Selective estrogen receptor degraders

Abstract

Novel selective estrogen receptor degraders (SERDs) according to the following formula and pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof: wherein R is selected from the group consisting of

Description

[0001] background

[0002] Selective estrogen receptor degraders (SERDs) bind to the estrogen receptor (ER) and downregulate ER-mediated transcriptional activity. This degradation and downregulation induced by SERDs can be used to treat cell proliferation disorders such as cancer. Several small-molecule examples of SERDs have been disclosed in the literature (see, for example, WO2005073204, WO2014205136, and WO2016097071). However, known SERDs are not yet as useful as needed for effective cancer treatment. For example, discovering SERDs with better pharmacokinetic (PK) and pharmacodynamic (PD) properties, higher clinical efficacy, and good oral bioavailability would be very helpful in cancer treatment. Highly selective antagonist SERDs with inhibition of ER-mediated transcription would be significantly beneficial in cancer treatment. New SERDs are needed to treat cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer, as well as mutations caused by emerging resistance. In particular, new SERDs are needed to treat ER-positive breast cancer, gastric cancer, and / or lung cancer.

[0003] This article discloses novel tetracyclic compounds that act as SERDs and their pharmaceutically acceptable salts. The newly invented SERDs described herein provide ER-mediated transcriptional inhibition, which could be used to treat cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer, as well as mutations caused by emerging resistance. These SERDs can be used as single agents or in combination with other classes of drugs to treat hormone receptor-positive cancers such as breast cancer, gastric cancer, and / or lung cancer, including selective estrogen receptor modulators (SERMs), aromatase inhibitors, CDK4 inhibitors, CDK6 inhibitors, PI3K inhibitors, and mTOR inhibitors.

[0004] The novel compound described in this article is represented by formula I:

[0005]

[0006] Where R is selected from

[0007]

[0008] Or its pharmaceutically acceptable salt.

[0009] Those skilled in the art will understand that compounds described by Formula I, or pharmaceutically acceptable salts thereof, contain a chiral center, the location of which is indicated by *. Those skilled in the art will also understand that the Cahn-Ingold-Prelog(R) or (S) nomenclature of the chiral center will vary depending on the mode of substitution around the chiral center. The chiral center in compounds of Formula I provides the R-enantiomer shown in Formula II:

[0010]

[0011] And the S-enantiomer form shown by Equation III:

[0012]

[0013] All individual stereoisomers, enantiomers and diastereomers, and mixtures of enantiomers and diastereomers (including racemates) of compounds according to Formulas I, II, and III are included within the scope of the compounds described herein. Compounds containing a chiral center for pharmaceutical use are often isolated as single enantiomers or diastereomers, and such isolated compounds of Formulas I, II, and III are included within the scope of the compounds disclosed herein. Those skilled in the art will also understand that compounds of Formulas I, II, and III described herein, and their pharmaceutically acceptable salts, may be deuterated (where hydrogen may be replaced by deuterium), and such molecules are considered to be included within the scope of the compounds disclosed herein.

[0014] This section shows specific examples of compounds of Formula I (including IUPAC nomenclature):

[0015]

[0016] [5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]hydrosulfate;

[0017]

[0018] (2S,3S,4S,5R,6S)-6-[[5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]oxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid;

[0019] Due to the chiral centers of Formula I indicated by *, each of these specific examples of Formula I compounds shown above has R- and S-enantiomers as shown in Table 1 (i.e., R-enantiomers of Formula II and S-enantiomers of Formula III).

[0020] Table 1: Enantiomers of Compounds of Formula I

[0021]

[0022]

[0023] This document also describes pharmaceutical compositions comprising compounds of formulas I, II, and III as described herein, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The pharmaceutical compositions described herein can be prepared using pharmaceutically acceptable additives. As used herein, the term "pharmaceutically acceptable additive" means one or more carriers, diluents, and excipients that are compatible with other additives in the composition or formulation and are harmless to the patient. Compounds of Formulas I, II, and III described herein, or pharmaceutically acceptable salts thereof, can be formulated into pharmaceutical compositions for administration via various routes, such as oral or intravenous (IV). Bioavailability is often a factor in cancer treatment, and the ability to select administration methods and pharmaceutical compositions to control or optimize the bioavailability of the active ingredient is useful. For example, orally bioavailable SERD compositions would be particularly useful. Compounds of Formulas I, II, and III described herein, or pharmaceutically acceptable salts thereof, are believed to have bioavailability. Examples of pharmaceutical compositions and methods of their preparation can be found in “Remington: The Science and Practice of Pharmacy”, LV Allen Jr, ed., 22nd ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include: physiological saline, water, starch, sugar, mannitol, and silica gel derivatives; binders such as carboxymethyl cellulose and other cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethylene glycols.

[0024] This article further describes methods for treating cancer. The methods described herein involve administering to a patient requiring such treatment an effective amount of a compound of formulas I, II, and III as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, the method of administering an effective amount of a compound of formulas I, II, and III as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be oral administration, or alternatively, intravenous administration. The cancer may be breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. Specifically, the cancer may be an estrogen-responsive cancer, such as ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.

[0025] This document also describes compounds of formulas I, II, and III as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in therapeutics. This document also provides compounds of formulas I, II, and III as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. Specifically, the cancer may be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer. For example, compounds of formulas I, II, and III, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may be administered orally.

[0026] Additionally, compounds of formulas I, II, and III as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be used to prepare medicaments for treating cancer. For example, these medicaments can be administered orally. Types of cancers for which the medicaments described herein can be used to treat include breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. Specifically, the cancer can be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.

