Novel substituted 2-carbonyl-benzothiophene-6-carboxylic acid derivatives, processes for their preparation and their therapeutic use

Abstract

As used herein, the term "compound of formula (I): [Formula 1] TIFF2025531033000103.tif42170 [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 represents -CH2-, -CH=, -CR8=, -O-, or -NH-, where R8 represents a fluorine atom or a (C1-C3) alkyl group; [Case 2] represents a single or double bond; X represents -CH=, -N=, or -CR"=, where R" represents a (C1-C3) alkyl group or a halogen atom such as a fluorine or 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; and R6 represents an optionally substituted monocyclic or bicyclic ring selected from a phenyl group, a 5- or 6-membered monocyclic heteroaryl group, and a 7-, 8-, 9-, or 10-membered bicyclic heterocyclic group, or a pharmaceutically acceptable salt thereof. Further disclosed are processes for their preparation, pharmaceutical compositions containing them, and said compounds of formula (I) for use as inhibitors and degraders of estrogen receptors, particularly in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

Description

[Technical Field]

[0001] Disclosed herein are novel substituted 2-carbonyl-benzothiophene-6-carboxylic acid derivatives, processes 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 tissues. ERs exist in two forms: estrogen receptor alpha (ERα) and estrogen receptor beta (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. When the hormone estrogen binds to ERs, they 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 contributed significantly to reducing breast cancer incidence, approximately one-third of ERα-positive patients exhibit de novo resistance or develop resistance to such 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 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 and confer 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] Publications 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] The present inventors have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in cancer therapy.

[0010] As used herein, the term "compound of formula (I): [ka] [In 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-, where 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"=, where R" represents a (C1-C3) alkyl group or 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 o phenyl group, o 5- or 6-membered monocyclic heteroaryl groups, and o 7-, 8-, 9-, or 10-membered bicyclic heterocyclic group represents a monocyclic or bicyclic ring selected from The monocyclic or bicyclic ring is optionally substituted by one, two, three or four groups selected from a halogen atom, a hydroxyl group; a (C1-C6) alkyl group optionally substituted with a cyano group or an -OH group; a (C3-C6) cycloalkyl group, a (C1-C6) fluoroalkyl group, a -CN group, a (C1-C6) alkoxy group, a (C1-C6) fluoroalkoxy group, a trifluoromethylsulfonyl group, a (C1-C4) alkylthio group, a (C1-C4) fluoroalkylthio group and a (C1-C4) alkylsulfonyl group. or a pharmaceutically acceptable salt thereof is described.

[0011] As used herein, the term "compound of formula (I): [ka] [In 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-, where 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"=, where R" represents a (C1-C3) alkyl group or 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 o phenyl group, o 5- or 6-membered monocyclic heteroaryl groups, and o 7-, 8-, 9-, or 10-membered bicyclic heterocyclic group represents a monocyclic or bicyclic ring selected from the monocyclic or bicyclic ring is optionally substituted by 1, 2, 3 or 4 groups selected from a halogen atom, a hydroxyl group; a (C1-C6) alkyl group optionally substituted with a cyano group or an -OH group; a (C3-C6) cycloalkyl group, a (C1-C6) fluoroalkyl group, a -CN group, a (C1-C6) alkoxy group, a (C1-C6) fluoroalkoxy group, a trifluoromethylsulfonyl group, a (C1-C4) alkylthio group, a (C1-C4) fluoroalkylthio group and a (C1-C4) alkylsulfonyl group, provided that compounds in which p=1 and Y is -O- are excluded. or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0012] The compounds of formula (I) may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers.

[0013] The compounds of formula (I) may also exist in tautomeric forms.

[0014] The compounds of formula (I) can exist in the form of bases, acids, zwitterions, or addition salts with acids or bases. Thus, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] 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.

[0016] Among the suitable salts of the compounds of formula (I) there may be mentioned the hydrochloride salt.

