Aminophenyl derivatives as selective androgen receptor modulators

1. A compound represented by formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

ring A, which comprises atoms Y 1 and Y 2 , is optionally substituted 8-azabicyclo[3.2.1]oct-8-yl

R 1 is selected from the group consisting of cyano and nitro;

Z 1 and Z 2 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halogen, cyano, hydroxy, optionally substituted aminoalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, —C(O)OR 4 , —C(O)NR 4 R 5 , —NHC(O)R 4 , —NHSO 2 R 4 , —CH═NOR 4 , CF 3 , —OC(O)R 4 , —OCR 4 , SR 4 , —S(O) n R 8 , and —SO 2 NR 8 R 9 ;

R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heteroarylalkyl or substituted heteroarylalkyl, and heteroaryl or substituted heteroaryl;

R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heteroarylalkyl or substituted heteroarylalkyl, heteroaryl or substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , NHC(O)R 4 , NR 4 C(O)R 5 , OC(O)R 4 , C(S)R 4 , C(S)OR4, C(S)NR 4 R 5 , NHC(S)R 4 , OC(S)R 4 , S(O)R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 , and alkyl substituted with OR 4 , NR 4 R 5 , SR 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , NHC(O)R 4 , NR 4 C(O)R 5 , OC(O)R 4 , C(S)R 4 , C(S)OR 4 , C(S)NR 4 R 5 , NHC(S)R 4 , OC(S)R 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , or NHSO 2 R 4 ;

R 8 and R 9 are each independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl, and heteroarylalkyl or substituted heteroarylalkyl; and

n is an integer from 1 to 3.

2. The compound of claim 1 , wherein: Z 1 and Z 2 are independently selected from the group consisting of unsubstituted —(C 1 -C 4 alkyl, —(C 1 -C 4 alkylOH, —(C 1 -C 4 alkyl(halo), halo, cyano, —OR 4 , —OC(O)R 4 , —CF 3 , —CHO and —CH═NOR 4 ; R 6 and R 7 are independently selected from the group consisting of hydrogen, unsubstituted —(C 1 -C 4 alkyl, —(C 1 -C 4 )alkylOH, —(C 1 -C 4 )alkyl(halo), halo, cyano, —OR 4 , —OC(O)R 4 and —CF 3 ; and, R 4 is selected from the group consisting of hydrogen, unsubstituted (C 1 -C 4 )alkyl, unsubstituted (C 3 -C 6 )cycloalkyl and unsubstituted aryl.

3. The compound of claim 1 , wherein optionally substituted 8-azabicyclo[3.2.1]oct-8-yl has the structure:

4. The compound of claim 3 , wherein R 6 is hydroxy.

5. The compound of claim 4 , wherein R 7 is —(C 1 -C 4 alkyl.

6. The compound of claim 5 , wherein R 7 is bonded to the same carbon atom to which R 6 is bonded.

7. The compound of claim 1 , wherein Z 1 is alkyl, halogen, haloalkyl or hydroxyalkyl.

8. The compound of claim 1 , wherein Z 2 is alkyl, halogen, haloalkyl or hydroxyalkyl.

9. The compound of claim 1 , wherein Z 1 is methyl or ethyl and Z 2 is halogen.

10. The compound of claim 1 , wherein Z 1 is methyl or ethyl and Z 2 is chloro.

11. The compound of claim 1 , wherein Z 1 is methyl, and Z 2 is chloro.

12. The compound of claim 1 , selected from the group consisting of:

endo-8-(3-chloro-2-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-3-methylbenzonitrile;

6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic acid;

3-Bromo-2-chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile;

endo-8-(2,3-Dimethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-iodobenzonitrile;

endo-8-[2-(hydroxymethyl)-3-methyl-4-nitrophenyl]-8-azabicyclo[3.2.1]octan-3-ol;

endo-8-(2-Chloro-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehyde;

endo-8-(3-Chloro-2-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-6-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-nitrobenzaldehyde oxime;

endo-8-(2-Chloro-3-hydroxymethyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

6-(3-endo-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methyl-3-nitrobenzoic acid;

endo-8-(2-Hydroxymethyl-3-methyl-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-ol;

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile;

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile hydrochloride; and,

2-Chloro-4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)-3-methylbenzonitrile mesylate.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

14. A compound represented by formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

ring A, which comprises atoms Y 1 and Y 2, is optionally substituted 8-azabicyclo[3.2.1]oct-8-yl;

