Estrogen receptor alpha antagonists and uses thereof

Abstract

The disclosure provides compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein n, X1, and R'-R3 are defined herein: Also provided are pharmaceutical compositions comprising a compound disclosed herein, methods of inhibiting estrogen receptor alpha (ERa), methods of treating an estrogen- mediated disease in a subject requiring inhibition of estrogen receptor (ER) alpha (ERa), methods of treating one or more symptoms of menopause in a subject in need thereof, and methods of treating one or more side effects of hormone replacement therapy.

Description

ESTROGEN RECEPTOR ALPHA ANTAGONISTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 63 / 520,799, filed August 21, 2023, the contents of which are incorporated by reference herein.TECHNICAL FIELD

[0002] The present disclosure provides compounds, compositions and methods for treating estrogen receptor alpha related conditions.BACKGROUND

[0003] One in eight women will be diagnosed with breast cancer in her lifetime, around 240,000 women per year in the United States. Around 70% of primary breast cancers are histologically classified by their overexpression of estrogen receptor alpha (ERa). Typically, such patients will be prescribed antiestrogens to prevent primary disease metastasis following primary interventions. These antiestrogens are given as enduring therapies for 5-15 years. Competitive antiestrogens, such as tamoxifen and fulvestrant, are effective antiestrogens but suffer from pharmacologic issues that can limit their efficacies. Moreover, acquired somatic mutations to the ESRI (ERa) gene can limit tamoxifen’s efficacy.

[0004] Thus, there remains a need to provide additional antiestrogen agents.SUMMARY

[0005] In some embodiments, the disclosure provides compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein n, X1, and RCR3are defined herein:

[0006] In other embodiments, the disclosure provides compounds of Formula II, HI, or IV, or pharmaceutically acceptable salts thereof, wherein R1is defined herein:

[0007] In further embodiments, the disclosure provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In yet other embodiments, the disclosure provides methods of inhibiting estrogen receptor alpha (ERa), comprising contacting the ERa with a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0009] In still further embodiments, the disclosure provides methods of treating an estrogen-mediated disease in a subject requiring inhibition of estrogen receptor (ER) alpha (ERa), comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0010] In other embodiments, the disclosure provides methods of treating one or more symptoms of menopause in a subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0011] In further embodiments, the disclosure provides methods of reducing the risk of developing osteoporosis in a menopausal subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0012] In yet other embodiments, the disclosure provides methods of treating one or more side effects of hormone replacement therapy in a subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0013] Other aspects and embodiments of the invention will be readily apparent from the following detailed description of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The present application is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the subject matter, there are shown in the drawings exemplary embodiments of the subject matter; however, the presently disclosed subject matter is not limited to the specific compositions and methods disclosed.

[0015] FIG. 1 is a bar graph showing the fold change of T47D cell count treated with compounds A, Al, B, Bl and B2.

[0016] FIG. 2 is a bar graph showing the fold change of MCF7 cell count treated with compounds A, Al, B, Bl and B2.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0017] The compounds described herein bind to estrogen receptor alpha and elicit a conformational change that prevents the formation of functional transcriptional complexes. Thus, the compounds inhibit ERa transcriptional activity, impact receptor nuclear lifetime (which correlates with side effect profiles), and inhibit cancer cellular proliferation, tumor growth, and metastasis.

[0018] In the present disclosure the singular forms “a,” “an” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, e.g., a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0019] When a value is expressed as an approximation by use of the descriptor “about” or “substantially” it will be understood that the particular value forms another embodiment. In general, use of “about” or “substantially” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about” or “substantially.” In other cases, the gradations used in a series of values may be used to determine the intended range available to “about” or “substantially” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0020] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as aseparate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C ”

[0021] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

[0022] The term “alkyl” refers to a straight-chain or branched groups containing from, for example, from about 1 to about 6 carbon atoms, e.g., from about 1 to about 4 carbon atoms. Examples of alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. This definition also applies wherever “alkyl” occurs as part of a group. The alkyl can be substituted or unsubstituted, as described herein. Even in instances in which the alkyl is an alkylene chain (e.g., -(CH2)n-), the alkyl group can be substituted or unsubstituted.

[0023] The term “haloalkyl” refers to a straight-chain or branched groups containing from, for example, from about 1 to about 6 carbon atoms, e.g., about 1 to about 4 carbon atoms, and at least one halo. In some embodiments, the haloalkyl contains at least one fluoro. In other embodiments, the haloalkyl contains at least one chloro. In further embodiments, the haloalkyl contains at least one bromo. In yet other embodiments, the halo alkyl contains at least one iodo. Examples of haloalkyl include CF3, CH2F, CHF2, CH2CF3, CH2CHF2, CH2CH2F, and the like. The haloalkyl can be substituted or unsubstituted, as described herein.

[0024] The term “nitrogen-containing, saturated ring” means a stable, saturated monocyclic, bicyclic, or spiro ring system containing 3 to 9 ring members of carbon atoms and at least 1 other atom that is nitrogen. In some embodiments, the nitrogen-containing, saturated ring is a 5, 6, or 7-membered monocyclic ring and contains one, two, or threenitrogen atoms. The nitrogen-containing, saturated ring can be attached to the parent structure through a carbon atom or the nitrogen atom that results in a stable structure. Examples of nitrogen-containing, saturated rings include pyrrolidinyl, piperidinyl, azepanyl, or azetidinyl. The nitrogen-containing, saturated ring can be substituted or unsubstituted, as described herein, at any position of the ring, provided that the substitution results in a stable structure.