[0027] Compounds of Formulas I, II, and III, as well as pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as described herein, may be clinically used as a single agent or in combination with one or more other therapeutic agents (e.g., anticancer agents) for the treatment of cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. When used in combination with other therapeutic agents (such as anticancer agents), compounds of Formulas I, II, and III, as well as pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as described herein, may be used simultaneously, sequentially, or separately from the other therapeutic agents. Examples of drug classes that can be combined with compounds of Formulas I, II, and III, as well as pharmaceutically acceptable salts thereof, as described herein, include SERMs, aromatase inhibitors, CDK4 inhibitors, CDK6 inhibitors, PI3K inhibitors, and mTOR inhibitors for the treatment of hormone receptor-positive breast cancer. More specific examples of drugs that can be combined with compounds of formulas I, II and III as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include abexicillin (CDK4 / 6 inhibitor), everolimus (mTOR inhibitor), apeliximab (PIK3CA inhibitor), and 8-[5-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one (PI3K / mTOR inhibitor).

[0028] As used herein, the term "effective amount" refers to the amount or dose of a compound of formulas I, II, and III as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which, upon administration to a patient in a single or multiple doses, provides the desired effect in the diagnosis or treatment of the patient. Preferably, the desired effect is inhibition of tumor cell proliferation, tumor cell death, or both. Compounds of formulas I, II, and III as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are generally effective over a wide dose range. For example, the daily dose typically falls within the daily range of about 100 mg to about 2000 mg.

[0029] As used in this article, “treat,” “treating,” or “treatment” means to suppress, slow down, stop, or reverse the progression or severity of existing symptoms or disorders.

[0030] The term “patient” as used in this article refers to a person suffering from a particular disease, disorder, or condition.

[0031] Compounds of Formulas I, II, and III, or pharmaceutically acceptable salts thereof, as described herein, can be prepared using a variety of procedures known in the art, some of which are illustrated in the preparation and examples below. The specific synthetic steps of each described route can be combined in different ways, or combined with steps from different procedures, to prepare compounds of Formulas I, II, and III, or pharmaceutically acceptable salts thereof, as described herein. Products can be recovered using conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization. Reagents and starting materials are readily available to those skilled in the art.

[0032] This specification is intended to include intermediates and methods for synthesizing compounds of formulas I, II, and III as described herein. Additionally, some of the intermediates described herein may contain one or more protecting groups. These variable protecting groups may be the same or different each time they appear, depending on the specific reaction conditions and the specific transformation to be performed. Protecting and deprotecting conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis," fourth edition, Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0033] Individual isomers, enantiomers, and diastereomers can be separated or resolved by those skilled in the art at any convenient point in the synthesis of compounds of formulas I, II, and III as described herein, by methods such as selective crystallization or chiral chromatography (see, for example, J. Jacques et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E.L. Leeel and S.H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). Although individual isomers, enantiomers, and diastereomers can be separated or resolved as indicated, the Cahn-Ingold-Prelog(R) or (S) nomenclature of their chiral centers may not yet be determined. In the absence of available Cahn-Ingold-Prelog(R) or (S) nomenclature, the identifiers “Isomer 1” and “Isomer 2” are used in combination with the IUPAC name, without the Cahn-Ingold-Prelog stereochemical nomenclature. Compounds of Formulas I, II, and III identified as “Isomer 1” or “Isomer 2” in this paper are separated as defined in the specific experimental description below. The isomer designation “1” or “2” indicates the order in which compounds of Formulas I, II, and III elute from the chiral column under the listed conditions; that is, “Isomer 1” is the first to elute from the column under the specified conditions. If chiral chromatography begins early in the synthesis, the same designation applies to subsequent intermediates and compounds of Formulas I, II, and III.

[0034] Unless otherwise specified, the abbreviations used in this article are defined according to Aldrichimica Acta, Vol. 17, No. 1, 1984. Other abbreviations are defined as follows: “BSA” for bovine serum albumin; “CRISPR” for clustered, regularly spaced short palindromic repeats; “DCM” for dichloromethane; “DMEA” for dimethylethanolamine; “DMEM” for Dulbecco's Modified Eagle's Medium; “DMF” for N,N-dimethylformamide; “DMSO” for dimethyl sulfoxide; “DNA” for deoxyribonucleic acid; “ee” for enantiomer excess; “ER” for estrogen receptor; “ERα” for estrogen receptor α; “ES / MS” for electrospray ionization / mass spectrometry; “EtOAc” for ethyl acetate; “EtOH” for ethanol; “FBS” for fetal bovine serum; “HCl” for hydrochloric acid; “IC…” for… 50"Indicates the concentration of the drug that produces 50% of the maximum possible inhibitory response (relative to IC50)" 50 ), or the concentration of the drug that produces 50% inhibition of target enzyme activity compared to the placebo control (absolute IC50). 50 ); "iPrOH" indicates isopropanol; "IV" indicates intravenous administration; "LC / MS" indicates liquid chromatography / mass spectrometry; "MeOH" indicates methanol; "MTBE" indicates methyl tert-butyl ether; "m / z" indicates mass-to-charge ratio; "PBS" indicates phosphate-buffered saline; "PR" indicates progesterone receptor; "PRα" indicates progesterone receptor α; "RNase" indicates ribonuclease; "SFC" indicates supercritical fluid chromatography; "THF" indicates tetrahydrofuran; "t (R) " indicates retention time; and "XPhos Pd G2" indicates chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0035] The following preparation and examples further illustrate the present invention.

[0036] Preparation and Examples

[0037] Scheme 1 describes the synthesis of compounds of formula I, II or III.

