Ester derivatives of androgen receptor modulators and methods for their use

Abstract

Compounds having a structure of Structure I: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , J 1 , J 2 , X, Z, n 1 and n 2 are as defined herein, and wherein at least one of R 1 , R 2 or R 3 is an alkyl, alkenyl, aryl or aralkyl ester, are provided. Uses of such compounds for treatment of various indications, including prostate cancer, as well as methods of treatment involving such compounds are also provided.

1 - 29 . (canceled) 
     
     
         30 . A compound having the following structure (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 J 1  and J 2  are each independently —O—, —S(O) m —, —NR 6 — or —(CR 6 R 7 )—; 
 X is a direct bond, —C(R 8 R 9 ), —C(═CR 8 R 9 ), —C(R 8 R 9 )-aryl-C(R 8 R 9 ), —C(═CR 8 R 9 )-aryl-C(═CR 8 R 9 ), —C(═CR 8 R 9 )-aryl-C(R 8 R 9 ), —C(R 8 R 9 )-aryl-C(═CR8R9), —O—, —S(O) m —, —N(R 6 )—, —CH(NR 6 R 7 ), —C(═NOR 6 )—, —C(═N—NHR 10 )—, —C(═NR 6 )— or —C(═O)—; 
 Z is, at each occurrence, independently —C(R 11 )— or —N—; 
 R 1  is hydroxyl, —OR 12  or —OC(═O)(C 1 -C 6  alkyl); 
 R 2  and R 3  are each independently hydroxyl, halo, —OR 12  or —OC(═O)R 13 ; 
 R 4  and R 5  are each independently H or halo; 
 R 6  and R 7  are, at each occurrence, independently H or C 1-10  alkyl; 
 R 8  and R 9  are, at each occurrence, independently, H, hydroxyl, halo, C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, C 1 -C 10  deuteroalkyl, C 1 -C 10  alkoxy, aryl, aralkyl, —S(O) m R 14  or —NR 6 R 7 , or R 8  and R 9  may join to form a mono-, bi- or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; 
 R 10  is H, C 1 -C 10  alkyl, aryl, aminocarbonyl, C 1 -C 10  alkylcarbonyl or C 1 -C 10  alkylaminocarbonyl; 
 R 11  is, at each occurrence, independently H, halo or C 1 -C 10  alkyl; 
 R 12  is, at each occurrence, independently C 1 -C 20  alkyl or C 2 -C 20  alkenyl; 
 R 13  is, at each occurrence, independently C 1 -C 20  alkyl, C 2 -C 20  alkenyl, aryl or aralkyl, wherein the C 1 -C 20  alkyl does not include optional amino or alkylamino substituents and each aliphatic carbon of the C 1 -C 20  alkyl, C 2 -C 20  alkenyl or aralkyl groups may optionally be replaced with —O— or —S(O) m —; 
 R 14  is H, C 1 -C 10  alkyl or aryl; 
 m is, at each occurrence, independently 0, 1 or 2; 
 n 1  and n 2  are each independently 0, 1, 2, 3, 4 or 5, 
 
       wherein at least R 1  is —OC(═O)(C 1 -C 6  alkyl) or at least R 2  is —OC(═O)R 13 ; 
     
     
         31 . The compound of  claim 30 , wherein the compound has one of the following structures (Ia) or (Ib): 
       
         
           
           
               
               
           
         
         wherein R 11a , R 11b , R 11c  and R 11d  are each independently H, halo or C 1 -C 10  alkyl. 
       
     
     
         32 . The compound of any one of  claim 30 , wherein J 1  and J 2  are each —O—. 
     
     
         33 . The compound of  claim 30 , wherein X is —C(R 8 R 9 )—. 
     
     
         34 . The compound of  claim 30 , wherein R 3  is —OR 12 . 
     
     
         35 . The compound of  claim 34 , wherein R 12  is C 1 -C 6  alkyl or R 12  is methyl, isopropyl or n-butyl. 
     
     
         36 . The compound of  claim 30 , wherein R 3  is halo. 
     
     
         37 . The compound of 1, wherein each R 13  is independently C 1 -C 6  alkyl or R 13  is independently methyl, ethyl or propyl. 
     
     
         38 . The compound of  claim 30 , wherein R 8  and R 9  are each independently C 1 -C 6  alkyl or R 8  and R 9  are each methyl. 
     
     
         39 . The compound of  claim 30 , wherein at least one R 11  is H or each R 11  is H. 
     
     
         40 . The compound of  claim 30 , wherein n 1  and n 2  are each 1. 
     
     
         41 . The compound of  claim 30 , wherein R 4  and R 5  are each H or R 4  and R 5  are each halo. 
     
     
         42 . The compound  claim 30 , wherein R 13  is C 1 -C 20  alkyl, C 2 -C 20  alkenyl or aralkyl, and at least one of the aliphatic carbons of the C 1 -C 20  alkyl, C 2 -C 20  alkenyl or aralkyl group is substituted with a substituent selected from hydroxyl, halo, oxo and alkoxy, or R 13  is aryl or aralkyl, and at least one of the aromatic carbons of the aryl or aralkyl group is substituted with a substituent selected from hydroxyl, halo and alkoxy. 
     
     
         43 . The compound of  claim 30 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 30  and a pharmaceutically acceptable carrier. 
     
     
         45 . A pharmaceutical composition comprising a compound of  claim 30 , an additional therapeutic agent and a pharmaceutically acceptable carrier. 
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration. 
     
     
         47 . The pharmaceutical composition of  claim 45 , wherein the additional therapeutic agent is enzalutamide, galeterone, ARN-509 (4-(7-(6-cyano-5-(tlifluoromethyl)pylidin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-5-yl)-2-fluoro-N-methylbenzamide), abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab, OSU-HDAC42 ((S)-(+)-N-Hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide, monoclonal antibody against the vascular integrin αvβ3, sunitumib, ZD-4054 (zibotentan), cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427 (apatorsen), OGX 011 (custirsen), finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260 ((1S,3aS,3bS,5aR,9aR,9bS,11aS)-9a,11a-dimethyl-7-oxo-N-(1,1,1-trifluoro-2-phenylpropan-2-yl)-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide), SKF105,111 (17β-(Di-isopropyl-aminocarbonyl)androsta-3,5-diene-3-carboxylic acid), radium 233, and related compounds thereof. 
     
     
         48 . A method for modulating androgen receptor activity, comprising administering a compound according to  claim 30  to a patient in need thereof. 
     
     
         49 . The method of  claim 48 , wherein modulating androgen receptor activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. 
     
     
         50 . The use of  claim 49 , wherein the indication is prostate cancer. 
     
     
         51 . The method of  claim 50 , wherein the prostate cancer is castration resistant prostate cancer or the prostate cancer is androgen-dependent prostate cancer.