[0025] The term “halo” refers to a halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0026] Suitable substituents include, e.g., halo, Ci-ealkyl, OH, NO2, CN, NH2, Ci- ealkoxy, Cs-scycloalkyl, aryl, heteroaryl, or heterocycloalkyl.

[0027] The term “alkoxy” as used herein refers to an alkyl moiety containing an oxygen atom. Examples of alkoxy include methoxy, ethoxy, isopropyloxy, butoxy, and the like. The alkoxy can be substituted or unsubstituted as described herein.

[0028] The term “cycloalkyl” as used herein refers to a cyclic alkyl moiety containing from, for example, 3 to 10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl can be substituted or unsubstituted as described herein.

[0029] The term “aryl” refers to a mono, bi, or tricyclic carbocyclic ring system having one, two, or three aromatic rings. The term “aryl” includes monocyclic and polycyclic aromatics such as, e.g., phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. An aryl moiety generally contains from, e.g., 6 to 30 carbon atoms (C6-30), 6 to 18 carbon atoms (Ce-is), 6 to 14 carbon atoms (Ce-u), or 6 to 10 carbon atoms (Ce-io). The aryl can be substituted or unsubstituted as described herein.

[0030] The term “heteroaryl” refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl,pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (l,2,3)-triazolyl, (l,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl. The heteroaryl can be substituted or unsubstituted as described herein.

[0031] The term “heterocycloalkyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, and spiro ring system containing 3 to 7 ring members of carbon atoms and at least 1 other atom that is nitrogen, sulfur, pr oxygen. In some aspects, the heterocycloalkyl is a 5, 6, or 7-membered monocyclic ring and contains one, two, or three heteroatoms that are nitrogen, oxygen, or sulfur. The heterocycloalkyl can be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Examples of such heterocycloalkyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl. The heterocycloalkyl can be substituted or unsubstituted as described herein.

[0032] In any of the embodiments above, whenever a range of the number of atoms in a structure is indicated (e.g., C1-12, C1-8, C1-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (Ci-s), 1-6 carbon atoms (Ci-e), 1-4 carbon atoms (C1-4), 1-3 carbon atoms (C1-3), or 2-8 carbon atoms (C2-8) as used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, and / or 8 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, etc., as appropriate).Compounds

[0033] The disclosure provides compounds of Formula I or pharmaceutically acceptable salts thereof:

[0034] According to the disclosure, n is 0 to 6. In some embodiments, n is 0 to 5, 0 to 4, 0 to 3, 0 to 2, 0 to 1, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, or 5 to 6. In other embodiments, n is 0. In further embodiments, n is 1. In yet other embodiments, n is 2. In still further embodiments, n is 3. In other embodiments, n is 4. In further embodiments, n is 5. In still other embodiments, n is 6.

[0035] According to the disclosure, X1is O or S. In some embodiments, X1is O. In other embodiments, X1is S.

[0036] According to the disclosure, R1is a -N(R3)- or an optionally substituted, nitrogen-containing, saturated ring. In some embodiments, R1is -N(R3)-. In other embodiments, R1is -NH-, i.e., R3is H. In further embodiments, R1is -N(Ci-6alkyl)-, i.e., R3is Ci-ealkyl. In yet other embodiments, R1is -NCH3-, i.e., R3is methyl. In still further embodiments, R1is -N(ethyl)-, i.e., R3is ethyl. In other embodiments, R1is -N(propyl), i.e., R3is propyl. In further embodiments R1is -N(butyl)-, i.e., R3is butyl. In still other embodiments, R1is -N(pentyl)-, i.e., R3is pentyl. In yet further embodiments, R1is - N(hexyl)-, i.e., R3is hexyl.

[0037] In other embodiments, R1is an optionally substituted, nitrogen-containing, saturated ring. For example, R1is a 3- to 10-membered, nitrogen-containing, saturated ring. Examples of R1include, without limitation, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azepanyl, or optionally substituted azetidinyl.

[0038] According to the disclosure, R2is H, halo, Ci-ealkyl, or Ci-ehaloalkyl. In some embodiments, R2is H. In other embodiments, R2is halo. In further embodiments, R2is Cl, Br, or F. Preferably, R2is F. In yet other embodiments, R2is Ci-ealkyl. In still further embodiments, R2is methyl, ethyl, propyl, butyl, pentyl, or hexyl. Preferably, R2is CH3, or preferably R2is CH2CH3, or preferably R2is CH2CH2CH3. In other embodiments, R2is Ci- ehaloalkyl. Preferably, R2is CH2F, or preferably R2is CH2CH2F, or preferably R2is CH2CH2CH2F.

[0039] In certain aspects, the compound is of Formula II:or a pharmaceutically acceptable salt thereof, wherein R1is defined herein.

[0040] In other aspects, the compound is of Formula III:or a pharmaceutically acceptable salt thereof, wherein R1is defined herein.

[0041] In further aspects, the compound is of Formula IV:or a pharmaceutically acceptable salt thereof, wherein R1is defined herein.

[0042] In yet other aspects, the compound is:a pharmaceutically acceptable salt thereof.

[0043] In still further aspects, the compound is:pharmaceutically acceptable salt thereof.

[0044] In other aspects, the compound is:pharmaceutically acceptable salt thereof.

[0045] In further aspects, the compound is:pharmaceutically acceptable salt thereof.

[0046] In yet other aspects, the compound is:pharmaceutically acceptable salt thereof.

