Bisphenol ether derivatives and methods for using the same

Abstract

Compounds having a structure of Formula I, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, L1, L2, L3, X, a, b, c, n, and m are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity and uses as therapeutics as well as methods for treatment of subjects in need thereof, including prostate cancer are also provided.

1 . A compound having a structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 X is —O—, —S(O) 0-2 , —C(═O)—, —C(OR 5 ) 2 —, —C(OR 5 )(OC(═O)R 13 )—, —C(R 3 R 4 )—, —C(═CR 3 R 4 )—, —N(R 5 )—, —N(COR 4 )—, —CHNR 5 R 6 —, —C(═NR 5 )—, —C(═NOR 5 )—, —C(═N—NHR 7 )—; 
 R 1  and R 2  are each independently H, halogen, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —OH, —OR 5 , —O(C 1 -C 6 )alkyl, —OC(═O)R 13 , C 1 -C 10  acyl, —S(O) 0-2 R 5 , —NO 2 , —CN, —NH 2 , —NHR 5 , —N(R 5 R 6 ), —CO 2 H, CO 2 R 14 , or CONR 5 R 6 ; 
 R 3  and R 4  are each independently H, halogen, —S(O) 0-2 R 14 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 C 10  alkynyl, aryl, aralkyl, C 1 -C 10  acyl, or —NR 5 R 6 , or R 3  and R 4  may join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; 
 R 5  and R 6  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; 
 R 7  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, aminocarbonyl, C 1 -C 10  alkylcarbonyl, C 2 -C 10  alkenylcarbonyl, C 2 -C 10  alkynylcarbonyl, C 1 -C 10  alkylaminocarbonyl, C 2 -C 10  alkenylaminocarbonyl, or C 2 -C 10  alkynylaminocarbonyl; 
 R 13  is each independently C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; 
 R 14  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, or aryl; 
 L 1  is hydroxyl or —OC(═O)R 13 ; 
 L 2  and L 3  are each independently H, halogen, hydroxyl, —OC(═O)R 13 , —OC 1 -C 10  alkyl, —OC 2 -C 10  alkenyl, —OC 2 -C 10  alkynyl, —OR 15 , —SR 5 , —NR 5 R 6 , —O(C 1 -C 10  acyl), —OC 1 -C 10  alkylene-(—O—C 1 -C 10  alkyl) p , —OC 1 -C 10  alkylene-(—O—C 2 -C 10  alkynyl) p , —OC 1 -C 10  alkylene-(—O—C 2 -C 10  alkenyl) p , —OC 2 -C 10  alkenylene-(—O—C 1 -C 10  alkyl) p , —OC 2 -C 10  alkenylene-(—O—C 2 -C 10  alkenyl) p , —OC 2 -C 10  alkenylene-(—O—C 2 -C 10  alkynyl) p , —OC 2 -C 10  alkynylene-(—O—C 1 -C 10  alkyl) p , —OC 2 -C 10  alkynylene-(—O—C 1 -C 10  alkenyl) p , —OC 2 -C 10  alkynylene-(—O—C 2 -C 10  alkynyl) p , carbocyclyl, aryl, heterocyclyl, or heteroaryl; 
 wherein at least one of L 2  and L 3  is substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; 
 R 15  is each independently selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and 
         a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6; 
         m and n are each independently 0,1, 2, 3, or 4; and 
         p is 1, 2, 3, or 4. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are each independently H, —CN, or halogen. 
     
     
         3 . The compound of  claim 1 , wherein X is —C(R 3 R 4 )—. 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein R 3  and R 4  are each methyl. 
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein R 5  is H or C 1 -C 10  alkyl. 
     
     
         8 . The compound of  claim 1 , wherein L 1  is hydroxyl or —OC(═O)CH 3 . 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein at least one of L 2  and L 3  is substituted or unsubstituted group selected from a pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, triazine, tetrazine, oxazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, or piperazine. 
     
     
         11 . The compound of  claim 1 , wherein a is 0 or 1. 
     
     
         12 . The compound of  claim 1 , wherein b is 0 or 1. 
     
     
         13 . The compound of  claim 1 , wherein c is 0 or 1. 
     