[0017] As used herein, the following terms have the following definitions throughout the specification unless otherwise stated: 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 (referred to as "(C1-C6) alkyl"). Examples may include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups; - cycloalkyl group: unless otherwise specified, a saturated or partially unsaturated and unsubstituted or substituted monocyclic alkyl group containing 3 to 7 carbon atoms, examples of which may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, etc., in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl or cyclohexenyl; heterocycloalkyl groups: saturated or partially unsaturated, 4- to 7-membered cycloalkyl groups containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen; - monocyclic heterocyclic group: a 3-, 4-, 5-, 6- or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, wherein the ring is saturated or unsaturated but not aromatic. A 3- or 4-membered ring may contain one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring may contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring may contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S; - 7-, 8-, 9- or 10-membered bicyclic heterocyclic group: a 7- to 10-membered bicyclic group in which a monocyclic heterocycloalkyl group is fused to either a phenyl group, a monocyclic cycloalkyl group such as a (C3-C6)cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocycloalkyl group, or a monocyclic heteroaryl group. The bicyclic heterocycle can be attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic or bicyclic heterocyclic portion of the bicyclic ring system; - 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 belonging to the alkyl group are replaced with fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl group. Examples include trifluoromethyl group or trifluoroethyl group, etc.; - alkoxy group: an -O-alkyl group, in which the alkyl group is as defined above. Examples may include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; - Fluoroalkoxy group: -O-alkyl, where 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 replaced with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms of the alkyl group are replaced with fluorine atoms, the fluoroalkoxy group can be named a perfluoroalkoxy group. Examples include trifluoromethoxy group, etc.; - (C1-C4) alkylthio group, also named (C1-C4) alkylsulfanyl group: an -S-alkyl group, wherein the alkyl group is as defined above. Examples may include, but are not limited to: methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.; - (C1-C4) alkylsulfonyl group: -SO2-alkyl group, wherein the alkyl group is as defined above. Examples may include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; - (C1-C4)fluoroalkylthio group, also named (C1-C4)fluoroalkylsulfanyl group: -S-fluoroalkyl group, in which the fluoroalkyl group is as defined above. Examples may include, but are not limited to: fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - 5- or 6-membered monocyclic heteroaryl group: a cyclic 5- or 6-membered aromatic group. A 5-membered ring consists of two double bonds and 1, 2, 3, or 4 nitrogen atoms and, optionally, 1 oxygen or sulfur atom. A 6-membered ring consists of three double bonds and 1, 2, 3, or 4 nitrogen atoms. A 5- or 6-membered heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.

[0018] In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0019] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3" both represent a hydrogen atom.

[0020] In another embodiment, in the compounds of formula (I) as defined above, R4 is a hydrogen atom.

[0021] In another embodiment, in the compounds of formula (I) as defined above, R5 and R5' both represent a hydrogen atom.

[0022] 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.

[0023] In another embodiment, in the compound of formula (I) as defined above, Y is -CH2-, -CH=, -O- or -NH-.

[0024] In another embodiment, [ka] represents a single bond.

[0025] In another embodiment, [ka] represents a double bond.

[0026] In another embodiment, in the compound of formula (I) as defined above, n is 0.

[0027] In another embodiment, in a compound of formula (I) as defined above, n is 0. In another embodiment, in a compound of formula (I) as defined above, n is 1. In another embodiment, in a compound of formula (I) as defined above, n is 2.

[0028] In another embodiment, in the compounds of formula (I) as defined above, X represents -CH=.

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

[0030] In another embodiment, Y is -CH2-, -CH=, or -CR8=.

[0031] In certain embodiments, X represents a carbon atom (i.e., a =CH- group) in a compound of formula (I). Thus, the compound of formula (II): [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , Y, n and p are as defined in formula (II) herein above. Described herein are compounds of the formula:

[0032] The embodiments as described above for compounds of formula (I) are also suitable for compounds of formula (II).

[0033] In another embodiment, in the compounds of formula (II) as defined above, R6 represents a phenyl group optionally substituted by 1, 2, 3 or 4 groups selected from halogen atoms, and more particularly a (C1-C6) alkyl group optionally substituted by 2, 3 or 4 groups selected from halogen, for example fluorine atoms, and methyl groups, even more particularly by one fluorine atom and two methyl groups. Among the compounds of formula (I) described herein, the following compounds are particularly preferred: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid (1), 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (2), 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid (3), 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid (4), (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (5), and - (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid (6) or a pharmaceutically acceptable salt thereof, in particular its hydrochloride salt.

[0034] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular as an inhibitor and degrader of the estrogen receptor.

[0035] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, particularly breast cancer.

[0036] 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.

[0037] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign 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 above list, or a pharmaceutically acceptable salt thereof.

