WO2013090829A1 - Estrogen receptor modulators and uses thereof - Google Patents

Estrogen receptor modulators and uses thereof Download PDF

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Publication number
WO2013090829A1
WO2013090829A1 PCT/US2012/069926 US2012069926W WO2013090829A1 WO 2013090829 A1 WO2013090829 A1 WO 2013090829A1 US 2012069926 W US2012069926 W US 2012069926W WO 2013090829 A1 WO2013090829 A1 WO 2013090829A1
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Prior art keywords
substituted
unsubstituted
phenyl
ceheteroalkyl
chromen
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English (en)
French (fr)
Inventor
Nicholas D. Smith
Steven P. Govek
Mehmet Kahraman
Jackaline D. Julien
Johnny Y. Nagasawa
Andiliy G. Lai
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Aragon Pharmaceuticals Inc
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Aragon Pharmaceuticals Inc
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Priority to EP12857161.9A priority Critical patent/EP2791132A4/en
Priority to US14/364,993 priority patent/US9187460B2/en
Priority to JP2014547524A priority patent/JP2015500346A/ja
Publication of WO2013090829A1 publication Critical patent/WO2013090829A1/en
Anticipated expiration legal-status Critical
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Definitions

  • Described herein are compounds, including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof, methods of making such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases or conditions that are estrogen sensitive, estrogen receptor dependent or estrogen receptor mediated.
  • the estrogen receptor (“ER”) is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17P-estradiol and estrones. ER has been found to have two isoforms, ER-a and ER- ⁇ .
  • Estrogens and estrogen receptors are implicated in a number of diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer, as well as others diseases or conditions.
  • compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) that diminish the effects of estrogens with estrogen receptors and/or lower the the concentrations of estrogen receptors, and therefore, are useful as agents for the treatment or prevention of diseases or conditions in which the actions of estrogens and/or estrogen receptors are involved in the etiology or pathology of the disease or condition, or contribute to at least one symptom of the disease or condition and wherein such actions of estrogens and/or estrogen receptors are undesirable.
  • compounds disclosed herein are estrogen receptor degrader compounds.
  • a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is useful for the treatment of ER-related diseases or conditions including, but not limited to, ER-a dysfunction associated with cancer (bone cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian and uterine cancer), central nervous system (CNS) defects (alcoholism, migraine), cardiovascular system defects (aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension), hematological system defects (deep vein thrombosis), immune and inflammation diseases (Graves' Disease, arthritis, mulitple sclerosis, cirrhosis), susceptibility to infection (hepatitis B, chronic liver disease), metabolic defects (bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteo
  • Compounds described herein are estrogen receptor modulators.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is an estrogen receptor antagonist.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is an estrogen receptor degrader.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is an estrogen receptor antagonist as well as an estrogen receptor degrader.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is an estrogen receptor antagonist as well as an estrogen receptor degrader.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) displays miminal or no estrogen receptor agonist activity.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) may offer improved therapeutic activity characterized by complete or longer-lasting tumor regression, a lower incidence or rate of development of resistance to treatment, and/or a reduction in tumor invasiveness.
  • R is H, F, Ci-C 6 alkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form is a monocyclic heterocycloalkyl or a bicyclic heterocycloalkyl;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 4 is H, halogen, -CN, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 alkoxy, Ci-C 4 fluoroalkoxy, C 3 - C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, C 3 -C 6 heterocycloalkyl, Ci-C 6 heteroalkyl, -Ci-
  • Cefluoroalkoxy substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Ci -Cefluoroalkyl, or a substituted or
  • Ci-Cealkyl substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci -Cefluoroalkyl;
  • R 7 is H or Ci-C 4 alkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted C 2 -Cioheterocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted aryl), and -Ci- C 2 alkylene-
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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-
  • R 7 is H or -CH 3 . In other embodiments, R 7 is H.
  • R 4 is d-C 4 alkyl
  • R 4 is d-C 4 alkyl
  • the com ound has the following structure:
  • the compound has one of the following structures:
  • R 9 is -OH, or -OR 11 ; m is 0 or 1; n is 0 or 1.
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci
  • R 2 is H or R 12 ;
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form
  • R is taken together with R and the intervening atoms connecting R to R to form a 5-7 membered ring;
  • t 0, 1, 2, 3, or 4;
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene-
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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- (3-Fluoro-5-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin- l - yl)propoxy)phenyl)-2H-chromen-6-ol; 3-(4-Fluoro-3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin- l - yl)propoxy)
  • R 9 is -OH or -OR 11 .