[0047] The term “pharmaceutically acceptable salt” refers to nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. For example, an inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid), an organic acid (e.g., oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid), an inorganic base (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide),an organic base (e.g., methylamine, di ethylamine, tri ethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine), or an amino acid (e.g., lysine, arginine, or alanine) can be used. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p.1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.

[0048] Compounds of Formula I, including compounds of Formula II-IV, can be prepared by any suitable synthetic method. Exemplary methods are set forth in the examples.

[0049] Compounds disclosed herein may exist in one or more enantiomeric or diastereomeric forms. Thus, a reference to a particular compound includes all isomeric forms, including racemic and other mixtures thereof. Such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatography and / or recrystallisation). Isomers may be prepared using methods known in the art (e.g., asymmetric synthesis).Pharmaceutical Compositions

[0050] The methods described herein comprise administering, to a subject in need thereof, compounds of Formula I-IV or pharmaceutically acceptable salts thereof in the form of a pharmaceutical composition. In particular, a pharmaceutical composition will comprise at least one compound of Formula I-IV or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0051] The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. Typically, the pharmaceutically acceptable carrier is one that is chemically inert to the active compounds and one that has no detrimental side effects or toxicity under the conditions of use.

[0052] The pharmaceutical compositions can be administered by via any suitable formulation, including oral, sublingual, transdermal, subcutaneous, topical, absorption through epithelial or mucocutaneous linings, intravenous, intranasal, intraarterial, intraperitoneal, intramuscular, intratumoral, peritumoral, intraperitoneal, intrathecal, rectal, vaginal, and aerosol formulations. In some aspects, the pharmaceutical composition is administered orally or intravenously.

[0053] In some embodiments, the pharmaceutical compositions can be administered orally to a subject in need thereof. Formulations suitable for oral administration include (a) liquid solutions containing a diluent (e.g., water, saline, or orange juice) and optional additive, such as cyclodextrin (e.g., a-, P-, or y-cyclodextrin, hydroxypropyl cyclodextrin) or polyethylene glycol (e.g., PEG400); (b) capsules, sachets, tablets, lozenges, and troches, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) emulsions and gels. Liquid formulations may include diluents, such as water and alcohols (e.g., ethanol, benzyl alcohol, and polyethylene alcohols), optionally containing pharmaceutically acceptable surfactants, suspending agents, or emulsifying agents. Capsules can be hard- or soft-shelled gelatin type containing, e.g., surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenges can comprise a flavor, e.g., sucrose and acacia or tragacanth.

[0054] Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions. The injections solutions and suspensions may also include, without limitation, suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compounds of Formula I-IV or a pharmaceutically acceptable salt thereof can be administered in a physiologically acceptable diluent in a pharmaceutical carrier. Suitable carriers include, without limitation, sterile liquid or mixture of liquids (e.g., water, saline, aqueous dextrose and related sugar solutions), alcohol (e.g., ethanol, isopropanol, or hexadecyl alcohol), glycols (e.g., propylene glycol or polyethylene glycol), glycerol ketals (e.g., 2,2-dimethyl-l,3-dioxolane-4-methanol), ethers (e.g., poly(ethyleneglycol) 400), oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides. The liquid solutions or suspensions may also contain pharmaceutically acceptable surfactants (e.g., soaps or detergents), suspending agents (e.g., pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose), emulsifying agents and other pharmaceutical adjuvants.

[0055] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts. Suitable detergents include (a) cationic detergents (e.g., dimethyl dialkyl ammonium halides, and alkyl pyridinium halides), (b) anionic detergents (e.g., alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates), (c) nonionic detergents (e.g. , fatty amine oxides, fatty acid alkanolamides, and poly oxy ethylene-polypropylene copolymers), (d) amphoteric detergents (e.g., alkyl-beta- aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts), and (3) mixtures thereof.

[0056] For parenteral solutions, suitable preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants. Suitable surfactants include polyethylene sorbitan fatty acid esters (e.g., sorbitan monooleate) and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be in unit-dose or multi -dose sealed containers (e.g., ampoules and vials), and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier (e.g., water) for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0057] The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

[0058] Topically applied compositions are generally in the form of liquids (e.g., mouthwash), patches creams, pastes, lotions and gels. Topical administration includes application to the skin and oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa. In some embodiments, topical compositions contain suitable vehicles or carriers. It may also contain other components, such as anti -irritants. The carrier can be a liquid, solid or semi-solid. In embodiments, the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components. In soneembodiments, the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral. The liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. The topical compositions can be solids (e.g., powders or granules). The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site. In other embodiments, the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols (e.g., glycerin), lipid materials (e.g., fatty acids), mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.Methods of Treatment

[0059] In some aspects, the compounds of Formula I-IV inhibit estrogen receptor alpha (ERa). Accordingly, the disclosure provides methods of inhibiting estrogen receptor alpha (ERa) in a cell comprising contacting the cell with compounds of Formula I-IV or pharmaceutically acceptable salts thereof. The ERa activity can be measured by any method, including assays described herein.

[0060] Because the compounds of Formula I-IV inhibit or suppress estrogen production, the compounds may be useful in treating an estrogen-mediated disease requiring inhibition of estrogen receptor alpha (Ea). See, e.g., Deroo (J Clin Invest, 2006, 116(3), 561- 570). The method comprises administering to a subject in need thereof one or more compounds of Formula I-IV.

