is substituted or unsubstituted heterocycle; 
 G is 
 
       
         
           
           
               
               
           
         
         and 
         R 6 , R 7  and R 8  are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         102 . The compound of  claim 101 , wherein G is 
       
         
           
           
               
               
           
         
       
     
     
         103 . The compound of  claim 102 , wherein R 6 , R 7 , and R 8  are H. 
     
     
         104 . The compound of  claim 102 , wherein
 R 7  and R 8  are H; and   R 6  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.   
     
     
         105 . The compound of  claim 104 , wherein R 6  is substituted lower alkyl. 
     
     
         106 . The compound of  claim 105 , wherein lower alkyl is substituted with a disubstituted amino group. 
     
     
         107 . The compound of  claim 102 , wherein
 R 6  and R 8  are H; and   R 7  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.   
     
     
         108 . The compound of  claim 107 , wherein R 7  is substituted lower alkyl. 
     
     
         109 . The compound of  claim 108 , wherein lower alkyl is substituted with a disubstituted amino group. 
     
     
         110 . The compound of  claim 101 , wherein G is 
       
         
           
           
               
               
           
         
       
     
     
         111 . The compound of  claim 110 , wherein R 6  is H. 
     
     
         112 . The compound of  claim 110 , wherein R 6  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. 
     
     
         113 . The compound of  claim 112 , wherein R 6  is substituted lower alkyl. 
     
     
         114 . The compound of  claim 113 , wherein lower alkyl is substituted with a disubstituted amino group. 
     
     
         115 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 101 , and a pharmaceutically acceptable excipient. 
     
     
         116 . The pharmaceutical composition of  claim 115  that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. 
     
     
         117 . The pharmaceutical composition of  claim 115 , further comprising an anticancer agent. 
     
     
         118 . The pharmaceutical composition of  claim 117 , wherein the anticancer agent is an alkylating agent, vinca alkaloid, epipodophyllotoxin, angiogenesis inhibitor, adrenocorticosteroid, progestin, estrogen, antiestrogen, androgen, antiandrogen, or gonadotropin releasing hormone analog, or a combination thereof. 
     
     
         119 . The pharmaceutical composition of  claim 117 , wherein the anticancer agent is bortezomib, carmustine, carboplatin, cisplatin, cyclophosphamide, chlorambucil, ifosfamide, doxorubicin, vincristine, etoposide, gemcitabine, fludarabine phosphate, fluorouracil, imatinib, geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, bortezomib, trastuzumab, bortezomib, trastuzumab, methotrexate, melphalan, prednisone, rituxan, dexamethasone, cytarabine, paclitaxel, amrubicin, or azacitidine, or a combination thereof. 
     
     
         120 . A method for treating a blood cell cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (A5) of  claim 101 . 
     
     
         121 . The method of  claim 120 , wherein the blood cell cancer is a mast cell malignancy. 
     
     
         122 . The method of  claim 120 , wherein the blood cell cancer is a lymphoma. 
     
     
         123 . The method of  claim 120 , wherein the blood cell cancer is a leukemia. 
     
     
         124 . The method of  claim 120 , wherein the blood cell cancer is diffuse large B-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, chronic lymphocytic lymphoma, primary effusion lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, plasma cell myeloma, plasmacytoma, Burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis. 
     
     
         125 . The method of  claim 120 , further comprising administering to the subject a therapeutically effective amount of an anticancer agent. 
     
     
         126 . The method of  claim 125 , wherein the compound of Formula (A5) and the anticancer agent are administered simultaneously or sequentially. 
     
     
         127 . The method of  claim 125 , wherein the anticancer agent is an alkylating agent, vinca alkaloid, epipodophyllotoxin, angiogenesis inhibitor, adrenocorticosteroid, progestin, estrogen, antiestrogen, androgen, antiandrogen, or gonadotropin releasing hormone analog, or a combination thereof. 
     
     
         128 . The method of  claim 125 , wherein the anticancer agent is bortezomib, carmustine, carboplatin, cisplatin, cyclophosphamide, chlorambucil, ifosfamide, doxorubicin, vincristine, etoposide, gemcitabine, fludarabine phosphate, fluorouracil, imatinib, geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, bortezomib, trastuzumab, bortezomib, trastuzumab, methotrexate, melphalan, prednisone, rituxan, dexamethasone, cytarabine, paclitaxel, amrubicin, or azacitidine, or a combination thereof.