  • the compound has one of the following structures:
  • R is H, F, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, C3-C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1 , 2, 3, or 4;
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Ci-C6alkoxy substituted or unsubstituted Ci-Ceheteroalkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted C 2 -Cioheterocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted aryl), and -Ci-C 2 alkylene
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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)-
  • R 7 is H;
  • each R 8 is independently selected from H, halogen, -CN, Ci-Cealkyl, Ci-Cefluoroalkyl, Ci-Cefluoroalkoxy, and Ci-Cealkoxy;
  • Y is -0-;
  • X is -0-;
  • p is 0 or 1.
  • R y is H, halogen, -CN, -OH, -OR 11 , -NHR 11 , -NR n R 12 , -SR
  • R 9 is -OH or -OR 11 .
  • each R 8 is H.
  • the com ound has one of the followin structures:
  • R 1 is Ci-Cealkyl
  • R 2 and R 3 are taken together with the N atom to which they are attached to form 3 ⁇ 4 —
  • 3 ⁇ 4 — is a monocyclic heterocycloalkyl
  • each R 23 is independently selected from CI, -CN, -OH, Ci-C 4 alkyl, Ci-C 4 alkoxy, and Ci-C 4 heteroalkyl.
  • R 1 is H or Ci-Cealkyl
  • R 2 and R 3 are taken together with the N atom to which they are attached to form v N "(R23)t is a monocyclic heterocycloalkyl
  • each R is independently selected from CI, -CN, -OH, Ci-C 4 alkyl, Ci-C 4 alkoxy, and Ci-C 4 heteroalkyl
  • t is 1, 2, 3, or 4.
  • R 23 is -CH 3 .
  • R 1 is -CH 3 ; and R 23 is -CH 3 .
  • Compounds disclosed herein are estrogen receptor modulators.
  • compounds disclosed herein have high specificity for the estrogen receptor and have desirable, tissue- selective pharmacological activities. Desirable, tissue-selective pharmacological activities include, but are not limited to, ER antagonist activity in breast cells and no ER agonist activity in uterine cells.
  • compounds disclosed herein are estrogen receptor degraders that display full estrogen receptor antagonist activity with negligible or minimal estrogen receptor agonist activity.
  • compounds disclosed herein are estrogen receptor degraders. In some embodiments, compounds disclosed herein are estrogen receptor antagonists. In some embodiments, compounds disclosed herein have minimial or negligible estrogen receptor agonist activity.
  • presented herein are compounds selected from active metabolites, tautomers, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or prodrugs of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).
  • compositions comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive ingredient.
  • the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a suspension, a solution, an emulsion, an ointment, or a lotion.
  • the pharmaceutical composition further comprises one or more additional therapeutically active agents selected from: corticosteroids, anti-emetic agents, analgesics, anti-cancer agents, anti-inflammatories, kinase inhibitors, antibodies, HSP90 inhibitors, histone deacetylase (HDAC) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, and aromatase inhibitors.
  • additional therapeutically active agents selected from: corticosteroids, anti-emetic agents, analgesics, anti-cancer agents, anti-inflammatories, kinase inhibitors, antibodies, HSP90 inhibitors, histone deacetylase (HDAC) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, and aromatase inhibitors.
  • a method comprising administering a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof, to a human with a diseases or condition that is estrogen sensitive, estrogen receptor meditated or estrogen receptor dependent.
  • the human is already being administered one or more additional therapeutically active agents other than a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof.
  • the method further comprises administering one or more additional therapeutically active agents other than a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof.
  • the one or more additional therapeutically active agents other than a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof are selected from: corticosteroids, anti-emetic agents, analgesics, anti-cancer agents, antiinflammatories, kinase inhibitors, antibodies, HSP90 inhibitors, histone deacetylase (HDAC) inhibitors, and aromatase inhibitors.
  • compositions described herein are administered to a mammal in a variety of ways, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), buccal, topical or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof, are administered orally.
  • the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof, are administered systemically.
  • the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are administered intravenously.
  • the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof are administered subcutaneously.
  • the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof are administered topically.
  • the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, balms, creams or ointments.
  • the compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof are administered topically to the skin of mammal.
  • the disease or condition is any of the diseases or conditions specified herein.
  • the effective amount of the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) adminstered non- systemically or locally to the mammal.
  • administrations of the effective amount of the compound including further embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.
  • the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
  • the length of the drug holiday varies from 2 days to 1 year.
  • a method of reducing ER activation in a mammal comprising administering to the mammal at least one compound having the structure of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt thereof.
  • the method comprises reducing ER activation in breast cells, lung cells, ovarian cells, colon cells, prostate cells, endometrial cellls, or uterine cells in the mammal.
  • the method comprises reducing ER activation in breast cells, ovarian cells, colon cells, prostate cells, endometrial cellls, or uterine cells in the mammal.
  • the method of reducing ER activation in the mammal comprises reducing the binding of estrogens to estrogen receptors in the mammal. In some embodiments, the method of reducing ER activation in the mammal comprises reducing ER concentrations in the mammal.
  • the disease or condition of the uterus is leiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis.