     
         14 . The compound of  claim 1 , wherein the compound has one of the following structures (Ia), (Ib), (Ic) or (Id): 
       
         
           
           
               
               
           
         
       
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 X is —O—, —S(O) 0-2 , —C(═O)—, —C(OR 5 ) 2 —, —C(OR 5 )(OC(═O)R 13 )—, —C(R 3 R 4 )—, —C(═CR 3 R 4 )—, —N(R 5 )—, —N(COR 4 )—, —CHNR 5 R 6 —, —C(═NR 5 )—, —C(═NOR 5 )—, —C(═N—NHR 7 )—; 
 R 1  and R 2  are each independently H, halogen, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —OH, —OR 5 , —O(C 1 -C 6 )alkyl, —OC(═O)R 13 , C 1 -C 10  acyl, —S(O) 0-2 R 5 , —NO 2 , —CN, —NH 2 , —NHR 5 , —N(R 5 R 6 ), —CO 2 H, CO 2 R 14 , or CONR 5 R 6 ; 
 R 3  and R 4  are each independently H, halogen, —S(O) 0-2 R 14 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 C 10  alkynyl, aryl, aralkyl, C 1 -C 10  acyl, or —NR 5 R 6 , or R 3  and R 4  may join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; 
 R 5  and R 6  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; 
 R 7  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, aminocarbonyl, C 1 -C 10  alkylcarbonyl, C 2 -C 10  alkenylcarbonyl, C 2 -C 10  alkynylcarbonyl, C 1 -C 10  alkylaminocarbonyl, C 2 -C 10  alkenylaminocarbonyl, or C 2 -C 10  alkynylaminocarbonyl; 
 R 13  is each independently C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; 
 R 14  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, or aryl; 
 L 1  is hydroxyl or —OC(═O)R 13 ; 
 L 2  and L 3  are each independently H, halogen, hydroxyl, —OC(═O)R 13 , —OC 1 -C 10  alkyl, —OC 2 -C 10  alkenyl, —OC 2 -C 10  alkynyl, —OR 15 , —SR 5 , —NR 5 R 6 , —O(C 1 -C 10  acyl), —OC 1 -C 10  alkylene-(—O—C 1 -C 10  alkyl) p , —OC 1 -C 10  alkylene-(—O—C 2 -C 10  alkynyl) p , —OC 1 -C 10  alkylene-(—O—C 2 -C 10  alkenyl) p , —OC 2 -C 10  alkenylene-(—O—C 1 -C 10  alkyl) p , —OC 2 -C 10  alkenylene-(—O—C 2 -C 10  alkenyl) p , —OC 2 -C 10  alkenylene-(—O—C 2 -C 10  alkynyl) p , —OC 2 -C 10  alkynylene-(—O—C 1 -C 10  alkyl) p , —OC 2 -C 10  alkynylene-(—O—C 1 -C 10  alkenyl) p , —OC 2 -C 10  alkynylene-(—O—C 2 -C 10  alkynyl) p , carbocyclyl, aryl, heterocyclyl, or heteroaryl; 
 wherein at least one of L 2  and L 3  is substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; 
 R 15  is each independently selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and 
         a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6; 
         m and n are each independently 0,1, 2, 3, or 4; and 
         p is 1, 2, 3, or 4. 
       
     
     
         17 . (canceled) 
     
     
         18 . The pharmaceutical composition of  claim 16 , further comprising a pharmaceutically acceptable carrier and an additional therapeutic agent. 
     
     
         19 . The pharmaceutical composition of  claim 18 , 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, age-related macular degeneration, or combinations thereof. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the additional therapeutic agent is enzalutamide, Galeterone, ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, radium 233, or related compounds thereof. 
     
     
         21 . A method for modulating androgen receptor activity, comprising:
 administering a pharmaceutical composition according to  claim 16  to a patient in need thereof.   
     
     
         22 . A method for treating a condition or disease that is responsive to modulation of androgen receptor activity, comprising: administering a pharmaceutical composition according to  claim 16  to a patient in need thereof,
 wherein said condition or disease is 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. 
 
     
     
         23 . The method of  claim 22 , wherein the condition or disease is prostate cancer. 
     
     
         24 . The method of  claim 22 , wherein the condition or disease is castration resistant prostate cancer. 
     
     
         25 . The method of  claim 22 , wherein the condition or disease is androgen-dependent prostate cancer. 
     
