Novel substituted benzothiophene-6-carboxylic acid derivatives, their preparation process and therapeutic uses

Abstract

Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt thereof: [Formula 1] TIFF2025526986000081.tif55170 (wherein R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3' and R3" independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; Y is -CH2-, -CH=, -CR8=, -O-, or -NH R8 represents a fluorine atom or a (C1-C3) alkyl group; represents a single bond or a double bond; X represents -CH=, -N=, or -CR"= (wherein R" represents a (C1-C3) alkyl group, a halogen atom, a cyano group, or a (C1-C3) fluoroalkyl group); R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom, or a (C1-C3) fluoroalkyl group; R6 represents a (C6-C 10 ) represents an aryl group or a 5- or 6-membered heteroaryl group).

Description

[Technical Field]

[0001] Disclosed herein are novel substituted benzothiophene-6-carboxylic acid derivatives, methods for their preparation, and their therapeutic use, particularly as anti-cancer agents through selective antagonism and degradation of estrogen receptors. [Background technology]

[0002] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily, which are involved in the regulation of eukaryotic gene expression, cell proliferation, and target tissue function. ERs exist in two forms, estrogen receptor α (ERα) and estrogen receptor β (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormone, ERs reside primarily in the cytosol of cells. Upon binding of the hormone estrogen, ERs translocate from the cytosol to the nucleus, form dimers, and then bind to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to regulate the transcription of target genes.

[0003] ERα is mainly expressed in reproductive tissues such as the uterus, ovaries, breast, bone, and white adipose tissue. Aberrant ERα signaling leads to the development of various diseases, such as cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and osteoporosis.

[0004] ERα is expressed in less than 10% of normal breast epithelium but in approximately 50–80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The pathogenetic role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, several strategies exist to inhibit the estrogen system in breast cancer, including: 1) blocking estrogen synthesis with aromatase inhibitors, which are used to treat patients with early-stage and advanced ERα-positive breast cancer; 2) antagonizing estrogen ligand binding to ERα with tamoxifen, which is used to treat patients with ERα-positive breast cancer in both premenopausal and postmenopausal settings; and 3) antagonizing and downregulating ERα levels with fulvestrant, which is used to treat breast cancer in patients whose disease has progressed despite endocrine therapy, such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have significantly contributed to reducing breast cancer incidence, approximately one-third or more of ERα-positive patients exhibit de novo resistance or develop resistance to existing therapies over time. Several mechanisms have been described to explain resistance to such hormone therapy, such as the hypersensitivity of ERα to low estrogen levels during aromatase inhibitor treatment, the switch in tamoxifen effect from antagonist to agonist during tamoxifen treatment, or the involvement of multiple growth factor receptor signaling pathways. Acquired mutations in ERα that occur after the initiation of hormone therapy may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), confer the ability to bind DNA in the absence of ligand, conferring hormone independence in cells harboring such mutant receptors.

[0006] Most of the identified endocrine therapy resistance mechanisms rely on ERα-dependent activity. One novel strategy to combat such resistance is to block ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data have shown that a significant number of resistance pathways can be circumvented by the use of SERDs.

[0007] There remains a need to provide SERDs with good decomposition efficacy.

[0008] WO 2017 / 140669 and WO 2018 / 091153 disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. Summary of the Invention [Means for solving the problem]

[0009] We have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in cancer therapy.

[0010] Disclosed herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3' and R3" independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; Y represents -CH2-, -CH=, -CR8=, -O-, or -NH-, and R8 represents a fluorine atom or a (C1-C3) alkyl group; · [ka] represents a single or double bond; p is 0 or 1; X represents -CH=, -N=, or -CR"= (wherein R" represents a (C1-C3) alkyl group, a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl); R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; n is 0, 1 or 2; R6 is (C6~C 10 ) an aryl group or a 5- or 6-membered heteroaryl group; Said (C6~C 10 ) the aryl group or 5- or 6-membered monocyclic heteroaryl group may be optionally substituted with 1 to 3 groups selected from -Z-R and R; During the ceremony, Z is methylene; R6a is ·-OH group, (C1-C6) alkyl groups optionally substituted with cyano or -OH groups, (C1-C6) alkylene groups, Halogen atoms, Nitro groups, cyano group, (C1-C6) fluoroalkyl groups, (C1-C6) fluoroalkoxy groups, (C3-C6) cycloalkyl groups, (C1-C6)alkoxy groups, ·-SF5 units, Trifluoromethylsulfonyl group, (C1-C4) alkylthio groups, (C1-C4) fluoroalkylthio group, (C1-C4) alkylsulfonyl group, ·-NR9R10 units, -C(O)R9 group, (C3-C7) cycloalkyl groups, and O, NH, C(O), and S(O) 0-2 a 4- to 7-membered saturated, unsaturated or partially saturated ring containing 1 to 4 heteroatoms or groups selected from Selected from; R9 and R10 are independently selected from a hydrogen atom and a (C1-C4) alkyl group, or R9 and R10 together with the nitrogen to which they are both attached are O, NH, and S(O) 0-2 and forming a 4- to 7-membered saturated ring containing another heteroatom or group selected from the group consisting of: DETAILED DESCRIPTION OF THE INVENTION

[0011] The compounds of formula (I) may contain one or more asymmetric carbon atoms and therefore may exist in enantiomeric forms.

[0012] The compounds of formula (I) may also exist in tautomeric forms.

[0013] The compounds of formula (I) can exist in the form of bases, acids, zwitterions, or addition salts with acids or bases. Accordingly, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] These salts may be prepared using pharmaceutically acceptable acids or bases, although other acid or base salts useful, for example, for purifying or isolating compounds of formula (I) are also provided.

[0015] Among suitable salts of the compounds of formula (I), mention may be made of the hydrochloride salt.

