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 . A compound of Formula (I) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 L a  is CH 2 , O, NH or S; 
 Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; and either
 (i) Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene and alkyleneheterocycloalkylene;
 Z is C(═O), NHC(═O), NR a C(═O), NR a S(═O) x , where x is 1 or 2, and R a  is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and either 
 (a) R 7  and R 8  are H;
  R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 (b) R 6  and R 8  are H; 
  R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 (c) 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 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 
 
 (ii) Y is an optionally substituted group selected from cycloalkylene or heterocycloalkylene;
 Z is C(═O), NHC(═O), NR a C(═O), NR a S(═O) x , where x is 1 or 2, and R a  is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and either
 (a) R 7  and R 8  are H; 
  R 6  is substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 (b) R 6  and R 8  are H; 
  R 7  is substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 (c) R 7  and R 8  taken together form a bond; 
  R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, 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. 
 
 
     
     
         2 . The compound of  claim 1 , wherein L a  is O. 
     
     
         3 . The compound of  claim 2 , wherein Ar is phenyl. 
     
     
         4 . The compound of  claim 3 , wherein:
 Z is C(═O), NHC(═O), or NCH 3 C(═O).   
     
     
         5 . The compound of any of  claims 1 - 4 , wherein
 Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene and alkyleneheterocycloalkylene;   Z is C(═O), NHC(═O), NR a C(═O), NR a S(═O) x , where x is 1 or 2, and R a  is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and either
 (a) R 7  and R 8  are H;
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 
 (b) R 6  and R 8  are H;
 R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 
 (c) 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 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl). 
 
   
     
     
         6 . The compound of  claim 5 , wherein
 R 7  and R 8  are H; and   R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         7 . The compound of  claim 6 , wherein Y is alkyleneheterocycloalkylene. 
     
     
         8 . The compound of  claim 6 , wherein:
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl)   
     
     
         9 . The compound of  claim 5 , wherein
 R 6  and R 8  are H; and   R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         10 . The compound of  claim 9 , wherein Y is alkyleneheterocycloalkylene. 
     
     
         11 . The compound of  claim 9 , wherein:
 R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl)   
     
     
         12 . The compound of  claim 5 , wherein
 R 7  and R 8  taken together form a bond; and   R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         13 . The compound of  claim 12 , wherein Y is alkyleneheterocycloalkylene. 
     
     
         14 . The compound of  claim 12 , wherein:
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl)   
     
     
         15 . The compound of any of  claims 1 - 4 , wherein
 Y is an optionally substituted group selected from cycloalkylene or heterocycloalkylene;   Z is C(═O), NHC(═O), NR a C(═O), NR a S(═O) x , where x is 1 or 2, and R a  is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and either
 (a) R 7  and R 8  are H;
 R 6  is substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 
 (b) R 6  and R 8  are H;
 R 7  is substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 
 (c) R 7  and R 8  taken together form a bond;
 R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl). 
 
   
     
     
         16 . The compound of  claim 15 , wherein:
 R 7  and R 8  are H; and   R 6  is substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         17 . The compound of  claim 16 , wherein:
 R 6  is substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         18 . The compound of  claim 15 , wherein:
 R 6  and R 8  are H; and   R 7  is substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         19 . The compound of  claim 18 , wherein:
 R 7  is substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         20 . The compound of  claim 15 , wherein:
 R 7  and R 8  taken together form a bond; and   R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 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 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         21 . The compound of  claim 16 , wherein:
 R 6  is substituted or unsubstituted C 1 -C 4 alkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         22 . A compound selected from among: (E)-4-(N-(2-hydroxyethyl)-N-methylamino)-1-(3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound 3); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d-]pyrimidin-1-yl)-3-(1H-imidazol-4-yl)prop-2-en-1-one (Compound 4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-morpholinobut-2-en-1-one (Compound 5); (E)-1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 7); (E)-N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-4-(dimethylamino)but-2-enamide (Compound 8); N-((1r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); (E)-1-((R)-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 11); (E)-1-((S)-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 12); 1-((R)-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 13); 1-((S)-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 14); 1((R)-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)but-2-yn-1-one (Compound 15); 1-((S)-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)but-2-yn-1-one (Compound 16); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-yn-1-one (Compound 17); (E)-N-((1,r,4r)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl-4-(dimethylamino)but-2-enamide (Compound 18); N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-methylacrylamide (Compound 19); (E)-1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-morpholinobut-2-en-1-one (Compound 20); (E)-1-((S_-2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-morpholinobut-2-en-1-one (Compound 21); N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)but-2-ynamide (Compound 22); N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)ethyl)acrylamide (Compound 23); (E)-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-morpholinobut-2-en-1-one (Compound 24); (E)-N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)-4-morpholinobut-2-enamide (Compound 25). 
     
