Androgen receptor modulator compounds and methods

Abstract

Compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. In particular, preparation and methods of use of non-steroidal compounds and compositions that are agonists, partial agonists, and antagonists for the androgen receptor (AR) are described. Further, described are the methods of making and use of critical intermediates including a stereoselective synthetic route to intermediates for the AR modulators.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
       wherein:  
       R x  is selected from among C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, allyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl;  
       R 4  is selected from among hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl; and  
       R 13  is selected from among hydrogen, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 3 -C 8  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl groups are optionally substituted.  
     
   
   
       2 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R x  is selected from among C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, allyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl;  
 R 4  is selected from among hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl;  
 R 6  is selected from among hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C8 haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl; and  
 R 13  is selected from among hydrogen, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 3 -C 8  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl groups are optionally substituted.  
 
   
   
       3 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 6  is selected from among hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl;  
 R 7  is selected from among hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, aryl, arylalkyl, heteroaryl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C 1 -C 4  alkyl, or C 1 -C 4  haloalkyl; and  
 R 13  is selected from among hydrogen, C 1 -C 8  alkyl, C 1 -C 8  heteroalkyl, C 1 -C 8  haloalkyl, C 3 -C 8  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, C 2 -C 8  alkynyl, and C 2 -C 8  alkenyl, wherein the alkyl, heteroalkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl groups are optionally substituted.