R 1 is selected from the group consisting of cyano and nitro;

Z 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, chloro, bromo, iodo, cyano, hydroxy, optionally substituted aminoalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, —C(O)OR 4 , —C(O)NR 4 R 5 , —NHC(O)R 4 , —NHSO 2 R 4 , —CH═NOR 4 , CF 3 , —OC(O)R 4 , —COR 4 , SR 4 , —S(O) n R 8 , and —SO 2 NR 8 R 9 ;

Z 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, halogen, cyano, hydroxy, optionally substituted aminoalkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, —C(O)OR 4 , —C(O)NR 4 R 5 , —NHC(O)R 4 , —NHSO 2 R 4 , —CH═NOR 4 , CF 3 , —OC(O)R 4 , —COR 4 , SR 4 , —S(O) n R 8 , and —SO 2 NR 8 R 9 ;

provided that if one of Z 1 or Z 2 is hydrogen, the other is not;

R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heteroarylalkyl or substituted heteroarylalkyl, and heteroaryl or substituted heteroaryl;

R 6 and R 7 are each independently selected from the group consisting of hydrogen, halo, cyano, hydroxy, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl, aryl or substituted aryl, heteroarylalkyl or substituted heteroarylalkyl, heteroaryl or substituted heteroaryl, OR 4 , NR 4 R 5 , SR 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , NHC(O)R 4 , NR 4 C(O)R 5 , OC(O)R 4 , C(S)R 4 , C(S)OR4, C(S)NR 4 R 5 , NHC(S)R 4 , OC(S)R 4 , S(O)R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , NHSO 2 R 4 , and alkyl substituted with OR 4 , NR 4 R 5 , SR 4 , C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 5 , NHC(O)R 4 , NR 4 C(O)R 5 , OC(O)R 4 , C(S)R 4 , C(S)OR 4 , C(S)NR 4 R 5 , NHC(S)R 4 , OC(S)R 4 , S(O) n R 4 , SO 2 NR 4 R 5 , OSO 2 R 4 , or NHSO 2 R 4 ;

R 8 and R 9 are each independently selected from the group consisting of hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocyclylalkyl or substituted heterocyclylalkyl, arylalkyl or substituted arylalkyl, and heteroarylalkyl or substituted heteroarylalkyl; and

n is an integer from 1 to 3;

provided that the compound is not:

15. The compound of claim 14 , wherein:

Z 1 is selected from the group consisting of hydrogen, unsubstituted —(C 1 -C 4 alkyl, —(C 1 -C 4 )alkylOH, —(C 1 -C C 4 )alkyl(halo), chloro, bromo, iodo, cyano, —OR 4 , —OC(O)R 4 , —CF 3 , —CHO and —CH═NOR 4 ;

Z 2 is selected from the group consisting of hydrogen, unsubstituted —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylOH, —(C 1 -C 4 )alkyl(halo), halo, cyano, —OR 4 , —OC(O)R 4 , —CF 3 , —CHO and —CH═NOR 4 ;

R 6 and R 7 are independently selected from the group consisting of hydrogen, unsubstituted —(C 1 -C 4 )alkyl, —(C 1 -C 4 alkylOH, —(C 1 -C 4 alkyl(halo), halo, cyano, —OR 4 , —OC(O)R 4 and —CF 3; and,

R 4 is selected from the group consisting of hydrogen, unsubstituted (C 1 -C 4 )alkyl, unsubstituted (C 3 -C 6 )cycloalkyl and unsubstituted aryl.

16. The compound of claim 15 , wherein the optionally substituted 8-azabicyclo[3.2.1]oct-8-yl group has the structure:

17. The compound of claim 16 , wherein R 6 is hydroxy.

18. The compound of claim 17 , wherein R 7 is —(C 1 -C 4 )alkyl.

19. The compound of claim 18 , wherein R 7 is bonded to the same carbon atom to which R 6 is bonded.

20. The compound of claim 14 , wherein Z 1 is alkyl, chloro, bromo, iodo, haloalkyl or hydroxyalkyl.

21. The compound of claim 14 , wherein Z 2 is alkyl, halogen, haloalkyl or hydroxyalkyl.

22. The compound of claim 14 , selected from the group consisting of:

4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-trifluoromethylbenzonitrile;

2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile; and

2-(trifluoromethyl)-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]octan-8-yl) benzonitrile.