Pyrimidinyl sulfonamides as inhibitors of ack1/tnk2 tyrosine kinase

Abstract

The present disclosure provides anti-cancer compounds and uses thereof, more particularly inhibitors of ACK1 tyrosine kinase and their use in the treatment of cancer.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1  is selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and aryl; 
         R 2  is selected from hydrogen and halo; 
         R 3  is selected from C 1 -C 6  alkyl and halo; 
         R 4  is selected from C 1 -C 6  alkoxy, aryloxy, and C 3 -C 6  cycloalkyoxy; 
         R 5  is C 1 -C 6  alkoxy, C 3 -C 6  cycloalkoxy, C 1 -C 6  alkyl, halo, cyano, and hydroxy; 
         L is selected from a bond, C 1 -C 3  alkyl, or —O—(C 1 -C 3  alkyl)-; 
         R 6  is selected from optionally substituted C 4 -C 8  heterocycle or optionally substituted heteroaryl; and 
         m is 0 or 1. 
       
     
     
         2 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1  is selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and aryl; 
         R 3  is selected from C 1 -C 6  alkyl and halo; 
         L is selected from a bond, C 1 -C 3  alkyl, or —O—(C 1 -C 3  alkyl)-; 
         R 6  is selected from optionally substituted C 4 -C 8  heterocycle or optionally substituted heteroaryl; 
         R 7  is selected from C 1 -C 6  alkoxy, C 3 -C 6  cycloalkoxy, C 1 -C 6  alkyl, halo, cyano, and hydroxy; and 
         n is 0, 1, or 2. 
       
     
     
         3 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         7 . A method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 7 , further comprising administering an additional therapeutic agent. 
     
     
         9 . The method of  claim 8 , wherein the additional therapeutic agent comprises an anti-cancer agent or an anti-inflammatory agent. 
     
     
         10 . The method of  claim 7 , further comprising administering an effective amount of ionizing radiation to the subject. 
     
     
         11 . A method of killing a tumor cell comprising contacting the tumor cell with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         13 . A method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of  claim 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 13 , further comprising administering an additional therapeutic agent. 
     
     
         15 . The method of  claim 14 , wherein the additional therapeutic agent comprises an anti-cancer agent or an anti-inflammatory agent. 
     
     
         16 . The method of  claim 13 , further comprising administering an effective amount of ionizing radiation to the subject. 
     
     
         17 . A method of killing a tumor cell comprising contacting the tumor cell with an effective amount of a compound of  claim 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A pharmaceutical composition comprising a compound of  claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of  claim 3 , or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 19 , further comprising administering an additional therapeutic agent. 
     
     
         21 . The method of  claim 20 , wherein the additional therapeutic agent comprises an anti-cancer agent or an anti-inflammatory agent. 
     
     
         22 . The method of  claim 19 , further comprising administering an effective amount of ionizing radiation to the subject. 
     
     
         23 . A method of killing a tumor cell comprising contacting the tumor cell with an effective amount of a compound of  claim 3 , or a pharmaceutically acceptable salt thereof.