Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors

Abstract

Described herein are irreversible Btk inhibitor compounds, and methods for using such irreversible inhibitors in the treatment of diseases and disorders characterized by the presence or development of solid tumors.

What is claimed is: 
     
         1 . A method for treating HER2 amplified breast cancer in an individual in need thereof comprising administering to an individual in need thereof a composition comprising a therapeutically-effective amount of a compound of Formula (C1) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is an optionally substituted group selected from among alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, and alkylheterocycloalkyl; 
 R 12  is H or lower alkyl; or 
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; 
 G is 
 
       
         
           
           
               
               
           
         
          where R a  is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and either 
         R 7  and R 8  are H;
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 
         R 6  and R 8  are H;
 R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 
         R 7  and R 8  taken together form a bond;
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl). 
 
       
     
     
         2 . The method of  claim 1 , wherein:
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; and   Z is C(═O).   
     
     
         3 . The method of  claim 2 , wherein
 R 6  and R 8  are H; and   R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         4 . The method of  claim 3 , wherein:
 Y and R 12  taken together form a 6-membered heterocyclic ring; and   R 6  and R 8  are H; and   R 7  is substituted or unsubstituted H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         5 . The method of  claim 1 , wherein the compound of Formula (I) is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , further comprising administering an additional therapeutic agent selected from: trastuzumab, paclitaxel, doxorubicin, cyclophosphamide, and cisplatin. 
     
     
         7 . The method of  claim 1 , further comprising administering trastuzumab. 
     
     
         8 . A method for treating HER2 amplified cancer in an individual in need thereof comprising administering to an individual in need thereof a composition comprising a therapeutically-effective amount of a compound of Formula (C1) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is an optionally substituted group selected from among alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, and alkylheterocycloalkyl; 
 R 12  is H or lower alkyl; or 
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; 
 G is 
 
       
         
           
           
               
               
           
         
          where R a  is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and either 
         R 7  and R 8  are H;
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 
         R 6  and R 8  are H;
 R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or 
 
         R 7  and R 8  taken together form a bond;
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC3-C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl). 
 
       
     
     
         9 . The method of  claim 8 , wherein:
 Y and R 12  taken together form a 4-, 5-, or 6-membered heterocyclic ring; and   Z is C(═O).   
     
     
         10 . The method of  claim 9 , wherein
 R 6  and R 8  are H; and   R 7  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         11 . The method of  claim 9 , wherein:
 Y and R 12  taken together form a 6-membered heterocyclic ring;   R 6  and R 8  are H; and   R 7  is substituted or unsubstituted H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylethers, C 1 -C 8 alkylamides, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         12 . The method of  claim 8 , wherein the compound of Formula (I) is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 8 , further comprising administering an additional therapeutic agent selected from: trastuzumab, paclitaxel, doxorubicin, cyclophosphamide, and cisplatin. 
     
     
         14 . The method of  claim 8 , further comprising administering trastuzumab.