[0016] As used herein, the following terms have the following definitions unless otherwise stated throughout the specification. Halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; Alkyl group: unless otherwise specified, a linear or branched saturated hydrocarbon-based aliphatic group containing 1 to 6 carbon atoms (written as "(C1-C6)-alkyl"). Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups; Alkylene group: unless otherwise specified, a straight or branched chain hydrocarbon-based aliphatic group containing 1 to 6 carbon atoms and at least one unsaturation (referred to as "(C1-C6) alkylene"). Examples include, but are not limited to, vinyl groups; Cycloalkyl group: unless otherwise specified, a saturated or partially unsaturated, substituted or unsubstituted monocyclic alkyl group containing 3 to 7 carbon atoms. Examples that may be mentioned, but are not limited to, are: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexyl, cyclohexyl, cycloheptyl, cycloheptenyl, groups, etc., in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl or cyclohexyl; Fluoroalkyl group: an alkyl group as defined above, in which the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include CH2F, CHF2, CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms of the alkyl group are substituted with fluorine atoms, the fluoroalkyl group can be called a perfluoroalkyl group. Examples include a trifluoromethyl group or a trifluoroethyl group; Alkoxy groups: -O-alkyl groups, wherein the alkyl group is as defined above. Examples that may be mentioned include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; Fluoroalkoxy group: an -O-alkyl group, wherein the alkyl group is as defined above and the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkoxy group can be named a perfluoroalkoxy group. Examples include a trifluoromethoxy group, etc.; (C1-C4) alkylthio groups are also named (C1-C4) alkylsulfanyl groups: -S-alkyl groups, in which the alkyl group is as defined above. Examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.; (C1-C4) alkylsulfonyl group: -SO2-alkyl group, in which the alkyl group is as defined above. Examples include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; (C1-C4)fluoroalkylthio group, also named (C1-C4)fluoroalkylsulfanyl group: an -S-fluoroalkyl group, in which the fluoroalkyl group is as defined above. Examples include, but are not limited to, fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; Five- or six-membered monocyclic heteroaryl group: a cyclic five- or six-membered aromatic group. A five-membered ring consists of two double bonds and one, two, three, or four nitrogen atoms and, optionally, one oxygen or sulfur atom. A six-membered ring consists of three double bonds and one, two, three, or four nitrogen atoms. A five- or six-membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the heteroaryl; ·(C6~C 10 ) Aryl group: A monocyclic or fused bicyclic aromatic ring assembly containing 6 to 10 ring carbon atoms.

[0017] In another embodiment, in the compounds of formula (I) as defined above, R 1 and R 2 are hydrogen atoms.

[0018] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3" both represent a hydrogen atom.

[0019] In another embodiment, in the compounds of formula (I) as defined above, R4 is a hydrogen atom.

[0020] In another embodiment, in the compounds of formula (I) as defined above, R5 and R5' both represent a hydrogen atom.

[0021] In another embodiment, in the compound of formula (I) as defined above, p is 0. In another embodiment, in the compound of formula (I) as defined above, p is 1.

[0022] In another embodiment, in the compounds of formula (I) as defined above, Y represents -O- or -NH-.

[0023] In another embodiment, in the compound of formula (I) as defined above, n is 0. In another embodiment, in the compound of formula (I) as defined above, n is 1. In another embodiment, in the compound of formula (I) as defined above, n is 2.

[0024] In another embodiment, in the compounds of formula (I) as defined above, X represents -CH=.

[0025] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group optionally substituted with 1, 2, 3 or 4 groups selected from halogen atoms and (C1-C6)fluoroalkyl groups, more particularly a phenyl group optionally substituted with 2 or 3 groups selected from halogen, for example fluorine atoms and (C1-C4)fluoroalkyl groups, and even more particularly a phenyl group optionally substituted with one fluorine atom and one difluoroethyl group, for example a 1,1-difluoroethyl group.

[0026] In another embodiment, in the compound of formula (I) as defined above, X represents -CH= and R6 represents a phenyl group optionally substituted with 1, 2, 3 or 4 groups selected from halogen atoms and (C1-C6)fluoroalkyl groups, more particularly a phenyl group optionally substituted with 2 or 3 groups selected from halogen, for example fluorine atoms and (C1-C4)fluoroalkyl groups, and even more particularly a phenyl group optionally substituted with one fluorine atom and one difluoroethyl group, for example a 1,1-difluoroethyl group.

[0027] In one embodiment, in the compound of formula (I), X represents a carbon atom (i.e., a =CH- group). Accordingly, the compound of formula (II) is described herein: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , Y, n, and p are as defined above in formula (II).

[0028] The embodiments described above for compounds of formula (I) are also suitable for compounds of formula (II).

[0029] In another embodiment, in the compound of formula (II) as defined above, R6 represents a phenyl group optionally substituted with 1, 2, 3 or 4 groups selected from halogen atoms and (C1-C6) alkyl groups, more particularly a phenyl group optionally substituted with 2, 3 or 4 groups selected from halogen, e.g. fluorine atoms and methyl groups, and even more particularly one fluorine atom and two methyl groups.

[0030] Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or their pharmaceutically acceptable salts, in particular their hydrochlorides: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid hydrochloride (1), 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (2), and (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (3).

[0031] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, particularly as an inhibitor and degrader of the estrogen receptor.

[0032] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular breast cancer.

[0033] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0034] Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0035] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0036] Another embodiment is a pharmaceutical composition comprising an active ingredient, an effective dose of a compound selected from the list above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0037] The compounds of formula (I) may be prepared by the following process.

[0038] Compounds of formula (I) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, solvents, temperatures, and other reaction conditions shown below may be varied as deemed appropriate by those skilled in the art.

[0039] In general, the following methods for preparing compounds of formula (I), optionally modified by the use of appropriate reagents, and conditions for introducing the various moieties found in formula (I), are described below.