[0038] 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 above list, or a pharmaceutically acceptable salt thereof.

[0039] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, an effective dose of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0040] The compounds of formula (I) can be prepared by the following process.

[0041] 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.

[0042] The following general methods for the preparation of compounds of formula (I), optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in formula (I), are set forth below.

[0043] The following abbreviations and empirical formulas are used: MeCN acetonitrile Cs2CO3 Cesium Carbonate DCM dichloromethane Et2O diethyl ether DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate H2 Hydrogen 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 K3PO4 Potassium Phosphate NaHCO3 Sodium bicarbonate NaH sodium hydride NaOH Sodium hydroxide Na2SO4 Sodium Sulfate SNAr Aromatic Nucleophilic Substitution TFA trifluoroacetic acid THF tetrahydrofuran Et3N Triethylamine H2O Water RT room temperature

[0044] Scheme 1a: Preparation of compounds of formula (I) - General process [ka]

[0045] According to Scheme 1a, in Scheme 1a, R3a is a carboxylic acid ester such as COOMe or COOEt, and R1, R2, R3', R3", R4, R5, R5', R6, R7, [ka] , n, p, X, and Y are defined as above, and compound 1A (prepared according to U.S. Patent Application Publication No. 20130231484) can be converted to compound 1B in step 1 by treatment with R6MgBr in solution in THF.

[0046] Compound 1B can be converted to compound 1D in step 2 by treatment with compound 1C via an SNAr reaction in a solvent such as DMF in the presence of a base, for example, cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0047] Alternatively, compound 1D can be obtained by treating compound 1B with compound 1E in step 3 by SNAr reaction in a solvent such as DMF in the presence of a base, for example sodium hydride (NaH), followed by a coupling reaction in step 4 between the resulting compound 1F and one of compounds 1G under coupling reaction conditions.

[0048] Compound 1D can be converted to compound I in step 5 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could afford the sodium or lithium salt of compound I. Acidification to pH 6-7 with an aqueous solution of HCl could afford the neutral form of compound I. Acidification to pH 1-2 with an aqueous solution of HCl could afford the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent could afford the formate or trifluoroacetate salt of compound I.

[0049] When Y=-CH=, compound I is reduced by hydrogenation in step 6 over a catalyst such as Pd / C or Pd(OH)2 / C under hydrogen (H2) pressure to give the corresponding saturated compound I'.

[0050] Scheme 1b: Alternative process for the preparation of compound 1D - General process [ka]

[0051] According to Scheme 1b, in Scheme 1b, R3a is a carboxylic acid ester such as COOOMe, COOEt, and R1, R2, R3', R3", R4, R5, R5', R6, R7, [ka] , n, p, X and Y are defined as above, and compound 1F can be converted in step 1 to compound 1H by a coupling reaction with one of compounds 1G' under coupling reaction conditions.

[0052] Alternatively, compound 1H can be obtained by treatment of compound 1B with compound 1C' in step 2 by SNAr reaction in a solvent such as DMF in the presence of a base, for example cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0053] Compound 1H can be converted to compound 1J in Step 3 by treatment with TFA or HCl.

[0054] Compound 1J can be converted to compound 1D by treatment with compound 1K (where W is Cl, Br, or I, or OSO2R where R = CH3, PhMe, CF3, or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate in DMF as a solvent.

[0055] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein the compound of formula 1D [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X and Y are defined as above, and R3a is a carboxylic acid ester such as COOMe or COOEt. is converted to a compound of formula (I) in the presence of a hydroxide ion source, such as NaOH or LiOH in solution in methanol or THF, optionally preceded by a step to obtain compound 1D, in which step a compound of formula 1F [ka] wherein R3′, R3″, R6, R7, n, and X are defined as above, and R3a is a carboxylic acid ester such as COOMe or COOEt, to give Compound 1G. [ka] (wherein R1, R2, R4, R5, R5' and p are as defined above). is subjected to a coupling step with one of

[0056] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein the compound of formula 1D [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, [ka] , n, p, X and Y are as defined above, and R3a is a carboxylic acid ester such as COOMe or COOEt) is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH or LiOH in a solution of methanol or THF, optionally preceded by a step to obtain compound 1D, in which step a compound of formula 1B [ka] wherein R, R" and R are defined as above and R is a carboxylic acid ester such as COOMe or COOEt, can be prepared by reacting a compound of formula 1C with a solvent such as DMF in the presence of a base. [ka] (In the formula, R1, R2, R4, R5, R5', p, n, R7, X, [ka] and Y is as defined above). It is subjected to an SNAr reaction with

