Inhibitors of brutons 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 (B2) having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         Y is alkylene or substituted alkylene, or a 4-, 5-, or 6-membered cycloalkylene ring; 
         each R a  is independently H, halogen, —CF 3 , —CN, —NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a  is a bond, O, S, —S(═O), —S(═O) 2 , NH, C(O), CH 2 , —NHC(O)O, —NHC(O), or —C(O)NH; 
         G is 
       
       
         
           
           
               
               
           
         
       
       wherein,
 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; 
 R 12  is H or lower alkyl; or 
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; or 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         102 . The compound according to  claim 101 , wherein G is selected from among 
       
         
           
           
               
               
           
         
       
     
     
         103 . The compound according to  claim 101 , wherein 
       
         
           
           
               
               
           
         
       
       is selected from among 
       
         
           
           
               
               
           
         
       
     
     
         104 . The compound according to  claim 101 , wherein the compound of Formula (B2) has the following structure of Formula (C 2 ): 
       
         
           
           
               
               
           
         
         wherein: 
         Y is alkylene or substituted alkylene, or a 4-, 5-, or 6-membered cycloalkylene ring; 
         R 12  is H or lower alkyl; or 
         Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; 
         G is 
       
       
         
           
           
               
               
           
         
       
       wherein,
 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. 
 
     
     
         105 . The compound of  claim 101 , wherein the compound is of formula (D2): 
       
         
           
           
               
               
           
         
         wherein: 
         L a  is CH 2 , O, NH or S; 
         Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; 
         Y is an optionally substituted group selected from among alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene; 
         Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , or 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, 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); or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         106 . The compound of  claim 105  having the following structure of Formula (D2): 
       
         
           
           
               
               
           
         
         wherein 
         L a  is CH 2 , O, NH or S; 
         Ar is an optionally substituted aryl or heteroaryl; 
         Y is an optionally substituted alkylene, heteroalkylene, carbocycloalkylene, or heterocycloalkylene, or a combination thereof; 
         Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , or NHS(═O) x , where x is 1 or 2; and 
         R 6 , R 7 , and R 8  are independently selected from H, alkyl, heteroalkyl, carbocycle, and heterocycle, or combinations thereof; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         107 . The compound according to  claim 105 , L a  is O. 
     
     
         108 . The compound according to  claim 105 , wherein Ar is phenyl. 
     
     
         109 . The compound according to  claim 105 , wherein Z is C(O). 
     
     
         110 . The compound according to  claim 105 , wherein Y is an optionally substituted group selected from among C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, 4-, 5-, 6- or 7-membered cycloalkylene, and 4-, 5-, 6- or 7-membered heterocycloalkylene. 
     
     
         111 . The compound according to  claim 105 , wherein Y is a 5-, or 6-membered cycloalkylene, or a 5-, or 6-membered heterocycloalkylene containing 1 or 2 N atoms. 
     
     
         112 . The compound according to  claim 105 , wherein each of R 7  and R 8  is H; or R 7  and R 8  taken together form a bond. 
     
     
         113 . The compound according to  claim 105 , 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 2 alkyl-N(C 1 -C 3 alkyl) 2 , substituted or unsubstituted aryl, 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). 
     
     
         114 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 101 , and a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         115 . A method of treating an autoimmune disorder, a heteroimmune disorder, inflammation, or a combination thereof in a subject, comprising administering a therapeutically effective amount a compound of  claim 101  to the subject. 
     
     
         116 . The method of  claim 115 , wherein the autoimmune disorder is rheumatoid arthritis, lupus, or a combination thereof. 
     
     
         117 . A method of treating an allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, or a combination thereof in a subject, comprising a therapeutically effective amount of  claim 101  to the subject. 
     
     
         118 . A method of B-cell proliferative disorder in a subject, comprising a therapeutically effective amount of a compound of  claim 101  to the subject. 
     
     
         119 . The method of  claim 118 , wherein the B-cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, or a combination thereof.