Androgen receptor modulators and methods for their use

Abstract

The present invention relates to compounds of formula (I)-(VI) and/or (A)-(H-I), or any subgenera thereof, or a pharmaceutically acceptable salt, tautomer or stereoisomer. The compounds of the present disclosure are useful in modulating androgen receptor activity and for treating cancer including prostate cancer.

What is claimed is: 
     
         1 . A compound having the structure of formula (IIIA): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
 A and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene; 
 C is a 3- to 10-membered ring; 
 X is a bond, —(CR 5 R 6 ) t —, or —NR 7 ; 
 Y is a bond, —(CR 8 R 9 ) m —, —O—, —S—, —S(═O)—, —SO 2 —, —NR 7 —, or —N(COCH 3 )—; 
 W is a bond, —(CR 8a R 9a ) m —, —C(═O)—, —N(R 7 )CO—, —CONR 7 —, or —NSO 2 R 7 —; 
 Z is a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—; 
 V is —CH 2 — and L is halogen, —NH 2 , —CHCl 2 , —CCl 3 , or —CF 3 ; or 
 V is —CH 2 CH 2 — and L is halogen or —NH 2 ; 
 R 1  and R 2  are each independently hydrogen, halogen, —CN, —CF 3 , —OH, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  alkoxy, optionally substituted —(C 1 -C 6  alkyl)-(C 1 -C 6  alkoxy), optionally substituted —(C 1 -C 6  alkyl)-OH, —NR 13 R 14 , optionally substituted —(C 1 -C 6  alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , optionally substituted —(C 1 -C 6  alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , optionally substituted —(C 1 -C 6  alkyl)-NR 14 COR 16 , —CONR 13 R 14 , optionally substituted —(C 1 -C 6  alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —(C 1 -C 6  alkyl)-SO 2 NR 14 R 15 , optionally substituted —SO 2 R 16  or optionally substituted —(C 1 -C 6  alkyl)-SO 2 R 16 ; 
 R 3  is selected from halogen, oxo, ═S, ═NR 16 , —CN, —CF 3 , —OH, —S(C 1 -C 3  alkyl), C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, C 1 -C 3  alkoxy, —NR 13 R 14 , —(C 1 -C 3  alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , —(C 1 -C 3  alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , —(C 1 -C 6  alkyl)-NR 14 COR 16 , —CONR 14 R 15 , —(C 1 -C 3  alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , —(C 1 -C 3  alkyl)-SO 2 NR 14 R 15 , —SO 2 (C 1 -C 3  alkyl), or —(C 1 -C 6  alkyl)-SO 2 (C 1 -C 3  alkyl); 
 R 5  and R 6  are each independently hydrogen, halogen, —OH, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, or C 1 -C 3  alkoxy; or R 5  and R 6  taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; 
 R 7  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 R 8  and R 9  are each independently hydrogen, halogen, or C 1 -C 3  alkyl; 
 R 8a  and R 9a  are each independently hydrogen, —OH, halogen, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, C 1 -C 3  alkoxy, —NR 13 R 14 , —(C 1 -C 3  alkyl)-NR 13 R 14 , —NR 14 COR 16 , —(C 1 -C 3  alkyl)-NR 14 COR 16 , —CONR 14 R 15 , or —(C 1 -C 3  alkyl)-CONR 14 R 15 ; or R 8a  and R 8b  taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; 
 R 13 , R 14  and R 15  are each independently hydrogen, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl; or R 14  and R 15  taken together form a 3- to 6-membered heterocyclyl; 
 R 16  is hydrogen, optionally substituted C 1 -C 3  alkyl, optionally substituted C 2 -C 3  alkenyl, optionally substituted C 2 -C 3  alkynyl, C 3 -C 6  cycloalky, or phenyl; 
 each m is independently 0, 1, or 2; 
 n1 and n2 are each independently 0, 1, or 2; 
 n3 is 1, 2, 3, 4 or 5; and 
 t is 0, 1 or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound has the structure of formula (IVA): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
 A and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene; 
 C is a 3- to 10-membered ring; 
 X is a bond, —(CR 5 R 6 ) t —, or —NR 7 ; 
 Y and Z are each independently a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—; 
 W is a bond, —CH 2 —, —C(CH 3 )H—, —C(═O)—, —N(R 7 )CO—, or —CONR 7 —; 
 V is —CH 2 — and L is halogen, —NH 2 , or —CF 3 ; or 
 V is —CH 2 CH 2 — and L is halogen or —NH 2 ; 
 R 1  and R 2  are each independently hydrogen, halogen, —CN, —CF 3 , —OH, optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  alkoxy, optionally substituted —(C 1 -C 6  alkyl)-(C 1 -C 6  alkoxy), optionally substituted —(C 1 -C 6  alkyl)-OH, —NR 13 R 14 , optionally substituted —(C 1 -C 6  alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , optionally substituted —(C 1 -C 6  alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , optionally substituted —(C 1 -C 6  alkyl)-NR 14 COR 16 , —CONR 13 R 14 , optionally substituted —(C 1 -C 6  alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —(C 1 -C 6  alkyl)-SO 2 NR 14 R 15 , optionally substituted —SO 2 R 16 , optionally substituted —(C 1 -C 6  alkyl)-SO 2 R 16 ; 
 R 3  is selected from halogen, oxo, ═S, ═NR 16 , —CN, —CF 3 , —OH, —S(C 1 -C 3  alkyl), C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, C 1 -C 3  alkoxy, —NR 13 R 14 , —(C 1 -C 3  alkyl)-NR 13 R 14 , —NR 14 SO 2 R 16 , —(C 1 -C 3  alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , —(C 1 -C 6  alkyl)-NR 14 COR 16 , —CONR 14 R 15 , —(C 1 -C 3  alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , —(C 1 -C 3  alkyl)-SO 2 NR 14 R 15 , —SO 2 (C 1 -C 3  alkyl), or —(C 1 -C 6  alkyl)-SO 2 (C 1 -C 3  alkyl); 
 R 5  and R 6  are each independently hydrogen, halogen, —OH, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, or C 1 -C 3  alkoxy; or R 5  and R 6  taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; 
 R 7  is H or C 1 -C 6  alkyl; 
 R 13 , R 14  and R 15  are each independently hydrogen, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl; or R 14  and R 15  taken together form a 3- to 6-membered heterocyclyl; 
 R 16  is hydrogen, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl; 
 n1 and n2 are each independently 0, 1, or 2; 
 n3 is 1, 2, 3, 4 or 5; and 
 t is 0, 1 or 2. 
 