[0057] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein the compound of formula 1D [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, n, p, X, [ka] and Y are defined as above and R3a is a carboxylic acid ester such as COOMe or COOEt) is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH or LiOH in a solution in methanol or THF, optionally preceded by a step to obtain compound 1D, in which step a compound of formula 1J is obtained. [ka] (In the formula, R3', R3'', Y, p, [ka] , X, R7, n, and R6 are defined as above, and R3a is a carboxylic acid ester such as COOMe or COOEt, in the presence of a base to form a compound of formula (I). [ka] where W is Cl, Br, or I, or OSO2R where R = CH3, PhMe, CF3, or CF2CF2CF2CF3.

[0058] As used herein, compounds of formulas 1D, 1F, 1H, 1J: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, n, p, [ka] , X and Y are defined above, and R3a is a carboxylic acid ester such as COOMe or COOEt. Also provided is an intermediate compound selected from any of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, there is also provided herein a process for the preparation of a compound of formula (I), comprising a deprotection step of a compound of formula 1D as defined above, optionally followed by a purification step.

[0060] Said purification step may consist, for example, in an acidification step, for example with an aqueous solution of hydrochloric acid, as exemplified in step 2 of Example 1 herein below.

[0061] 400 and 500MHz 1 H 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.

[0062] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and a flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1 × 30 mm, mobile phase H2O + 0.1% HC02H / CH3CN + 0.1% HC02H, light scattering detector Sedere and an SQD Waters mass spectrometer.

[0063] Tables 1a and 1b below respectively list specific compounds (names and structures) of formula (I) according to the present disclosure and their characterization ( 1 1 H NMR and liquid chromatography / mass).

[0064] [Table 1]

[0065] [Table 2]

[0066] [Table 3]

[0067] [Table 4]

[0068] [Table 5]

[0069] The following examples describe the preparation of several compounds of formula (I) described herein. The number of compounds exemplified below corresponds to those given in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0070] 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]

[0071] Intermediates: Intermediate 1: Methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate [ka]

[0072] Step 1: (4-fluoro-2,6-dimethyl-phenyl)magnesium bromide [ka] To a suspension of magnesium turnings (0.19 g, 7.83 mmol) in THF (7.61 ml) under nitrogen, 2-bromo-5-fluoro-1,3-dimethylbenzene (1.50 g, 7.39 mmol) was added dropwise. The reaction mixture was stirred at RT for 4 h. The reaction mixture was directly carried on to the next step without further treatment (assumed quantitative).

[0073] Step 2: Methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate [ka] To a solution of methyl 3-chloro-2-(chlorocarbonyl)benzo[b]thiophene-6-carboxylate (prepared according to U.S. Patent Application Publication No. 20130231484) (2.5 g, 8.65 mmol) in THF (12.5 mL) was added dropwise a solution of (4-fluoro-2,6-dimethyl-phenyl)magnesium bromide (11.3 mL, 11.3 mmol) at 0 °C. The reaction mixture was stirred at RT for 12 h. The reaction mixture was acidified with 1 M aqueous HCl (10 mL) at 0 °C (adjusting the pH to 2-2.5), extracted with EtOAc (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of 100 / 00 to 85 / 15 cyclohexane / EtOAc to give 1.95 g (60%) of methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+): 377

[0074] Intermediate 2: Methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate [ka] To a solution of methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 1) (1.3 g, 3.45 mmol) and 4-bromophenol (1.79 g, 10.35 mmol) in DMF (65 ml) was added NaH 60% in mineral oil (0.41 g, 10.35 mmol) at RT. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to RT, and then an aqueous solution of NaOH (1 N) (10 ml) was added. The mixture was extracted with EtOAc (3 × 30 ml). The organic layer was washed with water (30 ml), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 cyclohexane / EtOAc to afford 945 mg (53%) of methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate as a yellow solid. LC / MS(m / z, MH+):514

[0075] Intermediate 3: (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol [ka]

