Estrogen receptor ligands and methods of use thereof

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 CH2;
• R1, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, O-Alk-NR5R6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
• R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, NO2, or OH;
• R5 and R6 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 R5 and R6 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.

A method of lowering serum PSA levels 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 CH2;
• R1, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, 0-Alk-NR5R6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
• R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, NO2, or OH;
• R5 and R6 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 R5 and R6 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.

A method of increasing serum concentrations of sex or steroid hormone binding globulin (SHBG) in a 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, polymorph, hydrate or any combination thereof:

• wherein
• Y is C(O) or CH2;
• R1, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, O-Alk-NR5R6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
• R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, NO2, or OH;
• R5 and R6 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
• R5 and R6 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.

A method of reducing the levels of bone turnover markers 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, polymorph, hydrate or any combination thereof:

• wherein
• Y is C(O) or CH2;
• R1, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, O-Alk-NR5R6 or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
• R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, NO2, or OH;
• R5 and R6 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
• R5 and R6 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.