Inhibitors of bruton's tyrosine kinase

Abstract

Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are describeded, 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 . A compound of Formula (VIa) or (VIb) having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; 
         W is —C(R 2 )— or —N—; 
         X is —C(R 2 )— or —N—; 
         Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene; 
         Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; 
         each R 2  is independently H, substituted or unsubstituted C 1 -C 4 alkyl, —CN, or halogen; 
         each R 3  is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl; 
         R 5  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; 
         R 10a  is H, substituted or unsubstituted C 1 -C 4 alkyl; and 
         t is 1, 2, or 3; 
         or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof; 
         provided that 
         i) when the compound is of Formula (VIa), W is N, and R 10a  is H; then X is other than C-Et or N; and 
         ii) when W is N. 
       
     
     
         2 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein ring A is phenyl. 
     
     
         8 . The compound of  claim 1 , wherein Y is absent, —CH 2 O—, —OCH 2 —, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene. 
     
     
         9 . The compound of  claim 1 , wherein Z is substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein ring A is substituted or unsubstituted C 1 -C 12 heteroaryl. 
     
     
         13 . The compound of  claim 12 , wherein ring A is pyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl. 
     
     
         14 . The compound of  claim 1 , wherein X is —C(H)—. 
     
     
         15 . The compound of  claim 1 , wherein X is —N—. 
     
     
         16 . The compound of  claim 1 , wherein W is —C(H)—. 
     
     
         17 . The compound of  claim 1 , wherein W is —N—. 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         19 . A method for treating an autoimmune disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of  claim 1 . 
     
     
         20 . The method of  claim 19 , wherein the autoimmune disease is selected from rheumatoid arthritis or lupus.