  • the disease or condition of the uterus is a cancerous disease or condition of the uterus. In some other embodiments, the disease or condition of the uterus is a non-cancerous disease or condition of the uterus.
  • the disease or condition is breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is described herein.
  • the mammal is a human.
  • compounds provided herein are used to diminish, reduce, or eliminate the activity of estrogen receptors.
  • Articles of manufacture which include: packaging material; a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, or composition thereof, within the packaging material; and a label that indicates that the compound or pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, or composition thereof, or composition thereof, is used for reducing, diminishing or eliminating the effects of estrogen receptors, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from a reduction or elimination of estrogen receptor activity, are provided.
  • Estrogen receptor alpha (ER-a; NR3A1) and estrogen receptor beta (ER- ⁇ ; NR3A2) are steroid hormone receptors, which are members of the large nuclear receptor superfamily. Nuclear receptors share a common modular structure, which minimally includes a DNA binding domain (DBD) and a ligand binding domain (LBD). Steroid hormone receptors are soluble, intracellular proteins that act as ligand-regulated transcription factors. Vertebrates contain five closely related steroid hormone receptors (estrogen receptor, androgen receptor, progesterone receptor, glucocorticoid receptor, mineralcorticoid receptor), which regulate a wide spectrum of reproductive, metabolic and developmental activities. The activities of ER are controlled by the binding of endogenous estrogens, including 17P-estradiol and estrones.
  • the ER-a gene is located on 6q25.1 and encodes a 595 AA protein.
  • the ER- ⁇ gene resides on chromosome 14q23.3 and produces a 530 AA protein.
  • each of these genes can give rise to multiple isoforms.
  • these receptors contain an N- terminal (A/B) domain, a hinge (D) domain that links the C and E domains, and a C-terminal extension (F domain) (Gronemeyer and Laudet; Protein Profile 2: 1173-1308, 1995).
  • the ligand binding pocket of steroid hormone receptors is deeply buried within the ligand binding domain. Upon binding, the ligand becomes part of the hydrophobic core of this domain.
  • Hsp90 chaperones
  • Ligand-binding stabilizes the receptor and initiates sequential conformational changes that release the chaperones, alter the interactions between the various receptor domains and remodel protein interaction surfaces that allow these receptors to translocate into the nucleus, bind DNA and engage in interactions with chromatin remodeling complexes and the transcriptional machinery.
  • ER can interact with Hsp90, this interaction is not required for hormone binding and, dependent on the cellular context, apo-ER can be both cytoplasmic and nuclear. Biophysical studies indicated that DNA binding rather than ligand binding contributes to the stability of the receptor (Greenfield et ah, Biochemistry 40: 6646-6652, 2001).
  • ER can interact with DNA either directly by binding to a specific DNA sequence motif called estrogen response element (ERE) (classical pathway), or indirectly via protein-protein interactions (nonclassical pathway) (Welboren et ah, Endocrine-Related Cancer 16: 1073-1089, 2009).
  • ERP estrogen response element
  • nonclassical pathway protein-protein interactions
  • Both types of ER DNA interactions can result in gene activation or repression dependent on the transcriptional coregulators that are recruited by the respective ER-ERE complex (Klinge, Steroid 65: 227-251 , 2000).
  • the recruitment of coregulators is primarily mediated by two protein interaction surfaces, the AF2 and AF1.
  • AF2 is located in the ER E-domain and its conformation is directly regulated by the ligand (Brzozowski et ah, Nature 389: 753-758, 1997).
  • Full agonists appear to promote the recruitment of co-activators, whereas weak agonists and antagonists facilitate the binding of co- repressors.
  • the regulation of protein with the AF1 is less well understood but can be controlled by serine phosphorylation (Ward and Weigel, Biofactors 35: 528-536, 2009).
  • One of the involved phosphorylation sites appears to control the transcriptional activity of ER in the presence of antagonists such as tamoxifen, which plays an important role in the treatment of breast cancer. While full agonists appear to arrest ER in certain conformation, weak agonists tend to maintain ER in equilibrium between different conformations, allowing cell-dependent differences in co-regulator repertoires to modulate the activity of ER in a cell-dependent manner (Tamrazi et ah, Mol. Endocrinol. 17: 2593-2602, 2003).
  • Interactions of ER with DNA are dynamic and include, but are not limited to, the degradation of ER by the proteasome (Reid et ah, Mol Cell 1 1 : 695-707, 2003).
  • the degradation of ER with ligands provides an attractive treatment strategy for disease or conditions that estrogen- senstitive and/or resistant to available anti-hormonal treatments.
  • ER signaling is crucial for the development and maintenance of female reproductive organs including breasts, ovulation and thickening of the endometrium. ER signaling also has a role in bone mass, lipid metabolism, cancers, etc. About 70% of breast cancers express ER-a (ER-a positive) and are dependent on estrogens for growth and survival. Other cancers also are thought to be dependent on ER-a signaling for growth and survival, such as for example ovarian and endometrial cancers.