[0040] The following abbreviations and empirical formulas are used: CO Carbon monoxide Cs2CO3 Cesium Carbonate DCM dichloromethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOH ethanol EtOAc ethyl acetate H2 Hydrogen H2O2 Hydrogen Peroxide HCl Hydrochloric acid HPLC High-Performance Liquid Chromatography LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate N2 nitrogen Pd / C Palladium Carbon Pd(OH)2 palladium hydroxide K2CO3 Potassium Carbonate NaHCO3 Sodium bicarbonate NaH sodium hydride NaOH Sodium hydroxide NaI Sodium iodide NaNO2 Sodium Nitrite Na2SO4 Sodium Sulfate NaHSO3 Sodium hydrogen sulfate NBS N-Bromosuccinimide Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) SNAr Aromatic Nucleophilic Substitution TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TiCl3 Titanium(III) chloride RT room temperature

[0041] Scheme 1a Parts 1 and 2: Preparation of Compounds of Formula (I) - General Procedure Scheme 1a Part 1 [ka] Scheme 1a Part 2 [ka]

[0042] Scheme 1a - Part 1 and Part 2 (R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are defined as above), compound 1A (prepared according to WO2004009086) can be converted to compound 1Aa in step 1 by protecting the phenol moiety with a protecting group (PG) such as pivaloyl, benzyl, para-methoxybenzyl, or 2,4-dimethoxybenzyl.

[0043] Compound 1Aa can be converted to compound 1B in step 2 under oxidizing conditions such as hydrogen peroxide (H2O2).

[0044] Compound 1B can be converted to compound 1D in step 3 by treating it with compound 1C in an SNAr reaction in a solvent such as DMF in the presence of a base such as cesium carbonate (Cs2CO3) and heating the solvent to reflux.

[0045] Alternatively, compound 1D can be obtained in step 4 by treating compound 1B with compound 1E in an SNAr reaction in a solvent such as DMF in the presence of a base such as sodium hydride (NaH) by heating the solvent to reflux, followed by coupling the resulting compound 1F with one of compounds 1G under coupling reaction conditions in step 5.

[0046] Compound 1D can be converted to compound 1H in step 6 under reducing conditions such as TiCl3.

[0047] Compound 1H can be converted to compound 1J in step 7 by Suzuki coupling with an appropriate boron reagent R6B(OR')2 (wherein B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in a mixture of dioxane and water as solvent, in the presence of a base such as Cs2CO3, and using a DCM complex of Pd(dppf)Cl2 as a catalyst, by heating at RT or to reflux of the solvent.

[0048] Compound 1J can be converted to compound 1K in step 8 by cleaving the protecting group (PG) under conditions related to the nature of PG.

[0049] Compound 1K can be converted to compound 1L in step 9 by treatment with, for example, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (PhN(SOCF) in DCM solution in the presence of pyridine as a base.

[0050] Compound 1L can be converted to compound 1M in step 10 by carbonylation with carbon monoxide in DMF and MeOH solution in the presence of a palladium catalyst, such as the DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl).

[0051] Compound 1M can be converted to compound I in step 11 by treatment with an aqueous solution of 2N sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in the presence of a hydroxide ion source, specifically MeOH or THF. The sodium or lithium salt of compound I can be obtained by extraction of the product. The neutral form of compound I can be obtained by acidifying with aqueous HCl to pH 6-7. The hydrochloride salt of compound I can be obtained by acidifying with aqueous HCl to pH 1-2. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC with formic acid or trifluoroacetic acid in the eluent.

[0052] When Y=-CH=, compound I can be reduced by hydrogenation in step 12 under hydrogen (H) pressure at temperatures up to, for example, 70°C using a catalyst such as Pd / C or Pd(OH) to give the corresponding saturated compound I'.

[0053] Scheme 1b: Alternative process for preparing intermediate 1H [ka]

[0054] Scheme 1b (R1, R2, R3', R3'', R4, R5, R5', R7, [ka] , n, p, X, and Y are defined as above, and PG is a protecting group such as pivaloyl, benzyl, para-methoxybenzyl, or 2,4-dimethoxybenzyl), compound 1F can be converted to compound 1N in step 1 by reacting it with one of compounds 1G′ under coupling reaction conditions.

[0055] Alternatively, compound 1N can be obtained in step 2 by treating compound 1B with compound 1E in an SNAr reaction in a solvent such as DMF in the presence of a base such as cesium carbonate (CsCO) by heating the solvent to reflux.

[0056] Compound 1N can be converted to compound 1O in step 3 under reducing conditions such as TiCl3.

[0057] Compound 1O can be converted to compound 1P in step 4 by treatment with TFA or HCl.

[0058] Compound 1P can be converted to compound 1H in step 5 by treating it with compound 1Q (W is Cl, Br, I, or OSOR, and R = CH, PhMe, CF, or CFCFCFCFCF) in the presence of a base such as potassium carbonate in DMF as a solvent.

[0059] Scheme 1c Parts 1 and 2: Alternative Process for Preparing Intermediate 1M Scheme 1c Part 1 [ka] Scheme 1c Part 2 [ka]

[0060] Scheme 1c - Part 1 and Part 2 (R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are defined above), compound 1Q (prepared according to U.S. Patent Application Publication No. 20040009976) can be converted to compound 1S in step 1 by reacting with compound 1R in an SNAr reaction in a solvent such as DMF in the presence of a base such as NaOH by heating the solvent to reflux.

[0061] Compound 1S can be converted to compound 1T under decarboxylation conditions in step 2 by treatment with NaOH followed by heating to 135°C.

[0062] In step 3, compound 1T can be converted to compound 1U by carbonylation with carbon monoxide in DMF and MeOH solution in the presence of a palladium catalyst, for example, the DCM complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl).

[0063] Compound 1U can be converted to compound 1V in step 4 by treatment with a brominating reagent such as NBS.