[0061] The estrogen-mediated disease is any disease that is treatable by inhibiting ERa. ER a is overexpressed in many cancers. As such, inhibition of ERa is considered to be a viable treatment of cancers that overexpress ERa, e.g. , breast cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, and endometrial cancer. Thus, the disclosure is further directed to a method of treating ER-positive (including mutated ER) cancers comprising administering to a subject in need thereof a compound of Formula I-IV. The ER-positive cancer is any suitable cancer, including SERM- resistant ER+ luminal cancer, hormone refractory ER+ cancer, ER+ hormone-resistant cancer, hormone insensitive cancer, and cancer with a somatic mutation to ESRI (the gene for ERa) - any of which can be associated with any suitable tissue, such as tissue of the breast, ovaries, colon, rectum, prostate, lung, orendometrial lining of the uterus. In some embodiments, the estrogen-mediated disease is an ER-positive cancer. In further embodiments, the ER-positive cancer is breast cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, or endometrial cancer. In yet other embodiments, the estrogen-mediated disease is osteoporosis. In still further embodiments, the estrogen-mediated disease is vulvovaginal atrophy. In other embodiments, the estrogen- mediated disease is obesity. In further embodiments, the estrogen-mediated disease is a fibroid. In still other embodiments, the estrogen-mediated disease is a endometriosis. Anticancer activity can be measured by any suitable method, including the assays described herein.

[0062] The disclosure also provides methods of treating one or more symptoms of menopause in a subject in need thereof by administering a compound described herein to the subject. In some embodiments, the one or more symptoms of menopause is hot flashes, bone loss, vaginal dryness, night sweats, or mood swings. In other embodiments, the menopause symptom is hot flashes such as moderate to severe hot flashes. The term “hot flashes” as used herein refers to feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating. In further embodiments, the menopause symptom is bone loss. In yet other embodiments, the menopause symptom is vaginal dryness. In still further embodiments, the menopause symptom is night sweats. In other embodiments, the menopause symptom is mood swings.

[0063] The disclosure also provides methods of reducing the risk of developing osteoporosis in a menopausal patient in need thereof, comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0064] The disclosure further provides methods of treating one or more side effects of hormone replacement therapy in a subject in need thereof, comprising administering a compound described herein to the subject. In certain aspects, the hormone replacement therapy includes estrogen, progesterone, or a combination thereof. Side effects common to those needing hormone replacement therapy include, without limitation, fluid retention, bleeding between menstrual periods, spotting between menstrual periods, changes in menstrual flow, breast tenderness, among others. In some embodiments, the compounds described herein are administering in combination with conjugated estrogens or conjugated equine estrogens. Examples of conjugated estrogens / conjugated estrogens include, without limitation, estrone sulfate, equilin sulfate, among others, and are available as PREMARIN. The conjugated estrogen may be administered to the subject prior to, or concurrently with, or subsequent to the compound.

[0065] In some embodiments, the compounds of Formula I-IV can be coadministered with one or more therapeutic agents (e.g., a chemotherapeutic agent) and / or radiation therapy. In some aspects, the method comprises administering an amount of a compound of Formula I-IV that is effective to sensitize cells (e.g., cancer cells) to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy). The terms “coadministered” or “co-administration” refer to simultaneous or sequential administration. Compounds of Formula I-IV can be administered before, concurrently with, or after administration of another therapeutic agent (e.g., a chemotherapeutic agent).

[0066] One or more (e.g., one, two, three, four, or more) therapeutic agents can be administered. The therapeutic agent is any agent suitable for treating an estrogen-mediated disease. In some embodiment, the subject is or is becoming resistant to conventional therapies. In some aspects, the therapeutic agent can be a hormonal agent or an anti -cancer agent (e.g., chemotherapeutic agent).

[0067] Examples of hormonal agents include estrogens (e.g., estradiol, estriol, and estrone), progestin, and progesterone.

[0068] Examples of anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab, panitumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), enzymes (e.g., L- Asparaginase), biological agents (e.g., interferons and interleukins), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib, riboci clib), anti-cancer hormonal agents (e.g., tamoxifen, fulvestrant, raloxifene, leuprolide,bicalutamide, granisetron, flutamide, goserelin), aromatase inhibitors (e.g., exemestane, letrozole, and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase-2 (COX-2) inhibitors, cellular immunotherapy (e.g., chimeric antigen receptor T cell therapy, tumor-infiltrating lymphocyte therapy), aromatase inhibitors (e.g., letrozole, anastrozole, and exemestane), selective estrogen receptor degraders (e.g., fluvestrant, elacestrant, amcenestrant, camizestrant, giredestrant, imlunestrant, rintodestrant, borestrant, ZN-c5, D-0502), selective estrogen receptor covalent antagonists (e.g., H3B- 6545), complete estrogen receptor antagonists (e.g., OP-1250), proteolysis targeting chimer (e.g., ARV-471), chimeric estrogen receptor degraders (e.g., AC682), CDK4 / 6 inhibitors (e.g., palbociclib, abemaciclib), PI3K inhibitors (e.g., alpelisib), AKT inhibitors (e.g., capivasertib), mTOR inhibitors (e.g., everolimus), and other combinations (e.g., MEK and ERK inhibitors) or any combination thereof.

[0069] In some embodiments, the anti -cancer agent is a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib, riboci clib), an anti -cancer hormonal agent (e.g., tamoxifen, fulvestrant, raloxifene, leuprolide, bicalutamide, granisetron, flutamide, goserelin), or aromatase inhibitor (e.g., exemestane, letrozole, anastrozole).