[0076] Step 1: (R)-1-(3-fluoropropyl)pyrrolidin-3-ol [ka] A suspension of (3R)-3-pyrrolidinol (2.00 g, 1.91 mL, 21.8 mmol), 1-fluoro-3-iodopropane (4.28 g, 22.8 mmol), and K2CO3 (8.68 g, 62.2 mmol) in MeCN (20 mL) was stirred at 50 °C for 18 h. The reaction mixture was cooled to RT, and the suspension was filtered through Celite. The filtrate was evaporated under reduced pressure, solubilized in DCM (5 mL), and then brine (5 mL) was added. The layers were separated. The aqueous layer was further extracted with DCM (3 × 10 mL). The aqueous phase was concentrated under reduced pressure, solubilized with a saturated aqueous solution of NaHCO3 (pH = 9-10), and extracted with a solution of 10% MeOH in DCM (3 × 10 mL). All organic layers were combined, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2.11 g (66%) of (S)-1-(3-fluoropropyl)pyrrolidin-3-ol as an orange oil. LC / MS(m / z, MH+): 148

[0077] Step 2: (S)-3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] To a solution of 4-(benzyloxy)phenol (1.56 g, 7.8 mmol) in dry THF (11.50 ml) was added (S)-1-(3-fluoropropyl)pyrrolidin-3-ol (1.29 g, 7.8 mmol), triphenylphosphine (3 g, 11.7 mmol), and di-t-butyl azodicarboxylate (2.70 g, 11.7 mol). The mixture was stirred at 80 °C for 1 h under microwave irradiation. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crude product was acidified with an aqueous solution of HCl (1 M) (to pH = 2-3) and extracted with DCM (3 × 10 ml). The aqueous phase was basified with an aqueous solution of NaOH (3 M) (to pH = 14) and extracted with DCM (3 × 10 ml). The combined organic layers were washed with brine (5 ml), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 99 / 01 to 80 / 20 DCM / isopropanol to give 1.03 g (40%) of (S)-3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine as a brown sticky oil. LC / MS (m / z, MH+): 330

[0078] Step 3: (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol [ka] To a solution of (S)-3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine (400 mg, 1.21 mmol) in EtOAc (1.5 ml) was added Pd / C (10% on carbon) (160 mg, 0.15 mmol) at RT. The resulting mixture was purged with N three times, then filled with H (1 bar) and stirred at 25 °C for 24 h. The reaction mixture was filtered through Celite and concentrated to dryness to give 288 mg (99%) of (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol as a colorless oil. LC / MS (m / z, MH+): 240

[0079] Intermediate 4: 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol [ka]

[0080] Step 1: tert-Butyl 3-(4-(benzyloxy)phenoxy)azetidine-1-carboxylate [ka] To a solution of 1-Boc-3-iodoazetidine (5.0 g, 17.6 mmol) and 4-(benzyloxy)phenol (2.95 g, 15.0 mmol) in DMF (50 mL) was added CsCO (14.4 g, 44.2 mmol). The reaction mixture was stirred at 140 °C for 3 h. After cooling to RT and adding water (100 mL) and EtOAc (100 mL), the organic phase was separated, washed with water (40 mL), brine (40 mL), dried over NaSO, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc from 95 / 05 to 85 / 15 to afford 4.1 g (78%) of tert-butyl 3-(4-(benzyloxy)phenoxy)azetidine-1-carboxylate as a beige solid. LC / MS(m / z, MH+): 356

[0081] Step 2: 3-(4-(benzyloxy)phenoxy)azetidine [ka] To a solution of tert-butyl 3-(4-(benzyloxy)phenoxy)azetidine-1-carboxylate (3.1 g, 8.72 mmol) in DCM (6.5 ml) at 0° C. was slowly added TFA (6.50 ml, 87.0 mmol). The reaction mixture was allowed to warm to RT and stirred for 4 h. The solution was concentrated under reduced pressure, diluted with DCM (10 ml), and a saturated aqueous solution of NaHCO (20 ml) was added. The aqueous phase was separated and extracted with DCM (3×10 ml). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give 2.22 g (100%) of 3-(4-(benzyloxy)phenoxy)azetidine as a beige powder. LC / MS(m / z, MH+): 256