[0038]

[0039] Option 1

[0040] In step A, a Grignard reaction is completed. Grignard reactions as reactions that form carbon-carbon bonds are well known in the art. The reaction involves an organometallic reaction in which an aryl magnesium halide (a Grignard reagent) is added to the carbonyl group of compound 2, such as an acyl chloride, to produce the compound of step A. For example, in a solvent such as THF, a 4-chloro-substituted quinolone (compound 1) is treated with a Grignard reagent such as isopropyl magnesium chloride to form a Grignard intermediate, followed by the addition of an acyl chloride (4-fluorobenzoyl chloride, compound 2). At the end, the reaction can be quenched with water to produce compound 3.

[0041] In step B, the aryl methyl ether of compound 3 can be demethylated under a variety of conditions known to a skilled craftsman, such as treatment with boron tribromide. For example, compound 3 is slowly treated with boron tribromide in a solvent such as DCM at a temperature of about 0°C. The mixture is stirred at room temperature and quenched with dipotassium hydrogen phosphate to produce compound 4.

[0042] In step C, ether compound 6 can be formed by treating the corresponding p-fluorophenyl ketone 4 and the aziridine alkoxide 5 or the corresponding free base in a suitable polar aprotic solvent such as DMF or THF with a suitable base such as sodium hydride, sodium tert-butoxide or potassium tert-butoxide to produce ether compound 6.

[0043] Then, in step D, compound 6 is alkylated with a suitably substituted arylboronic acid (compound 7) in the Suzuki crosslinking reaction to produce compound 8. Those skilled in the art will recognize that various conditions exist that can be used to promote such cross-coupling reactions. Suitable palladium reagents may include XantPhos Pd G2, A Pd G3, bis(triphenylphosphine)palladium(II) dichloride, tris(dibenzylacetone)palladium(O) with tricyclohexylphosphine, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, tetra(triphenylphosphine)palladium, or palladium acetate(II). Suitable bases may include potassium fluoride, cesium carbonate, sodium carbonate, potassium carbonate, lithium tert-butoxide, or tripotassium phosphate monohydrate. For example, compound 6 can be reacted with a suitable boric acid, compound 7, such as 2-fluoro-4-(trifluoromethyl)phenylboronic acid, in a solvent such as 2-methyl-2-butanol with a base such as potassium carbonate and a catalyst such as XPhos Pd G2, and heated under microwave conditions to about 80°C to produce compound 8.

[0044] Those skilled in the art will recognize that step D, namely the Suzuki crosslinking reaction, can be completed before the formation of the aza-butane ether in step C.

[0045] In step E, those skilled in the art will recognize that compound 9 can be obtained by reduction of a ketone. This can be accomplished using a reducing agent such as lithium triethylborohydride in a solvent such as 1,4-dioxane and THF at a temperature of about 0°C to room temperature to produce the corresponding secondary alcohol 9, which can optionally be purified by chiral chromatography to produce an enantiomerically enriched secondary alcohol.

[0046] In step F, alcohol 9 can be intramolecularly cyclized by reacting with a base such as sodium hydride to produce cyclic ether 10. Those skilled in the art will recognize that a variety of suitable bases can be used in this step.

[0047] In step G, alcohol 10 is further reacted with the sulfur trioxide trimethylamine complex or methyl acetyl bromide-α-D-glucuronide, followed by ester hydrolysis to produce compounds of formula I, II or III.

[0048] In an optional step, pharmaceutically acceptable salts of compounds of formulas I, II, and III as described herein can be formed by reacting a suitable free base of a compound of formulas I, II, and III as described herein with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions. Additionally, the formation of these salts can occur simultaneously upon deprotection of the nitrogen protecting group. The possible formation of pharmaceutically acceptable salts is well known. See, for example, Gould, PL, “Salt selection for basic drugs,” International Journal of Pharmaceutics. 33 :201-217 (1986); Bastin, RJ, et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4 :427-435 (2000); and Berge, SM, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66 :1-19, (1977). Those skilled in the art will understand that compounds of formulas I, II, and III as described herein are readily converted to and can be isolated as pharmaceutically acceptable salts. Examples of useful salts include, but are not limited to, benzenesulfonates and 4-methylbenzenesulfonates. 4-Methylbenzenesulfonates are also known as toluenesulfonates.

[0049] Preparation 1

[0050] 2-[3-(fluoromethyl)azacyclobutan-1-yl]ethane-1-ol

[0051]

[0052] Sodium triacetoxyborohydride (405 g, 1.91 mol) was added fractionally to a stirred 0°C solution of 3-(fluoromethyl)azacyclobutane hydrochloride (160 g, 1.28 mol) in 2.4 L DCM over 15 minutes under nitrogen atmosphere, and the mixture was stirred at 0°C for 10 minutes. Six fractions of 1,4-dioxane-2,5-diol (99 g, 0.83 mol) were added over 1 hour at 0°C, and the mixture was stirred at 0–5°C for 15 minutes. The reaction was allowed to warm to room temperature and stirred under nitrogen atmosphere for 2 hours. The reaction was cooled to 10–15°C over 20 minutes, then warmed to 25–30°C and held at that temperature for 2 hours. Water (800 mL) was added over 25–30 minutes at 10–15°C, and the mixture was allowed to warm to room temperature and held for 5–10 minutes, after which the layers were separated. The aqueous layer was washed with DCM (800 mL), the layers were separated, and the combined aqueous layer was then cooled to 10–15 °C and the pH was adjusted to 13–14 using a 50% sodium hydroxide aqueous solution (~540 mL). The aqueous layer was allowed to warm to room temperature, extracted with DCM (4 x 800 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give the title compound (139 g, 82%) as a thick yellow oil. ES / MS (m / z): 134.1 (M+H).

