Estrogen receptor modulators and uses thereof

1. A method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt thereof:

wherein,

R 1 is H, F, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl;

R 3 is H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 4 fluoroalkyl;

each R 4 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , —C(═O)R 10 , —C(═O)OH, —C(═O)OR 10 , —C(═O)NHR 10 , —C(═O)N(R 10 ) 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkoxy, substituted or unsubstituted C 1 -C 6 alkoxy, and substituted or unsubstituted C 1 -C 6 heteroalkyl;

each R 5 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkoxy, substituted or unsubstituted C 1 -C 6 alkoxy, and substituted or unsubstituted C 1 -C 6 heteroalkyl;

each R 6 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkoxy, substituted or unsubstituted C 1 -C 6 alkoxy, and substituted or unsubstituted C 1 -C 6 heteroalkyl;

is azetidinyl or pyrrolidinyl;

R 7 is H or C 1 -C 4 alkyl;

each R 8 is independently selected from F, Cl, —CN, —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkoxy, substituted or unsubstituted C 1 -C 6 alkoxy, and substituted or unsubstituted C 1 -C 6 heteroalkyl;

or 1 R 8 is taken together with R 1 along with the intervening atoms joining R 8 to R 1 to form a 5-, 6-, or 7-membered ring;

each R 9 is independently selected from H, —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NHR 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 2 alkylene-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 2 alkylene-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl), —C 1 -C 2 alkylene-(substituted or unsubstituted aryl), and —C 1 -C 2 alkylene-(substituted or unsubstituted heteroaryl); or

each R 10 is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 2 alkylene-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 2 alkylene-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl), —C 1 -C 2 alkylene-(substituted or unsubstituted aryl), and —C 1 -C 2 alkylene-(substituted or unsubstituted heteroaryl);

Y is —O—, —S—, or —NR 11 —; R 11 is H, —C(═O)R 10 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl;

X is —O—, —S—, —CH 2 —, —NH— or —N(C 1 -C 6 alkyl)-;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, or 3;

p is 0, 1, 2, 3 or 4; and

t is 1, 2, 3 or 4;

wherein the cancer is a hormone dependent cancer or a cancer resistant to anti-hormonal treatment; and

wherein the cancer is selected from bone, breast, lung, colorectal, endometrial, prostate, ovarian, uterine, and cervical.

2. The method of claim 1 , further comprising administering to the mammal at least one additional anti-cancer agent.

3. The method of claim 1 , wherein:

R 1 is H or C 1 -C 4 alkyl;

R 3 is C 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl;

each R 4 is independently selected from H, halogen, —CN, —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C 1 -C 4 heteroalkyl;

each R 5 is independently selected from H, halogen, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C 1 -C 4 heteroalkyl;

each R 6 is independently selected from H, halogen, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, and C 1 -C 4 alkoxy;

R 7 is H or —CH 3 ;

Y is —O— or —S—;

X is —O—, —S—, —CH 2 —, —NH— or —N(CH 3 )—;

p is 0, 1, or 2.

4. The method of claim 3 , wherein:

each R 5 is independently selected from H, F, Cl, —OH, —CH 3 , —CF 3 , —OCF 3 and —OCH 3 ;

each R 6 is independently selected from H, F, Cl, —OH, —CH 3 , —CF 3 , —OCF 3 and —OCH 3 ;

R 7 is H;

each R 8 is independently selected from F, Cl, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, and C 1 -C 4 heteroalkyl.

5. The method of claim 4 , wherein:

6. The method of claim 1 , wherein the compound of Formula (VI) has the structure of Formula (VIII):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound of Formula (VI) has the structure of Formula (X):

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein:

R 1 is H or —CH 3 ;

R 3 is —CH 3 or —CF 3 ;

each R 8 is independently selected from F, Cl, —OH, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —OCF 3 , —OCH 2 CF 3 , —OCH 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , and —CH 2 OH;

R 9 is H;

X is —O—.

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

3-(3-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

(S)-3-(3-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

(R)-3-(3-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-(2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-((R)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-(2-((S)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol;

3-(3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((S)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-hydroxyphenyl)-4-methyl-2-(4-((R)-2-((S)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

2-(4-((S)-2-(3,3-Dimethylpyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol;

2-(4-(2-(3,3-Dimethylpyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((S)-2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-7-ol;

3-(4-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-7-ol;

4-Methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-phenyl-2H-chromen-6-ol;

3-(4-Fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

(S)-3-(4-Fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

(R)-3-(4-Fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Fluoro-4-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

2-(2-Fluoro-4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol;

3-(3-Hydroxy-4-methylphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Hydroxy-2-methylphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Hydroxy-2-methylphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Hydroxy-3-methylphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3-Fluoro-5-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Chlorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(2-Fluoro-4-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3,4-Difluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3,5-Difluoro-4-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(2,4-Difluoro-3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(3,4-Difluoro-5-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(2-Chloro-4-fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(2,4-Difluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Bromophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

4-Methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(o-tolyl)-2H-chromen-6-ol;

3-(4-Fluoro-3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Ethynylphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

4-Methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-(methylsulfonyl)phenyl)-2H-chromen-6-ol;

3-(2-Fluoro-3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

5-Fluoro-3-(3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(2-Fluoro-5-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

3-(4-Fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

2-(4-((S)-2-((R)-3-Fluoropyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol;

3-(4-Hydroxyphenyl)-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-4-(trifluoromethyl)-2H-chromen-6-ol;

3-(3-Hydroxyphenyl)-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-4-(trifluoromethyl)-2H-chromen-6-ol;

3-(3-Hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol; or

3-(4-Hydroxy-3-(trifluoromethyl)phenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the compound of Formula (VI) has the structure of Formula (IX):

or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein:

R 1 is H or —CH 3 ;

R 3 is —CH 3 ;

R 4 is —OH;

R 8 is —CH 3 ;

R 9 is H;

X is —O—;

Y is —O—;

n is 0;

m is 1.

12. The method of claim 6 , wherein:

R 1 is H or —CH 3 ;

R 3 is —CH 3 ;

R 4 is —OH;

R 8 is —CH 3 ;

R 9 is H;

X is —O—;

Y is —O—;

n is 0;

m is 1.

13. The method of claim 1 , wherein the compound of Formula (VI) has the following structure:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 6 , wherein the compound of Formula (VIII) has the following structure:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound of Formula (VI) has the following structure:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound of Formula (VI) has the following structure:

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound of Formula (VI) has the following structure:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound of Formula (VI) has the following structure:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound of Formula (VI) has the following structure:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, steroidal aromatase inhibitors, and non-steroidal aromatase inhibitors.

21. The method of claim 1 wherein the cancer is hormone receptor positive metastatic breast cancer.

22. The method of claim 21 wherein the compound of Formula (VI), or a pharmaceutically acceptable salt thereof is administered to a postmenopausal woman with disease progression following anti-estrogen therapy.