Selective estrogen receptor degrader

Abstract

formula: [Formula 1] TIFF2024511352000043.tif30128 (wherein R is [Case 2] TIFF2024511352000044.tif15128 or [C3] A novel selective estrogen receptor degrader (SERD) according to the present invention, which is selected from the group consisting of TIFF2024511352000045.tif25128, and a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition thereof.

Description

[Background technology]

[0001] Selective estrogen receptor degraders (SERDs) bind to estrogen receptors (ERs) and downregulate ER-mediated transcriptional activity. This degradation and downregulation caused by SERDs may be useful in the treatment of cell proliferation disorders such as cancer. Several small molecule examples of SERDs have been disclosed in the literature (see, for example, WO 2005073204, WO 2014205136, and WO 2016097071). However, the known SERDs are not as useful as they need to be to effectively treat cancer. For example, finding a SERD with good pharmacokinetic (PK) and pharmacodynamic (PD) properties, high efficiency in the clinic, and good oral bioavailability would be very helpful in the treatment of cancer. Highly selective antagonist SERDs that inhibit ER-mediated transcription would clearly be beneficial in the treatment of cancer. There is a need for new SERDs to treat cancers such as breast, ovarian, endometrial, prostate, uterine, gastric, and lung cancer, as well as new resistance mutations, particularly new SERDs to treat ER-positive breast, gastric, and / or lung cancer. Summary of the Invention

[0002] Novel tetracyclic compounds and pharmaceutical salts thereof that act as SERDs are disclosed herein. The newly invented SERDs described herein provide inhibition of ER-mediated transcription, which is useful for treating cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer, as well as new resistance mutations. These SERDs can be used as single agents or in combination with other classes of drugs, such as selective estrogen receptor modulators (SERMs), aromatase inhibitors, CDK4 inhibitors, CDK6 inhibitors, PI3K inhibitors, and mTOR inhibitors, to treat hormone receptor positive cancers such as breast cancer, gastric cancer, and / or lung cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0003] The novel compounds described herein have formula I:

[0004] [ka] (Wherein, R is

[0005] [ka] Or

[0006] [ka] (selected from

[0007] or a pharma- ceutically acceptable salt thereof.

[0008] Those skilled in the art will appreciate that compounds as described by Formula I, or pharma- ceutically acceptable salts thereof, contain chiral centers, the location of which is indicated with an *. Those skilled in the art will also appreciate that the Cahn-Ingold-Prelog priority (R) or (S) designation of a chiral center varies depending on the substitution pattern around the chiral center. The chiral centers of compounds of Formula I may be in the R-enantiomeric form, as shown by Formula II:

[0009] [ka] and the S-enantiomeric form represented by formula III:

[0010] [ka] results.

[0011] All individual stereoisomers, enantiomers, and diastereomers of the compounds according to formula I, formula II, and formula III, including racemates, and mixtures of enantiomers and diastereomers are included within the scope of the compounds described herein. Compounds for pharmaceutical use that contain chiral centers are often isolated as single enantiomers or diastereomers, and such isolated compounds of formula I, formula II, and formula III are included within the scope of the compounds disclosed herein. Those skilled in the art will also understand that the compounds of formula I, formula II, and formula III described herein, and their pharma- ceutically acceptable salts, can be deuterated (hydrogen can be replaced with deuterium), and such molecules are considered to be included within the scope of the compounds disclosed herein.

[0012] Specific examples of compounds of formula I (including their IUPAC nomenclature names) are shown below:

[0013] [ka] [5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl] hydrogen sulfate;

[0014] [ka] (2S,3S,4S,5R,6S)-6-[[5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]oxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid;

[0015] * Because of the chiral center of formula I depicted in Table 1, each of these specific examples of the compound of formula I above has R- and S-enantiomeric forms (i.e., R-enantiomeric compounds of formula II and S-enantiomeric compounds of formula III), as shown in Table 1.

[0016] [Table 1]

[0017] Also described herein are pharmaceutical compositions comprising the compounds of formula I, II, and III described herein, or pharma- ceutically acceptable salts thereof, together with one or more pharma- ceutically acceptable excipients, carriers, diluents, or vehicles. The pharmaceutical compositions described herein can be prepared using pharma- ceutically acceptable additives. The term "pharma- ceutically acceptable additive(s)" as used herein refers to one or more carriers, diluents, and excipients that are compatible with other excipients of the composition or formulation and are not harmful to the patient. The compounds of formula I, II, and III described herein, or pharma- ceutically acceptable salts thereof can be formulated as pharmaceutical compositions administered by various routes, such as orally or IV. Bioavailability is often a factor in cancer therapy, and the ability to select methods of administration and pharmaceutical compositions to control or optimize the bioavailability of active ingredients is useful. For example, orally bioavailable SERD compositions would be particularly useful. The compounds of formula I, II, and III described herein, or pharma- ceutically acceptable salts thereof are believed to be bioavailable. Examples of pharmaceutical compositions and processes for their preparation can be found in "Remington: The Science and Practice of Pharmacy", LV Allen Jr, Editor, 22nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharma- ceutically acceptable carriers, diluents, and excipients include saline, water, starch, sugars, mannitol, and silica derivatives; binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycols.