[0053] Preparation 2

[0054] 2-[3-(fluoromethyl)azacyclobutan-1-yl]ethane-1-ol hydrochloride

[0055]

[0056] 2-[3-(fluoromethyl)azacyclobutan-1-yl]ethane-1-ol (529 g, 4 mol) was dissolved in MTBE (2.6 L) and cooled to 0 °C. HCl / EtOH solution (492 mL, 30 wt%) was added dropwise over 30 minutes, followed by stirring at 0 °C for 30 minutes. The solid was filtered and the filter cake was washed with MTBE (2 x 200 mL). The mixture was dried under nitrogen for 8 hours to give the title compound (580 g, 86%) as a white solid. ES / MS (m / z): 134.0 (M+H).

[0057] Preparation 3

[0058] (3-Chloro-7-methoxyquinoline-4-yl)-(4-fluorophenyl)methyl ketone

[0059]

[0060] A mixture of 4-bromo-3-chloro-7-methoxyquinoline (70 g, 254 mmol) and THF (1 L) was cooled to -40 °C under nitrogen, resulting in precipitation. Isopropyl magnesium chloride (2 M in THF, 254 mL, 509 mmol) was added over 20 minutes, and the mixture was stirred for 1 hour. A solution of 4-fluorobenzoyl chloride (66 mL, 559 mmol) in THF (140 mL) was added dropwise, and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated aqueous NH4Cl solution (300 mL) and water (200 mL), and the layers were separated. The organic layer was washed with saturated aqueous NH4Cl solution (300 mL), dried over anhydrous MgSO4, filtered, and concentrated to provide an oily residue. The crude brown oil was filtered through silica gel and eluted with a mixture of MTBE / hexane (1:1) to give a crude product (84 g) as a yellow solid. The solid was treated with 10% methyl acetate / heptane (800 mL) and stirred overnight at room temperature. The solid was collected by filtration and stored. The filtrate was concentrated and purified on silica gel, eluted with 10–40% EtOAc / hexane, and then treated with 10% methyl acetate / heptane (200 mL) and stirred at room temperature for 3 hours. The resulting solid was filtered, combined with the solid from the previous filtration, and dried under vacuum overnight to give the title compound (31 g, 38%) as a yellow solid. ES / MS (m / z): 316.0 (M+H).

[0061] Preparation 4

[0062] (3-Chloro-7-hydroxyquinoline-4-yl)-(4-fluorophenyl)methyl ketone

[0063]

[0064] Boron tribromide (1 M in DCM, 295 mL, 295 mmol) was added to a mixture of (3-chloro-7-methoxyquinoline-4-yl)-(4-fluorophenyl) methyl ketone (31 g, 98 mmol) in DCM (217 mL), and the mixture was stirred at room temperature for 3 days. The mixture was slowly poured into a solution of dipotassium hydrogen phosphate (2 M, 700 mL) and water (200 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The solution was concentrated under vacuum to remove the organic solvent, filtered, and the filtrate was collected and dried under vacuum at 45 °C overnight. The solid was treated with DCM / heptane (1:1, 450 mL) and stirred overnight. The solid was collected and dried under vacuum overnight to give the title compound (32 g, quantitative yield) as a light brown solid. ES / MS (m / z): 302.0 (M+H).

[0065] Preparation 5

[0066] (3-Chloro-7-hydroxyquinoline-4-yl)-(4-{2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy}phenyl)methyl ketone

[0067]

[0068] 2-[3-(fluoromethyl)azacyclobutan-1-yl]ethane-1-ol hydrochloride (3.90 g, 23.0 mmol) was added to a stirred solution of (3-chloro-7-hydroxyquinoline-4-yl)-(4-fluorophenyl) methyl ketone (5.00 g, 15.3 mmol) in DMF (75 ml), followed by the addition of sodium hydride (60% in mineral oil, 3.02 g, 76.8 mmol). The mixture was stirred under nitrogen and heated to 40 °C for 45 minutes. The solution was quenched with water and concentrated. The residue was partitioned and separated between 20% iPrOH / CHCl3 and a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 2 x 20% iPrOH / CHCl3. The organic extracts were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give a crude product as a dark red oil. The crude compound was purified by silica gel column chromatography by elution with a 5–10% gradient of 7N NH3 in MeOH / DCM to yield the title compound as a yellow solid (5.31 g, 84%). ES / MS (m / z): 415.0 (M+H).

[0069] Preparation of 6

[0070] (4-{2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinoline-4-yl}methyl ketone

[0071]

[0072] In a microwave-safe tubular flask, a mixture of (3-chloro-7-hydroxyquinoline-4-yl)-(4-{2-[3-(fluoromethyl)azacyclobutan-1-yl]ethoxy}phenyl) ketone (200 mg, 0.48 mmol), 2-fluoro-4-(trifluoromethyl)phenylboronic acid (158 mg, 0.72 mmol), potassium carbonate (202 mg, 1.45 mmol), 2-methyl-2-butanol (3 mL), and water (1 mL) was degassed with nitrogen (5x). XPhos Pd G2 (12 mg, 0.015 mmol) was added, the flask was sealed, and the mixture was microwaved at 80 °C for 2 hours. The residue was partitioned between MTBE and a saturated aqueous solution of NH4Cl. The layers were separated, and the aqueous layer was extracted with MTBE. The organic extracts were combined, dried over anhydrous MgSO4, filtered, and the filtrate was concentrated to give an orange residue. The crude compound was purified by silica gel column chromatography, eluting with 5% MeOH / DCM to yield the title compound (205 mg, 78%) as a yellow solid. ES / MS (m / z): 543.2 (M+H).