     
     
         3 . The compound of  claim 2 , wherein C is 5- to 10-membered heteroaryl or aryl. 
     
     
         4 . The compound of  claim 3 , wherein C is 5- to 7-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member. 
     
     
         5 . The compound of  claim 4 , wherein C, which is substituted with (R 3 )n3, is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl. 
     
     
         6 . The compound of  claim 5 , wherein C, which is substituted with (R 3 )n3, is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R 3a  is C 1 -C 3  alkyl. 
     
     
         7 . The compound of  claim 6 , wherein R 1  and R 2  are each independently Cl, —CN, —CF 3 , —OH, methyl, methoxy, or —CONH 2 . 
     
     
         8 . The compound of  claim 2 , wherein:
 A and B are phenyl;   X is —(CR 5 R 6 ) t —;   Y and Z are each —O—;   V is —CH 2 — or —CH 2 CH 2 —;   L is halogen;   R 1  and R 2  are each independently hydrogen, halogen, —CN, —CF 3 , —OH, or optionally substituted C 1 -C 6  alkyl;   R 5  and R 6  are each independently hydrogen, halogen, —OH, or C 1 -C 3  alkyl; and   R 16  is hydrogen, C 1 -C 3  alkyl, C 2 -C 3  alkenyl, or C 2 -C 3  alkynyl.   
     