[0018] Further described herein is a method of treating cancer. The method described herein comprises administering to a patient in need of such treatment an effective amount of a compound of formula I, formula II, and formula III as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, the method of administering an effective amount of a compound of formula I, formula II, and formula III as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, can be oral administration, or alternatively intravenous administration. The cancer can be breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. In particular, the cancer can be estrogen-responsive cancer, such as ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.

[0019] Also described herein are compounds of formula I, II, and III, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, for use in treatment.Also provided herein are compounds of formula I, II, and III, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, for use in treatment of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer.In particular, the cancer may be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.For example, compounds of formula I, II, and III, or their pharmaceutically acceptable salts, or their pharmaceutical compositions, may be administered orally.

[0020] Furthermore, the compounds of formula I, formula II, and formula III described herein, or their pharma- ceutically acceptable salts, or their pharmaceutical compositions, can be used to manufacture medicaments for the treatment of cancer.For example, the medicaments can be administered orally.The types of cancer that 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.In particular, the cancer can be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.

[0021] The compounds of formula I, formula II, and formula III described herein, and their pharma- ceutically acceptable salts, or pharmaceutical compositions thereof, may have clinical utility as single agents or in combination with one or more other therapeutic agents (e.g., anti-cancer agents) for the treatment of cancer, such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, lung cancer, etc. When used in combination with other therapeutic agents (e.g., anti-cancer agents), the compounds of formula I, formula II, and formula III described herein, or their pharma- ceutically acceptable salts, or pharmaceutical compositions thereof, may be used simultaneously, sequentially, or separately with the other therapeutic agents. Examples of classes of drugs that can be combined with the compounds of formula I, formula II, and formula III described herein, or their pharma-ceutically acceptable salts, 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 the compounds of Formula I, Formula II, and Formula III described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, include abemaciclib (CDK4 / 6 inhibitor), everolimus (mTOR inhibitor), alpelisib (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]quinolin-2-one (PI3K / mTOR inhibitor).

[0022] As used herein, the term "effective amount" refers to the amount or dose of the compound of formula I, formula II, and formula III described herein, or its pharma- ceutically acceptable salt, or its pharmaceutical composition, which, upon administration to a patient in a single or multiple doses, provides the desired effect to the patient under diagnosis or treatment.Preferably, the desired effect is inhibition of tumor cell proliferation, tumor cell death, or both.The compound of formula I, formula II, and formula III described herein, or its pharma- ceutically acceptable salt, or its pharmaceutical composition, is generally effective over a wide dosage range.For example, the daily dosage is usually within the range of about 100 mg to about 2000 mg per day.

[0023] As used herein, "treating", "treatment", or "treat" refers to suppressing, slowing down, halting, or reversing the progression or severity of an existing symptom or disorder.

[0024] As used herein, the term "patient" refers to a human suffering from a particular disease, disorder, or condition.

[0025] The compounds of Formula I, Formula II, and Formula III described herein, or pharmaceutically acceptable salts thereof, can be prepared by various procedures known in the art, some of which are shown in the following preparations and examples. The specific synthetic steps of each described route may be combined with various methods or steps from different procedures to prepare the compounds of Formula I, Formula II, and Formula III described herein, or pharmaceutically acceptable salts thereof. The products can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Reagents and starting materials are readily available to those skilled in the art.

[0026] Intermediates and processes useful in the synthesis of the compounds of Formula I, Formula II, and Formula III described herein are intended to be included in this description. Further, certain intermediates described herein may contain one or more protecting groups. The variable protecting groups may be the same or different each time they appear, depending on the specific reaction conditions and specific transformations being carried out. Conditions for protection and deprotection are well known to those skilled in the art and are described in the literature (e.g., "Greene’s Protective Groups in Organic Synthesis", Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0027] Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of skill in the art at any convenient point in the synthesis of the compounds of Formula I, Formula II, and Formula III described herein using methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). Individual isomers, enantiomers, and diastereomers may be separated or resolved as described above, although the Cahn-Ingold-Prelog (R) or (S) designation of the chiral center may not yet be determined. When the Cahn-Ingold-Prelog (R) or (S) designation is not available, the identifiers "isomer 1" and "isomer 2" are used and combined with the IUPAC name without the Cahn-Ingold-Prelog stereochemical designation. Compounds of Formula I, Formula II, and Formula III identified herein as "isomer 1" or "isomer 2" are isolated as defined in the specific experimental description below. Whether an isomer is "1" or "2" refers to the order in which compounds of Formula I, Formula II, and Formula III elute from a chiral chromatography column under the conditions described, i.e., "isomer 1" is the first to elute from the column under the conditions described above. The same designations apply to subsequent intermediates and compounds of Formula I, Formula II, and Formula III if chiral chromatography is initiated early in the synthesis.

