Substituted n-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase btk inhibitors

Abstract

In one aspect, the invention relates to substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the BTK kinase; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds and compositions to treat disorders associated with dysfunction of the BTK kinase. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
         1 . A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is halogen; 
         R 2  is hydrogen; 
         R 3  is a group having a structure represented by the formula: 
       
       
         
           
           
               
               
           
         
         each of R 30 , R 31a , R 31b , R 32a  and R 32b  is hydrogen; 
         R 33  is a five-membered or six-membered C3-C6 heterocycle substituted with 0, 1, 2, or 3 groups selected from halogen, —NH 2 , —OH, —CN, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         each of R 4a , R 4b , R 4c , and R 4d  is independently selected from hydrogen, halogen and C1-C6 alkyl; 
         each of R 5 , R 6  is hydrogen; and 
         each of R 7a  and R 7b  is independently selected from hydrogen, C1-C6 alkyl, and —(C1-C3 alkyl)-N(C1-C3 alkyl)(C1-C3 alkyl); 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein each of R 4a , R 4b , R 4c , and R 4d  is independently selected from hydrogen and halogen. 
     
     
         3 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier. 
     
     
         4 . A method for the treatment of a disorder of uncontrolled cellular proliferation in a mammal in need thereof, the method comprising the step of administering to the mammal an effective amount of the compound of  claim 1 . 
     
     
         5 . The method of  claim 4 , wherein the disorder of uncontrolled cellular proliferation is associated with a protein kinase dysfunction; and wherein the protein kinase is a member of the Tec family of tyrosine protein kinases. 
     
     
         6 . The method of  claim 5 , wherein the protein kinase is tyrosine-protein kinase BTK. 
     
     
         7 . The method of  claim 5 , wherein the disorder of uncontrolled cellular proliferation is a cancer. 
     
     
         8 . The method of  claim 7 , wherein the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, and large B-cell lymphoma.