Inhibitors of brutons 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 described, 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.

What is claimed is: 
     
         1 . A compound of Formula (IA) 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; 
 G is 
 
       
       
         
           
           
               
               
           
         
         
           R 1  is —R 4 , —CH 2 R 4 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ; 
           R 1 ′ is —C(O)R 9′ , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ; 
           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; 
           each R 4  is independently H, substituted or unsubstituted C 1 -C 6 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 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; or R 1  and R 5  together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring; 
           each R 6  is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1  and R 6  are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring; 
           each R 7  is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; 
           R 9  is —R 4 , 
         
       
       
         
           
           
               
               
           
         
         
           R 10  is H, halogen, —CN, or -L 1 -L 2 ; 
           R 11  and R 12  are independently H, halogen, —CN, or -L 1 -L 2 ; or R 11  and R 12  taken together form a bond; 
           each L 1  is optionally present and when present each L 1  is independently 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, substituted or unsubstituted C 1 -C 12 heteroaryl, —C(═O)—, —O—, or —S—; 
           each L 2  is 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, substituted or unsubstituted C 1 -C 12 heteroaryl or —N(R 13 ) 2 ; 
           each R 13  is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 7  heterocycloalkyl, C 6 -C 12 aryl, or C 1 -C 12 heteroaryl; 
           n is 0-3; 
           p is 0-3; and 
           q is 0-3; 
         
         or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof; 
         provided that 
         i) when W is N, and R 1  is H, t-Boc, or —C(O)—CH═CH 2 ; then X is other than C-Et or N; and 
         ii) when W is N, G is 
       
       
         
           
           
               
               
           
         
          then X is CH or N; 
         iii) when W is N, and X is CH; then R 1 ′ is other than —C(O)Me, or t-Boc; and 
         iv) when n is 0; then each of p and q is independently 0, 1, or 2. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is of Formula (I) 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; 
 G is 
 
       
       
         
           
           
               
               
           
         
         
           R 1  is —R 4 , —CH 2 R 4 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ; 
           each R 2  is independently H, —CN, or halogen; 
           each R 3  is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl; 
           each R 4  is independently H, substituted or unsubstituted C 1 -C 6 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 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; or R 1  and R 5  together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring; 
           each R 6  is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1  and R 6  are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring; 
           each R 7  is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; 
           R 9  is —R 4 , or 
         
       
       
         
           
           
               
               
           
         
         
           R 10  is H, halogen, —CN, or -L 1 -L 2 ; 
           R 11  and R 12  are independently H, halogen, —CN, or -L 1 -L 2 ; or R 11  and R 12  taken together form a bond; 
           each L 1  is optionally present and when present each L 1  is independently 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, substituted or unsubstituted C 1 -C 12 heteroaryl, —C(═O)—, —O—, or —S—; 
           each L 2  is 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, substituted or unsubstituted C 1 -C 12 heteroaryl or —N(R 13 ) 2 ; 
           each R 13  is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 7  heterocycloalkyl, C 6 -C 12 aryl, or C 1 -C 12 heteroaryl; 
           p is 0-3; and 
           q is 0-3; 
           or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof. 
         
       
     
     
         3 . The compound of  claim 1 , wherein
 G is   
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , wherein
 G is   
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein the compound is of Formula (IV) having the structure: 
       
         
           
           
               
               
           
         
         wherein A, W, X, Y, Z, R 1 , R 5 , and R 6  are as in  claim 2 . 
       
     
     
         6 . The compound of  claim 5 , wherein R 6  is Me. 
     
     
         7 . The compound of  claim 5 , wherein ring A is phenyl. 
     
     
         8 . The compound of  claim 5 , 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 5 , 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 . The compound of  claim 5 , wherein R 1  is —C(O)R 9 . 
     
     
         11 . The compound of  claim 10 , wherein R 9  is —R 4 , and R 4  is substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl. 
     
     
         12 . The compound of  claim 5 , 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 5 , wherein X is —C(H)—. 
     
     
         15 . The compound of  claim 5 , wherein X is —N—. 
     
     
         16 . The compound of  claim 5 , wherein W is —C(H)—. 
     
     
         17 . The compound of  claim 5 , 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.