[0028] Unless otherwise noted, abbreviations used herein are defined according to Aldrichimica Acta, Vol. 17, No. 1, 1984. Other abbreviations are defined as follows: "BSA" refers to bovine serum albumin. "CRISPR" refers to clustered regularly interspaced short palindromic repeats. "DCM" refers to dichloromethane or methylene chloride. "DMEA" refers to dimethylethanolamine. "DMEM" refers to Dulbecco's modified Eagle's medium. "DMF" refers to N,N-dimethylformamide. "DMSO" refers to dimethylsulfoxide. "DNA" refers to deoxyribonucleic acid. "ee" refers to enantiomeric excess. "ER" refers to estrogen receptor. "ERα" refers to estrogen receptor alpha. "ES / MS" refers to electrospray ionization / mass spectrometry. "EtOAc" refers to ethyl acetate. "EtOH" refers to ethanol or ethyl alcohol. "FBS" refers to fetal bovine serum. "HCl" refers to hydrochloric acid. "IC 50 " is the maximum inhibitory response possible for that drug (relative IC 50 ) or placebo control (absolute IC 50 ) refers to the concentration of drug that results in 50% inhibition of target enzyme activity compared to . "iPrOH" refers to isopropanol or isopropyl alcohol. "IV" refers to intravenous administration. "LC / MS" refers to liquid chromatography / mass spectrometry. "MeOH" refers to methyl alcohol or methanol. "MTBE" refers to methyl t-butyl ether. "m / z" refers to mass-to-charge ratio. "PBS" refers to phosphate buffered saline. "PR" refers to progesterone receptor. "PRα" refers to progesterone receptor alpha. "RNase" refers to ribonuclease. "SFC" refers to supercritical fluid chromatography. "THF" refers to tetrahydrofuran. "t (R) " refers to retention time. "XPhos Pd G2" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II). EXAMPLES

[0029] The following preparations and examples further illustrate this invention.

[0030] Preparations and Examples Scheme 1 illustrates the synthesis of compounds of formula I, II or III.

[0031] [ka]

[0032] In step A, a Grignard reaction is accomplished. The Grignard reaction is well known in the art as a reaction for the formation of carbon-carbon bonds. This reaction involves an organometallic reaction in which an aryl magnesium halide, a Grignard reagent, adds to a carbonyl group, such as the acid chloride of compound 2, to give the compound of step A. For example, a 4-chloro substituted quinolone, compound 1, is treated with a Grignard reagent, such as isopropyl magnesium chloride, in a solvent, such as THF, to form a Grignard intermediate, followed by the addition of the acid chloride, 4-fluorobenzoyl chloride, compound 2. Once complete, the reaction can be quenched with water to give compound 3.

[0033] In step B, the aryl methyl ether of compound 3 can be demethylated under a variety of conditions that will be recognized by one of skill in the art, 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 potassium phosphate dibasic to give compound 4.

[0034] In step C, the azetidine ether 6 can be formed by treating the corresponding p-fluorophenyl ketone 4 and the azetidine alcohol salt 5, or the corresponding free base, with a suitable base, such as sodium hydride, sodium t-butoxide, or potassium t-butoxide, in a suitable polar aprotic solvent such as DMF or THF to produce the ether compound 6.

[0035] Next, in Step D, Compound 6 is alkylated with an appropriate substituted arylboronic acid, Compound 7, in a Suzuki cross-coupling reaction to obtain Compound 8. One of ordinary skill in the art will recognize that there are various conditions that may be useful for promoting such cross-coupling reactions. Suitable palladium reagents include XantPhos Pd G2, cataCXium® A Pd G3, bis(triphenylphosphine)palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0) containing tricyclohexylphosphine, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride, palladium tetrakistriphenylphosphine, or palladium(II) acetate. Suitable bases include potassium fluoride, cesium carbonate, sodium carbonate, potassium carbonate, lithium t-butoxide, or tribasic potassium phosphate monohydrate. For example, Compound 6 can be reacted with an appropriate boronic acid, such as Compound 7, 2-fluoro-4-(trifluoromethyl)phenylboronic acid, in a solvent such as 2-methyl-2-butanol containing a base such as potassium carbonate and a catalyst such as XPhos Pd G2, and heated to about 80° C. under microwave conditions to obtain Compound 8.

[0036] One of ordinary skill in the art will recognize that prior to the azetidine ether formation of Step C, Step D, the Suzuki cross-coupling reaction may be completed.

[0037] In Step E, one of ordinary skill in the art will recognize that Compound 9 can be obtained by reduction of the ketone. This can be achieved using a reducing agent such as lithium triethylborohydride in a solvent such as 1,4-dioxane and THF at a temperature from about 0° C. to room temperature to obtain the corresponding secondary alcohol 9, which can be optionally purified by chiral column chromatography to obtain an enantiomerically enriched secondary alcohol.

[0038] In step F, alcohol 9 can undergo intramolecular cyclization by reaction with a base, such as sodium hydride, to give cyclic ether 10. Those skilled in the art will recognize that a variety of suitable bases can be used in this step.

[0039] In step G, alcohol 10 is further reacted with either sulfur trioxide trimethylamine complex or acetobromo-α-D-glucuronic acid methyl ester, followed by ester hydrolysis, to give compounds of formula I, II or III.

[0040] In an optional step, pharma- ceutically acceptable salts of the compounds of formula I, II, and III described herein can be formed by reaction of a suitable free base of the compounds of formula I, II, and III described herein with a suitable pharma- ceutically acceptable acid in a suitable solvent under standard conditions. Moreover, such salt formation can occur simultaneously with the deprotection of nitrogen protecting groups. The possibility of forming pharma- ceutical 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 the compounds of formula I, formula II, and formula III described herein can be easily converted into pharmaceutically acceptable salts and isolated as pharmaceutically acceptable salts. Examples of useful salts include, but are not limited to, benzenesulfonate and 4-methylbenzenesulfonate. 4-methylbenzenesulfonate is also known as tosylate salt.

