Inhibitors of b lymphocyte 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 . 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:   
       
         
           
           
               
               
           
         
         
           wherein: 
           L a  is O or S; 
           Ar is an unsubstituted phenyl; 
           Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring, or 
           Y is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl; 
           Z is C(═O), OC(═O), NHC(═O), S(═O) x , or NHS(═O) x , where x is 2; 
           R 7  and R 8  are each H; or 
           R 7  and R 8  taken together form a bond; 
           R 6  is H; and 
              indicates the point of attachment between the inhibitor and the tyrosine kinase. 
         
       
     
     
         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.