Androgen receptor antagonists and uses thereof

Abstract

The present invention relates to novel substituted thioimidazolidinone compounds and pharmaceutical compositions comprising such compounds for treatment of androgen receptor-associated diseases or disorders, such as prostate cancer, benign prostatic hypertrophy, male hair loss, muscle loss, acne and hirsutism.

What we claim is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt, solvate, hydrate, prodrug or derivative thereof, 
         wherein R 1  is selected from 
       
       
         
           
           
               
               
           
         
         wherein Z is selected from hydrogen, CF 3 , alkoxy, CF 3 O, halogen, cyano and C 1 -C 4  alkyl optionally substituted with one or more halogens; 
         Y is selected from halogen, alkoxy, hydroxyl, CF 3 O and cyano; 
         W is selected from oxygen, sulfur and two hydrogens; 
         R 3  and R 4  are independently selected from C 1 -C 4  alkyl optionally substituted with one or more fluoro or hydroxyl groups, or R 3  and R 4  and the carbon to which they are attached together form a 3-6 membered cycloalkyl ring, wherein one or more carbons may be optional substituted with one or more fluoro or hydroxyl groups, and wherein one of the carbons is optionally an oxygen or nitrogen; and 
         R 2  is a substituted or unsubstituted alkyl, aryl, heteroaryl or heterocyclic group. 
       
     
     
         2 . The compound of  claim 1  wherein R 2  is an aryl group substituted with one or more C 1 -C 6  alkyl, C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″, C(O)OR″, CH 2 (CH 2 ) m Q, halogen or a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; and Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
     
     
         3 . The compound of  claim 1  wherein R 2  is a heteroaryl group substituted with one or more C 1 -C 6  alkyl, C(O)NHR″, SO 2 NHR″, cyano, C(S)NHR″, C(O)OR″, hydroxyl, alkoxy, CH 2 (CH 2 ) m Q, halogen or a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; and Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
     
     
         4 . The compound of  claim 1  wherein R 3  and R 4  are independently selected from methyl, ethyl, or methyl optionally substituted with one or more fluoro groups. 
     
     
         5 . The compound of  claim 1  wherein R 3  and R 4  and the carbon to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring which may be optionally substituted with one or more fluoro or hydroxyl groups. 
     
     
         6 . The compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt, solvate, hydrate, prodrug or derivative thereof, 
         wherein R′ 1  is selected from 
       
       
         
           
           
               
               
           
         
         wherein Z is selected from hydrogen, CF 3 , alkoxy, CF 3 O, halogen, cyano and C 1 -C 4  alkyl optionally substituted with one or more halogen; 
         Y′ is selected from alkyl and CF 3 ; 
         R′ is selected from C 1 -C 3  alkyl or CF 3 ; 
         W is selected from oxygen, sulfur and two hydrogens; 
         R′ 3  and R′ 4  and the carbon to which they are attached together form a 3-6 membered cycloalkyl ring wherein one or more carbons may be optional substituted with one or more fluoro or hydroxyl groups, and wherein one of the carbons is optionally an oxygen or nitrogen; and 
         R 2  is a substituted or unsubstituted alkyl, aryl, heteroaryl or heterocyclic group. 
       
     
     
         8 . The compound of  claim 7  wherein R 2  is an aryl group substituted with one or more C 1 -C 6  alkyl, C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″, C(O)OR″, CH 2 (CH 2 ) m Q, halogen or a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; and Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
     
     
         9 . The compound of  claim 7  wherein R 2  is a heteroaryl group substituted with one or more C 1 -C 6  alkyl, C(O)NHR″, SO 2 NHR″, cyano, C(S)NHR″, C(O)OR″, hydroxyl, alkoxy, CH 2 (CH 2 ) m Q, halogen or a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
     
     
         10 . The compound of  claim 7  wherein R′ 3  and R′ 4  and the carbon to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring which may be optionally substituted with one or more fluoro or hydroxyl groups. 
     
     
         11 . The compound of  claim 7  selected from 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt, solvate, hydrate, prodrug or derivative thereof, 
         wherein Z 1  is selected from CF 3 O, methyl, CH 2 F, CHF 2 , CF 3 , methoxy, halogen and cyano; 
         X is selected from halogen, alkoxy, CF 3 O, hydroxyl and cyano; 
         W is selected from oxygen, sulfur and two hydrogens; 
         R″ 3  and R″ 4  are methyl, or R″ 3  and R″ 4  and the carbon to which they are attached together form a 3-6 membered alkyl ring which may be optionally substituted with one or more fluoro or hydroxyl groups; and 
         R 2  is a substituted or unsubstituted alkyl, aryl, heteroaryl or heterocyclic group. 
       
     
     
         13 . The compound of  claim 12  wherein R 2  is an aryl group substituted with one or more C 1 -C 6  alkyl, C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″, C(O)OR″, CH 2 (CH 2 ) m Q, halogen or a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; and Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
     
     
         14 . The compound of  claim 12  wherein R 2  is a heteroaryl group substituted with one or more C 1 -C 6  alkyl, C(O)NHR″, SO 2 NHR″, cyano, C(S)NHR″, C(O)OR″, hydroxyl, alkoxy, CH 2 (CH 2 ) m Q, halogen or a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; and Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
     
     
         15 . The compound of  claim 12  wherein R″ 3  and R″ 4  are methyl, or R″ 3  and R″ 4  and the carbon to which they are attached together form a cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl ring which may be optionally substituted with one or more fluoro or hydroxyl groups. 
     
     
         16 . The compound of  claim 12  selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt, solvate, hydrate, prodrug or derivative thereof, wherein Z 1  is selected from CF 3 O, methyl, CH 2 F, CHF 2 , CF 3 , methoxy, halogen and cyano; 
         X is selected from halogen, alkoxy, CF 3 O, hydroxyl and cyano; 
         W is selected from oxygen, sulfur and two hydrogens; 
         R″ 3  and R″ 4  are methyl, or R″ 3  and R″ 4  and the carbon to which they are attached together form a 3-6 membered cycloalkyl ring optionally substituted with one or more fluoro or hydroxyl groups; 
         B is independently selected from one or more hydrogen, cyano, methyl, CF 3  or halogen; and 
         A is selected from C 1 -C 6  alkyl, C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″, C(O)OR″, CH 2 (CH 2 ) m Q, halogen and a 5-6 membered heteroaryl group, where R″ is selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  cycloalkyl and C 1 -C 6  alkenyl; m is an integer selected from 0 to 6; and Q is selected from C(O)NHR″, SO 2 R″, SO 2 NHR″, cyano, hydroxyl, alkoxy, C(S)NHR″ and C(O)OR″. 
       
     
     
         18 . The compound of  claim 17  wherein R″ 3  and R″ 4  are methyl, or R″ 3  and R″ 4  and the carbon to which they are attached together form a cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl ring which may be optionally substituted with one or more fluoro or hydroxyl groups. 
     
     
         19 . The compound of  claim 17  selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . A method for preventing, reducing the progression of, treating or regressing a disease or disorder related to androgen receptor activity by administering to a subject at risk for development thereof or afflicted therewith, a compound of  claim 1  or a pharmaceutical composition thereof.