[0064] Compound 1V can be converted to compound 1W in step 5 by Suzuki coupling with an appropriate boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in a mixture of dioxane and water as solvent, in the presence of a base such as Cs2CO3, and using a DCM complex of Pd(dppf)Cl2 as a catalyst, by heating at RT or to reflux of the solvent.

[0065] Compound 1W can be converted to compound 1X in step 6 by treatment with TFA or HCl.

[0066] Compound 1X can be converted to compound 1Z in step 7 by treatment with compound 1Y under reductive amination conditions.

[0067] Compound 1Z can be converted to compound 2A in step 8 by treatment with TFA or HCl.

[0068] Compound 2A can be converted to compound 1M in step 9 by treatment with compound 1Q (W is Cl, Br, I, or OSOR, and R = CH, PhMe, CF, or CFCFCFCFCF) in the presence of a base such as potassium carbonate in DMF as a solvent.

[0069] Alternatively, compound 1X can be converted to compound 2B in step 10 under Sandmeyer conditions by treatment with sodium nitrite (NaNO2) followed by treatment with sodium (NaI).

[0070] Compound 2B can be converted to compound 1M in step 11 by coupling with one of compounds 1G under coupling reaction conditions.

[0071] Provided herein is a process for the preparation of a compound of formula (I) as defined above, comprising the step of: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are as defined above) is converted to a compound of formula (I) in the presence of a hydroxide ion source, such as NaOH or LiOH, in a methanol or THF solution, and optionally, prior to said step, a compound of formula 1L [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are as defined above) is converted to compound 1M by carbonylation with carbon monoxide in the presence of a palladium catalyst in a solution of DMF and MeOH containing DCM to obtain compound 1M; A method is also provided.

[0072] Provided herein is a process for the preparation of a compound of formula (I) as defined above, comprising the step of: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are as defined above) is converted to a compound of formula (I) in the presence of a hydroxide ion source, such as NaOH or LiOH, in a methanol or THF solution, optionally followed by the addition of a compound of formula 2B [ka] wherein R3′, R3″, R6, R7, n, and X are as defined above, is converted to compound 1G under coupling reaction conditions. [ka] wherein R1, R2, R4, R5, R5', and p are as defined above, to obtain compound 1M, A method is also provided.

[0073] Hereinafter, there is provided a method for preparing a compound of formula (I) as defined above, the compound of formula 1M [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are as defined above) is converted to a compound of formula (I) in the presence of a hydroxide ion source, such as NaOH or LiOH, in a methanol or THF solution, optionally prior to said step, by the addition of a compound of formula 2A [ka] wherein R, R, R, R, n, p, and X are as defined above, are reacted with compound 1Q in the presence of a base such as potassium carbonate in DMF as a solvent. [ka] wherein W is Cl, Br, I, or OSOR, and R=CH, PhMe, CF, or CFCFCFCF, and R, R, R, R', R'', R, R, R', and p are as defined above, to obtain compound 1M; A method is also provided.

[0074] As used herein, compounds 1M, 1H, 1L, 1X [ka] [ka] (In the formula, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, n, p, [ka] , X, and Y are as defined above, and PG is a protecting group such as pivaloyl, benzyl, para-methoxybenzyl, or 2,4-dimethoxybenzyl. Also provided is an intermediate compound selected from:

[0075] In another aspect, there is also provided herein a process for the preparation of a compound of formula (I), comprising the step of deprotecting a compound of formula 1M as defined above, optionally followed by a purification step.

[0076] Said purification step may consist, for example, of an acidification step, for example with an aqueous solution of hydrochloric acid, as shown, for example, in step 4 of Example 1 hereinafter.

[0077] 400 and 500MHz 1H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0078] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1x30 mm, mobile phase H2O+0.1% HC02H / CH3CN+0.1% HC02H, light scattering detector Sedere and SQD Waters mass spectrometer.

[0079] Tables 1a and 1b below respectively list specific compounds (names and structures) of formula (I) according to the present disclosure along with their characterization ( 1 H NMR and liquid chromatography / mass).

[0080] [Table 1]

[0081] [Table 2]

[0082] The following examples describe the preparation of some compounds of formula (I) described herein. The number of compounds exemplified below corresponds to that in Table 1 above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0083] In the following examples, where the source of a starting product is not specified, it is to be understood that said product is a known compound. [Example]

[0084] Intermediates: Intermediate 1: Methyl 3-(4-aminophenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate [ka]

[0085] Step 1: Ethyl 6-bromo-3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-2-carboxylate [ka] To a solution of ethyl 6-bromo-3-chlorobenzo[b]thiophene-2-carboxylate (prepared according to U.S. Patent Application Publication No. 20040009976) (5 g, 15.64 mmol) in DMSO (50 ml) was added tert-butyl N-(4-hydroxyphenyl)carbamate (3.93 g, 18.77 mmol) and K2CO3 (2.38 g, 17.21 mmol). The reaction was stirred at 100 °C for 18 h. The reaction mixture was cooled to RT, after which water (10 ml) was added. The mixture was extracted with EtOAc (3 × 50 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 70 / 30 cyclohexane / EtOAc to afford 2.34 g (30%) of ethyl 6-bromo-3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-2-carboxylate as a yellow solid. LC / MS(m / z, MH+): 492

[0086] Step 2: tert-butyl (4-((6-bromobenzo[b]thiophen-3-yl)oxy)phenyl)carbamate [ka] To a mixture of ethyl 6-bromo-3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-2-carboxylate (1.37 g, 2.78 mmol) in 1-butylpyrrolidin-2-one (10 ml) and water (0.2 ml) was added aqueous NaOH (3 M) (1.30 ml, 3.81 mmol). The mixture was heated at 65° C. for 1 h and then at 135° C. for 18 h. The reaction mixture was cooled to RT, after which the mixture was diluted with EtOAc (20 ml) and water (20 ml). The organic layer was separated and washed again with water (2×20 ml), then dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 cyclohexane / EtOAc to afford 587 mg (50%) of tert-butyl (4-((6-bromobenzo[b]thiophen-3-yl)oxy)phenyl)carbamate as a white solid. LC / MS(m / z, MH+): 420