[0041] Preparation 1 2-[3-(fluoromethyl)azetidin-1-yl]ethan-1-ol

[0042] [ka]

[0043] Sodium triacetoxyborohydride (405 g, 1.91 mol) is added portionwise over 15 min under nitrogen to a stirred 0°C solution of 3-(fluoromethyl)azetidine hydrochloride (160 g, 1.28 mol) in DCM (2.4 L) and stirred at 0°C for 10 min. 1,4-Dioxane-2,5-diol (99 g, 0.83 mol) is added in six portions over 1 h at 0°C and stirred at 0-5°C for 15 min. The reaction is warmed to room temperature and stirred under nitrogen for 2 h. The reaction is cooled to 10-15°C over 20 min, then warmed to 25-30°C and maintained at this temperature for 2 h. Water (800 mL) is added over 25-30 min at 10-15°C and warmed to room temperature for 5-10 min before separating the layers. Wash the aqueous layer with DCM (800 mL) and separate the layers before cooling the combined aqueous layers to 10-15 °C and adjusting the pH to 13-14 using 50% aqueous sodium hydroxide (approximately 540 mL). Warm the aqueous layer to room temperature and extract with DCM (4 x 800 mL) and anhydrous NaOH (approximately 540 mL). 2 SO 4 Dry at rt, filter and concentrate to dryness to obtain the title compound (139 g, 82%) as a thick yellow oil. ES / MS (m / z): 134.1 (M+H).

[0044] Preparation 2 2-[3-(Fluoromethyl)azetidin-1-yl]ethan-1-ol hydrochloride

[0045] [ka]

[0046] Dissolve 2-[3-(fluoromethyl)azetidin-1-yl]ethan-1-ol (529 g, 4 mol) in MTBE (2.6 L) and cool to 0° C. Add HCl / EtOH solution (492 mL, 30 wt%) dropwise over 30 min and stir at 0° C. for 30 min. Filter the solid and wash the filter cake with MTBE (2×200 mL). Dry under nitrogen gas for 8 h to give the title compound (580 g, 86%) as a white solid. ES / MS (m / z): 134.0 (M+H).

[0047] Preparation 3 (3-Chloro-7-methoxyquinolin-4-yl)-(4-fluorophenyl)methanone

[0048]

Chem.

[0049] A mixture of 4-bromo-3-chloro-7-methoxyquinoline (70 g, 254 mmol) and THF (1 L) was cooled to -40 °C under nitrogen gas to precipitate the starting material. Isopropylmagnesium 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 then the mixture was warmed to room temperature. The reaction was quenched with saturated NH 4 Cl aqueous solution (300 mL) and water (200 mL), and the layers were separated. The organic layer was washed with saturated NH 4 Cl aqueous solution (300 mL), dried over anhydrous MgSO 4 , filtered, and concentrated to obtain an oily residue. The crude brown oil was filtered through silica gel eluting with a mixture of MTBE / hexane (1:1) to give the crude product as a yellow solid (84 g). The solid was treated with 10% methyl acetate / heptane (800 mL) and stirred at room temperature overnight. The solid was filtered to collect and stored. The filtrate was concentrated and purified by silica gel eluting with 10 - 40% EtOAc / hexane, and then the product was 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).

[0050] Preparation 4 (3-Chloro-7-hydroxyquinolin-4-yl)-(4-fluorophenyl)methanone

[0051]

Chem.

[0052] Add boron tribromide (1M in DCM, 295 mL, 295 mmol) to a mixture of (3-chloro-7-methoxyquinolin-4-yl)-(4-fluorophenyl)methanone (31 g, 98 mmol) in DCM (217 mL) and stir the mixture at room temperature for 3 days. Pour the mixture slowly into a 0° C. solution of aqueous potassium phosphate dibasic (2M, 700 mL) and water (200 mL). Allow the mixture to warm to room temperature and stir for 1 h. Concentrate the solution in vacuum to remove the organic solvent, filter, collect the filtrate, and dry the filtrate under vacuum at 45° C. overnight. Treat the solid with DCM / heptane (1:1, 450 mL) and stir overnight. Collect the solid and dry 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).

[0053] Preparation 5 (3-Chloro-7-hydroxyquinolin-4-yl)-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)methanone

[0054] [ka]

[0055] To a stirred solution of (3-chloro-7-hydroxyquinolin-4-yl)-(4-fluorophenyl)methanone (5.00 g, 15.3 mmol) in DMF (75 mL) is added 2-[3-(fluoromethyl)azetidin-1-yl]ethan-1-ol hydrochloride (3.90 g, 23.0 mmol) followed by sodium hydride (60% in mineral oil, 3.02 g, 76.8 mmol). Stir under nitrogen and warm to 40° C. for 45 min. Quench the solution with water and concentrate. The residue is dissolved in 20% iPrOH / CHCl 3 and saturated aqueous sodium bicarbonate, separated and diluted with 2×20% iPrOH / CHCl 3Extract the aqueous layer with 5-10% 7N NH in MeOH / DCM, combine the organic extracts, dry the combined organic layers over magnesium sulfate, filter, and concentrate the filtrate to give the crude product as a dark red oil. 3 The crude material is purified by silica gel column chromatography eluting with a gradient of to give the title compound (5.31 g, 84%) as a yellow solid. ES / MS (m / z): 415.0 (M+H).