     
         23 . A pharmaceutical formulation comprising a therapeutically effective amount of a compound of any of  claims 1 - 22 , and a pharmaceutically acceptable excipient. 
     
     
         24 . The pharmaceutical formulation of  claim 23  that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. 
     
     
         25 . A method for treating an autoimmune disease or condition comprising administering to a patient in need the pharmaceutical formulation of  claim 23 . 
     
     
         26 . The method of  claim 25 , wherein the autoimmune disease is selected from rheumatoid arthritis or lupus. 
     
     
         27 . A method for treating a heteroimmune disease or condition comprising administering to a patient in need the pharmaceutical formulation of  claim 23 . 
     
     
         28 . A method for treating a cancer comprising administering to a patient in need the pharmaceutical formulation of  claim 23 . 
     
     
         29 . The method of  claim 28 , wherein the cancer is a B-cell proliferative disorder. 
     
     
         30 . The method of  claim 29 , wherein the B-cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. 
     
     
         31 . A method for treating mastocytosis comprising administering to a patient in need the pharmaceutical formulation of  claim 23 . 
     
     
         32 . A method for treating osteoporosis or bone resorption disorders comprising administering to a patient in need the pharmaceutical formulation of  claim 23 . 
     
     
         33 . A method for treating an inflammatory disease or condition comprising administering to a patient in need the pharmaceutical formulation of  claim 23 . 
     
     
         34 . A method for treating lupus comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase or a Bruton's tyrosine kinase homolog. 
     
     
         35 . A method for treating a heteroimmune disease or condition comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase or a Bruton's tyrosine kinase homolog. 
     
     
         36 . A method for treating diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase or a Bruton's tyrosine kinase homolog. 
     
     
         37 . A method for treating mastocytosis, comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase or a Bruton's tyrosine kinase homolog. 
     
     
         38 . A method for treating osteoporosis or bone resorption disorders comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase or a Bruton's tyrosine kinase homolog. 
     
     
         39 . A method for treating an inflammatory disease or condition comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton's tyrosine kinase or a Bruton's tyrosine kinase homolog. 
     
     
         40 . A kinase inhibitor that selectively and irreversibly binds to a protein tyrosine kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog, in which the kinase inhibitor reversibly and non-selectively binds to a multiplicity of protein tyrosine kinases, and further in which the plasma half life of the kinase inhibitor is less than about 4 hours. 
     
     
         41 . The kinase inhibitor of  claim 40  that selectively and irreversibly binds to at least one of Btk, Jak3, Blk, Bmx, Tec, and Itk. 
     
     
         42 . The kinase inhibitor of  claim 41  that selectively and irreversibly binds to Btk. 
     
     
         43 . The kinase inhibitor of  claim 41  that selectively and irreversibly binds to Jak3. 
     
     
         44 . The kinase inhibitor of  claim 41  that selectively and irreversibly binds to Tec. 
     
     
         45 . The kinase inhibitor of  claim 41  that selectively and irreversibly binds to Btk and Tec. 
     
     
         46 . The kinase inhibitor of  claim 41  that selectively and irreversibly binds to Blk. 
     
     
         47 . The kinase inhibitor of  claim 40  that reversibly and non-selectively binds to a multiplicity of src-family protein kinase inhibitors. 
     
     
         48 . The kinase inhibitor of  claim 40 , in which the plasma half life of the kinase inhibitor is less than about 3 hours. 
     
     
         49 . The kinase inhibitor of  claim 40 , having the structure of Formula (VII): 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is a moiety that binds to the active site of a kinase, including a tyrosine kinase, further including a Btk kinase cysteine homolog;
 Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, heterocycloalkylene, cycloalkylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene, and alkyleneheterocycloalkylene; 
 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. 
 
     
     
         50 . The kinase inhibitor of  claim 49 , wherein 
       
         
           
           
               
               
           
         
       
       is a substituted fused biaryl moiety selected from 
       
         
           
           
               
               
           
         
       
     
     
         51 . The kinase inhibitor of  claim 49 , wherein:
 Z is C(═O), NHC(═O), NCH 3 C(═O), or S(═O) 2 .   
     
     
         52 . The kinase inhibitor of  claim 49 , wherein:
 each of R 7  and R 8  is H; or   R 7  and R 8  taken together form a bond.   
     