  • the ER- ⁇ antagonist tamoxifen has been used to treat early and advanced ER-a positive breast cancer in both pre- and post-menopausal women.
  • Fulvestrant a steroid-based ER antagonist is used to treat breast cancer in women which has have progressed despite therapy with tamoxifen.
  • Steroidal and non-steroidal aromatase inhibitors are also used to treat cancers in humans.
  • the steroidal and non-steroidal aromatase inhibitors block the production of estrogen from androstenedione and testosterone in post-menopausal women, thereby blocking ER dependent growth in the cancers.
  • progressive ER positive breast cancer is treated in some cases with a variety of other chemotherapeutics, such as for example, the anthracylines, platins, taxanes.
  • ER positive breast cancers that harbor genetic amplication of the ERB-B/HER2 tyrosine kinase receptor are treated with the monoclonal antibody trastuzumab (HerceptinTM) or the small molecule pan-ERB-B inhibitor lapatinib.
  • HerceptinTM monoclonal antibody trastuzumab
  • lapatinib small molecule pan-ERB-B inhibitor lapatinib.
  • SERMs selective estrogen receptor modulators
  • the SERMs described herein are selective estrogen receptor degraders (SERDs).
  • SERMs selective estrogen receptor degraders
  • the compounds described herein result in a reduction in steady state ER-a levels (i.e. ER degradation) and are useful in the treatment of estrogen sensitive diseases or conditions and/or diseases or conditions that have developed resistant to anti-hormonal therapies.
  • compounds disclosed herein are useful in the treatment of breast cancer, either alone or in combination with other agent agents that can modulate other critical pathways in breast cancer, including but not limited to those that target IGF1R, EGFR, erB-B2 and 3 the PBK/AKT/mTOR axis, HSP90, PARP or histone deacetylases.
  • compounds disclosed herein are useful in the treatment of breast cancer, either alone or in combination with other agent used to treat breast cancer, including but not limited to aromatase inhibitors, anthracylines, platins, nitrogen mustard alkylating agents, taxanes.
  • Illustrative agent used to treat breast cancer include, but are not limited to, paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, ixabepilone, as well as others described herein.
  • ER-related diseases or conditions include ER-a dysfunction is associated with cancer (bone cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian and uterine cancer), central nervous system (CNS) defects (alcoholism, migraine), cardiovascular system defects (aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension), hematological system defects (deep vein thrombosis), immune and inflammation diseases (Graves' Disease, arthritis, mulitple sclerosis, cirrhosis), susceptibility to infection (hepatitis B, chronic liver disease), metabolic defects (bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis), neurological defects
  • Alzheimer's disease Parkinson's disease, migraine, vertigo
  • psychiatric defects anorexia nervosa, attention deficity hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis) and reproductive defects (age of menarche, endometriosis, infertility.
  • ADHD attention deficity hyperactivity disorder
  • psychosis major depressive disorder
  • reproductive defects age of menarche, endometriosis, infertility.
  • compounds disclosed herein are used in the treatment of an estrogen receptor dependent or estrogen receptor mediated disease or condition in mammal.
  • the estrogen receptor dependent or estrogen receptor mediated disease or condition is selected from cancer, central nervous system (CNS) defects, cardiovascular system defects, hematological system defects, immune and inflammation diseases, susceptibility to infection, metabolic defects, neurological defects, psychiatric defects and reproductive defects.
  • CNS central nervous system
  • the estrogen receptor dependent or estrogen receptor mediated disease or condition is selected from bone cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, alcoholism, migraine, aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, deep vein thrombosis, Graves' Disease, arthritis, mulitple sclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease, Parkinson's disease, migraine, vertigo, anorexia nervosa, attention deficity hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis, age of menarche, endometriosis, and infertility.
  • ADHD attention deficity hyperactivity disorder
  • dementia major depressive
  • the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a hormone dependent cancer. In some embodiments, the cancer is an estrogen receptor dependent cancer. In some embodiments, the cancer is an estrogen- sensitive cancer. In some embodiments, the cancer is resistant to anti-hormonal treatment. In some embodiments, the cancer is an estrogen-sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormonal treatment. In some embodiments, the cancer is a hormone-sensitive cancer or a hormone receptor dependent cancer that is resistant to anti-hormonal treatment. In some embodiments, the cancer is a hormone-sensitive cancer or a hormone receptor dependent cancer that is resistant to anti-hormonal treatment. In some embodiments, the cancer is a hormone-sensitive cancer or a hormone receptor dependent cancer that is resistant to anti-hormonal treatment. In some embodiment
  • anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, steroidal aromatase inhibitors, and non-steroidal aromatase inhibitors.
  • compounds disclosed herein are used to treat hormone receptor positive metastatic breast cancer in a postmenopausal woman with disease progression following anti-estrogen therapy.
