Diglycidic ether derivative therapeutics and methods for their use

Abstract

This invention provides compound having a structure of Formula I or Formula II. Uses of such compounds for treatment of various indications, including prostrate cancer as well as methods of treatment involving such compounds are also provided.

1 .- 89 . (canceled) 
     
     
         90 . A compound having a structure of Formula II 
       
         
           
           
               
               
           
         
         wherein 
         each J and J′ is independently H; 
         each L and L′ is independently O; 
         each Q and Q′ is O; 
         each Z and Z′ is independently CH, CF, CCl, CBr, or CI; 
         R 1  and R 2  are each independently H, or a branched or unbranched, substituted or unsubstituted C 1 -C 10  alkyl; 
         X is CH 2 O (isopropyl), CH 2 OC 2 H 4 OC 4 H 9 , CH 2 I, CH 2 Br, or CH 2 F; 
         X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 F, CH 2 OJ′″, or CH 2 OG; 
         J′″ is independently H; 
         G is a branched or unbranched, non-aromatic cyclic, substituted or unsubstituted, saturated C 1 -C 10  alkyl; 
         wherein the optional substituent is selected from the group consisting of: oxo, COOH, R, OH, OR, F, Cl, Br, or I, wherein R is an unsubstituted C 1 -C 10  alkyl; and 
         wherein X′ is no —CH 2 O(CH 2 ) 2 CH 3 , or —CH 2 O(CH 2 ) 3 CH 3 ; and 
         wherein X is not —CH 2 O(CH 2 ) 2 —O—(CH 2 ) 3 CH 3  when X′ is CH 2 OH. 
       
     
     
         91 . The compound of  claim 90 , wherein each L and L′, when present, is O. 
     
     
         92 . The compound of  claim 90 , wherein each Z and Z′ is CH. 
     
     
         93 . The compound of  claim 90 , wherein each R 1  and R 2  is CH 3 . 
     
     
         94 . The compound of  claim 90 , wherein X is CH 2 F, or CH 2 O (isopropyl). 
     
     
         95 . The compound of  claim 90 , wherein X′ is CH 2 F, CH 2 Cl or CH 2 OG. 
     
     
         96 . The compound of  claim 90 , wherein X′ is CH 2 F, CH 2 Cl, CH 2 OCH 3  or CH 2 O (isopropyl). 
     
     
         97 . The compound of  claim 90 , wherein X′ is CH 2 OH. 
     
     
         98 . A pharmaceutical composition comprising a compound according to  claim 90  and a pharmaceutically acceptable excipient. 
     
     
         99 . A method for modulating androgen receptor (AR) activity for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration;
 wherein, the method comprises administering to a subject in need thereof, a compound according to  claim 90 .   
     
     
         100 . The method of  claim 99 , wherein the modulating AR activity is transactivation of the AR N-terminal domain (NTD). 
     
     
         101 . The method of  claim 99 , wherein the indication is prostate cancer. 
     
     
         102 . The method of  claim 101 , wherein the prostate cancer is castration-resistant prostate cancer. 
     
     
         103 . A method for modulating androgen receptor (AR) activity for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration;
 wherein, the method comprises administering to a subject in need thereof, a compound having a structure of Formula II′:   
       
         
           
           
               
               
           
         
         wherein 
         each L and L′ is O; 
         X is CH 2 F, CH 2 I, CF 2 Br, CH 2 OH, CH 2 OCH 3 , or CH 2 O (isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 ; 
         X′ is CH 2 Cl, CH 2 F, CH 2 I, CH 2 Br, CH 2 OCH 3 , CH 2 O (isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 ; 
         each Q and Q′ is O; 
         each Z and Z′ is independently CH, CF, CCl, CBr, or CI; 
         R 1  and R 2  are each independently H, or a branched or unbranched, substituted or unsubstituted C 1 -C 10  alkyl; 
         J and J′ are each independently H; and 
         wherein the optional substituent is selected from the group consisting of: oxo, COOH, R, OH, OR, F, Cl, Br, or I, wherein R is an unsubstituted C 1 -C 10  alkyl. 
       
     
     
         104 . The method of  claim 103 , wherein X is CH 2 OH. 
     
     
         105 . The method of  claim 103 , wherein X is CH 2 F, CH 2 I, CH 2 Br, or CH 2 OCH 3 . 
     
     
         106 . The method of  claim 103 , wherein X′ is CH 2 Cl. 
     
     
         107 . The method of  claim 103 , wherein X′ is CH 2 Cl, CH 2 F, CH 2 I, CH 2 Br, or CH 2 OCH 3 . 
     
     
         108 . The method of  claim 103 , wherein Z and Z′ is CH. 
     
     
         109 . The method of  claim 103 , wherein R 1  and R 2  is CH 3 . 
     
     
         110 . The method of  claim 103 , wherein the modulating AR activity is transactivation of the AR N-terminal domain (NTD). 
     
     
         111 . The method of  claim 103 , wherein the indication is prostate cancer. 
     
     
         112 . The method of  claim 111 , wherein the prostate cancer is castration-resistant prostate cancer.