Ibrutinib prodrugs, pharmaceutical compositions thereof, and methods of use

Abstract

Prodrugs of ibrutinib, pharmaceutical compositions comprising the prodrugs, and methods of using the prodrugs and pharmaceutical compositions for treating autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions are disclosed.

1 . A method for treating a non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, or chronic lymphocytic leukemia with 17p delection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable solvate, hydrate, or salt thereof, wherein:
 A is N; 
 each R 1a , R 1b , R 1d , and R 1e  is H; 
 R 1c  is phenoxy. 
 R 2  is H; 
 R 3  is the following structure: 
 
       
         
           
           
               
               
           
         
       
       and
 Z is selected from the following structures: 
 
       
         
           
           
               
               
           
         
         wherein each R 11 , R 12 , and R 13  is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, and substituted or unsubstituted lower aryl, wherein each substituent is independently selected from —F, —Cl, —CF 3 , —CN, —NO 2 , —OH, —OCH 3 , and —NH 2 . 
       
     
     
         2 . The method of  claim 1 , wherein the non-Hodgkin lymphoma is selected from the group consisting of diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt lymphoma. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the compound is administered orally. 
     
     
         7 . A method for treating a non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, or chronic lymphocytic leukemia with 17p delection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), wherein the compound is selected from the compounds of Formula (I-A-1), Formula (I-A-3), Formula (I-A-5), Formula (I-A-7), and Formula (I-B-1): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7 , wherein the non-Hodgkin lymphoma is selected from the group consisting of diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt lymphoma. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 7 , wherein the compound is administered orally. 
     
     
         13 . A method for treating a non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, or chronic lymphocytic leukemia with 17p delection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I-A-3). 
     
     
         14 . The method of  claim 13 , wherein the non-Hodgkin lymphoma is selected from the group consisting of diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and Burkitt lymphoma. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 13 , wherein the compound is administered orally.