  • compounds disclosed herein are used to treat a hormonal dependent benign or malignant disease of the breast or reproductive tract in a mammal.
  • the benign or malignant disease is breast cancer.
  • the compound used in any of the methods described herein is an estrogen receptor degrader; is an estrogen receptor antagonist; has minimal or negligible estrogen receptor agonist activity; or combinations thereof.
  • methods of treatment with compounds described herein include a treatment regimen that includes administering radiation therapy to the mammal.
  • methods of treatment with compounds described herein include administering the compound prior to or following surgery.
  • methods of treatment with compounds described herein include administering to the mammal at least one additional anti-cancer agent.
  • compounds disclosed herein are used to treat cancer in a mammal, wherein the mammal is chemotherapy-nai ' ve.
  • compounds disclosed herein are used in the treatment of cancer in a mammal. In some embodiments, compounds disclosed herein are used to treat cancer in a mammal, wherein the mammal is being treated for cancer with at least one anti-cancer agent. In one embodiment, the cancer is a hormone refractory cancer.
  • compounds disclosed herein are used in the treatment or prevention of diseases or conditions of the uterus in a mammal.
  • the disease or condition of the uterus is leiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis.
  • the disease or condition of the uterus is a cancerous disease or condition of the uterus.
  • the disease or condition of the uterus is a non-cancerous disease or condition of the uterus.
  • compounds disclosed herein are used in the treatment of endometriosis in a mammal.
  • compounds disclosed herein are used in the treatment of leiomyoma in a mammal.
  • the leiomyoma is a uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma, or small bowel leiomyoma.
  • compounds disclosed herein are used in the treatment of fibroids in a mammal.
  • compounds disclosed herein are used in the treatment of uterine fibroids in a mammal.
  • estrogen receptor modulators are estrogen receptor modulators.
  • the compounds described herein are estrogen receptor degraders.
  • the compounds described herein are estrogen receptor antagonists.
  • the compounds described herein are estrogen receptor degraders and estrogen receptor antagonists with minimal or no estrogen receptor agonist activity.
  • compounds disclosed herein are estrogen receptor degraders and estrogen receptor antagonists that exhibit: no estrogen receptor agonism; and/or anti-pro liferative activity against breast cancer, ovarian cancer, endometrial cancer, cervical cancer cell lines; and/or maximal anti-proliferative efficacy against breast cancer, ovarian cancer, endometrial cancer, cervical cell lines in- vitro; and/or minimal agonism in the human endometrial (Ishikawa) cell line; and/or no agonism in the human endometrial (Ishikawa) cell line; and/or no agonism in the immature rat uterine assay in- vivo; and/or inverse agonism in the immature rat uterine assay in- vivo; and/or anti- tumor activity in breast cancer, ovarian cancer, endometrial cancer, cervical cancer cell lines in xenograft assays in- vivo or other rodent models of these cancers.
  • compounds described herein have reduced or minimal interaction with the hERG (the human Ether-a-go-go-Related Gene) channel and/or show a reduced potential for QT prolongation and/or a reduced risk of ventricular tachyarrhythmias like torsades de pointes.
  • hERG the human Ether-a-go-go-Related Gene
  • compounds described herein have reduced or minimal potential to access the hypothalamus and/or have reduced or minimal potential to modulate the Hypothalamic-Pituitary- Ovarian (HPO) axis and/or show a reduced potential to cause hyper-stimulation of the ovaries and/or show a reduced potential for ovary toxicity.
  • HPO Hypothalamic-Pituitary- Ovarian
  • compounds described herein for use in the treatment of a disease or condition in a pre-menopausal woman have reduced or minimal potential to access the hypothalamus and/or have reduced or minimal potential to modulate the Hypothalamic-Pituitary-Ovarian (HPO) axis and/or show a reduced potential to cause hyper-stimulation of the ovaries and/or show a reduced potential for ovary toxicity.
  • the disease or condition in the pre-menopausal woman is endometriosis.
  • the disease or condition in the pre-menopausal woman is an uterine disease or condition.
  • R is H, F, Ci-C 6 alkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 5 is a substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 - Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is H or Ci-C 4 alkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted C 2 -Cioheterocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted aryl), and -Ci- C 2 alkylene-
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2.
  • R 7 is H or -CH 3 .
  • R 7 is H.
  • R 4 is Ci-C4alkyl
  • R 5 is a substituted or unsubstituted C 3 -Cecycloalkyl, substituted or unsubstituted C2-C 6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl
  • R 9 is -OH. In some embodiments, R 9 is -OH or -OR 11 ; p is 0 or 1.
  • p is 0, 1 , or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1. In some embodiments, p is 0.
  • n is 0, 1 , or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 1 or 2.