     
         9 . The compound of  claim 8 , wherein:
 R 5  and R 6  are each independently hydrogen, or C 1 -C 3  alkyl;   W is —CH 2 — or —C(CH 3 )H—;   V is —CH 2 CH 2 —; and   R 1  and R 2  are each independently hydrogen, halogen, or —CN.   
     
     
         10 . The compound of  claim 1 , wherein the compound has the structure of formula (A-I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
 C is a 5- to 7-membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member; 
 X is a bond, —(CR 5 R 6 ) t —, or —NR 7 ; 
 Y is a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—; 
 Z is a bond, —CH 2 —, —O—, or —NH—; 
 W is a bond, —CH 2 —, —C(CH 3 )H—, —C(═O)—, —N(R 7 )CO—, or —CONR 7 —; 
 V is —CH 2 — and L is halogen, —NH 2 , or —CF 3 ; or 
 V is —CH 2 CH 2 — and L is halogen or —NH 2 ; 
 R 1  and R 2  are each independently hydrogen, halogen, —CN, —CF 3 , methyl, or —CONH 2 ; 
 at least one R 3  is selected from —CN, C 1 -C 3  alkoxy, —CONH 2 , —NHSO 2 CH 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , or —SO 2 CH 3  and the other R 3 , if present, is selected from —CN, —CF 3 , C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, C 1 -C 3  alkoxy, —S(C 1 -C 3  alkyl), —SO 2 (C 1 -C 3  alkyl), —NH 2 , —(C 1 -C 3  alkyl)NH 2 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , —CH 2 NHSO 2 CH 3 , —CH 2 N(CH 3 )SO 2 CH 3 , —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 3  alkyl) 2 , —CONH(C 1 -C 3  alkyl), —NHCO(C 1 -C 3  alkyl), —N(CH 3 )COO(C 1 -C 3  alkyl), —NHCO(C 1 -C 3  alkyl), or —N(CH 3 )COO(C 1 -C 3  alkyl); 
 R 5  and R 6  are each independently hydrogen, halogen, —OH, or C 1 -C 3  alkyl; 
 R 7  is H or C 1 -C 6  alkyl; 
 n1 and n2 are each independently 0, 1, or 2; 
 n3 is 1, 2, 3, 4 or 5; and 
 t is 0, 1 or 2. 
 
     
     
         11 . The compound of  claim 10 , wherein:
 X is a bond or —(CR 5 R 6 ) t ;   W is a bond, —CH 2 —, or —C(CH 3 )H—;   Y is —O—;   Z is —O—;   V is —CH 2 — or —CH 2 CH 2 —; and   L is halogen.   
     
     
         12 . The compound of  claim 1 , wherein:
 at least one R 3  is selected from —NHSO 2 CH 3 , —NHSO 2 CH 2 CH 3 , or —SO 2 CH 3  and the other R 3 , if present, is selected from —CN, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, —SO 2 (C 1 -C 3  alkyl), —NH 2 , —(C 1 -C 3  alkyl)NH 2 , —NHSO 2 CH 3 , —N(CH 3 )SO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —N(CH 3 )SO 2 CH 2 CH 3 , —SO 2 NH 2 , —CONH 2 , —CON(C 1 -C 3  alkyl) 2 , —CONH(C 1 -C 3  alkyl), —NHCO(C 1 -C 3  alkyl), —N(CH 3 )COO(C 1 -C 3  alkyl), —NHCO(C 1 -C 3  alkyl), or —N(CH 3 )COO(C 1 -C 3  alkyl).   
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for treating cancer, comprising administering the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug of the compound of  claim 1 , to a subject in need thereof. 
     
     
         15 . The method of  claim 14 , wherein the cancer is prostate cancer. 
     
     
         16 . The method of  claim 14 , wherein the prostate cancer is metastatic castration-resistant prostate cancer. 
     
     
         17 . The method of  claim 16 , wherein the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.