     
         53 . The kinase inhibitor of  claim 49 , 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).   
     
     
         54 . The kinase inhibitor of  claim 49 , wherein:
 Y is a 4-, 5-, 6-, or 7-membered cycloalkylene ring; or   Y is a 4-, 5-, 6-, or 7-membered heterocycloalkylene ring; or   Y is a C 1 -C 4  alkylene, or 4-, 5-, 6-, or 7-membered heterocycloalkylene ring.   
     
     
         55 . A pharmaceutical formulation comprising the kinase inhibitor of any of  claims 40 - 54  and a pharmaceutically acceptable excipient. 
     
     
         56 . The pharmaceutical formulation of  claim 55  that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. 
     
     
         57 . The pharmaceutical formulation of  claim 56  that is formulated for oral administration. 
     
     
         58 . A method for treating rheumatoid arthritis comprising administering to a subject the kinase inhibitor of  claim 41  that selectively and irreversibly binds to Btk and Tec. 
     
     
         59 . A method for increasing the selectivity of a test protein tyrosine kinase inhibitor that irreversibly and selectively binds to at least one protein kinase inhibitor selected from Btk, a Btk homolog, or a Btk kinase cysteine homolog, in which the test protein tyrosine kinase inhibitor is chemically modified to decrease the plasma half life to less than about 4 hours. 
     
     
         60 . The method of  claim 59 , in which the test protein tyrosine kinase inhibitor is chemically modified to decrease the plasma half life to less than about 3 hours. 
     
     
         61 . The method of  claim 59  or  claim 60 , in which the test protein tyrosine kinase inhibitor has the structure of Formula (VII): 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is a moiety that binds to the active site of a kinase, including a tyrosine kinase, further including a Btk kinase cysteine homolog;
 Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, heterocycloalkylene, cycloalkylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene, and alkyleneheterocycloalkylene; 
 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; and 
 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, 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). 
 
     
     
         62 . The method of  claim 59 , in which the test protein tyrosine kinase inhibitor non-selectively and reversibly binds to a multiplicity of src-family protein tyrosine kinases. 
     
     
         63 . A method for treating a B-cell proliferative disorder or a mast cell proliferative disorder comprising administering to a patient in need the pharmaceutical composition of  claim 55 . 
     
     
         64 . A method for treating a rheumatoid arthritis or condition comprising administering to a patient in need the pharmaceutical composition of  claim 55 . 
     
     
         65 . A method for treating a disease characterized by hyperactive B cells comprising administering to a patient in need the pharmaceutical composition of  claim 55 . 
     
     
         66 . A method for treating a disease characterized by hyperactive mast cells comprising administering to a patient in need the pharmaceutical composition of  claim 55 . 
     
     
         67 . A method for treating a disease characterized by both hyperactive B cells and hyperactive mast cells comprising administering to a patient in need the pharmaceutical composition of  claim 55 . 
     
     
         68 . The methods of any of  claims 63  to  67 , in which the pharmaceutical composition is administered once a day. 
     
     
         69 . A method of identifying an irreversible inhibitor of a kinase selected from Btk, a Btk homolog, or a Btk kinase cysteine homolog comprising:
 (1) contacting a multiplicity of kinases selected from Btk, a Btk homolog, or a Btk kinase cysteine homolog with a compound that comprises a Michael acceptor moiety;   (2) contacting at least one non-kinase molecule having at least one accessible SH group with the compound that comprises a Michael acceptor moiety; and   (3) determining the covalent binding of the compound that comprises a Michael acceptor with the multiplicity of kinases and the at least one non-kinase molecule; and   repeating steps (1), (2), and (3) for at least one other compound that comprises a Michael acceptor moiety.   
     
     
         70 . The method of  claim 69 , further comprising
 (4) comparing the covalent binding of the compound that comprises a Michael acceptor with the multiplicity of kinases and the at least one non-kinase molecule; and   repeating steps (1), (2), (3) and (4) for at least one other compound that comprises a Michael acceptor moiety.   
     
     
         71 . The method of  claim 69 , wherein the at least one non-kinase molecule having at least one accessible SH group includes glutathione and/or hemoglobin. 
     
     
         72 . The method of  claim 71 , wherein a desired irreversible inhibitor is selective for a particular kinase relative to other kinases, glutathione and hemoglobin. 
     
     
         73 . The method of  claim 69 , further comprising contacting each kinase with an Activity Probe. 
     