  • m is 0, 1 , 2, 3 or 4. In some embodiments, m is 1 , 2, 3 or 4. In some embodiments, m is 0, 1 , 2, or 3. In some embodiments, m is 0, 1 , or 2. In some embodiments, m is 0, or 1. In some embodiments, m is 1 , 2, or 3. In some embodiments, m is 1 , or 2. In some embodiments, m is 1.
  • R 1 is H, F, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl C 3 -C 6 cycloalkyl, C3-C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is H or Ci-C 4 alkyl
  • Cefluoroalkyl substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl;
  • R 9 is substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C 2 - Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted C2-Cioheterocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted aryl), and -Ci- C2alkylene-(substitute
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 - C cycloalkyl, or substituted or unsubstituted Ci-Ceheteroalkyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • R 4 is d-C 4 alkyl
  • Y is -0-. In some embodiments, X is -0-.
  • R 5 is -OH. In some embodiments, R 5 is -OH or -OR 11 ; p is 0 or 1.
  • R is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 4 is H, halogen, -CN, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 alkoxy, Ci-C 4 fluoroalkoxy, C 3 -
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkoxy substituted or unsubstituted Ci-Ceheteroalkyl
  • Ci-Cealkyl substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Ci -Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted C2-Cioheterocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted aryl), and -Ci-C2alkylene- (substit
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2.
  • R 4 is d-C 4 alkyl
  • R is H, F, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, C3-C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form
  • Ci-C 6 alkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci- Ceheteroalkyl;
  • R on adject carbon atoms are taken together with the carbon atoms to which they are attached to form a C 3 -C 6 Cycloalkyl; or 1 R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 4 is H, halogen, -CN, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 alkoxy, Ci-C 4 fluoroalkoxy, C 3 - Cecycloalkyl, C3-C 6 fluorocycloalkyl, C 3 -Ceheterocycloalkyl, Ci-Ceheteroalkyl, -Ci-
  • Cefluoroalkoxy substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci- Ceheteroalkyl, substituted or unsubstituted Ci -Cefluoroalkyl, or a substituted or
  • Ci-Cealkyl substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci -Cefluoroalkyl;
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted C2-Cioheterocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted aryl), and -Ci- C2alkylene-(substit
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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-l-yl)propoxy)phenyl)-2H- chromen-6-ol; 3-(3-Fluorophenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-l- yl)propoxy)phenyl)-2H-chro
  • R 4 is d-C 4 alkyl
  • the com ound of Formula (I) has the following structure:
  • the compound of Formula (I) has one of the following structures:
  • R is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci
  • R 2 is H or R 12 ;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 4 is H, halogen, -CN, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 alkoxy, Ci-C 4 fluoroalkoxy, C 3 -
  • Cealkyl substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted Ci- Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, substituted or unsubstituted Ci- Ceheteroalkyl, or substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 7 is H or Ci-C 4 alkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene-
  • n 0, 1, 2, 3 or 4;
  • n 1 or 2;
  • p 0, 1, or 2;
  • the compound is not 5-Fluoro-3-(3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3- methylpyrrolidin- 1 -yl)propoxy)phenyl)-2H-chromen-6-ol.
  • R 4 is Ci-C 4 alkyl
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • the compound has one of the following structures:
  • R 5 is -OH; R 11 is H.
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl C 3 -C 6 cycloalkyl, Cs-Cefluorocycloalkyl, or C
  • R 2 is H or R 12 ;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1 , 2, 3, or 4;
  • R 7 is H or Ci-C 4 alkyl
  • Ci-C6alkoxy substituted or unsubstituted Ci-Ceheteroalkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 -
  • Ciocycloalkyl substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Ci-Cealkoxy substituted or unsubstituted Ci-Ceheteroalkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted or unsubstituted
  • Ci-Cealkyl substituted or unsubstituted Ci -Cefluoroalkyl, substituted or unsubstituted C 3 - C cycloalkyl, or substituted or unsubstituted Ci-Ceheteroalkyl;
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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- (2-Fluoro-4-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-l- 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
  • R 4 is d-C 4 alkyl
  • the compound has one of the following structures:
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 -Cefluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1 , 2, 3, or 4;
  • R 7 is H or Ci-C 4 alkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted C 2 -Cioheterocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted aryl), and -Ci- C 2 alkylene-
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 3-(3-Fluoro-4-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3- methylpyrrolidin- 1 -yl)propoxy)phenyl)-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-
  • R 4 is d-C 4 alkyl
  • the com ound has one of the following structures:
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl C 3 -C 6 cycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1 , 2, 3, or 4;
  • Ci-Cefluoroalkyl or substituted or unsubstituted Ci-Cefluoroalkyl
