Inhibitors of bruton's tyrosine kinase

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

1 .- 21 . (canceled) 
     
     
         22 . An inhibited tyrosine kinase comprising an inhibitor irreversibly and covalently bound to a cysteine residue of a Bruton's tyrosine kinase cysteine homolog selected from BMX, TEC, TXK, ITK, ErbB2, ErbB4, JAK3, and BLK. 
     
     
         23 . The inhibited tyrosine kinase of  claim 22 , wherein the irreversible covalent bond is formed between a portion of a Michael acceptor moiety on the inhibitor and a portion of the cysteine residue of the Bruton's tyrosine kinase cysteine homolog. 
     
     
         24 . The inhibited tyrosine kinase of  claim 22 , wherein the Michael acceptor moiety is an acrylamide, vinyl sulfonamide or propargylamide. 
     
     
         25 . The inhibited tyrosine kinase of  claim 22 , wherein the inhibitor is irreversibly and covalently bound to cysteine residue 481. 
     
     
         26 . The inhibited tyrosine kinase of  claim 22  wherein the Bruton's tyrosine kinase cysteine homolog is activated. 
     
     
         27 . The inhibited tyrosine kinase of  claim 22  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 8  is H; R 7  is H, unsubstituted C 1 -C 4  alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, or C 1 -C 4 alkyl(phenyl); or 
 R 7  and R 8  taken together form a bond; 
 R 6  is H, unsubstituted, C 1 -C 4 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, or C 1 -C 4 alkyl(phenyl); and   indicates the point of attachment between the inhibitor and the Bruton's tyrosine kinase homolog. 
 
     
     
         28 . The inhibited tyrosine kinase of  claim 27  wherein La is O. 
     
     
         29 . The inhibited tyrosine kinase of  claim 27  wherein R 6 , R 7 , and R 8  are each H. 
     
     
         30 . The inhibited tyrosine kinase of  claim 27  wherein Y is piperidinyl. 
     
     
         31 . The inhibited tyrosine kinase of  claim 27  wherein Z is C(═O). 
     
     
         32 . The inhibited tyrosine kinase of  claim 27  wherein the inhibitor is irreversibly and covalently bound to cysteine residue 481.