[0087] Step 3: Methyl 3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-6-carboxylate [ka] A mixture of tert-butyl (4-((6-bromobenzo[b]thiophen-3-yl)oxy)phenyl)carbamate (550 mg, 1.31 mmol), EtN (397 mg, 0.55 ml, 3.93 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (214 mg, 0.26 mmol) in MeOH (12 ml), previously purged with N, was heated at 100 °C under a CO atmosphere (5 bar) for 18 h. The reaction mixture was cooled to RT and then evaporated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 100 / 00 to 90 / 10 cyclohexane / EtOAc to afford 408 mg (78%) of methyl 3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-6-carboxylate as a white solid. LC / MS (m / z, MH+): 400

[0088] Step 4: Methyl 2-bromo-3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-6-carboxylate [ka] To a solution of methyl 3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-6-carboxylate (408 mg, 1.02 mmol) in DCM (10 ml) at RT was added NBS (191 mg, 1.07 mmol). The solution was stirred at RT for 18 h. Saturated aqueous NaHCO3 (20 ml) was added. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 460 mg (94%) of methyl 2-bromo-3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-6-carboxylate as a white solid. LC / MS(m / z, MH+):478

[0089] Step 5: Methyl 3-(4-((tert-butoxycarbonyl)amino)phenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate [ka] A mixture of methyl 2-bromo-3-(4-((tert-butoxycarbonyl)amino)phenoxy)benzo[b]thiophene-6-carboxylate (460 mg, 0.96 mmol), 2-[2-(1,1-difluoroethyl)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared according to J. Med. Chem., 2018, 61(7), 2837-2864) (590 mg, 1.44 mmol), and KCO (266 mg, 1.92 mmol) in a mixture of dioxane (8 mL) and water (1.6 mL) was purged with N. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (39 mg, 0.05 mmol) was added, and the mixture was again purged with N2 and then heated at 80 °C for 18 h. After cooling to RT, EtOAc (20 mL) and water (20 mL) were added. The aqueous layer was separated, re-extracted with EtOAc (2 × 20 mL), dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography eluting with DCM to give 390 mg (72%) of methyl 3-(4-((tert-butoxycarbonyl)amino)phenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate as a white solid. LC / MS(m / z, MH+):558

[0090] Step 6: Methyl 3-(4-aminophenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate [ka] Methyl 3-(4-((tert-butoxycarbonyl)amino)phenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate (320 mg, 0.57 mmol) was dissolved in HCl in dioxane (4 M) (10 mL, 28.7 mmol). The reaction mixture was stirred at RT for 36 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with EtO (2 × 10 mL). The crude product was redissolved in DCM (20 mL), basified with aqueous NaHCO, and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 224 mg (85%) of methyl 3-(4-aminophenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+): 458

[0091] Intermediate 2: 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene 1-oxide [ka]

[0092] Step 1: 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene [ka] A solution of 2,3-dibromobenzothiophen-6-ol (prepared according to WO 2004009086) (6.2 g, 20.1 mmol) in DMF (100 ml) was added dropwise to a 60% suspension of NaH (1.2 g, 30.2 mmol) in DMF (200 ml) at 0 °C. After stirring for 20 min, benzyl bromide (6.89 g, 40.3 mmol) was added. The ice bath was removed. The reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into water (1 L). The solid that formed was filtered and dried to give 8 g (99%) of 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene. LC / MS(m / z, MH+): 397

[0093] Step 2: 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene 1-oxide [ka] To a mixture of 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene (6 g, 15.1 mmol) in DCM (30 mL) was added TFA (30 mL). The reaction mixture was stirred at RT for 10 min, and then 30% aqueous HO (2.05 g, 18.1 mmol) was added. The reaction mixture was stirred at RT for 4 h. NaHSO (0.6 g) and water (30 mL) were added. The reaction mixture was stirred for 15 min and then concentrated under reduced pressure. To the resulting residue were added DCM (100 mL) and saturated NaHCO solution (100 mL). After decantation, the organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with DCM to give 3 g (48%) of 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene 1-oxide. LC / MS(m / z, MH+): 413

[0094] Example Method A: Example 1: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid hydrochloride [ka]

[0095] Step 1: tert-butyl 3-((4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)phenyl)amino)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (130 mg, 0.76 mmol) in EtOH (5 ml) was added methyl 3-(4-aminophenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate (Intermediate 1) (174 mg, 0.38 mmol) and acetic acid (44 μl, 0.76 mmol). The reaction mixture was stirred at RT for 30 min, then sodium cyanoborohydride (72 mg, 1.14 mmol) was added, and the reaction mixture was stirred at 60° C. for 96 h. The reaction mixture was cooled to RT and then concentrated under reduced pressure. EtOAc (20 ml) and water (20 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of 90 / 10 to 60 / 40 cyclohexane / EtOAc to afford 111 mg (47%) of tert-butyl 3-((4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)phenyl)amino)azetidine-1-carboxylate as a yellow solid. LC / MS(m / z, MH+):613

[0096] Step 2: Methyl 3-(4-(azetidin-3-ylamino)phenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate [ka] To a solution of tert-butyl 3-((4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)phenyl)amino)azetidine-1-carboxylate (100 mg, 0.16 mmol) in DCM (2 ml) at RT was added TFA (0.24 ml, 3.26 mmol). The reaction mixture was stirred at RT for 12 h. The mixture was made basic with saturated aqueous NaHCO3 to pH = 8-9 and extracted with DCM (3 × 5 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 62 mg (74%) of methyl 3-(4-(azetidin-3-ylamino)phenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate as a white solid. LC / MS(m / z, MH+):513