  • R 7 is H or Ci-C 4 alkyl
  • Cefluoroalkyl substituted or unsubstituted Ci -Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl;
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci -Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Cefluoroalkyl substituted or unsubstituted Ci -Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C3-Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene- (substituted or unsubstituted C3-Ciocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted C 2 -Cioheterocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted aryl), and -Ci-C2alkylene- (substit
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 3-(3-Fluoro-4-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3- methylpyrrolidin- 1 -yl)propoxy)phenyl)-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- (4-Hydroxy-2-methylphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-l- 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)
  • R 4 is Ci-C 4 alkyl
  • the compound has one of the following structures:
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci
  • R 2 is H or R 12 ;
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci- Ceheteroalkyl;
  • R 23 on adject carbon atoms are taken together with the carbon atoms to which they are attached to form a C 3 -Cecycloalkyl; or 1 R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 4 is H, halogen, -CN, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 alkoxy, Ci-C 4 fluoroalkoxy, C 3 - Cecycloalkyl, C3-C 6 fluorocycloalkyl, C 3 -Ceheterocycloalkyl, Ci-Ceheteroalkyl, -Ci-
  • R 7 is H or Ci-C 4 alkyl
  • Cefluoroalkyl substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl;
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Cefluoroalkyl substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl;
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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- (3-Fluoro-5-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-l- yl)propoxy)phenyl)-2H-chromen-6-ol; 3-(4-Fluoro-3-hydroxyphenyl)-4-methyl-2-(4-((S)-2- ((R)-3-methylpyrrolidin- 1 -yl)propoxy)phenyl)
  • R 9 is -OH or -OR 11 .
  • the compound has one of the followin structures:
  • R 1 is H, F, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, C3-C 6 fluorocycloalkyl, or Ci
  • R 2 is H or R 12 ;
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkoxy substituted or unsubstituted Ci-Ceheteroalkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 -
  • Ciocycloalkyl substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Ci-Cealkoxy substituted or unsubstituted Ci-Ceheteroalkyl
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted C2-Cioheterocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted aryl), and -Ci- C2alkylene-(substit
  • n 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2;
  • the compound is not 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-
  • R 9 is -OH or -OR 11 .
  • the compound has one of the following structures:
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci
  • R 2 is H or R 12 ;
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci- Ceheteroalkyl;
  • R 23 on adject carbon atoms are taken together with the carbon atoms to which they are attached to form a C 3 -Cecycloalkyl; or 1 R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1, 2, 3, or 4;
  • R 4 is H, halogen, -CN, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 alkoxy, Ci-C 4 fluoroalkoxy, C 3 - Cecycloalkyl, C3-C 6 fluorocycloalkyl, C 3 -Ceheterocycloalkyl, Ci-Ceheteroalkyl, -Ci-
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene-
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2.
  • R 4 is d-C 4 alkyl
  • X is - 0-.
  • R 5 is -OH or -OR 11 ;
  • R 9 is -OH or -OR 11 ;
  • p is 0 or 1.
  • described herein is a compound of Formula (VIII), or a pharmaceutically acceptable salt, or solvate thereof:
  • R 2 is H or R 12 :
  • R 2 and R 3 are taken to ether with the N atom to which they are attached to form
  • R is taken together with R and the intervening atoms connecting R to R to form a
  • t 0, 1 , 2, 3, or 4;
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C2-Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C2alkylene- (substituted or unsubstituted C3-Ciocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted C2-Cioheterocycloalkyl), -Ci-C2alkylene-(substituted or unsubstituted aryl), and -Ci- C2alkylene-(substitute
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2.
  • R 4 is d-C 4 alkyl
  • Ceheteroalkyl substituted or unsubstituted C3-Cecycloalkyl, substituted or unsubstituted C2-
  • R 5 is -OH or -OR 11 ;
  • R 9 is -OH or -OR 11 ;
  • p is 0 or 1.
  • R 1 is H, F, Ci-C 6 alkyl, Ci-Cefluoroalkyl C 3 -Cecycloalkyl, C 3 -C 6 fluorocycloalkyl, or Ci-
  • R 2 is H or R 12 ;
  • R 4 is H, halogen, -CN, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, C 3 -
  • R 7 is H or Ci-C 4 alkyl
  • Ci-Cealkyl substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci -Ceiluoroalkyl, substituted or unsubstituted Ci-Cefluoroalkoxy, substituted or unsubstituted Ci-Cealkoxy, and substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted C 3 - Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • each R 12 is independently selected from substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, substituted or unsubstituted Ci-Cefluoroalkyl, substituted or unsubstituted C 3 -Ciocycloalkyl, substituted or unsubstituted C 2 -Cioheterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -Ci-C 2 alkylene- (substituted or unsubstituted C 3 -Ciocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted C 2 -Cioheterocycloalkyl), -Ci-C 2 alkylene-(substituted or unsubstituted aryl), and -Ci- C 2 alkylene-
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • p 0, 1, or 2.