[0082] Step 3: 3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)azetidine [ka] A mixture of 3-(4-(benzyloxy)phenoxy)azetidine (2.21 g, 8.70 mmol), 1-fluoro-3-iodopropane (1.79 g, 9.52 mmol), and K2CO3 (3.50 g, 24.7 mmol) in MeCN (18 ml) and DMF (8 ml) was stirred at 80 °C for 20 h. After cooling to RT, the suspension was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure, solubilized in EtOAc (30 ml), and then brine (20 ml) was added. After decantation, the aqueous layer was extracted with EtOAc (3 × 10 ml). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 98 / 02 to 80 / 20 DCM / isopropanol to afford 416 mg (16%) of 3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)azetidine as a beige solid. LC / MS(m / z, MH+): 316

[0083] Step 4: 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol [ka] To a solution of 3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)azetidine (270 mg, 0.86 mmol) in MeOH (5 mL) at RT was added Pd(OH) (540 mg, 0.77 mmol). The resulting mixture was purged with N three times, then filled with H (1 bar) and stirred at 25 °C for 3 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness to give 168 mg (87%) of 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol as a colorless oil. LC / MS(m / z, MH+):226

[0084] Intermediate 5: 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol [ka]

[0085] Step 1: tert-Butyl (E)-3-(((2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)methyl)azetidine-1-carboxylate [ka] To a solution of 4-methoxybenzenesulfonyl hydrazide (8.68 g, 43.0 mmol) in MeOH (86 mL) was added tert-butyl 3-formylazetidine-1-carboxylate (8.75 g, 47.5 mmol). The mixture was stirred at 25 °C until complete conversion. The precipitated white solid was filtered, washed with MeOH (3 × 7 mL), n-pentane (3 × 7 mL), and EtO (3 × 7 mL), and then dried to give 8.89 g (51%) of tert-butyl (E)-3-((2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)methyl)azetidine-1-carboxylate as a white solid. LC / MS(m / z, MH+): 370

[0086] Step 2: tert-Butyl 3-(4-(benzyloxy)benzyl)azetidine-1-carboxylate [ka] To a solution of tert-butyl (E)-3-((2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)methyl)azetidine-1-carboxylate (7.1 g, 19.1 mmol) in 1,4-dioxane (118 ml) was added 4-benzyloxybenzeneboronic acid (6.50 g, 28.6 mmol) and K2CO3 (4.00 g, 28.6 mmol). The mixture was stirred at 110 °C for 24 h. The solution was cooled to RT. The mixture was diluted with EtOAc (50 ml) and a saturated aqueous solution of NaHCO3. The solution was filtered, extracted with EtOAc (5 × 50 ml), and washed with brine (70 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 98 / 02 to 80 / 20 cyclohexane / EtOAc to afford 0.98 g (15%) of tert-butyl 3-(4-(benzyloxy)benzyl)azetidine-1-carboxylate as a white solid. LC / MS(m / z, MH+): 354

[0087] Step 3: 3-(4-(benzyloxy)benzyl)azetidine [ka] To a solution of tert-butyl 3-(4-(benzyloxy)benzyl)azetidine-1-carboxylate (472 mg, 1.12 mmol) in DCM (1 ml) at 0 °C was slowly added TFA (0.8 ml, 11.2 mmol). The reaction mixture was allowed to warm to RT and stirred for 2 h. The solution was concentrated under reduced pressure, diluted with DCM (2 ml), and a saturated aqueous solution of NaHCO (7 ml) was added. The aqueous layer was separated and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give 192 mg (68%) of 3-(4-(benzyloxy)benzyl)azetidine as a brown sticky oil. LC / MS(m / z, MH+): 254

[0088] Step 4: 3-(4-(benzyloxy)benzyl)-1-(3-fluoropropyl)azetidine [ka] To a suspension of 3-(4-(benzyloxy)benzyl)azetidine (227 mg, 0.68 mmol) in DMF (2 ml) was added 1-fluoro-3-iodopropane (153 mg, 0.82 mmol) and K2CO3 (264 mg, 1.91 mmol). The reaction mixture was stirred at 50 °C for 2 h. After cooling to RT, the suspension was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure, solubilized in DCM (2 ml), and then brine (2 ml) was added. The layers were separated. The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of 98 / 02 to 80 / 20 DCM / isopropanol to give 107 mg (50%) of 3-(4-(benzyloxy)benzyl)-1-(3-fluoropropyl)azetidine as a yellow sticky oil. LC / MS(m / z, MH+): 314