[0097] Step 3: Methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate [ka] A mixture of methyl 3-(4-(azetidin-3-ylamino)phenoxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophene-6-carboxylate (50 mg, 0.098 mmol), 1-fluoro-3-iodopropane (20 mg, 0.11 mmol), and K2CO3 (34 mg, 0.24 mmol) in THF (1 ml) and water (0.1 ml) was stirred at 50 °C for 2.5 h. The mixture was cooled to RT, and water (10 ml) and EtOAc (20 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of (100 / 00) to (80 / 20) DCM / isopropanol to afford 37 mg (66%) of methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate as a yellow solid. LC / MS(m / z, MH+):573

[0098] Step 4: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid hydrochloride [ka] To a suspension of methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate (40 mg, 0.07 mmol) in a mixture of water (0.40 ml) and THF (0.40 ml) was added LiOH.HO (15 mg, 0.35 mmol). The mixture was stirred at 50 °C for 10 h. The reaction mixture was cooled to RT and then acidified with aqueous HCl (1 N) to pH = 2. The mixture was extracted with EtOAc (3 × 5 ml). The organic layer was washed with water (5 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was triturated with DCM (3 × 1 ml) and collected by centrifugation (3500 rpm, 15 min) to give 14 mg (36%) of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid hydrochloride as a yellow solid.

[0099] Method B: Example 2: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka]

[0100] Step 1: 6-(benzyloxy)-2-bromo-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene 1-oxide [ka] To a solution of 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene 1-oxide (Intermediate 2) (880 mg, 2.13 mmol) and 4-[1-(3-fluoropropyl)azetidin-3-yl]oxyphenol (prepared according to WO2019157020) (479 mg, 2.13 mmol) in N-methylpyrrolidone (25 mL) was added Cs2CO3 (1.38 g, 4.25 mmol). The reaction mixture was stirred at 60 °C for 3 h. After cooling to RT, water (10 mL) and EtOAc (20 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 00 / 100 petroleum ether / EtOAc to afford 1 g (84%) of 6-(benzyloxy)-2-bromo-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene 1-oxide as a brown solid. LC / MS(m / z, MH+):558

[0101] Step 2: 3-(4-((6-(benzyloxy)-2-bromobenzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)azetidine [ka] To a solution of 6-(benzyloxy)-2-bromo-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene 1-oxide (0.22 g, 0.39 mmol) in MeOH (8 ml) and chloroform (4 ml) was added a 15% solution of TiCl in aqueous HCl (0.624 g, 0.788 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO. DCM (50 ml) was added and after decantation, the organic phase was washed with brine, dried over MgSO, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 DCM / MeOH to afford 190 mg (89%) of 3-(4-((6-(benzyloxy)-2-bromobenzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)azetidine as a brown solid. LC / MS(m / z, MH+):542

[0102] Step 3: 3-(4-((6-(benzyloxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)azetidine [ka] To a solution of 3-(4-((6-(benzyloxy)-2-bromobenzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)azetidine (190 mg, 0.35 mmol) and 2-[2-(1,1-difluoroethyl)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared according to J. Med. Chem., 2018, 61(7), 2837-2864) (110 mg, 0.385 mmol) in dioxane (16 ml) and water (4 ml) was added Pd(dppf)Cl (51 mg, 0.07 mmol) and CsCO (342 mg, 1.05 mmol). The reaction mixture was stirred at 100 °C for 16 h. Water (10 ml) and DCM (20 ml) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 75 / 25 petroleum ether / EtOAc to afford 200 mg (92%) of 3-(4-((6-(benzyloxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):622

[0103] Step 4: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-ol [ka] A mixture of 3-(4-((6-(benzyloxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)azetidine (517 mg, 0.83 mmol), Pd / C (10%) (250 mg), and Pd(OH) / C (250 mg) in MeOH (20 ml) and EtOAc (20 ml) was stirred under H (1 bar) at RT for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC (eluted with 78-82% MeOH in basic water (0.05% NH4HCO3)) to give 362 mg (82%) of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-ol. LC / MS(m / z, MH+):532

[0104] Step 5: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-yl trifluoromethanesulfonate [ka] To a stirred mixture of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-ol (30 mg, 0.056 mmol) and EtN (17 mg, 0.17 mmol) in DCM (10 ml) was added 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (30 mg, 0.084 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was partitioned between DCM (10 ml) and water (5 ml). After decantation, the organic phase was dried over MgSO and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 65 / 35 to 60 / 40 petroleum ether / EtOAc to afford 30 mg (80%) of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-yl trifluoromethanesulfonate as a yellow oil. LC / MS(m / z, MH+):664

[0105] Step 6: Methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate [ka] To a solution of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-yl trifluoromethanesulfonate (110 mg, 0.166 mmol) in MeOH (10 ml) was added Pd(dppf)Cl (18 mg, 0.025 mmol) and N-ethyl-N-isopropyl-propan-2-amine (214 mg, 1.66 mmol). The reaction mixture was stirred at 68 °C under 1 bar of CO for 1 h. The reaction mixture was filtered, after which the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (10 ml) and water (5 ml). After decantation, the organic phase was dried over MgSO and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc from 95 / 5 to 85 / 15 to afford 90 mg (95%) of methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+):574

[0106] Step 7: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 7 of Example 2 was prepared from methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to step 4 of Example 1 to afford 30 mg (56%) of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid as a white solid.

