Small molecule inhibitors of n-terminus activation of the androgen receptor

Abstract

Compounds having a structure of Formula (A) are provided. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are provided. Uses of compounds having a structure of Formula (F) for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provided.

1 .- 47 . (canceled) 
     
     
         48 . A method of treating a disease or a condition, comprising administering to a subject in need thereof an effective amount of a compound of the Formula (A): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is C or N; 
 Y is O or S; 
 R 1  is H, OH, J, OJ, SJ, or NJJ′, wherein J or J′ are each independently a one to ten carbon linear, branched, non-aromatic cyclic, or aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 , and wherein R is a linear, or branched saturated and unsubstituted C 1 -C 10  alkyl; 
 R 2  is H or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 , and wherein R is a linear, or branched saturated and unsubstituted C 1 -C 10  alkyl; 
 R 3  is H, OH, OG, SG, NGG′ or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein G and G′ are each independently a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group and wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 ; 
 R 4  and R 6  are each independently H or a one to ten carbon linear, branched, aromatic cyclic, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, OR, R, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 , and wherein R is a linear, or branched saturated and unsubstituted C 1 -C 10  alkyl; 
 R 5  is H or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 ; 
    is a single bond or a double bond; 
 
       wherein the disease or a condition is prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty or age-related macular degeneration. 
     
     
         49 . The method of  claim 48 , wherein the compound has a structure of Formula (B): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically salt thereof, wherein:
 X is C or N; 
 Y is O or S; 
 R 1  is H, OH, J, OJ, SJ, or NJJ′, wherein J or J′ are each independently a one to ten carbon linear, branched, non-aromatic cyclic, or aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 ; 
 R 2  is H or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 , and wherein R is a linear, or branched saturated and unsubstituted C 1 -C 10  alkyl; 
 R 3  is H, OH, OG, SG, NGG′ or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein G and G′ are each independently a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated alkyl group and wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 ; and 
 R 4  is H or a one to ten carbon linear, branched, aromatic cyclic, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, OR, R, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 ,and wherein R is an unsubstituted C 1 -C 10  alkyl; 
 R 5  is H or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 ; 
 Z is an optionally substituted butyl, propyl, ethyl, or methyl, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 ; and 
    is a single bond or a double bond. 
 
     
     
         50 . The method of  claim 49 , wherein   is a double bond. 
     
     
         51 . The method of  claim 48 , wherein the compound has a structure of Formula (C): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is butyl, propyl, ethyl, or methyl; 
 M is H, OH, OBu, OPr, OEt, OMe, butyl, propyl, ethyl, or methyl; 
 T is 
 
       
         
           
           
               
               
           
         
         E is butyl, propyl, ethyl, or methyl; 
         Q is 
       
       
         
           
           
               
               
           
         
         L is butyl, propyl, ethyl, or methyl; 
         R 8  is Cl 3 C, Cl 2 HC, ClH 2 C butyl, propyl, ethyl, or methyl; and 
         R 9  is Cl 3 C, Cl 2 HC, ClH 2 C, butyl, propyl, ethyl, or methyl; 
       
       and wherein,
 A, T, E, Q, and L are optionally substituted, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 . 
 
     
     
         52 . The method of  claim 48 , wherein the compound has a structure of Formula (D): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is butyl, propyl, ethyl, or methyl; 
 D is butyl, propyl, ethyl, or methyl; 
 E is butyl, propyl, ethyl, or methyl; 
 L is butyl, propyl, ethyl, or methyl; 
 R 8  is Cl 3 C, Cl 2 HC, ClH 2 C, butyl, propyl, ethyl, or methyl; and 
 R 9  is Cl 3 C, Cl 2 HC, ClH 2 C, butyl, propyl, ethyl, or methyl. 
 
     
     
         53 . The method of  claim 48 , wherein the compound has a structure of Formula (E): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 8  is Cl 3 C, Cl 2 HC, ClH 2 C, ethyl, or methyl; and 
 R 9  is Cl 3 C, Cl 2 HC, ClH 2 C, ethyl, or methyl. 
 
     
     
         54 . The method of  claim 48 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method of  claim 48 , wherein the subject is a human. 
     
     
         56 . The method of  claim 48 , wherein the condition or the disease is prostate cancer. 
     
     
         57 . The method of  claim 56 , wherein the prostate cancer is castration resistance prostate cancer. 
     
     
         58 . The method of  claim 56 , wherein the prostate cancer is androgen-independent prostate cancer. 
     
     
         59 . The method of  claim 56 , wherein the prostate cancer androgen-dependent prostate cancer.