[0089] Step 5: 4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenol [ka] To an N-purged suspension of 3-(4-(benzyloxy)benzyl)-1-(3-fluoropropyl)azetidine (132 mg, 0.34 mmol) in MeOH (3.5 ml) was added Pd(OH) (66 mg, 0.10 mmol) at 25 °C. The resulting mixture was purged with N three times, then filled with H (1 bar) and stirred at 25 °C for 24 h. The reaction mixture was filtered through Celite and concentrated to dryness to give 76 mg (100%) of 4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenol as a colorless oil. LC / MS(m / z, MH+):224

[0090] Intermediate 6: 1-(3-fluoropropyl)azetidin-3-amine [ka]

[0091] Step 1: tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] A mixture of tert-butyl N-(azetidin-3-yl)carbamate hydrochloride (5 g, 23.48 mmol), 1-fluoro-3-iodopropane (4.86 g, 25.83 mmol), and K2CO3 (8.19 g, 58.7 mmol) in THF (50 mL) and water (0.21 g, 0.21 mL, 11.74 mmol). The reaction mixture was stirred at 70 °C for 5 h. The reaction mixture was allowed to cool to RT. Water (20 mL) was added and the reaction mixture was extracted with EtOAc (2 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 7 g (78%) of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate. LC / MS(m / z, MH+): 233

[0092] Step 2: 1-(3-fluoropropyl)azetidin-3-amine [ka] tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate (700 mg, 3.013 mmol) was dissolved in DCM (3 ml). A solution of hydrochloric acid (2 M) in EtO (30 ml, 60.3 mmol) was added and the reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with EtO (5 ml). The white solid was dissolved in MeOH (20 ml), Amberlyst A26 (960 mg) was added and the mixture was stirred at RT for 12 h. The resin was filtered and the filtrate was concentrated under reduced pressure to give 400 mg (100%) of 1-(3-fluoropropyl)azetidin-3-amine as a yellow oil. LC / MS(m / z, MH+): 133

[0093] Intermediate 7: (S)-1-(3-fluoropropyl)pyrrolidin-3-amine [ka]

[0094] Step 1: tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate [ka] Step 1 of Intermediate 7 was prepared from tert-butyl (S)-pyrrolidin-3-ylcarbamate and 1-fluoro-3-iodopropane according to a procedure similar to that for Step 1 of Intermediate 6 to afford 6.03 g (91%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate. LC / MS(m / z, MH+): 247

[0095] Step 2: (S)-1-(3-fluoropropyl)pyrrolidin-3-amine [ka] Step 2 of intermediate 7 was prepared from tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate according to a procedure similar to that for step 2 of intermediate 6 to afford 237 mg (40%) of (S)-1-(3-fluoropropyl)pyrrolidin-3-amine. LC / MS(m / z, MH+): 147

[0096] Intermediate 8: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine [ka]

[0097] Step 1: 3-((4,4,5,5-tetramethyl-1,3,2-diborolanedioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid [ka] TFA (2.89 ml, 38.96 mmol, 5 equiv.) was added to a solution of commercially available tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-1-carboxylate (2.3 g, 7.79 mmol) in DCM (20 ml) at RT. The solution was stirred for 18 h. The crude oil was evaporated under reduced pressure to give 2.67 g (crude) of 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid. LC / MS(m / z, MH+): 196

[0098] Step 2: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine [ka] Step 2 of intermediate 8 was prepared from 3-((4,4,5,5-tetramethylthyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane according to a procedure similar to that for step 3 of intermediate 4 to afford 1.05 g (60%) of 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethylthyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine. LC / MS(m / z, MH+): 256

[0099] Intermediate 9: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylate [ka]

[0100] Method 1 Step 1: tert-Butyl 3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)benzylidene)azetidine-1-carboxylate [ka] To a solution of methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 2) (800 mg, 1.56 mmol), tert-butyl 3-methylideneazetidine-1-carboxylate (791 mg, 4.67 mmol), and EtN (0.43 mL, 3.12 mmol) in 1,4-dioxane (12 mL), tri-tert-butylphosphonium tetrafluoroborate (135.6 mg, 0.47 mmol) and tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.22 mmol) were added. The reaction mixture was stirred at 50 °C for 72 h. The reaction mixture was cooled to RT and then concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of 100:00 to 00:100 cyclohexane / DCM to afford 480 mg (51%) of tert-butyl 3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)benzylidene)azetidine-1-carboxylate as a yellow oil. LC / MS(m / z, MH+):602