[0070] The dose of the compound of Formula I-IV is an amount that is sufficient to affect the desired response. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the age, condition or disease state, predisposition to disease, genetic defect or defects, and body weight of the mammal. The size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular inhibitor and the desired effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.

[0071] The methods comprise administering an effective amount of a compound of Formula I-IV. The term “treat” as used herein do not necessarily imply 100% or complete treatment or prevention. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the methods can provide any amount of any level of treatment of an estrogen- mediated diseased (e.g., cancer) in a mammal. Furthermore, the treatment provided by the methods can include treatment of one or more conditions or symptoms of the disease beingtreated. For example, treatment can include promoting the regression of at least one symptom of the disease, such as a tumor.

[0072] Also, for purposes herein, “prevention” can encompass delaying the onset of the disease, or a symptom or condition thereof. Alternatively or additionally, “prevention” can encompass preventing or delaying the recurrence of the disease, or a symptom or condition thereof.

[0073] An “effective amount” means an amount sufficient to show a meaningful benefit in an individual, e.g., promoting at least one aspect of tumor cell cytotoxicity (e.g., inhibition of growth, inhibiting survival of a cancer cell, reducing proliferation, reducing size and / or mass of a tumor (e.g., solid tumor)), or treatment, healing, prevention, delay of onset, halting, or amelioration of other relevant medical condition(s) associated with a particular estrogen- mediated disease. The meaningful benefit observed in the subject can be to any suitable degree (10, 20, 30, 40, 50, 60, 70, 80, 90% or more). Effective amounts may vary depending upon the biological effect desired in the individual, condition to be treated, and / or the specific characteristics of the compounds of Formula I-IV and the individual. In this respect, any suitable dose of the compounds of Formula I-IV or pharmaceutically acceptable salts thereof can be administered to the subject (e.g., human), according to the type of disease to be treated (e.g., breast cancer). Various general considerations taken into account in determining the “effective amount” are known to those of skill in the art and are described, e.g., in Gilman et al., eds., Goodman and Gilman’s: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington’s Pharmaceutical Sciences, 17th Ed., Mack Publishing Co., Easton, Pa., 1990, each of which is herein incorporated by reference. The dose of the compound of Formula I-IV comprises about 0.01 mg per kilogram (kg) of the body weight of the subject (mg / kg) or more (e.g., about 0.05 mg / kg or more, 0.1 mg / kg or more, 0.5 mg / kg or more, 1 mg / kg or more, 2 mg / kg or more, 5 mg / kg or more, 10 mg / kg or more, 15 mg / kg or more, 20 mg / kg or more, 30 mg / kg or more, 40 mg / kg or more, 50 mg / kg or more, 75 mg / kg or more, 100 mg / kg or more, 125 mg / kg or more, 150 mg / kg or more, 175 mg / kg or more, 200 mg / kg or more, 225 mg / kg or more, 250 mg / kg or more, 275 mg / kg or more, 300 mg / kg or more, 325 mg / kg or more, 350 mg / kg or more, 375 mg / kg or more, 400 mg / kg or more, 425 mg / kg or more, 450 mg / kg or more, or 475 mg / kg or more) per day. Typically, the dose will be about 500 mg / kg or less (e.g., about 475 mg / kg or less, about 450 mg / kg or less, about 425 mg / kg or less, about 400 mg / kg or less, about 375 mg / kg or less, about 350 mg / kg or less, about 325 mg / kg or less, about 300 mg / kg or less, about 275 mg / kg or less, about 250 mg / kg or less, about 225 mg / kg or less, about 200 mg / kg or less,about 175 mg / kg or less, about 150 mg / kg or less, about 125 mg / kg or less, about 100 mg / kg or less, about 75 mg / kg or less, about 50 mg / kg or less, about 40 mg / kg or less, about 30 mg / kg or less, about 20 mg / kg or less, about 15 mg / kg or less, about 10 mg / kg or less, about 5 mg / kg or less, about 2 mg / kg or less, about 1 mg / kg or less, about 0.5 mg / kg or less, or about 0.1 mg / kg or less). Any two of the foregoing endpoints can be used to define a close- ended range, or a single endpoint can be used to define an open-ended range.

[0074] For purposes of the present invention, the term “subject” or “patient” preferably is directed to a mammal. Mammals include, but are not limited to, mice, rats, rabbits, cats, dogs, cows, pigs, horses, monkeys, apes, or humans. An especially preferred mammal is a human.Aspects

[0075] Aspect 1 : A compound of Formula I:wherein: n is 0 to 6;X1is O or S;R1is a -N(R3)- or an optionally substituted, nitrogen-containing, saturated ring;R2is H, halo, Ci-ealkyl, or Ci-ehaloalkyl; andR3is H or Ci-ealkyl; or a pharmaceutically acceptable salt thereof.

[0076] Aspect 2: The compound of Aspect 1, wherein n is 0.

[0077] Aspect 3: The compound of Aspect 1, wherein n is 1.

[0078] Aspect 4: The compound of Aspect 1, wherein n is 2.

[0079] Aspect 5: The compound of any one of Aspects 1-4, wherein X1is O.

[0080] Aspect 6: The compound of any one of Aspects 1-4, wherein X1is S.

[0081] Aspect 7: The compound of any one of Aspects 1-6, wherein R1is -N(R3)-.

[0082] Aspect 8: The compound of Aspect 7, wherein R3is H.

[0083] Aspect 9: The compound of Aspect 7, wherein R3is Ci-ealkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl, or such as CH3.