  • R 2 is H, substituted or unsubstituted Ci-Cealkyl, substituted or unsubstituted Ci-Ceheteroalkyl, or substituted or unsubstituted Ci-Cefluoroalkyl;
  • R 4 is d-C 4 alkyl;
  • R 7 is H; Y is -0-; X is -0-.
  • the com ound has the following structure:
  • R 1 is H, F, Ci-C 6 alkyl, Ci-C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, C 3 - Cefluorocycloalkyl, or Ci-Ceheteroalkyl;
  • R 2 is H or R 12 ;
  • R 1 is H, Ci-Cealkyl, C 3 -Cecycloalkyl, or Ci-Ceheteroalkyl
  • R 2 is H or R 12
  • R 1 is F, Ci-Cealkyl, Ci-Cefluoroalkyl C 3 -Cecycloalkyl, C 3 - Cefluorocycloalkyl, or Ci-Ceheteroalkyl;
  • R 2 is H or R 12 ;
  • R 1 is Ci-Cealkyl, C 3 -Cecycloalkyl, or Ci-Ceheteroalkyl
  • R 2 is H or R 12
  • R 1 is F, Ci-Cealkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 - Cefluorocycloalkyl, or C -Ceheteroalkyl; R 2 and R 3 are taken together with the N atom to which they are attached to form 3 ⁇ 4
  • R 1 is Ci-Cealkyl, C 3 -Cecycloalkyl, or Ci-Ceheteroalkyl; R 2 and R 3 are taken together with the N atom to which they are attached to form V
  • R 1 is H, F, Ci-Cealkyl, Ci-Cefluoroalkyl, C 3 -Cecycloalkyl, C 3 - Cefluorocycloalkyl, or Ci-Ceheteroalkyl; R 2 and R 3 are taken together with the N atom to which they
  • R is H, Ci-Cealkyl, C 3 -Cecycloalkyl, or Ci-Ceheteroalkyl; R and R are taken together with the N atom to which they are attached to form V 3 ⁇ 4 N v ⁇ — ) ⁇ ( R23 ) t ; t is 1 , 2, 3, or
  • R 1 is F, Ci-Cealkyl, Ci-Cefluoroalkyl C 3 -Cecycloalkyl, C 3 - Ceiluorocycloalkyl, or Ci-Ceheteroalkyl;
  • R 2 is H or R 12 ;
  • R 1 is Ci-Cealkyl, C 3 -Cecycloalkyl, or Ci-Ceheteroalkyl
  • R 2 is H or R 12
  • R 2 and R 3 are taken together with the N atom to which they are attached to form
  • — is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 3-azabicyclo[3.2.0]heptan-3-yl, or octahydrocyclopenta[c]pyrroly
  • R 1 is Ci-Cealkyl; 2 and R 3 are taken together with the N atom to which they are attached to form z -— ; is a monocyclic heterocycloalkyl; each R is independently selected from CI, -CN, -OH, Ci-C4alkyl, Ci-C4alkoxy, and Ci-C4heteroalkyl.
  • R 1 is H or Ci-Cealkyl
  • R 2 and R 3 are taken together with the N atom to is a monocyclic heterocycloalkyl
  • each R 23 is independently selected from CI, -CN, -OH, Ci-C4alkyl, Ci-C4alkoxy, and Ci-C4heteroalkyl;
  • each R 23 is independently selected from F, CI, -CN, -OH, Ci-C4alkyl, Ci-C4iluoroalkyl, Ci-C4fluoroalkoxy, Ci-C4alkoxy, and Ci-C4heteroalkyl. In some embodiments, each R 23 is independently selected from CI, -CN, -OH, Ci-C4alkyl, Ci-C4alkoxy, and Ci-C4heteroalkyl.
  • each R 23 is independently selected from CI, -CN, -OH, Ci-C4alkyl, Ci-
  • each R is independently selected from F, CI, -CN, -OH, -CH 3 , - CH2CH3, -CH(CH 3 ) 2 , -CF 3 , -CH2CF3, -OCF3, -OCH2CF3, -OCH3, -OCH2CH3, -CH2OCH3, - CH 2 OCH 2 CH 3 , and -CH 2 OH.
  • each R 23 is independently selected from CI, -CN, -OH, -CH 3 , -CH 2
  • R 23 is -CH 3 .
  • R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl.
  • R 1 is -CH 3 ;
  • R 4 is -CH 3 .
  • R 1 is -CH 3 ; and R 23 is -CH 3 .
  • R 1 is -CH 3 ;
  • R 4 is -CH 3 ; and
  • R 23 is -CH 3 .
  • Compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), include, but are not limited to, compounds in the following tables.

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PCT/US2012/069926 2011-12-14 2012-12-14 Estrogen receptor modulators and uses thereof Ceased WO2013090829A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP12857161.9A EP2791132A4 (en) 2011-12-14 2012-12-14 ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
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