[0056] Preparation 6 (4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinolin-4-yl}methanone

[0057] [ka]

[0058] A mixture of (3-chloro-7-hydroxyquinolin-4-yl)-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)methanone (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) in a microwave vial is degassed with nitrogen gas (5 times). XPhos Pd G2 (12 mg, 0.015 mmol) is added, sealed, and microwaved at 80 °C for 2 h. MTBE and saturated NH 4 Partition the residue between aqueous Cl. Separate the layers and extract the aqueous layer with MTBE. Combine the organic extracts and add anhydrous MgSO. 4 Dry over 100° C., filter, and concentrate the filtrate to give an orange residue. Purify the crude material by silica gel column chromatography eluting with 5% MeOH / DCM to give the title compound (205 mg, 78%) as a yellow solid. ES / MS (m / z): 543.2 (M+H).

[0059] Preparation 7 Racemic 4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)(hydroxy)methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinolin-7-ol

[0060] [ka]

[0061] Add (4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinolin-4-yl}methanone (305 g, 562.2 mmol) and THF (1.5 L) together under nitrogen gas and cool the solution to 0-5 °C. Add lithium triethylborohydride (1 M in THF, 1.5 L, 1.5 mol) dropwise. Stir the mixture at 0-5 °C for 1 h. Add water (300 mL) dropwise and add saturated NH 4 Add aqueous Cl (1 L). Allow the mixture to warm to room temperature. Add EtOAc (2 L) and collect the organic layer. Wash the organic layer with brine (500 mL) and anhydrous MgSO 4 Dry on a kettle, filter and concentrate to dryness. Dissolve the residue in a 95:5 mixture of acetone and 2M ammonia in MeOH and filter through silica gel to give the title compound (264 g, 86.2%) as an orange solid. ES / MS (m / z): 545.2 (M+H).

[0062] Preparation 8 4-[(R)-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-hydroxy-methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinolin-7-ol

[0063] [ka]

[0064] Column: Chiralpak® AD-H, 150×50 mm, flow rate: 200 g / min, UV: 270 nm, mobile phase: 0.5% DMEA / CO 2 Purify racemic 4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)(hydroxy)methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinolin-7-ol (5.5 g, 0.10 mol) using chiral chromatography under the following conditions: 35% iPrOH containing 1,2-dichloro-1,2-diphenyl-2,4 ... (R) = 0.79 min, Column: 4.6 × 150 mm Chiralpak® AD-H, CO 2 Chiral analytical SFC eluting with a mobile phase of 35% iPrOH containing 0.5% DMEA in water at a flow rate of 0.6 mL / min with UV detection at 350 nm confirms enantiomeric enrichment of isomer 1 to greater than 96% ee.

[0065] Preparation 9 (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol

[0066] [ka]

[0067] Sodium hydride (60% dispersion in mineral oil, 1.00 g, 15 mmol) is added to a stirred solution of 4-[(R)-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-hydroxy-methyl]-3-[2-fluoro-4-(trifluoromethyl)phenyl]quinolin-7-ol (2.60 g, 5 mmol) in THF (50 mL) and the resulting solution is warmed to 65 °C under nitrogen gas. After 1 h, the reaction is cooled to room temperature and quenched with water (50 mL). The resulting mixture is diluted with EtOAc (50 mL) and saturated NH 4Partition between aqueous Cl (50 mL). Separate the layers and extract the aqueous phase with fresh EtOAc (50 mL). Remove the combined organic layers with anhydrous MgSO. 4 Dry over medium, filter and concentrate to give a yellow solid. Purify the crude mixture by column chromatography (4-6% MeOH / DCM) to give the title compound as a yellow solid (1.98 g, 80%). ES / MS (m / z): 525.2 (M+H).

[0068] Example 1 Hydrogen sulfate [(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]

[0069] [ka]

[0070] A solution of sodium methoxide in MeOH (0.5 M, 0.6 mL, 0.3 mmol) is added to a solution of (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-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) is added in 4 equal portions every hour for 4 h. The solvent is then evaporated under a stream of nitrogen gas and the reaction mixture is diluted with water (5 mL). Aqueous NaOH (1 M, 2 drops) is added and the pH is adjusted to 8. The solution is loaded directly onto an Iterchim automated chromatography system (30 g RediSep® Rf Gold reverse phase C18 column) and eluted with a gradient of 10-90% acetonitrile in water to give the title product (46 mg, 74%) as a pale yellow solid. ES / MS (m / z): 605.6 (M+H).

[0071] Preparation 10 (2S,3S,4S,5R,6S)-6-[[(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]oxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylate methyl ester

[0072] [ka]

[0073] Lithium hydroxide (90.9 mg, 3.80 mmol) is added to a suspension of (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol (830.0 mg, 1.58 mmol) in anhydrous MeOH (16 mL) at room temperature. The mixture is stirred until the starting material is dissolved (approximately 20 min). Acetobromo-α-D-glucuronic acid methyl ester (1.19 g, 3.01 mmol) is added. The reaction is stirred at room temperature for 4 h, at which point LC / MS analysis of the reaction mixture indicates 28% conversion to the desired product and 60% unreacted starting material. Additional lithium hydroxide (92.0 mg, 3.84 mmol) is added. After stirring for 10 min, additional acetobromo-α-D-glucuronic acid methyl ester (1.19 g, 3.01 mmol) is added. After an additional 3 h, LC / MS analysis shows 35% conversion to product and 50% unreacted starting material. The reaction is stopped and the mixture is used in the next step without purification.