[0084] Aspect 10: The compound of any one of Aspects 1-6, wherein R1is an optionally substituted, nitrogen-containing, saturated ring.

[0085] Aspect 11 : The compound of Aspect 10, wherein R1is a 3- to 10-membered, nitrogen-containing, saturated ring.

[0086] Aspect 12: The compound of Aspect 10 or 11, wherein R1is optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azepanyl, or optionally substituted azetidinyl.

[0087] Aspect 13: The compound of any one of Aspects 1-12, wherein R2is H.

[0088] Aspect 14: The compound of any one of Aspects 1-12, wherein R2is halo, such as Cl, Br, or F, or such as F.

[0089] Aspect 15: The compound of any one of Aspects 1-12, wherein R2is Ci- ealkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl, or such as CH3, or such as CH2CH3, or such as CH2CH2CH3.

[0090] Aspect 16: The compound of any one of Aspects 1-12, wherein R2is Ci- ehaloalkyl, such as CH2F, or such as CH2CH2F, or such as CH2CH2CH2F.

[0091] Aspect 17: The compound of Aspect 1, that is of Formula II, III, or IV:or a pharmaceutically acceptable salt thereof.

[0092] Aspect 18: The compound of Aspect 1, that is:thereof.

[0093] Aspect 19: The compound of Aspect 18, that is:pharmaceutically acceptable salt thereof.

[0094] Aspect 20: A pharmaceutical composition comprising the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0095] Aspect 21 : A method of inhibiting estrogen receptor alpha (ERa), comprising contacting the ERa with the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof.

[0096] Aspect 22: A method of treating an estrogen -mediated disease in a subject requiring inhibition of estrogen receptor (ER) alpha (ERa), comprising administering the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, to the subject.

[0097] Aspect 23: The method of Aspect 22, wherein the estrogen-mediated disease is an ER-positive cancer, osteoporosis, endometriosis, vulvovaginal atrophy, obesity, or a fibroid.

[0098] Aspect 24: The method of Aspect 23, wherein the estrogen-mediated disease is an ER-positive cancer.

[0099] Aspect 25: The method of Aspect 24, wherein the ER-positive cancer is breast cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, or endometrial cancer.

[0100] Aspect 26: The method of Aspect 23, wherein the estrogen-mediated disease is osteoporosis.

[0101] Aspect 27: The method of Aspect 23, wherein the estrogen-mediated disease is vulvovaginal atrophy.

[0102] Aspect 28: The method of Aspect 23, wherein the estrogen-mediated disease is obesity.

[0103] Aspect 29: The method of Aspect 23, wherein the estrogen-mediated disease is a fibroid.

[0104] Aspect 30: The method of Aspect 23, wherein the estrogen-mediated disease is a endometriosis.

[0105] Aspect 31 : The method of any one of Aspects 21-30, further comprising administering at least one other therapeutic agent.

[0106] Aspect 32: The method of Aspect 31, wherein the at least one other therapeutic agent is a hormonal agent or an anti -cancer agent.

[0107] Aspect 33: The method of Aspect 32, wherein the anti -cancer agent is a CDK4 / 6 inhibitor, an anti-cancer hormonal agent, or an aromatase inhibitor, or a combination thereof.

[0108] Aspect 34: A method of treating one or more symptoms of menopause in a subject in need thereof, comprising administering the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, to the subject.

[0109] Aspect 35: The method of Aspect 34, further comprising administering a conjugated estrogen.

[0110] Aspect 36: The method of Aspect 35, wherein the conjugated estrogen is administered to the subject prior to, concurrently with, or subsequent to the compound.

[0111] Aspect 37: The method of Aspect 34, wherein the one or more symptoms of menopause is hot flashes, bone loss, vaginal dryness, night sweats, or mood swings.

[0112] Aspect 38: A method of reducing the risk of developing osteoporosis in a menopausal subject in need thereof, comprising administering the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, to the subject.

[0113] Aspect 39: A method of treating one or more side effects of hormone replacement therapy in a subject in need thereof, comprising administering the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, to the subject.

[0114] The following examples are provided to illustrate some of the concepts described within this disclosure. While each Example is considered to provide specific individual embodiments of composition, methods of preparation and use, none of the Examples should be considered to limit the more general embodiments described herein.

[0115] Example 1: Preparation of Compound A

[0116] Compound A was prepared as described in Scheme 1.H-9

[0117] HPLC: injection volume: 5pL; column: Eclipse Plus C18, 100x4.6 mm, 3.5 pm; Mobile Phase A: 0.05% TFA in water; Mobile Phase B: 0.05% TFA in acetonitrile: elution: time / %B-0 / 5, 2 / 5, 6 / 60, 9 / 98, 12 / 98, 12.1 / 15, 15 / 5; diluent: ACN:water (l :l)(%v / v); flow: 1.0 mL / min; sample temperature: ambient; column temperature: ambient. See, Table 1.

[0118] 'H-NMR (400 MHz, DMSO-d6): 8 9.26 (s, 1H), 7.46-7.44 (m, 1H), 7.43- 7.36 (m, 2H), 7.23-7.21 (m, 2H), 7.13-7.11 (m, 2H), 6.89 (d, J= 8.40 Hz, 2H), 6.50-6.42 (m, 3H), 5.87-5.17 (m, 1H), 4.54 (t, J =6.00 Hz, 1H), 4.43 (t, J= 6.00 Hz, 1H), 3.87-3.85 (m, 2H), 3.55-3.50 (m, 1H), 3.28-3.23 (m, 1H), 3.15-3.09 (m, 1H), 2.64-2.55 (m, 4H), 2.53-2.39 (m, 3H), 2.19-2.15 (m, 1H), 1.96-1.87 (m, 1H), 1.85-1.77 (m, 2H), 1.52-1.51 (m, 1H), 1.09- 0.94 (m, 1H), 0.73-0.43 (m, 3H); MS (MM) m / z 529.30 [M + H]+.