[0073] Preparation 7

[0074] Racemic 4-{2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy}phenyl)(hydroxy)methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinoline-7-ol

[0075]

[0076] Under nitrogen atmosphere, (4-{2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinoline-4-yl} methyl ketone (305 g, 562.2 mmol) and THF (1.5 L) were added together, and the solution was cooled to 0–5 °C. Triethyllithium borohydride (1 M in THF, 1.5 L, 1.5 mol) was added dropwise. The mixture was stirred at 0–5 °C for 1 hour. Water (300 mL) and saturated NH4Cl aqueous solution (1 L) were added dropwise. The mixture was warmed to room temperature. EtOAc (2 L) was added, and the organic layer was collected. The organic layer was washed with brine (500 mL), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was dissolved in a 95:5 mixture of acetone and 2M ammonia in MeOH and filtered through silica gel to yield the title compound as an orange solid (264 g, 86.2%). ES / MS (m / z): 545.2 (M+H).

[0077] Preparation of 8

[0078] 4-[(R)-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-hydroxy-methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinoline-7-ol

[0079]

[0080] Purification of racemic 4-{2-[3-(fluoromethyl)azacyclobutan-1-yl]ethoxy}phenyl)(hydroxy)methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinoline-7-ol (5.5 g, 0.10 mol) using chiral chromatography under the following conditions: column AD-H, 150 x 50 mm, flow rate 200 g / min, UV 270 nm, mobile phase 35% iPrOH / CO2 containing 0.5% DMEA, column temperature 35 °C, to produce the title compound (2.6 g, 47%). Enantiomer enrichment of isomer 1 was confirmed by chiral analytical SFC, >96% ee, t (R) = 0.79 minutes, column: 4.6 × 150 mm AD-H was eluted with a 35% iPrOH / CO2 mobile phase containing 0.5% DMEA at a flow rate of 0.6 mL / min and detected by UV at 350 nm.

[0081] Preparation 9

[0082] (5R)-5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol

[0083]

[0084] Sodium hydride (60% dispersion in mineral oil, 1.00 g, 15 mmol) was added to a stirred solution of 4-[(R)-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-hydroxy-methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinoline-7-ol (2.60 g, 5 mmol) in THF (50 mL), and the resulting solution was heated to 65 °C under nitrogen. After 1 hour, the reaction was cooled to room temperature and quenched with water (50 mL). The resulting mixture was partitioned between EtOAc (50 mL) and a saturated aqueous solution of NH4Cl (50 mL). The layers were separated, and the aqueous phase was extracted with fresh EtOAc (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to produce a yellow solid. The crude mixture was purified by column chromatography (4–6% MeOH / DCM) to give the title compound (1.98 g, 80%) as a yellow solid. ES / MS (m / z): 525.2 (M+H).

[0085] Example 1

[0086] [(5R)-5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]hydrosulfate

[0087]

[0088] A solution of sodium methoxide (0.5 M, 0.6 mL, 0.3 mmol) in MeOH was added to a solution of (5R)-5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol (54 mg, 0.1 mmol) in anhydrous THF (10 mL). After stirring at room temperature for 0.5 h, sulfur trioxide trimethylamine complex (57 mg, 0.4 mmol) was added in quadrature hourly over a period of 4 h. The solvent was then evaporated under a nitrogen stream, and the reaction mixture was diluted with water (5 mL). The pH was adjusted to 8 by adding 2 drops of 1 M NaOH aqueous solution. The solution was directly loaded into an Iterchim automated chromatography system (30 g). Elution was performed on an Rf Gold reversed-phase C18 column with a gradient of 10 to 90% acetonitrile in water to produce the title product (46 mg, 74%) as a pale yellow solid. ES / MS (m / z): 605.6 (M+H).

[0089] Preparation 10

[0090] (2S,3S,4S,5R,6S)-6-[[(5R)-5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-yl]oxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid methyl ester

[0091]

[0092] Lithium hydroxide (90.9 mg, 3.80 mmol) was added to a suspension of (5R)-5-[4-[2-[3-(fluoromethyl)azacyclobutan-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol (830.0 mg, 1.58 mmol) in anhydrous MeOH (16 mL) at room temperature. The mixture was stirred until the starting material dissolved (approximately 20 min). Methyl acetyl bromide-α-D-glucuronate (1.19 g, 3.01 mmol) was added. The reaction was stirred at room temperature for 4 h, at which point LC / MS analysis of the reaction mixture indicated 28% conversion to the desired product and 60% unreacted starting material. Additional lithium hydroxide (92.0 mg, 3.84 mmol) was added. After stirring for 10 min, additional methyl acetyl bromide-α-D-glucuronate (1.19 g, 3.01 mmol) was added. Three hours later, LC / MS analysis indicated a 35% conversion to the product and 50% unreacted starting material. The reaction was then stopped, and the mixture was used in subsequent steps without purification.

[0093] Example 2

[0094] (2S,3S,4S,5R,6S)-6-[[(5R)-5-[4-[2-[3-(fluoromethyl)azacyclobutane-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]oxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid

[0095]

[0096] The reaction mixture from Preparation 10 was added to a solution of lithium hydroxide (114.5 mg, 4.78 mmol) in water (10 mL). The reaction was stirred for 2 hours, at which point LC / MS analysis of the reaction mixture indicated incomplete hydrolysis. Further lithium hydroxide (114.5 mg, 4.78 mmol) and MeOH (8 mL) were added sequentially. The reaction was stirred at room temperature for 1.5 hours, and LC / MS analysis indicated complete hydrolysis. The pH of the mixture was adjusted to pH 7 with concentrated acetic acid, and the mixture was separated into two equal portions. Each portion was loaded onto a reverse-phase C18 column (275 g). Elution was performed on an Rf Gold reversed-phase C18 column using a gradient of 0 to 100% acetonitrile in water. Fractions were combined and concentrated under reduced pressure at 25 °C. The residue was lyophilized to yield the title compound as a pale yellow solid (80 mg, 7% yield in two steps). ES / MS (m / z): 701.6 (M+H).