     
         74 . The method of  claim 69 , wherein steps (1) and (2) are conducted in vivo and step (3) is conducted in part using an Activity Probe. 
     
     
         75 . The method of  claim 69 , wherein the determining step uses mass spectrometry. 
     
     
         76 . The method of  claim 69 , wherein the determining step uses fluorescence. 
     
     
         77 . The method of  claim 70 , wherein the compound further comprises an active site binding moiety. 
     
     
         78 . The method of  claim 77 , wherein the compound further comprises a linker moiety that links the Michael acceptor moiety to the active site binding moiety. 
     
     
         79 . The method of  claim 69 , wherein the at least one compound has the structure of Formula (VII): 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
       
       is a moiety that binds to the active site of a kinase, including a tyrosine kinase, further including a Btk kinase cysteine homolog;
 Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, heterocycloalkylene, cycloalkylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene, and alkyleneheterocycloalkylene; 
 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; and 
 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, 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). 
 
     
     
         80 . The method of  claim 78 , further comprising analyzing the structure-function activity relationship between the structure of the linker moiety and/or the Michael acceptor moiety of each compound, and the binding and/or selectivity of each compound to at least one kinase. 
     
     
         81 . The method of  claim 79 , further comprising analyzing the structure-function activity relationship between the structure of Y—Z and/or 
       
         
           
           
               
               
           
         
       
       of each compound, and the binding and/or selectivity of each compound to at least one kinase. 
     
     
         82 . The method of  claim 80 , wherein the structure of the active site binding moiety of each compound is not varied. 
     
     
         83 . The method of  claim 79 , wherein the structure of 
       
         
           
           
               
               
           
         
       
       each compound is not varied. 
     
     
         84 . An assay comprising the method of any of  claims 70  to  83 . 
     
     
         85 . A system comprising the assay of  claim 80  or any method of  claims 70  to  63 . 
     
     
         86 . An irreversible inhibitor of a kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog, wherein the inhibitor is identified using any method of  claims 70  to  83 , the assay of  claim 84 , or the system of  claim 85 . 
     
     
         87 . The irreversible inhibitor of  claim 86 , wherein the inhibitor is selective for one kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog over at least one other kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog. 
     
     
         88 . The irreversible inhibitor of  claim 87 , wherein the inhibitor is at least 5 times more selective for one kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog over at least one other kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog. 
     
     
         89 . The irreversible inhibitor of  claim 88 , wherein the inhibitor is at least 50 times more selective for one kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog over at least one other kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog. 
     
     
         90 . The irreversible inhibitor of  claim 86 , wherein the inhibitor is selective for at least one kinase selected from Btk, a Btk homolog, and a Btk kinase cysteine homolog over at least one other non-kinase molecule having an accessible SH group. 
     
     
         91 . A pharmaceutical composition comprising the compound of any of  claim 86 ,  87 , or  88 . 
     
     
         92 . A method for improving the kinase selectivity of an inhibitor comprising use of the methods of  claims 70  to  83 . 
     
     
         93 . A method for treating an autoimmune disease or condition comprising administering to a patient in need a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Blk or a Blk homolog. 
     
     
         94 . The method of  claim 91 , wherein the autoimmune disease is selected from rheumatoid arthritis or lupus. 
     
     
         95 . A method for treating a B-cell proliferative disorder comprising administering to a patient in need a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Blk or a Blk homolog. 
     
     
         96 . The method of  claim 93 , wherein the B-cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. 
     
     
         97 . A method for treating an inflammatory disease or condition comprising administering to a patient in need a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Blk or a Blk homolog. 
     
     
         98 . A method for identifying biomarkers suitable for determining patient response to a compound of Formula (I) comprising administering to a test subject a composition containing an amount of compound of Formula (I) sufficient to inhibit B cell receptor signaling and correlating B cell receptor signaling with apoptosis. 
     
     
         99 . A method for selecting a patient for treatment for lymphoma with a compound of Formula (I) comprising measuring pErk levels or Erk transcriptional target levels in a patient sample, correlating a high level of pERK or ERK transcriptional target levels with a positive response to the treatment, and selecting or excluding the patient for treatment based on the pErk level or Erk transcriptional target levels. 
     
     
         100 . A method for measuring a patient's response to treatment comprising administering to the patient a compound of Formula (I), measuring pErk levels or Erk transcriptional target levels in a patient sample, correlating a reduced level of pERK or Erk transcriptional targets with a positive response to the administration of the compound of Formula (I), and continuing or stopping treatment of the patient with the compound based on the pErk levels or the Erk transcriptional target levels.