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:
 L a  is a bond, —CH 2 —, —CH(OH)—, —C(O)—, —CH 2 O—, —OCH 2 —, —SCH 2 , —CH 2 S—, —N(R 21 )—, —N(R 21 )C(O)—, —C(O)N(R 21 )—, —N(R 21 )C(O)N(R 21 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 21 )S(O) 2 —, or —S(O) 2 N(R 21 )—; 
 Ar is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; 
 R 3  is optionally substituted C 3 -C 6  alkyl, substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —(C═O)C 1 -C 6  alkyl, —(C═O)OR 4 , —(C═O)NR 4 R 4 , —(C═O)SR 4 , -G-X, or 
 
       
         
           
           
               
               
           
         
         G is optionally substituted aryl, or optionally substituted heteroaryl; 
         X is optionally substituted cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl, optionally substituted heteroaryl, —OR 4 , —SR 4 , or —NR 4 R 4 ; 
         each R 4  is each independently H, C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 3 -C 6  cycloalkyl, or C 2 -C 6  heterocycloalkyl; 
         Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, aryl, and heteroaryl; 
         Z is C(═O), OC(═O), N(R 21 )C(═O), C(═S), S(═O) x , OS(═O) x , or N(R 21 )S(═O) x , where x is 1 or 2; 
         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)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, 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; 
         p is 0-2; 
         R 6  is H, or L-J-W; 
         R 7  and R 8  are independently H or L-J-W; or R 7  and R 8  taken together form a bond; 
         L and J are each independently a bond, 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; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein L a  is —O—, or —OCH 2 —. 
     
     
         3 . The compound of  claim 2 , wherein Ar is phenyl. 
     
     
         4 . The compound of  claim 3 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 4 , wherein Z is C(═O), NHC(═O), N(CH 3 )C(═O), or S(═O) 2 . 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 5 , wherein R 6  and R 8  are H; and R 7  is L-J-W. 
     
     
         11 . The compound of  claim 10 , wherein L is a bond, substituted or unsubstituted C 1 -C 6  alkylene, or substituted or unsubstituted C 3 -C 6  cycloalkylene; and J is a bond, 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, or substituted or unsubstituted C 3 -C 12  heteroarylene. 
     
     
         12 . The compound of  claim 11 , wherein L is a bond; J is —CH 2 —; and W is NR 25 R 26 . 
     
     
         13 . The compound of  claim 12 , wherein R 25  is H, substituted or unsubstituted C 1 -C 6  alkyl, or substituted or unsubstituted C 3 -C 6  cycloalkyl; and R 26  is 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. 
     
     
         14 - 38 . (canceled) 
     
     
         39 . A compound having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . (canceled) 
     
     
         41 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. 
     
     
         42 . The compound of  claim 13 , wherein R 25  is —CH 3  and R 26  is cyclopropyl or cyclobutyl. 
     
     
         43 . The compound of  claim 42 , wherein Y is phenyl. 
     
     
         44 . The compound of  claim 43 , wherein Z is C(═O). 
     
     
         45 . A compound having the structure: