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 kinase inhibitor having the structure of Formula (VII): 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
          is a moiety that binds to the active site of a kinase, including a tyrosine kinase;
 Z is C(═O), OC(═O), NHC(═O), NCH 3 C(═O), C(═S), S(═O) x , OS(═O) x , NHS(═O) x , where x is 1 or 2; 
 R 7  and R 8  are independently selected from among H, unsubstituted C 1 -C 4  alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 heterocycloalkyl; or 
 R 7  and R 8  taken together form a bond; 
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); and
 pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof. 
 
 
       
     
     
         102 . The kinase inhibitor of  claim 101 , wherein 
       
         
           
           
               
               
           
         
         is a substituted fused biaryl moiety selected from 
       
       
         
           
           
               
               
           
         
       
     
     
         103 . The kinase inhibitor of  claim 101 , wherein:
 Z is C(═O), NHC(═O), NCH 3 C(═O), or S(═O) 2 .   
     
     
         104 . The kinase inhibitor of  claim 101 , wherein:
 each of R 7  and R 8  is H; or   R 7  and R 8  taken together form a bond.   
     
     
         105 . The kinase inhibitor of  claim 101 , wherein:
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         106 . The kinase inhibitor of  claim 101 , wherein at least one of R 6 , R 7 , and R 8  is not H. 
     
     
         107 . The kinase inhibitor of  claim 101 , wherein R 6  is H, R 7  is H, and R 8  is H. 
     
     
         108 . A kinase inhibitor having the structure of Formula (VII): 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
          is a moiety that binds to the active site of a kinase, including a tyrosine kinase;
 R 7  and R 8  are independently selected from among H, unsubstituted C 1 -C 4  alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 heterocycloalkyl; or 
 R 7  and R 8  taken together form a bond; 
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); and
 pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof. 
 
 
       
     
     
         109 . The kinase inhibitor of  claim 108 , wherein at least one of R 6 , R 7 , and R 8  is not H. 
     
     
         110 . The kinase inhibitor of  claim 108 , wherein R 6  is H, R 7  is H, and R 8  is H. 
     
     
         111 . The kinase inhibitor of  claim 101  or  claim 108  that selectively and irreversibly binds to Btk. 
     
     
         112 . The kinase inhibitor of  claim 101 , in which the plasma half life of the kinase inhibitor is less than about 4 hours. 
     
     
         113 . The kinase inhibitor of  claim 101 , in which the plasma half life of the kinase inhibitor is less than about 3 hours. 
     
     
         114 . A pharmaceutical formulation comprising the kinase inhibitor of  claim 101  and a pharmaceutically acceptable excipient. 
     
     
         115 . The pharmaceutical formulation of  claim 114  formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. 
     
     
         116 . The pharmaceutical formulation of  claim 115  formulated for oral administration.