     
         26 . A method for treating a condition or disease 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, comprising:
 administering to a patient in need thereof a compound having the following structure (I):   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 X is —O—, —S(O) 0-2 , —C(═O)—, —C(OR 5 ) 2 —, —C(OR 5 )(OC(═O)R 13 )—, —C(R 3 R 4 )—, —C(═CR 3 R 4 )—, —N(R 5 )—, —N(COR 4 )—, —CHNR 5 R 6 —, —C(═NR 5 )—, —C(═NOR 5 )—, —C(═N—NHR 7 )—; 
 R 1  and R 2  are each independently H, halogen, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, —OH, —OR 5 , —O(C 1 -C 6 )alkyl, —OC(═O)R 13 , C 1 -C 10  acyl, —S(O) 0-2 R 5 , —NO 2 , —CN, —NH 2 , —NHR 5 , —N(R 5 R 6 ), —CO 2 H, CO 2 R 14 , or CONR 5 R 6 ; 
 R 3  and R 4  are each independently H, halogen, —S(O) 0-2 R 14 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 C 10  alkynyl, aryl, aralkyl, C 1 -C 10  acyl, or —NR 5 R 6 , or R 3  and R 4  may join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms; 
 R 5  and R 6  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; 
 R 7  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, aminocarbonyl, C 1 -C 10  alkylcarbonyl, C 2 -C 10  alkenylcarbonyl, C 2 -C 10  alkynylcarbonyl, C 1 -C 10  alkylaminocarbonyl, C 2 -C 10  alkenylaminocarbonyl, or C 2 -C 10  alkynylaminocarbonyl; 
 R 13  is each independently C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; 
 R 14  is each independently H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, or aryl; 
 L 1  is hydroxyl or —OC(═O)R 13 ; 
 L 2  and L 3  are each independently H, halogen, hydroxyl, —OC(═O)R 13 , —OC 1 -C 10  alkyl, —OC 2 -C 10  alkenyl, —OC 2 -C 10  alkynyl, —OR 15 , —SR 5 , —NR 5 R 6 , —O(C 1 -C 10  acyl), —OC 1 -C 10  alkylene-(—O—C 1 -C 10  alkyl) p , —OC 1 -C 10  alkylene-(—O—C 2 -C 10  alkynyl) p , —OC 1 -C 10  alkylene-(—O—C 2 -C 10  alkenyl) p , —OC 2 -C 10  alkenylene-(—O—C 1 -C 10  alkyl) p , —OC 2 -C 10  alkenylene-(—O—C 2 -C 10  alkenyl) p , —OC 2 -C 10  alkenylene-(—O—C 2 -C 10  alkynyl) p , —OC 2 -C 10  alkynylene-(—O—C 1 -C 10  alkyl) p , —OC 2 -C 10  alkynylene-(—O—C 1 -C 10  alkenyl) p , —OC 2 -C 10  alkynylene-(—O—C 2 -C 10  alkynyl) p , carbocyclyl, aryl, heterocyclyl, or heteroaryl; 
 wherein at least one of L 2  and L 3  is substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; 
 R 15  is each independently selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein aa is a naturally occurring amino acid side chain and n is an integer from 1 to 200; and 
         a, b and c, are each independently 0, 1, 2, 3, 4, 5, or 6; 
         m and n are each independently 0,1, 2, 3, or 4; and 
         p is 1, 2, 3, or 4. 
       
     
     
         27 . The method of  claim 26 , wherein the condition or disease is prostate cancer. 
     
     
         28 . The method of  claim 26 , wherein the condition or disease is castration resistant prostate cancer or androgen-dependent prostate cancer. 
     
     
         29 . The compound of  claim 1 , wherein L 2  is H and L 3  is substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. 
     
     
         30 . The compound of  claim 1 , wherein at least one of L 2  and L 3  is carbocyclyl, aryl, heterocyclyl, or heteroaryl, each substituted with halogen, cyano, nitro, oxo,alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, —NR g R h , —NR g C(═O)R h , —NR g C(═O)NR g R h , —NR g C(═O)OR h , —NR g SO 2 R h , —OC(═O)NR g R h , —OR g , —SR g , —SOR g , —SO 2 R g , —OSO 2 R g , —SO 2 OR g , —SO 2 NR g R h , —C(═O)R g , —C(═O)OR g , —C(═O)NR g R h , —CH 2 SO 2 R g , or —CH 2 SO 2 —NR g R h , wherein R g  and R h  are each hydrogen, alkyl, or haloalkyl. 
     
     
         31 . The compound of  claim 1 , wherein at least one of L 2  and L 3  is carbocyclyl, aryl, heterocyclyl, or heteroaryl, each substituted with NR g SO 2 R h  or SO 2 R g , wherein R g  and R h  are each hydrogen or alkyl.