[0074] Example 2 (2S,3S,4S,5R,6S)-6-[[(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-yl]oxy]-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid

[0075] [ka]

[0076] The reaction mixture from preparation 10 is added to a solution of lithium hydroxide (114.5 mg, 4.78 mmol) in water (10 mL). The reaction is stirred for 2 h, at which point LC / MS analysis of the reaction mixture indicates that the hydrolysis is not complete. Additional lithium hydroxide (114.5 mg, 4.78 mmol) and MeOH (8 mL) are added sequentially. The reaction is stirred at room temperature for 1.5 h, at which point LC / MS analysis indicates that the hydrolysis reaction is complete. The pH of the mixture is adjusted to pH 7 with concentrated acetic acid and divided into two equal portions. Each portion is loaded onto a reversed-phase C18 column (275 g RediSep® Rf Gold reversed-phase C18 column) eluted with a gradient of 0-100% acetonitrile in water. The fractions are combined and concentrated under reduced pressure at 25° C. The residue is lyophilized to give the title compound as a pale yellow solid (80 mg, 7% yield for two steps). ES / MS(m / z):701.6(M+H).

[0077] Biological assays Evidence for a relationship between ER expression and certain cancers is well known in the art.

[0078] The results of the following assays indicate that the compounds of Formula I, Formula II, and Formula III of the Examples are active SERDs and are believed to be useful in the treatment of cancer.

[0079] ERα degradation assay in MCF7 cells The purpose of the following ERα degradation assay is to measure the degradation of ERα by test compounds in an ERα positive breast cancer cell line such as MCF7.

[0080] Culture MCF7 (purchased from ATCC HTB-22) cells in DMEM medium supplemented with 10% FBS, 0.01 mg / mL human insulin 1, and 1% penicillin / streptomycin antibiotics, and seed them into 384-well flat-bottom plates at a density of 4,000 cells per well in phenol red-free DMEM medium (20 µL) containing 10% charcoal-stripped FBS. Keep in a cell culture incubator (5% CO). 2 Incubate the cells overnight at 37 °C (95% relative humidity and 37 °C) to allow the cells to attach to the plate. The next day, dose the cells with test compound. Prepare test compound serial dilutions (1:3) ranging from 6 μM to 0.0003 μM using an Echo555 acoustic dispenser. Dose the cells by adding 5 μL from the serial dilution plate to the cell plate, resulting in a final DMSO concentration of 0.2% and a final test compound concentration ranging from 2 to 0.0001 μM. For the maximum point, use medium with 0.2% DMSO and for the minimum point, use fulvestrant diluted in growth medium with 0.2% DMSO to a final concentration of 2 μM. After dosing with the test compound, incubate the cells at 37 °C and 5% CO 2Incubate cell plates at RT for 24 hours. Fix cells by adding 10 μL of 14% paraformaldehyde for 30 minutes. Wash cells once with PBS (20 μL) and incubate with 20 μL of PBS containing 0.5% (v / v) TWEEN® 20 for 1 hour. Wash cells (twice) with PBS containing 0.05% TWEEN® 20 and block with 20 μL / well of 3% BSA in PBS containing 0.05% TWEEN® 20 and 0.1% TRITON™ X-100 for 1 hour at room temperature. Add 1:500 primary antibody (20 μL) diluted in 1% BSA in PBS containing 0.05% TWEEN® 20 per well (ERα (clone SP1) monoclonal rabbit antibody #RM-9101-S, Thermo Scientific) and seal plates and incubate overnight at 4°C. The next day, cells are washed (2x) with PBS containing 0.05% TWEEN® 20 and incubated with secondary antibody (20μL / well) (1:1000 dilution, goat anti-rabbit IgM ALEXA FLUOR™ 488) in PBS 1% BSA for 105 min at room temperature. After washing the plate with PBS (2x20μL), RNase (Sigma) (20μL of 50μg / mL) and a 1:1000 dilution of propidium iodide in PBS per well (20μL) are added. The plate is sealed and incubated for 1 hour at room temperature on the bench (protected from light). The plate is scanned with ACUMEN EXPLORER™ (laser-scanning fluorescence microplate cytometer from TTP LABTECH LTD) to measure ERα. Image analysis is based on cell fluorescence signal to identify positive cells. ER positive cells are identified by average intensity. Total intensity at 575-640 nm from the propidium iodide / DNA assay is used to identify individual cells. The output of the assay is % ER positive cells. IC was calculated by curve fitting a four parameter logistic to each output using GENE DATA™. 50 Determine the relative IC of Examples 1 and 2. 50The values ​​are shown in Table 2. The results of this assay demonstrate the degradation of ERα induced by Examples 1 and 2 described herein in MCF7 breast cancer cells.

[0081] [Table 2]

[0082] PRα induction assay in MCF7 cells The purpose of the following PRα induction assay is to determine whether a test compound has agonist activity at the ERα receptor (agonists are predicted to activate the receptor).