[0097] Biological assay

[0098] Evidence of a relationship between ER expression and certain cancers is well known in the field.

[0099] The results of the following measurements confirm that the compounds of Formulas I, II and III in the examples are active SERDs and are considered to be useful for the treatment of cancer.

[0100] ERα degradation assay in MCF7 cells

[0101] The purpose of the following ERα degradation assay is to measure the degradation of ERα by the test compound in ERα-positive breast cancer cell lines such as MCF7.

[0102] MCF7 (ATCC HTB-22) cells were cultured in DMEM supplemented with 10% FBS, 0.01 mg / mL human insulin, and 1% penicillin / streptomycin antibiotics. Cells were seeded at a density of 4,000 cells / well in 384-well flat-bottomed plates in 20 μL of phenol red-free DMEM medium containing 10% charcoal-tripped FBS. Cells were incubated overnight in a cell culture incubator (5% CO2, 95% RH, and 37°C) to allow cell attachment to the plate. The following day, the test compound was administered to the cells. Serial dilutions (1:3) of the test compound were prepared using an Echo 555 acoustic dispenser, ranging from 6 μM to 0.0003 μM. Cells were administered by adding 5 μL from the serial dilution plate to the cell plate, resulting in a final DMSO concentration of 0.2%, with the final test compound concentration dose ranging from 2 to 0.0001 μM. For the maximum point, medium containing 0.2% DMSO was used, and for the minimum point, fulvestrant was diluted to a final concentration of 2 μM in growth medium containing 0.2% DMSO. After application of the test compounds, the cell plates were incubated at 37°C and 5% CO2 for 24 hours. Cells were fixed by adding 14% paraformaldehyde (10 μL) and maintaining at room temperature for 30 minutes. Cells were washed once with PBS (20 μL) and then incubated with medium containing 0.5% (v / v) fulvestrant. Incubate the cells together with 20 μL of PBS for 1 hour. Then, use a solution containing 0.05% PBS... Wash with 20 μL PBS (2×) and rinse with 3% PBS (containing 0.05% PBS). 20 and 0.1% TRITON TM BSA (20 μL / well) in X-100 was blocked at room temperature for 1 hour. Each well was then added to 1% BSA / PBS (containing 0.05% BSA). 20) The 1:500 dilution of primary antibody (20 μL) (ERα (clone SP1) monoclonal rabbit antibody #RM-9101-S, Thermo Scientific) was used to dilute the cells. The plate was sealed and incubated overnight at 4°C. The next day, the cells were dipped in a solution containing 0.05%... Wash with 20 μL of PBS (2×) and then with secondary antibody (20 μL / well) in PBS and 1% BSA (1:1000 dilution, goat anti-rabbit IgM ALEXA FLUOR). TM 488) Incubate together at room temperature for 105 minutes. After washing the plate with PBS (2 × 20 μL), add 20 μL of RNase (Sigma) (50 μg / mL) and 20 μL of 1:1000 propidium iodide dilution in PBS to each well. Seal the plate and incubate at room temperature for 1 hour (protected from light). Use ACUMEN EXPLORER. TM (Laser scanning fluorescence microplate cell counter manufactured by TTP LABTECH LTD) The plate was scanned to measure ERα. Image analysis was based on the cellular fluorescence signal used to identify positive cells. ER-positive cells were identified by average intensity. Individual cells were identified using the total intensity of propidium iodide / DNA at 575-640 nm. The measurement output is the percentage of ER-positive cells. GENE DATA was used. TM IC is determined by curve fitting to the four-parameter logic of each output. 50 Relative ICs of Examples 1 and 2 50 The values ​​are shown in Table 2. The results of this assay demonstrate the degradation of ERα induced in MCF7 breast cancer cells as described in Examples 1 and 2 herein.

[0103] Table 2: ERα degradation assay in MCF7 cells

[0104] Example # <![CDATA[Relative to IC 50 (μM)]]> 1 0.115±0.0184,n＝4 2 0.211±0.0692,n＝4

[0105] PRα induction assay in MCF7 cells

[0106] The purpose of the PRα induction assay described below is to determine whether the test compound has agonistic activity against the ERα receptor (the agonist is expected to activate the receptor).

[0107] MCF7 cells (purchased from ATCC HTB-22) were cultured in DMEM medium supplemented with 10% FBS, 0.01 mg / mL human insulin, and 1% penicillin / streptomycin antibiotics. Cells (before reaching 70% confluence) were seeded at a density of 4,000 cells / well in 20 μL of phenol red-free DMEM medium containing 10% FBS (carbon-adsorbed) in 384-well flat-bottomed plates. Cells were incubated overnight in a cell culture incubator (5% CO2, 95% relative humidity at 37°C) to allow cell attachment to the plate. The test compound was administered to the cells the following day. Serial dilutions (1:3) of the compound were prepared using an Echo 555 acoustic dispenser, ranging from 6 μM to 0.0003 μM. Cells were administered by adding 5 μL of the test compound from the serial dilution plate to the cell plate, resulting in a final DMSO concentration of 0.2%, with the final test compound concentration dose range being 2 to 0.0001 μM. For the maximum point, medium containing 0.2% DMSO was used, and for the minimum point, fulvestrant was diluted to a final concentration of 2 μM in growth medium containing 0.2% DMSO. After application of the test compounds, the cell plates were incubated at 37°C and 5% CO2 for 24 hours. Cells were fixed by adding 14% paraformaldehyde (10 μL) and maintaining at room temperature for 30 minutes. Cells were washed once with PBS (20 μL) and then incubated with 0.5% (v / v) fulvestrant. Incubate the cells together with 20 μL of PBS for 1 hour. Then, use a solution containing 0.05% PBS... Wash twice with 20 μL of PBS and rinse with 3% PBS containing 0.05% PBS. 20 and 0.1% TRITON TM BSA (20 μL / well) in X-100 solution was blocked at room temperature for 1 hour. Each well was then added to 1% BSA / PBS (containing 0.05 μL of PBS). 20) 1:500 primary antibody (20 μL) (PR monoclonal mouse anti-human antibody, clone PgR 636Dako, M3569) dilution, sealed plate and incubated overnight at 4°C.