[0119] Example 2: Preparation of Compound Al

[0120] Compound Al was prepared as shown in Scheme 2.1) POCI3,ACN, 90 °C, 2 h2) NaBH4, MeOH CH2CI2, rt, 16 h rt, 16 hScheme 2

[0121] 'H-NMR (400 MHz, CDC13): 6 7.47-7.35 (m, 5H), 7.26-7.15 (m, 2H), 6.83-6.81 (m, 2H), 6.63-6.62 (m, 1H), 6.57-6.55 (m, 1H), 6.41 (s, 1H), 4.90-4.79 (m, 1H), 3.76- 3.69 (m, 4H), 3.65-3.48 (m, 4H), 3.36-3.31 (m, 1H), 3.24-3.18 (m, 1H), 2.09-2.10 (m, 3H), 1.67 (s, 2H), 1.48 (s, 9H), 1.09-0.98 (m, 1H), 0.76-0.75 (m, 2H); MS (MM) m / z 569.29 [M + H]+. LCMS: 515.54 m / z.

[0122] Example 3: Preparation of Compound B

[0123] Compound B was prepared as described in Scheme 3.Compound-B H-12Scheme 3

[0124] HPLC conditions: injection volume: 5 L; column: Eclipse Plus Cl 8, 100 x 4.6 mm, 3.5 pm; Mobile Phase A: 0.05% TFA in water; Mobile Phase B: 0.05% TFA in acetonitrile: elution: time / %B-0 / 5, 2 / 5, 6 / 60, 9 / 98, 12 / 98, 12.1 / 15, 15 / 5; diluent: ACN:water (l : l)(%v / v); flow: l.O mL / min; sample temperature: ambient; column temperature: ambient. See, Table 2.

[0125] 'H-NMR (400 MHz, DMSO-d6): 8 9.26 (s, 1H), 7.46-7.44 (m, 1H), 7.43- .37 (m, 2H), 7.23-7.21 (m, 2H), 7.13-7.11 (m, 2H), 6.89 (d, J= 8.80 Hz, 2H), 6.50-6.42 (m, H), 5.87-5.19 (m, 1H), 4.07 (t, J= 6.00 Hz, 2H), 3.55-3.50 (m, 1H), 3.28-3.23 (m, 1H), .12-3.07 (m, 1H), 2.81 (s, 2H), 2.64-2.55 (m, 3H), 2.19-2.15 (m, 1H), 1.70 (s, 5H), 1.06- .94 (m, 1H), 0.73-0.58 (m, 3H); MS (MM) m / z 483.48 [M + H]+.

[0126] Example 4: Preparation of Compound Bl

[0127] Compound Bl was prepared as described in Scheme 4.H-12Scheme 4

[0128] 'H-NMR (400 MHz, DMSO-d6): 8 9.23 (s, 1H), 7.46-7.42 (m, 1H), 7.40- 7.36 (m, 2H), 7.23-7.21 (m, 2H), 7.12-7.10 (m, 2H), 6.89 (d, 7=8.80 Hz, 2H), 6.50-6.42 (m, 3H), 5.84-5.62 (m, 1H), 4.07-4.04 (m, 2H), 3.54-3.50 (m, 1H), 3.28-3.23 (m, 1H), 3.12-3.07 (m, 1H), 2.67 (s, 2H), 2.50-2.44 (m, 4H), 2.22-2.12 (m, 1H), 1.53-1.47 (m, 4H), 1.41-1.38 (m, 2H), 1.08-1.00 (m, 1H), 0.73-0.57 (m, 3H); MS (MM) m / z 497.27 [M + H]+. LCMS:497.27

[0129] Example 5: Preparation of Compound B2

[0130] Compound B2 was prepared as described in Scheme 5.

[0131] LCMS: 511.20; 'H-NMR (400 MHz, DMS0-d6): 6 9.26 (s, 1H), 7.46-7.43 (m, 1H), 7.40-7.36 (m, 2H), 7.23-7.21 (m, 2H), 7.17-7.11 (m, 2H), 6.90-6.88 (m, 2H), 6.50- 6.43 (m, 3H), 5.81-5.23 (m, 1H), 4.06-4.03 (m, 2H), 3.54-3.50 (m, 1H), 3.26-3.23 (m, 1H),3.12-3.07 (m, 1H), 2.88 (s, 2H), 2.70-2.68 (m, 3H), 2.19-2.15 (m, 1H), 1.76-1.54 (m, 9H), 1.09-1.00 (m, 1H), 0.73-0.69 (m, 1H), 0.62-0.58 (m, 2H); MS (MM) m / z 511.29 [M + H]+.

[0132] Example 6

[0133] These compounds are prepared using similar procedure described forCompound A in Example 1, but usingrespectively, instead of

[0134] Example 7

[0135] This compound is prepared using the procedure described for Compound A in Example 1, but using

[0136] Example 8

[0137] This compound is prepared using the procedure for Compound B inExample 3, but usinginstead of

[0138] Example 9

[0139] These compounds are prepared using a similar procedure for Compound

[0141] This compound is prepared using the procedure for Compound Al inExample 2, but usinginstead of

[0142] Example 11

[0143] These compounds are prepared by using the synthetic methodologies described herein.

