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 or NR 8 Ar 1 , or R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring;
 wherein R 8  is selected from hydrogen and C1-C6 alkyl; 
 wherein Ar 1  is phenyl substituted with 0-3 groups independently selected from cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO 2 R 9 , C1-C3 alkylamine, and C1-C3 dialkylamino or Ar 1  is monocyclic heteroaryl substituted with 0-3 groups independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO 2 R 9 , C1-C3 alkylamine, and C1-C3 dialkylamino; 
 wherein R 9  is selected from hydrogen and C1-C6 alkyl; 
 
         wherein R 2  is hydrogen, or R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring; 
         wherein R 3  is hydrogen, halogen, C1-C6 alkyl, or a group having a structure represented by the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein R 10  is selected from hydrogen and C1-C6 alkyl; 
           wherein each of R 11a  and R 11b  is independently selected from hydrogen, halogen, and C1-C6 alkyl; 
           wherein each of R 12a  and R 12b  is independently selected from hydrogen, halogen, and C1-C6 alkyl; and 
           wherein R 13  is a five-membered or six-membered C3-C6 heterocycle substituted with 0-3 groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         
         wherein each of R 4a , R 4b , R 4c , and R 4d  is independently selected from hydrogen, halogen, and C1-C6 alkyl; 
         wherein R 5  is selected from hydrogen and C1-C6 alkyl; 
         wherein R 6  is selected from hydrogen and C1-C6 alkyl; and 
         wherein each of R 7a  and R 7b  is independently selected from hydrogen and C1-C6 alkyl, 
         or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is NR 8 Ar 1 . 
     
     
         3 . The compound of  claim 1 , wherein R 1  is halogen. 
     
     
         4 . The compound of  claim 1 , wherein R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring. 
     
     
         5 . The compound of  claim 4 , wherein the compound the heterocyclic ring is an optionally substituted pyrazole ring. 
     
     
         6 . The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R1 is halogen. 
       
     
     
         9 . A method for the treatment of a disorder of uncontrolled cellular proliferation in a mammal, the method comprising the step of administering to the mammal an effective amount of least one compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is NR 8 Ar 1 , or R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring;
 wherein R 8  is selected from hydrogen and C1-C6 alkyl; 
 wherein Ar 1  is phenyl substituted with 0-3 groups independently selected from cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO 2 R 9 , C1-C3 alkylamine, and C1-C3 dialkylamino or Ar 1  is monocyclic heteroaryl substituted with 0-3 groups independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO 2 R 9 , C1-C3 alkylamine, and C1-C3 dialkylamino; 
 wherein R 9  is selected from hydrogen and C1-C6 alkyl; 
 
         wherein R 2  is hydrogen, or R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring; 
         wherein R 3  is hydrogen, halogen, C1-C6 alkyl, or a group having a structure represented by the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein R 10  is selected from hydrogen and C1-C6 alkyl; 
           wherein each of R 11a  and R 11b  is independently selected from hydrogen, halogen, and C1-C6 alkyl; 
           wherein each of R 12a  and R 12b  is independently selected from hydrogen, halogen, and C1-C6 alkyl; and 
           wherein R 13  is a five-membered or six-membered C3-C6 heterocycle substituted with 0-3 groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         
         wherein each of R 4a , R 4b , R 4c , and R 4d  is independently selected from hydrogen, halogen, and C1-C6 alkyl; 
         wherein R 5  is selected from hydrogen and C1-C6 alkyl; 
         wherein R 6  is selected from hydrogen and C1-C6 alkyl; and 
         wherein each of R 7a  and R 7b  is independently selected from hydrogen and C1-C6 alkyl, 
         or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, thereby treating the disorder. 
       
     
     
         10 . The method of  claim 9 , further comprising the step of identifying a mammal in need of treatment of a disorder of uncontrolled cellular proliferation. 
     
     
         11 . The method of  claim 9 , wherein the mammal has been diagnosed with a need for treatment of a disorder of uncontrolled cellular proliferation prior to the administering step. 
     
     
         12 . The method of  claim 9 , 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. 
     
     
         13 . The method of  claim 12 , wherein the protein kinase is tyrosine-protein kinase BTK. 
     
     
         14 . The method of  claim 9 , wherein the disorder of uncontrolled cellular proliferation is a cancer. 
     
     
         15 . The method of  claim 14 , wherein the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, and large B-cell lymphoma. 
     
     
         16 . A method for the treatment of an inflammatory disorder in a mammal, the method comprising the step of administering to the mammal an effective amount of least one compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is NR 8 Ar 1 , or R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring;
 wherein R 8  is selected from hydrogen and C1-C6 alkyl; 
 wherein Ar 1  is phenyl substituted with 0-3 groups independently selected from cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO 2 R 9 , C1-C3 alkylamine, and C1-C3 dialkylamino or Ar 1  is monocyclic heteroaryl substituted with 0-3 groups independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO 2 R 9 , C1-C3 alkylamine, and C1-C3 dialkylamino; 
 wherein R 9  is selected from hydrogen and C1-C6 alkyl; 
 
         wherein R 2  is hydrogen, or R 1  and R 2  are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring; 
         wherein R 3  is hydrogen, halogen, C1-C6 alkyl, or a group having a structure represented by the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein R 10  is selected from hydrogen and C1-C6 alkyl; 
           wherein each of R 11a  and R 11b  is independently selected from hydrogen, halogen, and C1-C6 alkyl; 
         
         wherein each of R 12a  and R 12b  is independently selected from hydrogen, halogen, and C1-C6 alkyl; and
 wherein R 13  is a five-membered or six-membered C3-C6 heterocycle substituted with 0-3 groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
 
         wherein each of R 4a , R 4b , R 4c , and R 4d  is independently selected from hydrogen, halogen, and C1-C6 alkyl; 
         wherein R 5  is selected from hydrogen and C1-C6 alkyl; 
         wherein R 6  is selected from hydrogen and C1-C6 alkyl; and 
         wherein each of R 7a  and R 7b  is independently selected from hydrogen and C1-C6 alkyl, 
         or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, thereby treating the disorder. 
       
     
     
         17 . The method of  claim 16 , further comprising the step of identifying a mammal in need of treatment of an inflammatory disorder. 
     
     
         18 . The method of  claim 16 , wherein the mammal has been diagnosed with a need for treatment of an inflammatory disorder prior to the administering step. 
     
     
         19 . The method of  claim 16 , wherein the inflammatory disorder is an arthritic disease. 
     
     
         20 . The method of  claim 19 , wherein the arthritic disease is selected from inflammatory arthritis, osteoarthritis, lymphocyte-independent arthritis, rheumatoid arthritis.