[0107] Example 3: (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka]

[0108] Step 1: 6-(benzyloxy)-2-bromo-3-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene 1-oxide [ka] Step 1 of Example 3 was prepared from 6-(benzyloxy)-2,3-dibromobenzo[b]thiophene 1-oxide (Intermediate 2) and (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol (prepared according to WO2020037251) according to a procedure similar to Step 1 of Example 2 to afford 3.4 g (79%) of 6-(benzyloxy)-2-bromo-3-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene 1-oxide. LC / MS(m / z, MH+):572

[0109] Step 2: (S)-3-(4-((6-(benzyloxy)-2-bromobenzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] Step 2 of Example 3 was prepared from 6-(benzyloxy)-2-bromo-3-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene 1-oxide according to a procedure similar to Step 2 of Example 2 to afford 4.2 g (86%) of (S)-3-(4-((6-(benzyloxy)-2-bromobenzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine as a white solid. LC / MS(m / z, MH+):554

[0110] Step 3: (S)-3-(4-((6-(benzyloxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] Step 3 of Example 3 was prepared from methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate and 2-[2-(1,1-difluoroethyl)-4-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared according to J.Med.Chem., 2018,61(7),2837-2864) according to a procedure similar to Step 3 of Example 2 to afford 390 mg (49%) of (S)-3-(4-((6-(benzyloxy)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine as a white solid. LC / MS(m / z, MH+):636

[0111] Step 4: (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-ol [ka] Step 4 of Example 3 was prepared from methyl 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to Step 4 of Example 2 to afford 100 mg (51%) of (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-ol as a white solid. LC / MS(m / z, MH+):546

[0112] Step 5: (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-yl trifluoromethanesulfonate [ka] Step 5 of Example 3 was prepared from (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-ol according to a procedure similar to step 5 of Example 2 to afford 130 mg (70%) of (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophen-6-yl trifluoromethanesulfonate as a white solid. LC / MS(m / z, MH+):678

[0113] Step 6: Methyl (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate [ka] Step 6 of Example 3 was prepared from (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-yl trifluoromethanesulfonate according to a procedure similar to step 6 of Example 2 to afford 100 mg (89%) of methyl (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate as a white solid. LC / MS(m / z, MH+):588

[0114] Step 7: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 7 of Example 3 was prepared from methyl (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to step 4 of Example 1 to afford 81 mg (83%) of 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid as a white solid.

[0115] The compounds listed in Table 1 above were subjected to pharmacological testing to determine their disruptive effects on the estrogen receptor.

[0116] Test: Estrogen receptor degrading activity The test involves measuring the in vitro degradation activity of the compounds of Table 1.

[0117] Degradation activity was measured using breast cancer cell ERα in a cell Western assay as described below.

[0118] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells per well in phenol red-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran-striped FBS. The following day, nine serial 1:5 dilutions of each compound were added to the cells in 2.5 μL, ranging from 0.3 to 0.0000018 μM (Table 2), or fulvestrant (used as a positive control) at a final concentration of 0.1 μM. Four hours after compound addition, cells were fixed by adding 25 μL of formalin (5% formalin with 0.1% Triton) for 10 min at RT, followed by two washes with PBS. Next, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 min at RT. The LI-COR blocking buffer was removed, and the cells were incubated overnight in the cold with 50 μL of anti-ER rabbit monoclonal antibody (Thermo Scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% Tween-20. Wells treated with blocking buffer but without antibody served as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 μM final concentration). The cells were then washed three times in PBS and scanned in an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0119] The degradative activity of the estrogen receptor in this test is expressed as the concentration (or IC ) required to degrade 50% of the estrogen receptor in nM. 50 ) is given by

[0120] The % reduction in ERα levels was determined as follows: % inhibition = 100 * (1 - (sample - fulvestrant:DMSO - fulvestrant)).

[0121] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1 tested at 0.3 μM, demonstrating that the compounds have significant degrading activity against the estrogen receptor.

[0122] [Table 3]

[0123] Therefore, it is clear that the tested compounds have degradation activity on estrogen receptors with IC50 of less than 1 μM and degradation levels of more than 50%. Therefore, the compounds of formula (I) can be used to prepare drugs, particularly drugs that are estrogen receptor degraders.

[0124] Accordingly, also provided herein is a medicament comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0125] There is also provided herein a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above for use as a pharmaceutical.

[0126] Also provided herein are compounds of formula (I), as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, in particular as inhibitors and degraders of estrogen receptors.

[0127] There is also provided herein a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation.

[0128] A particular embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of cancer.

[0129] In some embodiments, the cancer is a hormone-dependent cancer.

[0130] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0131] In another embodiment, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer and lung cancer, or metastases thereof.

[0132] In another embodiment, the metastasis is a cerebral metastasis.

[0133] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0134] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0135] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR or PI3K inhibitors.

[0136] According to another aspect, provided herein is a method of treating the above-noted pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments of this method of treatment, the subject is a human.

[0137] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions set out above, more particularly useful in treating cancer.

[0138] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions also contain an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0139] Said excipients are selected according to the desired pharmaceutical form and method of administration from the conventional excipients known to those skilled in the art.

[0140] The active ingredient of formula (I) above, or its base, acid, zwitterion or salt thereof, in unit dosage form, in admixture with conventional pharmaceutical excipients, may be administered to animals and humans for the treatment of the above disorders or diseases in oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration.

[0141] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, it is possible to use the compounds of formula (I) in creams, gels, ointments or lotions.

