Benzothiophene estrogen receptor modulators

1. A method of treating a hormone-related cancer that is estrogen mediated comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or Formula III or a pharmaceutically acceptable salt thereof; wherein the compound of Formula I or Formula III is selected from:

wherein A is:

Y is

m is 0, 1, or 2;

n is 1, 2, or 3;

o is 0, 1, 2, 3, 4, or 5;

Z is selected from —O—, —C(R 3 ) 2 —, —CHR 3 —, —CH 2 —, —CHF—, —CF 2 —, and —S—;

Z A and Z B are independently selected from —O—, —C(R 3 ) 2 —, —CHR 3 —, —CH 2 —, —CHF—, —CF 2 —, and —S—;

each R 1 is independently selected from C 1 -C 3 alkyl, halogen, and C 1 -C 3 haloalkyl;

R 2 is selected from:

a) 4-6 membered heterocycle optionally substituted with one, two, or three groups independently selected from R 4 ;

b) —NH 2 , —NH(C 1 -C 3 alkyl or C 2 -C 3 haloalkyl), and —N((independently)C 1 -C 3 alkyl or C 2 -C 3 haloalkyl) 2 ;

c) monocyclic 7-8 membered heterocycle optionally substituted with one, two, or three groups independently selected from R 4 ; and

d) 6-12 membered bicyclic or bridged heterocycle optionally substituted with one, two, or three groups independently selected from R 4 ;

R 3 is independently selected from —F, —Cl, —Br, —CH 3 , —CH 2 F, —CHF 2 , and —CF 3 ;

R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and

R 5 is selected from hydrogen, halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 2 wherein the hormone-related cancer that is estrogen mediated is breast cancer.

4. The method of claim 2 wherein the hormone-related cancer that is estrogen mediated is ovarian cancer.

5. The method of claim 2 wherein the hormone-related cancer that is estrogen mediated is endometrial cancer.

6. The method of claim 2 , wherein an effective amount of an additional therapeutic agent is administered.

7. The method of claim 6 , wherein the additional therapeutic agent is selected from:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein the additional therapeutic agent is:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the two therapeutic agents are administered together in the same dosage form.

10. The method of claim 9 , wherein the dosage form is a solid dosage form.

11. The method of claim 7 , wherein the two therapeutic agents are administered in separate dosage form.

12. The method of claim 2 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 , wherein Z is —O—.

14. The method of claim 2 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 2 , wherein o is 3.

16. The method of claim 2 , wherein o is 2.

17. The method of claim 2 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 , wherein at least one R 1 is fluoro.

19. The method of claim 17 , wherein at least one R 1 is methyl.

20. The method of claim 17 , wherein R 2 is —N(CH 2 CH 3 ) 2 .

21. The method of claim 17 , wherein R 2 is selected from

22. A method of treating a hormone-related cancer that is estrogen mediated comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, Formula III, or Formula IV or a pharmaceutically acceptable salt thereof; wherein the compound of Formula I, Formula III, or Formula IV is selected from:

wherein A is:

m is 0, 1, or 2;

n is 1, 2, or 3;

o is independently 0, 1, 2, 3, 4, or 5;

Z is selected from —O—, —C(R 3 ) 2 —, —CHR 3 —, —CH 2 —, —CHF—, —CF 2 —, and —S—;

Z A and Z B are independently selected from —O—, —C(R 3 ) 2 —, —CHR 3 —, —CH 2 —, —CHF—, —CF 2 —, and —S—;

each R 1 is independently selected from C 1 -C 3 alkyl, halogen, and C 1 -C 3 haloalkyl;

R 2 is selected from:

a) 4-6 membered heterocycle optionally substituted with one, two, or three groups independently selected from R 4 ;

b) —NH 2 , —NH(C 1 -C 3 alkyl or C 2 -C 3 haloalkyl), and —N((independently)C 1 -C 3 alkyl or C 2 -C 3 haloalkyl) 2 ;

c) monocyclic 7-8 membered heterocycle optionally substituted with one, two, or three groups independently selected from R 4 ;

d) 6-12 membered bicyclic or bridged heterocycle optionally substituted with one, two, or three groups independently selected from R 4 ; and

e) hydroxyl, alkoxy, —NH—(CH 2 ) n1 —NH 2 , —NH—(CH 2 ) n1 —NH(C 1 -C 12 alkyl or C 2 -C 12 haloalkyl), —NH—(CH 2 ) n1 —N((independently)C 1 -C 12 alkyl or C 2 -C 12 haloalkyl), —NHC 4 -C 12 alkyl, and —N(C 1 -C 12 alkyl) 2 ;

n1 is 2, 3, 4, 5, or 6;

R 3 is independently selected from —F, —Cl, —Br, —CH 3 , —CH 2 F, —CHF 2 , and —CF 3 ;

R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;

or R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, —COOH, —COOC 1 -C 12 alkyl, —CONH 2 , —CON(H)alkyl, and —CON(alkyl) 2 ;

R 5 is selected from hydrogen, halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and

R 7 is a 4, 5, 6, 7, 8, 9, or 10 membered heterocycle optionally substituted with 1, 2, or 3 groups selected from R 4 .

23. The method of claim 22 , wherein the subject is a human.

24. The method of claim 23 , wherein the hormone-related cancer that is estrogen mediated is breast cancer.

25. The method of claim 23 , wherein the hormone-related cancer that is estrogen mediated is ovarian cancer.

26. The method of claim 23 , wherein the hormone-related cancer that is estrogen mediated is endometrial cancer.

27. The method of claim 23 , wherein an effective amount of an additional therapeutic agent is administered.

28. The method of claim 27 , wherein the additional therapeutic agent is selected from:

or a pharmaceutically acceptable salt thereof.

29. The method of claim 28 , wherein the additional therapeutic agent is:

or a pharmaceutically acceptable salt thereof.

30. The method of claim 29 , wherein the two therapeutic agents are administered together in the same dosage form.

31. The method of claim 30 , wherein the dosage form is a solid dosage form.

32. The method of claim 28 , wherein the two therapeutic agents are administered in separate dosage form.

33. The method of claim 23 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

34. The method of claim 33 , wherein Z is —O—.

35. The method of claim 34 , wherein R 2 is selected from hydroxyl, alkoxy, —NH—(CH 2 ) n1 —NH 2 , —NH—(CH 2 ) n1 —NH(C 1 -C 12 alkyl or C 2 -C 12 haloalkyl), —NH—(CH 2 ) n1 —N((independently)C 1 -C 12 alkyl or C 2 -C 12 haloalkyl), —NHC 4 -C 12 alkyl, a and —N(C 1 -C 12 alkyl) 2 .

36. The method of claim 23 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

37. The method of claim 36 , wherein Z is —O—.

38. The method of claim 37 , wherein at least one R 1 is fluoro.

39. The method of claim 37 , wherein at least one R 1 is methyl.

40. A method of treating a hormone-related cancer that is estrogen mediated comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof; wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

41. The method of claim 40 , wherein the subject is a human.

42. The method of claim 41 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

43. The method of claim 41 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

44. The method of claim 41 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

45. The method of claim 41 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.