Novel bicyclic compounds as modulators of androgen receptor function

Abstract

There are provided bicyclic compounds according to formula I, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of androgen receptor-associated conditions, such as age-related diseases, for example sarcopenia, wherein R 1 , R 2 , R 2 ′, R 5 , G, n and W are defined herein. Other embodiments are also provided.

1 . A method for preventing, inhibiting or treating the progression or onset of diseases or disorders associated with nuclear hormone receptors, comprising administering to a patient a therapeutically effective amount of a compound of the formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 R 1  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, arylalkyl, substituted arylalkyl, CO 2 R 4 , CONR 4 R 4  and CH 2 OR 4 ;  
 R 2  is independently selected at each occurrence from the group consisting of H, alkyl, substituted alkyl, OR 3 , SR 3 , halo, NHR 3 , NHCOR 4 , NHCO 2 R 4 , NHCONR 4 R 4  and NHSO 2 R 4 ;  
 R 2 ′ is selected from the group consisting of OR 3 , SR 3 , halo, NHR 3 , NHCOR 4 , NHCO 2 R 4 , NHCONR 4 R 4  and NHSO 2 R 4 ;  
 R 3  is independently selected at each occurrence from the group consisting of H, alkyl, substituted alkyl, CHF 2 , CF 3  and COR 4 ;  
 R 4  is independently selected at each occurrence from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 R 5  is independently selected at each occurrence from the group consisting of H, OR 3 , CF 3 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein R 5  and R 5  taken together can form a double bond with O, S, NR 4  or CR 7 R 7  when   is a single bond, it being understood that only one R 5  is present when   is a double bond;  
 W is CR 6 R 6 , SO or SO 2 ;  
 R 6  is independently selected at each occurrence from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein at least one R 6  is H, or R 6  and R 6  taken together can form a double bond with O, S, NR 7  or CR 7 R 7 ;  
 R 7  is independently selected at each occurrence from the group consisting of H, OR 4 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 G is selected from the group consisting of aryl, heterocyclo and heteroaryl, wherein said aryl, heterocyclo or heteroaryl is mono- or polycyclic, and is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halo, CN, CF 3 , OR 4 , CO 2 R 4 , NR 4 R 4 , CONR 4 R 4 , CH 2 OR 4 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and  
 n is 1 or 2.  
 
     
     
         2 . The method according to  claim 1 , wherein the nuclear hormone receptor is the androgen receptor.  
     
     
         3 . The method according to  claim 2 , wherein the disease or disorder associated with the androgen receptor is selected from the group consisting of maintenance of muscle strength and function; reversal or prevention of frailty or age-related functional decline (ARFD) in the elderly; prevention of catabolic side effects of glucocorticoids; prevention and treatment of reduced bone density or growth; treatment of chronic fatigue syndrome (CFS); chronic myalgia; treatment of acute fatigue syndrome and muscle loss following elective surgery; treatment of urinary incontinence; acceleration of wound healing; accelerating bone fracture repair; treatment of wasting secondary to fractures and wasting in connection with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic state, eating disorders and chemotherapy.  
     
     
         4 . The method according to  claim 2 , further comprising a therapeutically effective amount of at least one other therapeutic agent.  
     
     
         5 . The method according to  claim 2 , wherein the compound is  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The method of  claim 2  wherein the compound is  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         7 . The method of  claim 2  wherein the compound is  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.