[0142] As an example, a unit dosage form of a compound of formula (I) in tablet form may contain the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Cornstarch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0143] There may be particular cases in which higher or lower dosages are appropriate. According to normal practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3′ and R3″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; ・Y is -CH ２ represents -, -CH=, -CR8=, -O-, or -NH-, and R8 is a fluorine atom or (C １ ~C ３ ) represents an alkyl group; ・ 【Chemistry 2】 represents a single or double bond; p is 0 or 1; X is -CH=, -N=, or -CR"= (wherein R" is (C １ ~C ３ ) alkyl group or a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R7 is independently a (C １ ~C ３ ) alkyl group, halogen atom such as fluorine atom, cyano group, or trifluoromethyl １ ~C ３ ) represents a fluoroalkyl group; n is 0, 1 or 2; ・R6 is (C ６ ~C １０ ) an aryl group or a 5- or 6-membered heteroaryl group; Said (C ６ ~C １０ ) the aryl group or the 5- or 6-membered monocyclic heteroaryl group is optionally substituted with 1 to 3 groups selected from -Z-R6a and R6a; During the ceremony, Z is methylene; R6a is ・-OH group, Optionally substituted with a cyano group or an —OH group (C １ ~C ６ ) alkyl groups, ・(C １ ~C ６ ) an alkylene group, - halogen atoms, nitro group, cyano group, ・(C １ ~C ６ ) a fluoroalkyl group, ・(C １ ~C ６ ) a fluoroalkoxy group, ・(C ３ ~C ６ ) a cycloalkyl group, ・(C １ ~C ６ ) an alkoxy group, ・-SF ５ base, - trifluoromethylsulfonyl group, ・(C １ ~C ４ ) alkylthio groups, ・(C １ ~C ４ ) a fluoroalkylthio group, ・(C １ ~C ４ ) an alkylsulfonyl group, ・-NR9R10 groups, ・-C(O)R9 group, ・(C ３ ~C ７ ) cycloalkyl groups, and O, NH, C(O), and S(O) ０－２ a 4- to 7-membered saturated, unsaturated or partially saturated ring containing 1 to 4 heteroatoms or groups selected from Selected from: R9 and R10 are each a hydrogen atom and (C １ ~C ４ ) alkyl groups, or R9 and R10 together with the nitrogen to which they are both attached are selected from O, NH, and S(O) ０－２ and forming a 4- to 7-membered saturated ring containing one other heteroatom or group selected from the group consisting of (C １ ~C ４ ) optionally substituted with an alkyl group).

2. 2. The compound of formula (I) according to claim 1, wherein R1 and R2 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.

3. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that R3' and R3" both represent a hydrogen atom.

4. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that R4 represents a hydrogen atom.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that R5 and R5' both represent a hydrogen atom.

6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that Y is -O- or -NH-. 【Request 7】 【Chemical 3】 A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that represents a single bond.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that n is 0.

9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that X represents -CH=.

10. R6 is a halogen atom and (C １ ~C ６ phenyl groups optionally substituted with 1, 2, 3, or 4 groups selected from fluoroalkyl groups, more particularly halogens, such as fluorine atoms, and (C １ ~C ４ 10. The compound of formula (I) according to claim 1, wherein the phenyl group optionally substituted with two or three groups selected from 1,1-difluoroethyl, ...

11. X represents -CH=, R6 is a halogen atom and (C １ ~C ６ ) fluoroalkyl groups, more specifically halogens, such as fluorine atoms, and (C １ ~C ４ 11. The compound of formula (I) according to claim 1, wherein the phenyl group optionally substituted with two or three groups selected from 1,1-difluoroethyl, ...

12. The compound is the following compound: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid hydrochloride (1), 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (2), and (S)-2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (3) A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in particular the hydrochloride thereof, characterized in that it is selected from:

13. A process for preparing a compound of formula (I) according to any one of claims 1 to 12, comprising the step of: 【Chemistry 4】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 5】 , n, p, X and Y are defined in any one of claims 1 to 11) is converted to a compound of formula (I) in the presence of a hydroxide ion source, for example NaOH or LiOH, in a methanol or THF solution, optionally prior to said step, by the addition of a compound of formula 1L 【Chemistry 6】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 7】 , n, p, X, and Y are as defined above) is converted to compound 1M by carbonylation with carbon monoxide in the presence of a palladium catalyst in a DMF and MeOH solution to obtain compound 1M; method.

14. A process for preparing a compound of formula (I) according to any one of claims 1 to 12, comprising the step of: 【Chemistry 8】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 9】 , n, p, X and Y are defined in any one of claims 1 to 11) is converted to a compound of formula (I) in the presence of a hydroxide ion source, for example NaOH or LiOH, in a methanol or THF solution, optionally prior to said step, by the addition of a compound of formula 2B 【Chemistry 10】 wherein R3′, R3″, R6, R7, n, and X are as defined above, is converted to compound 1G under coupling reaction conditions. 【Chemistry 11】 wherein R1, R2, R3′, R3″, R4, R5, R5′, and p are as defined above, to obtain compound 1M, method.

15. A process for preparing a compound of formula (I) according to any one of claims 1 to 12, comprising the step of: 【Chemistry 12】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 13】 , n, p, X and Y are defined in any one of claims 1 to 11) is converted to a compound of formula (I) in the presence of a hydroxide ion source, for example NaOH or LiOH, in a methanol or THF solution, optionally prior to said step, by the addition of a compound of formula 2A 【Chemistry 14】 wherein R, R, R, R, n, p, and X are as defined above, is reacted with compound 1Q in the presence of a base such as potassium carbonate in dichloromethane as a solvent. 【Chemistry 15】 (Wherein W is Cl, Br, I, or OSO ２ R, where R=CH ３ , PhMe, CF ３ , or CF ２ CF ２ CF ２ CF ３ wherein R1, R2, R3′, R3″, R4, R5, R5′, and p are as defined above, to obtain compound 1M; method.

16. A compound selected from compounds 1M, 1H, 1L, and 1X 【Chemistry 16】 【Chemistry 17】 (In the formula, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, n, p, 【Chemistry 18】 , X and Y are as defined in any one of claims 1 to 11, and PG is a protecting group such as pivaloyl, benzyl, para-methoxybenzyl or 2,4-dimethoxybenzyl).

17. A medicament comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for use as an inhibitor and degrader of estrogen receptors.

20. 13. A compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

21. 21. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to claim 20 for use in the treatment of cancer.

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