Heterocycle derivatives useful as selective androgen receptor modulators (SARMs)

1. A compound of formula (I)

wherein

W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, cyano and —SO 2 —C 1-4 alkyl;

R 1 is selected from the group consisting of C 1-4 alkyl and halogenated C 1-4 alkyl;

R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —C(O)—C 1-4 alkyl and —C(O)-(halogenated C 1-4 alkyl);

a is an integer from 0 to 1;

 is phenyl;

R 3 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, benzyl, —O-phenyl, —C(O)-phenyl, —S(O) 0-2 —C 1-4 alkyl, C 1-4 alkylamino, di C 1-4 alkylamino, —O—C 1-4 alkyl, —NR A —C(O)—C 1-4 alkyl and —S(O) 0-2 -phenyl, wherein R A is either hydrogen or C 1-4 alkyl;

R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, benzyl, —O-phenyl, —C(O)-phenyl, —S(O) 0-2 —C 1-4 alkyl, C 1-4 alkylamino, di C 1-4 alkylamino, —O—C 1-4 alkyl, —NR B —C(O)—C 1-4 alkyl and —S(O) 0-2 -phenyl, wherein R B is either hydrogen or C 1-4 alkyl;

provided that at least one of R 3 of R 4 other than hydrogen;

R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, cyano, —C(O)O—C 1-4 alkyl and —S(O) 0-2 —C 1-4 alkyl;

 is selected from the group consisting of

wherein R 5′ is selected from the group consisting of halogen and C 1-4 alkyl; and wherein R 10 is selected from hydrogen, C 1-4 alkyl, benzyl or —C(O)—CF 3 ;

R 5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cycloalkyl, aryl, aralkyl, —C(O)—C 1-4 alkyl, —C(O)-(halogenated C 1-4 alkyl), —C(O)O—C 1-4 alkyl, —C(O)O-aryl, —C 1-4 alkyl-S(O) 0-2 —C 1-4 alkyl, t-butyl-dimethyl-silyl and trimethylsilyl;

wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, cyano, nitro, —NR C —C(O)—C 1-4 alkyl, NR C —C(O)-(halogenated C 1-4 alkyl), —C(O)O—C 1-4 alkyl, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein R C and R D are each independently selected from hydrogen or C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound as in claim 1 , wherein

W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, C 1-2 alkoxy, cyano and —SO 2 —C 1-2 alkyl;

R 1 is selected from the group consisting of C 1-4 alkyl and halogenated C 1-2 alkyl;

R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogenated C 1-2 alkyl and —C(O)-(halogenated C 1-2 alkyl);

a is an integer from 0 to 1;

 is phenyl;

R 3 is selected from the group consisting of hydrogen, halogen, halogenated C 1-4 alkyl and cyano;

R 4 is selected from the group consisting of halogen, cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O) 0-2 —C 1-4 alkyl and —S(O) 0-2 -phenyl;

R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, C 1-2 alkyl, C 1-2 alkoxy, cyano, —C(O)O—C 1-2 alkyl, —S—C 1-4 alkyl and —SO 2 —C 1-4 alkyl;

 is selected from the group consisting of

wherein R 5′ is halogen; and wherein R 10 is selected from hydrogen, C 1-4 alkyl, benzyl or —C(O)—CF 3 ;

R 5 is selected from the group consisting of hydrogen, carboxy, C 1-4 alkyl, halogenated C 1-4 alkyl, —C 1-4 alkyl-OH, cycloalkyl, aryl, aralkyl, C 1-4 alkyl-S—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —C(O)-(halogenated C 1-4 alkyl) and trimethylsilyl;

wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-4 alkyl, —O—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —NH—C(O)—C 1-4 alkyl, —NH—C(O)-(halogenated C 1-4 alkyl) or t-butyl-dimethyl-silyloxy;

or a pharmaceutically acceptable salt thereof.

3. A compound as in claim 2 , wherein

W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and —SO 2 -methyl;

R 1 is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl;

R 2 is selected from the group consisting of hydrogen, methyl, trifluoroethyl and —C(O)—CF 3 ;

a is an integer from 0 to 1;

 is phenyl;

R 3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano;

R 4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO 2 -methyl and —SO 2 -phenyl;

R 6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO 2 -ethyl;

R 7 is selected from the group consisting of hydrogen, chloro and ethyl;

 is selected from the group consisting of

wherein R 5′ is chloro; and wherein R 10 is selected from hydrogen, methyl, ethyl, benzyl or —C(O)—CF 3 ;

R 5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl;

or a pharmaceutically acceptable salt thereof.