[0108] The following day, the cells were treated with 0.05% PBS. Wash with 20 μL (2 × 20 μL) of secondary antibody in PBS and 1% BSA (20 μL / well) (1:1000 dilution, goat anti-rabbit IgM ALEXA FLUOR). TM488) were incubated together at room temperature for 105 minutes. After washing with PBS (2 × 20 μL), RNase (20 μL of 50 μg / mL) (Sigma) and a 1:1000 dilution of propidium iodide in PBS were added to each well. The plate was sealed and incubated at room temperature on the workbench for 1 hour (protected from light). ACUMENE EXPLORER was used. TM (Laser scanning fluorescence microplate cell counter manufactured by TTP LABTECH LTD) The plate was scanned to measure PRα. Image analysis was based on the cellular fluorescence signal used to identify positive cells. PR-positive cells were identified by average intensity. Individual cells were identified using the total intensity of propidium iodide / DNA at 575-640 nm. The measurement output is PR-positive cell percentage. GENE DATA was used. TM IC is determined by curve fitting to the four-parameter logic of each output. 50 The results of this assay demonstrated that Examples 1 and 2 did not exhibit significant agonistic activity in MCF7 breast cancer cells. For the tested compounds, the relative IC50 in this assay was... 50 >2 μM. The results of this assay demonstrate that the tested example compounds did not exhibit significant agonistic activity in MCF7 breast cancer cells. These results also demonstrate that the tested example compounds are ERα antagonists in MCF7 breast cancer cells (i.e., they possess SERD activity).

[0109] Assay for PRα inhibition (ERα antagonism) in MCF7-ESR1 Y537N 682CRISPR cells

[0110] The purpose of the following PRα inhibition (ERα antagonistic effect) cellular assay is to determine the antagonistic activity of the test compound against the Y537N mutant ERα receptor. The antagonist in this assay is expected to block ERα receptor function. PRα is a downstream transcriptional target of ERα, and therefore ERα antagonists are expected to inhibit PRα expression.

[0111] MCF7-ESR1Y537N-682 cells (generated by CRISPR / Cas9 gene editing of the ESR1 gene in MCF7 cells, clone #682) were cultured in DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin antibiotics. Cells (before reaching 70% confluence) were seeded at a density of 4,000 cells / well in 384-well flat-bottomed plates in DMEM medium without phenol red and 10% FBS (20 μL volume) (carbon-adsorbed). Cells were incubated overnight in a cell culture incubator (5% CO2, 95% relative humidity, and 37°C) to allow cell attachment to the plate. The test compound was administered to the cells the following day. Serial dilutions (1:3) of the compound were prepared using an Echo 555 acoustic dispenser in the range of 6 μM to 0.0003 μM. Cells were administered by adding 5 μL of the serial dilution medium to the cell plate to produce a final DMSO concentration of 0.2%. The final test compound concentration dose ranged from 2 to 0.0001 μM. For the maximum point, medium containing 0.2% DMSO was used, and for the minimum point, fulvestrant was diluted to a final concentration of 2 μM in growth medium containing 0.2% DMSO. After administration of the test compound, the cell plates were incubated at 37°C and 5% CO2 for 72 hours. Cells were fixed by adding 10 μL of 14% paraformaldehyde and maintaining at room temperature for 30 minutes. Cells were washed with PBS (1 × 20 μL) and then with 0.5% (v / v) DMSO. Incubate the cells together with 20 μL of PBS for 1 hour. Then, transfer the cells to PBS (2 × 20 μL) and 0.05% PBS. Wash 20 times and rinse with 3% BSA / PBS 0.05%. 20, 0.1% TRITON TM X-100 (20 μL / well) was blocked at room temperature for 1 hour. 0.05 μL of 1% BSA / PBS was added to each well. 20 μL of 1:500 primary antibody (PR monoclonal mouse anti-human antibody, clone PgR 636Dako, M3569) was diluted in 20 μL, sealed in a plate, and incubated overnight at 4°C.

[0112] The next day, the cells were treated with PBS Wash (2 × 20 μL) and with secondary antibody (20 μL / well) in PBS 1% BSA (1:1000 dilution, goat anti-rabbit IgM ALEXA FLUOR) TM488) were incubated together at room temperature for 105 minutes. After washing with PBS (2 × 20 μL), RNase (20 μL of 50 μg / mL) (Sigma) and a 1:1000 dilution of propidium iodide in PBS were added to each well. The plate was sealed and incubated at room temperature on the workbench for 1 hour (protected from light). ACUMENE EXPLORER was used. TM (Laser scanning fluorescence microplate cell counter manufactured by TTP LABTECH LTD) The plate was scanned to measure PRα. Image analysis was based on the cellular fluorescence signal used to identify positive cells. PR-positive cells were identified by average intensity. Individual cells were identified using the total intensity of propidium iodide / DNA at 575-640 nm. The measurement output is PR-positive cell percentage. GENE DATA was used. TM IC is determined by curve fitting to the four-parameter logic of each output. 50 .

