Novel ureas having androgen receptor degradation activity and uses thereof

Abstract

The present disclosure relates to novel compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and related diseases and conditions. In some embodiments, the compounds disclosed herein exhibit androgen receptor degradation activity.

1 - 129 . (canceled) 
     
     
         130 . A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (1), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof: 
         wherein:
 X 1  is CR 1  or N; 
 X 2  is CR 2  or N; 
 X 3  is CR 3  or N; 
 X 4  is CR 4  or N; 
 each of R 1 , R 2 , R 3 , and R 4  is independently selected from hydrogen, halogen, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R S ; 
 each R 5  is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, —N(R 9 ) 2 , and —CN, each of which is substituted with 0, 1, 2, or 3 R S ; 
 each R 6  is independently selected from hydrogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R S ; 
 each R 7  is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, —N(R 9 ) 2 , and —CN, each of which is substituted with 0, 1, 2, or 3 R S ; 
 each R 8  is independently selected from hydrogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl, each of which is substituted with 0, 1, 2, or 3 R S , or two R 8  groups are taken together to form an oxo; 
 each R 9  is independently selected from hydrogen, C 1 -C 3 alkyl, —C(═O)—(C 1 -C 3 alkyl), —C(═O)—O—(C 1 -C 3 alkyl), and —C(═O)—NH—(C 1 -C 3 alkyl), each of which is substituted with 0, 1, 2, or 3 R S , or two R 9  groups are taken together to form a 3- to 6-membered heterocycle or heteroaryl; 
 each R S  is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, —N(R 9 ) 2 , and —CN; 
 L is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are optionally replaced by C(═O), O, N(R 9 ), S, C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the R 9 , C 2 alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R S ; 
 m is 0, 1, 2, or 3; and 
 n is 0, 1, 2, or 3, 
 wherein each hydrogen atom is independently and optionally replaced by a deuterium atom. 
 
       
     
     
         131 . The method according to  claim 130 , wherein the cancer is selected from prostate cancer, head and neck cancer, skin cancer, sarcoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, lung cancer, gastric carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, colorectal cancer, connective tissue cancer, glioblastoma multiforme, cervical cancer, uterine cancer, ovarian cancer, and breast cancer. 
     
     
         132 . The method according to  claim 131 , wherein the cancer is prostate cancer. 
     
     
         133 . The method according to  claim 131 , wherein the cancer is breast cancer. 
     
     
         134 . The method according to  claim 130 , wherein the cancer is androgen receptor positive. 
     
     
         135 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt thereof according to  claim 130  and a pharmaceutically acceptable carrier. 
     
     
         136 . The method according to  claim 135 , wherein the subject has been previously treated with an anti-cancer agent. 
     
     
         137 . The method according to  claim 136 , wherein the anti-cancer agent is enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, abiratarone, or a combination thereof. 
     
     
         138 . The method according to  claim 137 , wherein the anti-cancer agent is enzalutamide. 
     
     
         139 . The method according to  claim 130 , wherein L is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         140 . The method according to  claim 130 , wherein the compound of Formula (1) is a compound of Formula (1A), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         141 . The method according to  claim 130 , wherein the compound is selected from:
 (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)oxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propoxy)propoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5yl)piperazin-1-yl)butoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)oxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)butoxy)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(ethyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((((1s,3s)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2-methylpiperazine-1-carboxamide;   (3S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-3-methylpiperazine-1-carboxamide;   (3R)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-3-methylpiperazine-1-carboxamide;   4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2S,5R)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,6-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-fluoro-5-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-fluoro-5-methoxyphenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-fluoro-5-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,5-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-(trifluoromethyl)phenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(2-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(4-cyano-3-methoxyphenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide;   (2R,5S)-4-(3-chloro-4-cyanophenyl)-N-(4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)-2,5-dimethylpiperazine-1-carboxamide; and pharmaceutically acceptable salts thereof.   
     
     
         142 . A method of inhibiting cell growth, comprising contacting a cell with a compound or a pharmaceutically acceptable salt thereof according to  claim 130 . 
     
     
         143 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof.