US 7,923,568 B2 · Estrogen receptor modulators

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget's disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease, sexual dysfunction, hypertension, retinal degeneration and cancer, in particular of the breast, uterus and prostate.

A compound of the formula:

wherein Y is N;
Z is N or CRf;
R1 is hydrogen, C1-6alkyl, C2-6alkenyl or C2-6alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with ORc, SRc, NRbRc, C(═O)Rc, C(═O)CH2OH, bromo, 1-3 chloro, 1-5 fluoro or phenyl, wherein said phenyl group is optionally substituted with C1-4alkyl, OH or O(C1-4alkyl);
R2 is hydrogen, hydroxy, iodo, O(C═O)Rc, C(═O)Rc, CO2Rc, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with ORc, SRc, NRbRc, C(═O)Rc, C(═O)CH2OH, or phenyl, wherein said phenyl group is optionally substituted with C1-4alkyl, OH or O(C1-4alkyl);
or R1 and R2, when taken together with the carbon atom to which they are attached, form a carbonyl group;
or R1 and R2, when taken together with the carbon atom to which they are attached, form a C3-7 cycloalkyl or C3-7 heterocycloalkyl group, wherein said heterocycloalkyl group is optionally substituted with C1-4 alkyl, OH, O(C1-4 alkyl) or oxo;
or R1 and R2, when taken together, form a C1-6 alkylidene group, wherein said alkylidene group is optionally substituted with hydroxy, O(C1-4alkyl), N(C1-4alkyl)2, or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, OH, O(C1-4alkyl), NH2, NH(C1-4alkyl), NH(C1-4alkyl)2, halo, CN, NO2, CO2H, CO2(C1-4alkyl), C(O)H and C(O)(C1-4alkyl);
R3 is hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, NRaRc, ORa, S(O)Ra, SO2Ra, SRa, C(═O)Ra, CO2Rc, CONRaRc, C1-10alkenyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, 4-7 membered heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, ORa, NRaRc, O(C═O)Ra, O(C═O)NRaRc, NRa(C═O)Rc, NRa(C═O)ORc, C(═O)Ra, CO2Ra, CONRaRc, CSNRaRc, SRa, S(O)Ra, SO2Ra, SO2NRaRc, LRd, and MLRd;
R4 is hydrogen, hydroxy, amino, methyl, CF3, fluoro, chloro or bromo;
R5 is hydrogen, hydroxy, amino, methyl, CF3, fluoro, chloro or bromo;
R6 is hydrogen, (C═O)Ra, (C═O)ORa or SO2Ra;
R7 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, fluoro, chloro, bromo, cyano, hydroxy, O(C1-6 alkyl), azido, amino, NH(C1-4alkyl) or N(C1-4alkyl)2;
R8 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, fluoro, chloro, bromo, cyano, hydroxy, O(C1-6 alkyl), azido, amino, NH(C1-4alkyl) or N(C1-4alkyl)2;
or R7 and R8, when taken together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring;
or R7 and R8, when taken together with the carbon atom to which they are attached, form a carbonyl group;
or R7 and R8, when taken together, form a C1-6alkylidene group, wherein said alkylidene group is optionally substituted with cyano, C(═O)H, C(═O)(C1-4alkyl) or C(═O)OC1-4alkyl;
R9 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-6cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl groups are optionally substituted with bromo, iodo, ORb, SRb, C(═O)Rb, 1-3 chloro or 1-5 fluoro;
or R9 and R1, when taken together with the three intervening carbon atoms to which they are attached, form a 5-6 membered cycloalkyl or cycloalkenyl ring wherein said cycloalkyl or cycloalkenyl ring is optionally substituted with 1-3 groups independently selected from the group consisting of oxo, hydroxy, fluoro, chloro, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylidenyl, C3-6cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl, wherein said alkyl, alkenyl, alkynyl, alkylidenyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl groups are optionally substituted with a group selected from chloro, bromo, iodo, ORb, SRb, C1-3alkyl, C(═O)Rb or 1-5 fluoro;
or R9 and R8, when taken together with the two intervening carbon atoms to which they are attached, form a cyclopropyl ring which is optionally substituted with 1 or 2 groups independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl groups are optionally substituted with chloro, bromo, iodo, ORb, SRb, C1-3alkyl, C(═O)Rb or 1-5 fluoro;
R10 is hydrogen, C1-10alkyl or C2-10alkenyl;
R11 is hydrogen or ORa;
Ra is hydrogen, C1-10alkyl or phenyl, wherein said alkyl group is optionally substituted with hydroxy, amino, O(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)2, phenyl, or 1-5 fluoro, and wherein said phenyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, OH, O(C1-4alkyl), NH2, NH(C1-4alkyl), NH(C1-4alkyl)2, halo, CN, NO2, CO2H, CO2(C1-4alkyl), C(O)H and C(O)(C1-4alkyl);
Rb is hydrogen, C1-10alkyl, benzyl or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, OH, O(C1-4alkyl), NH2, NH(C1-4alkyl), NH(C1-4alkyl)2, halo, CN, NO2, CO2H, CO2(C1-4alkyl), C(O)H and C(O)(C1-4alkyl);
Rc is hydrogen, C1-10alkyl or phenyl, wherein said phenyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-4alkyl, OH, O(C1-4alkyl), NH2, NH(C1-4alkyl), NH(C1-4alkyl)2, halo, CN, NO2, CO2H, CO2(C1-4alkyl ), C(O)H and C(O)(C1-4alkyl);
or Ra and Rc, whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;
Rd is NRbRc, ORa, CO2Ra, O(C═O)Ra, CN, NRc(C═O)Rb, CONRaRc, SO2NRaRc, or a 4-7 membered N-heterocycloalkyl ring that is optionally interrupted by O, S, NRc, or C═O;
Re is hydrogen, C1-6alkyl, C2-6alkenyl, CF3, halo, O(C1-4alkyl), NH2, NH(C1-4alkyl) or N(C1-4alkyl)2;
Rf is hydrogen, C1-6alkyl, C2-6alkenyl, CF3, halo, O(C1-4alkyl), NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2;
L is CRbRc, C2-6 alkylene or C2-6 alkenylene, wherein said alkylene and alkenylene groups are optionally interrupted by O,S or NRc;
M is O, S, NRc, C═O, O(C═O), (C═O)O, NRc(C═O) or (C═O)NRc;
or a pharmaceutically acceptable salt or stereoisomer thereof.

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Estrogen receptor modulators

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Estrogen receptor modulators

Life of this patent

Abstract

Claims8