[0083] Culture MCF7 (purchased from ATCC HTB-22) in DMEM medium supplemented with 10% FBS, 0.01 mg / mL human insulin 1, and 1% penicillin / streptomycin antibiotics, and seed the cells (before they are 70% confluent) into 384-well flat-bottom plates at a density of 4,000 cells per well in a volume of 20 µL in DMEM phenol red-free medium containing 10% FBS (charcoal-treated). Keep in a cell culture incubator (5% CO). 2 Incubate the cells overnight at 37 °C (37 °F, 95% relative humidity) to allow the cells to attach to the plate. The next day, dose the cells with test compound. Prepare compound serial dilutions (1:3) ranging from 6 μM to 0.0003 μM using an Echo555 acoustic dispenser. Dose the cells by adding test compound (5 μL) from the serial dilution plate to the cell plate, producing a final DMSO concentration of 0.2%, with final concentrations of test compound ranging from 2 to 0.0001 μM in doses. For the maximum point, use medium containing 0.2% DMSO, and for the minimum point, use fulvestrant diluted in growth medium containing 0.2% DMSO to a final concentration of 2 μM. After dosing with the test compound, incubate the cells at 37 °C and 5% CO 2Incubate cell plates at RT for 24 h. Fix cells by adding 10 μL of 14% paraformaldehyde for 30 min. Wash cells once with PBS (20 μL) and incubate with 20 μL of PBS containing 0.5% (v / v) TWEEN® 20 for 1 h. Wash cells twice with 20 μL of PBS containing 0.05% TWEEN® 20 and block with 20 μL / well of 3% BSA in PBS containing 0.05% TWEEN® 20 and 0.1% TRITON™ X-100 for 1 h at RT. Add 20 μL of 1:500 primary antibody (PR monoclonal mouse anti-human antibody, clone PgR 636 Dako, M3569) diluted in 1% BSA / PBS containing 0.05 TWEEN® 20 per well, seal plates and incubate overnight at 4°C.

[0084] The next day, cells are washed with PBS 0.05% TWEEN® 20 (2×20 μL) and incubated with secondary antibody (20 μL / well) (1:1000 dilution, goat anti-rabbit IgM ALEXA FLUOR™ 488) in PBS 1% BSA for 105 min at room temperature. 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 per well are added. The plate is sealed and incubated for 1 h at room temperature on the bench (protected from light). The plate is scanned with ACUMEN EXPLORER™ (laser-scanning fluorescence microplate cytometer from TTP LABTECH LTD) to measure PRα. Image analysis is based on cell fluorescence signal to identify positive cells. PR positive cells are identified by average intensity. Total intensity at 575-640 nm from the propidium iodide / DNA assay is used to identify individual cells. The output of the assay is % PR positive cells. IC was calculated by curve fitting a four parameter logistic to each output using GENE DATA™. 50The results of this assay show no significant agonist activity of Examples 1 and 2 in MCF7 breast cancer cells. The relative IC in this assay is determined for the compounds tested. 50 is >2 μM. The results of this assay show no significant agonist activity of the exemplified compounds tested in MCF7 breast cancer cells. These results also show that the exemplified compounds tested are antagonists of ERα in MCF7 breast cancer cells (i.e., they have SERD activity).

[0085] PRα inhibition (ERα functional antagonism) cellular assay in MCF7-ESR1 Y537N 682 CRISPR cells The purpose of the following PRα inhibition (ERα functional antagonism) cellular assay is to determine the antagonist activity of test compounds against the Y537N mutant ERα receptor. Antagonists in this assay are expected to block ERα receptor function. Because PRα is a downstream transcriptional target of ERα, antagonists of ERα are expected to inhibit expression of PRα.

[0086] Culture MCF7-ESR1 Y537N-682 (generated by CRISPR / Cas9 gene editing of the ESR1 gene in MCF7 cells, clone #682) in DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin antibiotics, and seed the cells (before reaching 70% confluence) into 384-well flat-bottom plates at a density of 4,000 cells per well in DMEM phenol red-free medium, 10% FBS (20 μL volume) (charcoal-treated) in a cell culture incubator (5% CO). 2Incubate the cells overnight at 37 °C (37 °F, 95% relative humidity) to allow the cells to attach to the plate. The next day, dose the cells with test compound. Prepare compound serial dilutions (1:3) ranging from 6 μM to 0.0003 μM using an Echo555 acoustic dispenser. Dose the cells by adding 5 μL from the serial dilution plate to the cell plate, resulting in a final DMSO concentration of 0.2% and a dose range of 2 to 0.0001 μM final test compound concentrations. For the maximum point, use medium with 0.2% DMSO and for the minimum point, use fulvestrant diluted in growth medium with 0.2% DMSO to a final concentration of 2 μM. After dosing with the test compound, incubate the cells at 37 °C and 5% CO 2 Incubate cell plates at 4°C for 72 hours. Fix cells by adding 10 μL of 14% paraformaldehyde for 30 minutes at room temperature. Wash cells with PBS (1×20 μL) and incubate with PBS containing 0.5% (v / v) TWEEN® 20 (20 μL) for 1 hour. Wash cells with PBS containing 0.05% TWEEN® 20 (2×20 μL) and block with 3% BSA / PBS 0.05% TWEEN® 20, 0.1% TRITON™ X-100 (20 μL / well) for 1 hour at room temperature. Add 1:500 primary antibody (20 μL) diluted in 1% BSA / PBS 0.05 TWEEN® 20 per well (PR monoclonal mouse anti-human antibody, clone PgR 636 Dako, M3569), seal plate, and incubate overnight at 4°C.