[0144] Example 12: Assays

[0145] A. T47D Breast Cancer Assay

[0146] A cellular proliferation assay was used to assess efficacy in T47D breast cancer cells that harbor WT ESRI. Cells were plated in 96 well plates at approximately 1,000 cells / well and serum starved of hormone for 48 hours. Cells were treated with vehicle (DMSO), 1 nM 17-beta-estradiol (E2), or 1 nM E2 + 1 pM Compound A, Compound Al, Compound B, Compound Bl, or Compound B2 for 7 days. Cells were label-free counted using a Biotek Cytation 5 and data were normalized to starting cell count. See, FIG. 1. A significant reduction in proliferation was observed for each compound.

[0147] B. MCF7 Breast Cancer Assay

[0148] A cellular proliferation assay was used to measure efficacy in MCF7 breast cancer cells harboring a homozygous Y537S ESRI mutation that enables hormone therapy resistance. Cells were plated in 96 well plates at approximately 1,000 cells / well and serum starved of hormone for 48 hours. Cells were treated with vehicle (DMSO), 1 nM E2, or 1 nM E2 + 1 pM Compound A, Compound Al, Compound B, Compound Bl, or Compound B2 for 3 days, after which time the E2-only wells became fully confluent. Cells were label-free counted using a Biotek Cytation 5 and data were normalized to starting cell count. See, FIG. 2. Only T6I-B2 showed a significant reduction in proliferation in these cells.

[0149] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, each in its entirety, for all purposes.

Claims

What is claimed:wherein: n is 0 to 6;X1is O or S;R1is a -N(R3)- or an optionally substituted, nitrogen-containing, saturated ring;R2is H, halo, Ci-ealkyl, or Ci-ehaloalkyl; andR3is H or Ci-ealkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1, wherein n is 1.

4. The compound of claim 1, wherein n is 2.

5. The compound of claim 1, wherein X1is O.

6. The compound of claim 1, wherein X1is S.

7. The compound of claim 1, wherein R1is -N(R3)-.

8. The compound of claim 7, wherein R3is H.

9. The compound of claim 7, wherein R3is Ci-ealkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl, or such as CH3.

10. The compound of claim 1, wherein R1is an optionally substituted, nitrogencontaining, saturated ring.

11. The compound of claim 10, wherein R1is a 3- to 10-membered, nitrogen-containing, saturated ring.

12. The compound of claim 10, wherein R1is optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azepanyl, or optionally substituted azetidinyl.

13. The compound of claim 1, wherein R2is H.

14. The compound of claim 1, wherein R2is halo, such as Cl, Br, or F, or such as F.

15. The compound of claim 1, wherein R2is Ci-ealkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl, or such as CH3, or such as CH2CH3, or such as CH2CH2CH3.

16. The compound of claim 1, wherein R2is Ci-ehaloalkyl, such as CH2F, or such as CH2CH2F, or such as CH2CH2CH2F.

17. The compound of claim 1, that is of Formula n, III, or IV:or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, that is:thereof.

19. The compound of claim 18, that is:pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A method of inhibiting estrogen receptor alpha (ERa), comprising contacting the ERa with the compound of claim 1, or a pharmaceutically acceptable salt thereof.

22. A method of treating an estrogen-mediated disease in a subject requiring inhibition of estrogen receptor (ER) alpha (ERa), comprising administering the compound of claim 1, or a pharmaceutically acceptable salt thereof, to the subject.

23. The method of claim 22, wherein the estrogen-mediated disease is an ER-positive cancer, osteoporosis, endometriosis, vulvovaginal atrophy, obesity, or a fibroid.

24. The method of claim 23, wherein the estrogen-mediated disease is an ER-positive cancer.

25. The method of claim 24, wherein the ER-positive cancer is breast cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, or endometrial cancer.

26. The method of claim 23, wherein the estrogen-mediated disease is osteoporosis.

27. The method of claim 23, wherein the estrogen-mediated disease is vulvovaginal atrophy.

28. The method of claim 23, wherein the estrogen-mediated disease is obesity.

29. The method of claim 23, wherein the estrogen-mediated disease is a fibroid.

30. The method of claim 23, wherein the estrogen-mediated disease is a endometriosis.

31. The method of claim 21, further comprising administering at least one other therapeutic agent.

32. The method of claim 31, wherein the at least one other therapeutic agent is a hormonal agent or an anti-cancer agent.

33. The method of claim 32, wherein the anti -cancer agent is a CDK4 / 6 inhibitor, an anticancer hormonal agent, or an aromatase inhibitor, or a combination thereof.

34. A method of treating one or more symptoms of menopause in a subject in need thereof, comprising administering the compound of claim 1, or a pharmaceutically acceptable salt thereof, to the subject.

35. The method of claim 34, further comprising administering a conjugated estrogen.

36. The method of claim 35, wherein the conjugated estrogen is administered to the subject prior to, concurrently with, or subsequent to the compound.

37. The method of claim 36, wherein the one or more symptoms of menopause is hot flashes, bone loss, vaginal dryness, night sweats, or mood swings.

38. A method of reducing the risk of developing osteoporosis in a menopausal subject in need thereof, comprising administering the compound of claim 1, or a pharmaceutically acceptable salt thereof, to the subject.

39. A method of treating one or more side effects of hormone replacement therapy in a subject in need thereof, comprising administering the compound of claim 1, or a pharmaceutically acceptable salt thereof, to the subject.

Images