4. A compound as in claim 1 , wherein

W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, cyano, C 1-4 alkyl, C 1-2 alkoxy and —SO 2 —C 1-2 alkyl;

R 1 is selected from the group consisting of C 1-4 alkyl and halogenated C 1-4 alkyl;

R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogenated C 1-2 alkyl and —C(O)-(halogenated C 1-2 alkyl);

a is an integer from 0 to 1;

 is phenyl;

R 3 is selected from the group consisting of hydrogen, halogen, halogenated C 1-4 alkyl and cyano;

R 4 is selected from the group consisting of halogen, cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O) 0-2 —C 1-4 alkyl and —S(O) 0-2 -phenyl;

R 6 R 7 are each independently selected from the group consisting of hydrogen, halogen, C 1-2 alkyl, C 1-2 alkoxy, cyano, —C(O)O—C 1-2 alkyl, —S—C 1-4 alkyl and —SO 2 —C 1-4 alkyl;

 is selected from the group consisting of

wherein R 5′ is halogen; and wherein R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, benzyl and —C(O)—CF 3 ;

R 5 is selected from the group consisting of hydrogen, carboxy, C 1-4 alkyl, halogenated C 1-4 alkyl, —C 1-4 alkyl-OH, cycloalkyl, aryl, aralkyl, —C 1-4 alkyl-S—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —C(O)-(halogenated C 1-4 alkyl) and trimethylsilyl;

wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C 1-4 alkyl, —O—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —NH—C(O)—C 1-4 alkyl, —NH—C(O)-(halogenated C 1-4 alkyl) or t-butyl-dimethyl-silyloxy;

or a pharmaceutically acceptable salt thereof.

5. A compound as in claim 4 , wherein

W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and —SO 2 -methyl;

R 1 is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl;

R 2 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and —C(O)—CF 3 ;

a is an integer from 0 to 1;

 is phenyl;

R 3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano;

R 4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO 2 -methyl and —SO 2 -phenyl;

R 6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO 2 -ethyl;

R 7 is selected from the group consisting of hydrogen, chloro and ethyl;

 is selected from the group consisting of

wherein R 5′ is chloro; and wherein R 10 is selected from hydrogen, methyl, ethyl, benzyl or —C(O)—CF 3 ;

R 5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl;

or a pharmaceutically acceptable salt thereof.

6. A compound as in claim 3 , wherein

W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy);

R 1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl;

R 2 is selected from the group consisting of hydrogen and methyl;

a is an integer from 0 to 1;

 is phenyl;

R 3 is selected from the group consisting of hydrogen and trifluoromethyl;

R 4 is selected from the group consisting of bromo, cyano, nitro and —SO 2 -phenyl;

R 6 is selected from the group consisting of hydrogen, iodo, chloro and —S-ethyl;

R 7 selected from the group consisting of hydrogen and ethyl;

 is selected from the group consisting of

wherein R 5′ is chloro; and wherein R 10 is selected from the group consisting of hydrogen, methyl and ethyl;

R 5 is selected from the group consisting of methyl, trifluoromethyl, 1,1,2,2,2-pentafluoro-ethyl, —C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4-trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl;

or a pharmaceutically acceptable salt thereof.

7. A compound as in claim 3 , wherein

W is selected from the group consisting of O and N(ethyl);

R 1 methyl;

R 2 is selected from the group consisting of hydrogen and methyl;

a is an integer from 0 to 1;

 is phenyl;

R 3 is trifluoromethyl;

R 4 is selected from the group consisting of chloro, cyano and nitro;

R 6 is selected from the group consisting of hydrogen, chloro, ethyl and —SO 2 -ethyl;

R 7 is selected from the group consisting of hydrogen, chloro and ethyl;

 wherein R 10 is selected from the group consisting of hydrogen and ethyl;

R 5 is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, and cyclohexyl;

or a pharmaceutically acceptable salt thereof.

8. A compound as in claim 3 , selected from the group consisting of

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide;

3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide;

5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide;

5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide;

3-Methyl-5-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide;

and pharmaceutically acceptable salts thereof.

9. A compound as in claim 8 selected from the group consisting of (R)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; (S)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 2 .