Purinone compounds as kinase inhibitors

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. 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 . A compound of Formula (I) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 24  is each independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SR 21 , —N(R 21 )S(═O) 2 R 23 , —S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)H, —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , —N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , —N(R 21 )C(═O)OR 22 , —N(R 21 )C(═O)N(R 21 )(R 22 ), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl; 
 R 21  and R 22  are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; 
 R 23  is each independently substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; 
 n is 0-4; 
 R 9  is substituted or unsubstituted heteroaryl; 
 R 10  is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; 
 R 6  is L-J-W; 
 R 7  is V-Q-W; 
 R 8  is X-A-W; or R 7  and R 8  taken together form a bond; 
 L and J are each optionally present and when present are each independently substituted or unsubstituted C 1 -C 6  alkylene, substituted or unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted C 1 -C 6  heteroalkylene, substituted or unsubstituted C 2 -C 7  heterocycloalkylene, substituted or unsubstituted C 6 -C 12  arylene, substituted or unsubstituted C 3 -C 12  heteroarylene, —CO—, —O—, or —S—; 
 V and Q are each optionally present and when present are each independently substituted or unsubstituted C 1 -C 6  alkylene, substituted or unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted C 1 -C 6  heteroalkylene, substituted or unsubstituted C 2 -C 7  heterocycloalkylene, substituted or unsubstituted C 6 -C 12  arylene, substituted or unsubstituted C 3 -C 12  heteroarylene, —CO—, —O—, or —S—; 
 X and A are each optionally present and when present are each independently substituted or unsubstituted C 1 -C 6  alkylene, substituted or unsubstituted C 3 -C 6  cycloalkylene, substituted or unsubstituted C 1 -C 6  heteroalkylene, substituted or unsubstituted C 2 -C 7  heterocycloalkylene, substituted or unsubstituted C 6 -C 12  arylene, substituted or unsubstituted C 3 -C 12  heteroarylene, —CO—, —O—, or —S—; 
 W is H, or NR 25 R 26 ; 
 R 25  and R 26  are each independently H, substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted C 1 -C 6  heteroalkyl, substituted or unsubstituted C 2 -C 7  heterocycloalkyl, substituted or unsubstituted C 6 -C 12  aryl, or substituted or unsubstituted C 3 -C 12  heteroaryl; 
 and pharmaceutically active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof. 
 
     
     
         2 - 40 . (canceled)