ESTROGEN RECEPTOR LIGANDS AND METHODS OF USE THEREOF

1 . A method for lowering serum free testosterone concentration to levels comparable to those achieved in a male subject who has undergone surgical orchiectomy, in a male subject suffering from high risk advanced prostate cancer or at high risk for progression to castration resistant prostate cancer (CRPC), comprising administering a therapeutically effective amount of a compound represented by the structure of formula I, or its isomer, pharmaceutical acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof:

wherein

Y is C(O) or CH 2 ;

R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;

R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;

R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;

j and k are independently 1-4; and

Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.

2 . The method of claim 1 , wherein said compound of formula I is selected from:

3 . (canceled)

4 . The method of claim 1 , wherein said subject further receives androgen deprivation therapy (ADT).

5 . The method of claim 1 , wherein said method lowers the prostate specific antigen (PSA) levels.

6 . The method of claim 1 , wherein said method increases the serum sex or steroidal hormone binding globulin (SHBG) levels.

7 . The method of claim 1 , wherein said method increases radiographic progression free survival (rPFS) in said subject having metastatic cancer.

8 . The method of claim 1 , wherein said method increases metastasis-free survival (MFS) in a subject having non-metastatic cancer.

9 . The method of claim 1 , wherein said method decreases symptomatic bone fractures in said subject.

10 . The method claim 1 , wherein men with advanced prostate cancer who are at high risk for progression to castration resistant prostate cancer are selected from the group consisting of: men on ADT with serum total testosterone concentrations greater than 20 ng/dL; or men with advanced prostate cancer who at the time of starting ADT had either (1) confirmed Gleason pattern 4 or 5 prostate cancer, (2) metastatic prostate cancer, (3) a PSA doubling time <3 months, (4) a PSA ≧20 ng/mL, or (5) a PSA relapse in <3 years after definitive local therapy (radical prostatectomy or radiation therapy).

11 . The method of claim 1 , wherein said method reduces or ameliorates side effects associated with androgen deprivation therapy (ADT).

12 . The method of claim 11 , wherein said side effects are selected from the group consisting of: hot flashes, gynecomastia, increased body fat, bone loss, decreased bone mineral density, or increased risk of bone fracture.

13 . The method of claim 1 , wherein said compound or isomer, pharmaceutical acceptable salt, pharmaceutical product, hydrate or any combination thereof, is administered at a dose of 40 mg per day, 80 mg per day, 125 mg per day, 250 mg per day or 500 mg per day.

14 . A method of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression to castration resistant prostate cancer (CRPC) and its symptoms, or increasing the overall or progression-free survival of men with advanced or castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I, or its isomer, pharmaceutical acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof:

wherein

Y is C(O) or CH 2 ;

R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;

R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;

R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;

j and k are independently 1-4; and

Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.

15 . The method of claim 14 , wherein said compound of formula I is selected from:

16 . (canceled)

17 . The method of claim 14 , wherein said subject further receives androgen deprivation therapy (ADT).

18 . The method of claim 14 , wherein said method lowers the prostate specific antigen (PSA) levels.

19 . The method of claim 14 , wherein said method increases the serum sex or steroidal hormone binding globulin (SHBG) levels.

20 . The method of claim 14 , wherein said method increases radiographic progression free survival (rPFS) in a subject having metastatic cancer.

21 . The method of claim 14 , wherein said method increases metastasis-free survival (MFS) in a subject having non-metastatic cancer.

22 . The method of claim 14 , wherein said method decreases symptomatic bone fractures in said subject.

23 . The method of claim 14 , wherein said CRPC is metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC) or high-risk nmCRPC.

24 . (canceled)

25 . (canceled)

26 . The method of claim 14 , wherein said administering of said compound reduces or ameliorates side effects associated with androgen deprivation therapy (ADT).

27 . The method of claim 17 , wherein said administering of said compound reduces or ameliorates side effects associated with androgen deprivation therapy (ADT).

28 . The method of claim 27 , wherein said side effects are selected from the group consisting of: hot flashes, gynecomastia, increased body fat, bone loss, decreased bone mineral density, and increased risk of bone fracture.

29 . The method of claim 14 , wherein said compound or isomer, pharmaceutical acceptable salt, pharmaceutical product, hydrate or any combination thereof, is administered at a dose of 40 mg per day, 80 mg per day, 125 mg per day, 250 mg per day or 500 mg per day.

30 . A method of lowering serum PSA levels, increasing serum concentrations of sex or steroid hormone binding globulin (SHBG) or reducing the levels of bone turnover markers in a male subject in a male subject suffering from advanced prostate cancer or castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I, or its isomer, pharmaceutical acceptable salt, pharmaceutical product, hydrate or any combination thereof:

wherein

Y is C(O) or CH 2 ;

R 1 , R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3 , N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-NR 5 R 6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;

R 3 , R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF 3 , NHCOR, N(R) 2 , sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl;

R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl, CN, NO 2 , or OH;

R 5 and R 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycle, a 5 to 7 membered aryl; or R 5 and R 6 form a 3 to 7 membered ring with the nitrogen atom;

j and k are independently 1-4; and

Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.

31 . The method of claim 30 , wherein said compound of formula I is selected from:

32 . (canceled)

33 . The method of claim 30 , wherein said method increases the serum sex or steroidal hormone binding globulin (SHBG) levels.

34 . The method of claim 30 , wherein said method increases radiographic progression free survival (rPFS) in a subject having metastatic cancer.

35 . The method of claim 30 , wherein said method increases metastasis-free survival (MFS) in a subject having non-metastatic cancer.

36 . The method of claim 30 , wherein said method decreases symptomatic bone fractures in said subject.

37 . The method of claim 30 , wherein said CRPC is metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC) or high-risk nmCRPC.

38 . (canceled)

39 . (canceled)

40 . The method of claim 30 , wherein said subject further receives androgen deprivation therapy (ADT).

41 . The method of claim 40 , wherein said administering of said compound reduces or ameliorates side effects associated with androgen deprivation therapy (ADT).

42 . The method of claim 41 , wherein said side effects are selected from the group consisting of: hot flashes, gynecomastia, increased body fat, bone loss, decreased bone mineral density, and increased risk of bone fracture.

43 . The method of claim 30 , wherein said compound or isomer, pharmaceutical acceptable salt, pharmaceutical product, hydrate or any combination thereof, is administered at a dose of 40 mg per day, 80 mg per day, 125 mg per day, 250 mg per day or 500 mg per day.

44 - 74 . (canceled)