[0113] In this determination, the relative IC values ​​of Examples 1 and 2 50 As shown in Table 3 below, the results of this assay demonstrate the inhibitory and functional antagonistic effects of Examples 1 and 2 on PRα in MCF7 (ESR1 Y537N, heterozygous mutant) breast cancer cells. PRα (PGR) is also a transcriptional target of ERα, and the results of this assay demonstrate the inhibition of ERα-mediated PRα transcription.

[0114] Table 3: PRα inhibition (ERα antagonism) assay in MCF7 Y537N 682CRISPR cells

[0115] Example # <![CDATA[Relative to IC 50 (μM)]]> 1 0.330±0.116,n＝3 2 0.470±0.058,n＝3

[0116] Cell proliferation assays in MCF7 and MCF7-ESR1 Y537N-682 cells

[0117] The purpose of the following cell proliferation assays is usually to detect whether the test compound has an effect on cell proliferation.

[0118] MCF7 (purchased from ATCC HTB-22) cells were seeded at a density of 2,000 cells per well in DMEM phenol red-free medium with 10% FBS (20 μL volume) (carbon-adsorbed) into clear-bottom 384-well cell culture plates. MCF7-ESRY537N-682 cells (generated by CRISPR / Cas9 gene editing of the ESr1 gene in MCF7 cells, clone #682) were seeded at a density of 1,000 cells per well in DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin antibiotics. The plates were incubated at 37°C and 5% CO2. The following day, the cells were administered the test compound. Serial dilutions (1:3) of the test compound were prepared using an Echo 555 acoustic dispenser in the range of 60 μM to 0.003 μM. Cells were administered by adding 5 μL of the serial dilution buffer to the cell plate to produce a final DMSO concentration of 0.2%. The final test compound concentration dose ranged from 20 to 0.001 μM. For the maximum point, medium containing 0.2% DMSO was used, and for the minimum point, fulvestrant was diluted to a final concentration of 2 μM in growth medium containing 0.2% DMSO. After administration of the test compound, the cell plate was incubated at 37°C and 5% CO2. Seven days after the addition of the test compound, the plate was removed from the incubator, and 65 μL of cold EtOH 96% was added to each well. After 30 minutes, the medium was removed, and RNase (20 μL of 50 μg / mL) (Sigma) and a 1:1000 dilution of propidium iodide in PBS were added to each well. The plate was sealed and incubated at room temperature on the bench for 1 hour (protected from light). The results were obtained using ACUMEN EXPLORER. TM (Laser scanning fluorescence microplate cell counter manufactured by TTP LABTECH LTD) Scanning plate. MCF-7 cell lines grow to form aggregates, and the cell number as the number of objects may not be usable as a reading; therefore, the cell number can be evaluated by estimation (calculated using an area parameter, which is the ratio of the total area of ​​the total cell population (a specified range of peak intensity of FL-1(PI)) to the average area of ​​a single cell population (defined by perimeter)). GENE DATA was used. TM IC is determined by curve fitting to the four-parameter logic of each output. 50 Examples 1 and 2 show the relative IC50 values ​​in MCF7 ESR1 wild-type and MCF7-ESR1 Y537N mutant cells. 50 As shown in Table 4 below, the results of this assay demonstrate the antiproliferative activity and cell growth inhibition of Examples 1 and 2 in MCF7 (ESR1 wild-type) and MCF7 (ESR1Y537N mutant) breast cancer cells. The relative IC50 values ​​of the example compounds are shown in Table 4. 50In MCF7 ESR1 wild-type, the concentrations ranged from approximately 0.0035 to 1.176 μM, and in MCF7 (ESR1 Y537N mutant) breast cancer cells, the concentrations ranged from 0.014 to 1.86 μM, indicating that the example compounds in all experiments exhibited antiproliferative activity and cell growth inhibition in both MCF7 (ESR1 wild-type) and MCF7 (ESR1 Y537N mutant) breast cancer cells.

[0119] Table 4: Cell proliferation assays in MCF7 and MCF7-ESR1Y537N-682 cells

[0120]

Claims

1. A compound of the formula: wherein R is selected from or a pharmaceutically acceptable salt thereof. or 2. The compound according to claim 1, wherein the compound is wherein R is selected from ， or a pharmaceutically acceptable salt thereof. or , 3. The compound according to claim 1, wherein the compound is wherein R is selected from ， or a pharmaceutically acceptable salt thereof. or , 4. The compound according to claim 1 or 2, wherein the compound is or a pharmaceutically acceptable salt thereof. ， 5. The compound according to claim 1 or 2, wherein the compound is or a pharmaceutically acceptable salt thereof. ， 6. The compound according to claim 4, wherein the compound is 7. The compound according to claim 5, wherein the compound is 。 8. The compound according to claim 1 or 3, wherein the compound is 。 or a pharmaceutically acceptable salt thereof. ， 9. The compound according to claim 1 or 3, wherein the compound is or a pharmaceutically acceptable salt thereof. ， 10. The compound according to claim 8, wherein the compound is 11. The compound according to claim 9, wherein the compound is 。 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. 。 13. The pharmaceutical composition according to claim 12, comprising one or more other therapeutic agents.

14. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 or 13, in the manufacture of a medicament for the treatment of a cancer associated with the estrogen receptor (ER) in a patient in need of such treatment, wherein the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer or lung cancer.

15. The use according to claim 14, wherein the breast cancer is ER-positive breast cancer.

16. The use according to claim 14, wherein the gastric cancer is ER-positive gastric cancer.

17. The use according to claim 14, wherein the lung cancer is ER-positive lung cancer. ​

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