[0087] The next day, wash the cells with PBS 0.05% (2 x 20 μL) and incubate with secondary antibody (20 μL / well) (1:1000 dilution, goat anti-rabbit IgM ALEXA FLUOR™ 488) in PBS 1% BSA for 105 min at room temperature. After washing with PBS (2 x 20 μL), add RNase (20 μL of 50 μg / mL) (Sigma) and a 1:1000 dilution of propidium iodide in PBS per well. Seal the plate and incubate for 1 h at room temperature on the bench (protected from light). Scan the plate with ACUMEN EXPLORER™ [laser-scanning fluorescence microplate cytometer from TTPLABTECH LTD] to measure PRα. Image analysis is based on cell fluorescence signal to identify positive cells. Identify PR-positive cells by the average intensity. Use the total intensity at 575-640 nm from propidium iodide / DNA to identify individual cells. The output of the assay is % PR positive cells. IC values ​​were calculated by curve fitting a four parameter logistic to each output using GENE DATA™. 50 Determine.

[0088] Relative IC of Examples 1 and 2 in this assay 50 are shown below in Table 3. The results of this assay demonstrate the inhibition and functional antagonism of PRα by Examples 1 and 2 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 transcription of PRα.

[0089] [Table 3]

[0090] Cell proliferation assay of MCF7 and MCF7-ESR1 Y537N-682 The purpose of the cell proliferation assays below is generally to detect whether a test compound affects cell proliferation.

[0091] MCF7 (purchased from ATCC HTB-22) cells are seeded in a clear-bottom 384-well cell culture plate at a density of 2,000 cells per well in DMEM phenol red-free medium 10% FBS (20 μL volume) (charcoal-treated). MCF7-ESRY537N-682 (generated by CRISPR / Cas9 gene editing of the ESr1 gene in MCF7 cells, clone #682) in DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin antibiotics are seeded at a density of 1,000 cells per well. Incubate at 37 °C and 5% CO. 2 Incubate the plate at 4 °C for 30 min. The next day, dose the cells with test compound. Prepare test compound serial dilutions (1:3) ranging from 60 μM to 0.003 μM using an Echo555 acoustic dispenser. Dose the cells by adding 5 μL from the serial dilution plate to the cell plate, resulting in a final DMSO concentration of 0.2% and a final test compound concentration ranging from 20 to 0.001 μM in doses. For the maximum point, use medium containing 0.2% DMSO, and for the minimum point, use fulvestrant diluted in growth medium containing 0.2% DMSO to a final concentration of 2 μM. After dosing the test compound, incubate the cells at 37 °C and 5% CO 2Incubate the cell plate with 500 mM NaCl. 7 days after adding the test compounds, remove the plate from the incubator and add cold EtOH 96% (65 μL) to each well. After 30 minutes, remove the medium and add RNase (20 μL of 50 μg / mL) (Sigma) and a 1:1000 dilution of propidium iodide in PBS per well. Seal the plate and incubate for 1 hour at room temperature on the bench (protected from light). Scan the plate with ACUMEN EXPLORER™ (a laser-scanning fluorescence microplate cytometer from TTP LABTECH LTD). MCF-7 cell line proliferates and forms aggregates, so cell number as a number of interest may not be used as readout, therefore cell number can be assessed by estimated cell number (calculated by area parameter (ratio of total area of ​​total cell population (specified range of peak intensity of FL-1(PI) and average area of ​​single cell population (defined by perimeter))). IC was calculated by curve fitting a four parameter logistic for each output using GENE DATA™. 50 Determine the relative IC of Examples 1 and 2 in MCF7 ESR1 wild type and MCF7-ESR1 Y537N mutant cells. 50 The results of this assay show antiproliferative activity and cell growth inhibition by Examples 1 and 2 in MCF7 (ESR1 wild type) and MCF7 (ESR1 Y537N mutant) breast cancer cells. Relative IC 50 ranges from about 0.0035-1.176 μM in MCF7 ESR1 wild type and 0.014-1.86 μM in MCF7 (ESR1 Y537N mutant) breast cancer cells, indicating that all exemplary compounds tested demonstrate anti-proliferative activity and cell growth inhibition in MCF7 (ESR1 wild type) and MCF7 (ESR1 Y537N mutant) breast cancer cells.

[0092] [Table 4]

Claims

1. formula: 【Chemistry 1】 (Wherein, R is 【Chemistry 2】 or 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

2. The compound is 【Chemistry 4】 (Wherein, R is 【Chemistry 5】 or 【Chemistry 6】 (selected from 2. The compound of claim 1, wherein:

3. The compound is 【Chemistry 7】 (Wherein, R is 【Chemistry 8】 or 【Chemistry 9】 (selected from 2. The compound of claim 1, wherein:

4. The compound is 【Chemistry 10】 3. The compound of claim 1 or 2, wherein:

5. The compound is 【Chemistry 11】 3. The compound of claim 1 or 2, wherein:

6. The compound is 【Chemistry 12】 5. The compound of claim 1, 2, or 4,

7. The compound is 【Chemistry 13】 6. The compound of claim 1, 2, or 5,

8. The compound is 【Chemistry 14】 4. The compound of claim 1 or 3, wherein:

9. The compound is 【Chemistry 15】 4. The compound of claim 1 or 3, wherein:

10. The compound is 【Chemistry 16】 9. The compound of claim 1, 3, or 8,

11. The compound is 【Chemistry 17】 10. The compound of claim 1, 3, or 9,

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

13. 13. The pharmaceutical composition of claim 12, further comprising one or more other therapeutic agents.

14. A therapeutic agent for cancer, comprising the compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

15. The method of claim 14, wherein the breast cancer is ER-positive breast cancer.

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

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

Images