Inhibitors of bruton's tyrosine kinase

Abstract

Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. 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 composition comprising rituximab and a compound of Formula (D) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 L a  is CH 2 , O, NH or S; 
 Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; 
 Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , or NHS(═O) x , where x is 1 or 2; 
 R 7  and R 8  are independently selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 heterocycloalkyl; or 
 R 7  and R 8  taken together form a bond; 
 R 6  is selected from the group consisting of H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 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 4 alkyl(C 3 -C 8 cycloalkyl), and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
 or a pharmaceutically active metabolite, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof, 
 or a stereoisomer thereof. 
 
     
     
         2 . The composition of  claim 1 , wherein L a  is O. 
     
     
         3 . The composition of  claim 2 , wherein Ar is phenyl. 
     
     
         4 . The composition of  claim 3 , wherein:
 Z is C(═O), NHC(═O), or S(═O) 2 .   
     
     
         5 . The composition of  claim 4 , wherein:
 each of R 7  and R 8  is H; or   R 7  and R 8  taken together form a bond.   
     
     
         6 . The composition of  claim 5 , wherein:
 R 6  is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl).   
     
     
         7 . The composition of  claim 6 , wherein:
 Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or   Y is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.   
     
     
         8 . The composition of  claim 1 , wherein the compound is selected from the group consisting of: 
       1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound 5); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene (Compound 6); 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one (Compound 8); 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 9); N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 11); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound 12); 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13); 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14); and (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15). 
     
     
         9 .- 17 . (canceled) 
     
     
         18 . A method for treating a cancer comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of rituximab and a compound or a pharmaceutically acceptable solvate or salt thereof, wherein the compound is a compound of Formula (D), or a stereoisomer thereof, having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 L a  is CH 2 , O, NH or S; 
 Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; 
 Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
 Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , NHS(═O) x , where x is 1 or 2; 
 R 7  and R 8  are independently selected from the group consisting of H, unsubstituted C 1 -C 4  alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl, substituted C 1 -C 4 heteroalkyl, unsubstituted C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, unsubstituted C 2 -C 6 heterocycloalkyl, and substituted C 2 -C 6 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 6 alkoxyalkyl, C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 , substituted or unsubstituted C 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, C 1 -C 4 alkyl(heteroalkyl), C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl). 
 
     
     
         19 . The method of  claim 18 , wherein the cancer is a B-cell proliferative disorder. 
     
     
         20 . The method of  claim 19 , wherein the B-cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. 
     
     
         21 . The method of  claim 18 , wherein the compound has the following structure: