Androgen receptor modulator compounds and methods

1. A method for modulating an activity of an androgen receptor comprising contacting an androgen receptor with a compound of Formula (II):

wherein:

R 1 is NO 2 or CN;

R 2 is selected from among F, Cl, Br, I, SR A , NO 2 , and CF 3 ;

R 3 and R 4 are each independently selected from hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is hydrogen;

R 10 is hydrogen;

R 6a and R 7a are each independently hydrogen or an optionally substituted C 1 -C 6 alkyl;

R 9 is selected from an optionally substituted C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, CH(R D )OR A , CH(R D )NR A R B , and COR A ;

R 12 and R 13 are each independently selected from hydrogen, F, Cl, OR A , and (CH 2 ) m R C ;

R A is hydrogen;

R B is hydrogen;

R C is selected from an optionally substituted aryl and an optionally substituted heteroaryl that is optionally with a substituent selected from F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is hydrogen or CF 3 ;

Z is CR A R B ;

n is 0; and

in is 1 or 2,

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the androgen receptor is in a cell.

3. The method of claim 1 , wherein the compound is an androgen receptor agonist.

4. The method of claim 1 , wherein the compound is an androgen receptor antagonist.

5. The method of claim wherein the compound is selected from:

(2R)-N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1 -(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile;

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol;

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine; and

(R)-N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 , wherein the modulation of an activity of an androgen receptor treats a condition susceptible to treatment with an androgen receptor modulator in a patient; and wherein the patient has a condition selected from among treatment of muscular atrophy, osteoporosis, male sexual dysfunction, female sexual dysfunction, hypogonadism, frailty and cancer cachexia.

7. The method of according to claim 6 , wherein the sexual dysfunction is decreased libido.

8. The method according to claim 1 , wherein the modulation of an activity of an androgen receptor treats a condition susceptible to treatment with an androgen receptor modulator in a patient; and wherein the patient has a condition selected from among acne, male-pattern baldness, wasting diseases, hirsutism, hypogonadism, infertility, impotence and prostate cancer.

9. The method of claim 1 , wherein the compound is selected from:

(2R)-N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1 -(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyI)-pyrrolidine;

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile;

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol;

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine; and

(R)-N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;

or pharmaceutically acceptable salts thereof.

10. The method of claim 1 , wherein the compound of Formula (II) is a compound of Formula (IIB), or pharmaceutically acceptable salts thereof:

wherein:

R 1 is N 2 or CN;

R 2 is CF 3 ;

R 3 , R 4 , and R 5 are each hydrogen;

R 6a and R 7a are each independently selected from hydrogen and an optionally substituted C 1 -C 6 alkyl;

R 9 is COR A , CH(R D )OR A , and CH(R D )NR A R B ;

R 10 is hydrogen; and

R 12 and R 13 are each independently selected from hydrogen, F, Cl, OR A , and (CH 2 ) m R C .

11. The method of claim 1 , wherein:

R 1 is NO 2 or CN;

R 2 is CF 3 ;

R 3 , R 4 , and R 5 are each hydrogen;

R 6a is hydrogen;

R 7a is hydrogen or methyl;

R 9 is selected from formyl, hydroxymethyl and 1-hydroxy-2,2,2-trifluoroethyl;

R 10 is hydrogen;

R 12 is hydrogen; and

R 13 is, F, OH and benzyl.

12. The method of claim 1 , wherein the compound of Formula (II) has formula

or pharmaceutically acceptable salts thereof.

13. The method of claim 1 , wherein the compound of Formula (II) has Formula

or pharmaceutically acceptable salts thereof.

14. The method of claim 6 , wherein the compound of Formula (II) is a compound of Formula (IIB), or pharmaceutically acceptable salts thereof:

wherein:

R 1 is NO 2 or CN;

R 2 is CF 3 ;

R 3 , R 4 , and R 5 are each hydrogen;

R 6a and R 7a are each independently selected from hydrogen and an optionally substituted C 1 -C 6 alkyl;

R 9 is COR A , CH(R D )OR A , and CH(R D )NR A R B ;

R 10 is hydrogen; and

R 12 and R 13 are each independently selected from hydrogen, F, CI, OR A , and (CH 2 ) m R C .

15. The method of claim 6 , wherein the compound of Formula (II) has Formula

or pharmaceutically acceptable salts thereof.

16. The method of claim 6 , wherein the compound is selected from:

(2R)-N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile;

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol;

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine; and

(R)-N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;

or pharmaceutically acceptable salts thereof.

17. The method of claim 8 , wherein the compound is selected from:

(2R)-N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

(2R)-N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2 R)-N-(3 -Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile;

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol;

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine; and

(R)-N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;

or pharmaceutically acceptable salts thereof.