Ripk2 inhibitors and method of treating cancer with same

Abstract

The invention is a compound represented by Structural Formula (I):or a pharmaceutically acceptable salt thereof. Values for the variables are provided herein. Also included is a pharmaceutical composition comprising the compound represented by Structural Formula (I) and a pharmaceutically acceptable carrier or diluent and methods of treating a subject with cancer with the compound of Structural Formula (I).

1 . A method for treating a subject with cancer, comprising:
 administering to the subject an effective amount of a compound represented by Formula (I):   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Cy is cycloaliphatic, heterocyclyl, aryl, or heteroaryl; 
 Y is absent, —CR b R b —, —O—, —NR b —, —S(O) n —; 
 R 1  is cycloaliphatic, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with 1 to 3 groups individually represented by R a ; 
 R 3  is H, heterocyclyl or heteroaryl optionally substituted with 1 to 3 groups selected from —F, —Cl, —Br, I, —CN, —NO 2 , —OR b , —C 1 -C 4 alkyl, —(C 1 -C 3 )alkylene-OR b , —(C 1 -C 3 )alkylene-NR b R b , —C 1 -C 4 haloalkyl, —C 1 -C 4 haloalkoxy, (C 3 -C 8 )cycloalkyl, —NR b R b , —C(═O)NR b R b , —NR b (C═O)NR b R b , —S(O) n NR b R b , C(═O)OR b , —OC(═O)OR b , —S(O) n R b , —NR b S(O) n R b , —C(═S)OR b , —O(C═S)R b , —NR b C(═O)R b , —C(═S)NR b R b , —NR b C(═S)R b , —NR b (C═O)OR b , —O(C═O)NR b R b , —NR b (C═S)OR b , —O(C═S)NR b R b , —NR b (C═S)NR b R b , —C(═S)R b  or —C(═O)R b ; 
 each R 4  is independently selected from —F, —Cl, —Br, I, —CN, —NR b R b , —OR b , —C 1 -C 4 alkyl, —(C 1 -C 3 )alkylene-OR b , —(C 1 -C 3 )alkylene-NR b R b , —C 1 -C 4 haloalkyl, or —C 1 -C 4 haloalkoxy; 
 each R a  is independently selected from —F, —Cl, —Br, I, —CN, OR b , —C 1 -C 4 alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 haloalkoxy, —(C 1 -C 3 )alkylene-OR b , or —(C 1 -C 3 )alkylene-NR b R b ; 
 each R b  is independently —H or —C 1 -C 4 alkyl; 
 x is 0, 1, 2, 3, or 4; 
 each m is independently 0, 1, 2, or 3; and 
 each n is independently 0, 1, or 2. 
 
       
     
     
         2 . The method of  claim 1 , wherein the compound is represented by structural formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The method of  claim 2 , wherein the compound is represented by structural formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 3 , wherein R 1  is optionally substituted phenyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted thienyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted furanyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted isothiazolyl, optionally substituted pyrmidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted oxadiazolyl, optionally substituted tetrahydropyranyl, optionally substituted triazolyl, or optionally substituted thiadiazolyl. 
     
     
         5 . The method of  claim 4 , wherein R 1  is optionally substituted phenyl, optionally substituted cyclopentyl, optionally substituted thienyl, or optionally substituted tetrahydropyranyl. 
     
     
         6 . The method of  claim 5 , wherein R 3  is optionally substituted monocyclic heterocyclyl or optionally substituted monocyclic heteroaryl. 
     
     
         7 . The method of  claim 6 , wherein m is 0. 
     
     
         8 . The method of  claim 7 , wherein R 3  is optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted tetrahydropyranyl, optionally substituted pyrrolidinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted homomorpholinyl, optionally substituted homopiperazinyl, optionally substituted thiomorpholine dioxide, or optionally substituted thiomorpholine oxide. 
     
     
         9 . The method of  claim 8 , wherein R 3  is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, or optionally substituted thiomorpholinyl. 
     
     
         10 . The method of  claim 9 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 5  is —C 1 -C 4 alkyl or —(C 1 -C 3 )alkylene-OR b . 
       
     
     
         11 . The method of  claim 9 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein Y is absent or —CH 2 —; and Y is attached to the meta or para position of the phenyl ring. 
       
     
     
         12 . The method of  claim 9 , wherein the compound is represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 5  is —H, C 1 -C 4 alkyl, —(C 1 -C 3 )alkylene-OR b ; Y is absent or —CH 2 —; and Y is attached to the meta or para position of the phenyl ring. 
       
     
     
         13 . The method of  claim 9 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 13 , wherein each R a  is independently selected from —F, —Cl, or —CH 3 . 
     
     
         15 - 16 . (canceled) 
     
     
         17 . A method for treating a subject with an autoinflammatory disease, comprising: administering to the subject an effective amount of a compound as defined in  claim 1 . 
     
     
         18 . A method for treating a subject with an autoimmune disease, comprising: administering to the subject an effective amount of a compound as defined in  claim 1 . 
     
     
         19 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 1 , wherein the cancer is leukemia, acute myeloid leukemia, chronic myelogenous leukemia, breast cancer, brain cancer, colon cancer, colorectal cancer, head and neck cancer, hepatocellular carcinoma, lung adenocarcinoma, metastatic melanoma, pancreatic cancer, prostate cancer, ovarian cancer and renal cancer.