2-(Quinolonyl)-fused heterocycles as androgen receptor modulators

Abstract

The present invention is directed to novel 2-(quinolonyl)-fused heterocyclyl derivatives of the general formula (I) wherein R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , R 6 and R 7 are as herein defined, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

1 - 4 . (canceled)  
     
     
         5 . A compound of the formula (Ib)  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl and alkoxycarbonyl;  
         R 2  is selected from the group consisting of hydrogen, halogen and alkyl;  
         R 3  is selected from the group consisting of hydrogen and fluorinated alkyl;  
         R 3a  is absent or hydroxy;  
         
           
             
             
                 
                 
             
           
         
         represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;  
         R 4  and R 5  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, alkyl, halogenated alkyl, alkoxy, alkoxycarbonyl, alkyl-C(O)—O—, alkyl-C(O)—, alkyl-C(O)—NH—, carboxamide, formyl, cyano, mercapto, thioalkyl, nitro, amino, alkylamino and dialkylamino;  
         R 6  and R 7  are taken together with the carbon atoms to which they are bound to form a five to eight membered, heterocyclyl group containing at least two heteroatoms selected from the group consisting of O, N and S; wherein the heterocyclyl group is optionally substituted with one to four substituents independently selected from halogen, alkyl, halogenated alkyl, alkoxy, cyano, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl or oxo; provided that when the substituent is oxo, then the substituent is bound to a S atom of the heterocyclyl group;  
         provided that when R 1  is hydrogen, R 2  is hydrogen, R 3  is tifluoromethyl, R 3 a is absent,  
         
           
             
             
                 
                 
             
           
         
         represents a double bond, R 4  is hydrogen, R 5  is alkoxy, and R 6  and R 7  are taken together with the carbon atoms to which they are bound to form a heterocyclyl group, said heterocyclyl group is not 2,4-dioxol-1-yl;  
         or a pharmaceutically acceptable salt, ester or prodrug thereof.  
       
     
     
         6 . A compound as in  claim 5  wherein 
 R 1  is selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl, lower alkylsulfonyl, aminocarbonyl, lower alkylaminocarbonyl, di(lower alkyl)aminocarbonyl and lower alkoxycarbonyl;    R 2  is selected from the group consisting of hydrogen, halogen and lower alkyl;    R 3  is selected from the group consisting of hydrogen and fluorinated lower alkyl;    R 3a  is absent or hydroxy;                          represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;    R 4  and R 5  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkyl-C(O)—O—, lower alkyl-C(O)—, lower alkyl-C(O)—NH—, carboxamide, formyl, cyano, mercapto, thioalkyl, nitro, amino, lower alkylamino and di(lower alkyl)amino;    R 6  and R 7  are taken together with the carbon atoms to which they are bound to form a five to six membered, heterocyclyl group containing at least two heteroatoms selected from the group consisting of O, N and S; wherein the heterocyclyl group is optionally substituted with one to four substituents independently selected from halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, cyano, lower alkylcarbonyl, lower alkylsulfonyl, aminocarbonyl, lower alkylaminocarbonyl, di(lower alkyl)aminocarbonyl, lower alkoxycarbonyl or oxo; provided that when the substituent is oxo, then the substituent is bound to a S atom of the heterocyclyl group;    provided that when R 1  is hydrogen, R 2  is hydrogen, R 3  is tifluoromethyl, R 3 a is absent,                          represents a double bond, R 4  is hydrogen, R 5  is alkoxy, and R 6  and R 7  are taken together with the carbon atoms to which they are bound to form a heterocyclyl group, said heterocyclyl group is not 2,4-dioxol-1-yl;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         7 . A compound of the formula (Ic)  
       
         
           
           
               
               
           
         
         wherein  
         R 2  is selected from the group consisting of hydrogen, halogen and alkyl;  
         R 3  is selected from the group consisting of hydrogen and fluorinated alkyl;  
         R 3a  is absent or hydroxy;  
         
           
             
             
                 
                 
             
           
         
         represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;  
         R 4 , R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, alkyl, halogenated alkyl, alkoxy, alkoxycarbonyl, alkyl-C(O)—O—, alkyl-C(O)—, alkyl-C(O)—NH—, carboxamide, formyl, cyano, mercapto, thioalkyl, nitro, amino, alkylamino and dialkylamino;  
         R 7  and R 1  are taken together with the carbon atoms to which they are bound to form a five to eight membered, heterocyclyl group containing at least two heteroatoms selected from the group consisting of O, N and S; wherein the heterocyclyl group is optionally substituted with one to four substituents independently selected from halogen, alkyl, halogenated alkyl, alkoxy, cyano, alkylcarbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl or oxo; provided that when the substituent is oxo, then the substituent is bound to a S atom of the heterocyclyl group;  
         or a pharmaceutically acceptable salt, ester or prodrug thereof.  
       
     
     
         8 . A compound as in  claim 7  wherein 
 R 2  is selected from the group consisting of hydrogen, halogen and lower alkyl;    R  3  is selected from the group consisting of hydrogen and fluorinated lower alkyl;    R 3a  is absent or hydroxy;                          represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;    R 4 , R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, lower alkyl, halogenated lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkyl-C(O)—O—, lower alkyl-C(O)—, lower alkyl-C(O)—NH—, carboxamide, formyl, cyano, mercapto, thioalkyl, nitro, amino, lower alkylamino and di(lower alkyl)amino;    R 7  and R 1  are taken together with the carbon atoms to which they are bound to form a five to six membered, heterocyclyl group containing at least two heteroatoms selected from the group consisting of O, N and S; wherein the heterocyclyl group is optionally substituted with one to four substituents independently selected from halogen, lower alkyl, halogenated lower alkyl, lower alkoxy, cyano, lower alkylcarbonyl, lower alkylsulfonyl, aminocarbonyl, lower alkylaminocarbonyl, di(lower alkyl)aminocarbonyl, lower alkoxycarbonyl or oxo; provided that when the substituent is oxo, then the substituent is bound to a S atom of the heterocyclyl group;    
     
     
         9 . A compound as in  claim 8  wherein 
 R 2  is hydrogen;    R 3  is halogenated lower alkyl;    R 3a  is absent or hydroxy;                          represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;    R 4  is amino;    R 5  is hydrogen;    R 6  is hydrogen;    R 7  and R 1  are taken together with the carbon atoms to which they are bound to form a six membered, heterocyclyl group containing two heteroatoms selected from the group consisting of O, N and S;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         10 . A compound as in  claim 9  wherein 
 R 2  is hydrogen;    R 3  is trifluoromethyl;    R 3a  is absent or is OH;                          represents an optional double bond; such that when R 3a  is absent, the double bond extends from the carbon atom of the ring bound to R 2  to the carbon atom of the ring bound to R 3 ;    R 4  is amino;    R 5  is hydrogen;    R 6  is hydrogen;    R 7  and R 1  are taken together with the carbon atoms to which they are bound to form thiomorpholinyl or morpholinyl;    or a pharmaceutically acceptable salt, ester or prodrug thereof.    
     
     
         11 - 13 . (canceled)  
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 5 .  
     
     
         15 . A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 5 .  
     
     
         16 . A method of treating a condition selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hisiutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, male contraception, and male performance, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 5 .  
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 7 .  
     
     
         18 . A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 7 .  
     
     
         19 . A method of treating a condition selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hisiutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, male contraception, and male performance, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 7.