[0101] Step 2: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylate [ka] To a solution of tert-butyl 3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)benzylidene)azetidine-1-carboxylate (330 mg, 0.44 mmol) in DCM (3.5 ml) at RT was added TFA (0.33 ml, 4.39 mmol). The mixture was stirred at RT for 3 h. The reaction was quenched with an aqueous solution of KCO (1.21 g, 8.80 mmol) in HO (1.50 ml), and 1-fluoro-3-iodopropane (99 mg, 0.53 mmol) was added to the mixture and allowed to stir at RT for 4 h. The reaction was extracted with DCM (3 × 3 ml), washed with brine (3 ml), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 100 / 00 to 80 / 20 DCM / isopropanol to afford 17 mg (6%) of methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+):562

[0102] Method 2 Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylate [ka] A mixture of methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 2) (150 mg, 0.29 mmol), KPO (186 mg, 0.88 mmol), SPhos (6 mg, 0.015 mmol), palladium acetate (2.42 mg, 0.015 mmol), and 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethylethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine (Intermediate 8) (447 mg, 0.88 mmol) in THF (0.48 mL) and HO (0.010 mL) was heated at 40 °C for 18 h. After cooling to RT, MgSO was added. The crude mixture was diluted with EtOAc and then filtered. The filtrate was evaporated under reduced pressure and then purified by flash chromatography eluting with 100 / 00 to 80 / 20 DCM / isopropanol to give 117 mg (71%) of methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+):562

[0103] Example Method A: Example 1: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 1: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate [ka] A mixture of 1-(3-fluoropropyl)azetidin-3-amine (Intermediate 6) (320 mg, 2.42 mmol), methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 2) (414 mg, 0.807 mmol), CsCO (661 mg, 2.02 mmol), BrettPhos (87 mg, 0.16 mmol), and BrettPhos Pd G (73 mg, 0.081 mmol) in dioxane (7 ml) was stirred at 100 °C for 12 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 DCM / isopropanol to afford 270 mg (59%) of methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate as an orange solid. LC / MS(m / z, MH+):565

[0104] Step 2: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] To a solution of methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate (230 mg, 0.41 mmol) in a mixture of water (2 ml) and THF (2 ml) was added LiOH·HO (85 mg, 2.04 mmol). The mixture was stirred at 60 °C for 10 h. The mixture was acidified with an aqueous solution of HCl (1 N) (2 ml) to pH = 2. The mixture was extracted with EtOAc (3 × 10 ml). The organic layer was washed with water (10 ml), dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and the resulting residue was purified by HPLC (C18, Interchim, IR_50SI-F0012, 98 / 2 to 0 / 100 water / MeCN) to afford 120 mg (54%) of 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid as a yellow solid.

[0105] Example 6: (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka]

[0106] Step 1: Methyl (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate [ka] Step 1 of Example 6 was prepared from methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 2) and (S)-1-(3-fluoropropyl)pyrrolidin-3-amine (Intermediate 7) according to a procedure similar to that of Step 1 of Example 1 to afford 155 mg (51%) of methyl (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+):579

[0107] Step 2: (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 2 of Example 6 was prepared from methyl (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to that for Step 2 of Example 1 to afford 110 mg (59%) of (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid.

[0108] Method B: Example 2: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka]

[0109] Step 1: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate [ka] To a solution of methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 1) (120 mg, 0.32 mmol) in DMF (5.5 ml) was added (fluoropropyl)azetidin-3-yl)oxy)phenol (Intermediate 4) (185 mg, 0.79 mmol) and CsCO (251 mg, 0.77 mmol). The reaction was stirred at 100 °C for 2 h. The solution was cooled to RT, and then brine (3 ml) was added. The mixture was concentrated under reduced pressure. The crude product was extracted with EtOAc (3 × 5 ml). The combined organic layers were washed with brine (2 ml), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 98 / 02 to 80 / 20 DCM / isopropanol to afford 120 mg (67%) of methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate as a yellow viscous oil. LC / MS(m / z, MH+):566

[0110] Step 2: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 2 of Example 2 was prepared from methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to that for Step 2 of Example 1 to afford 49 mg (56%) of 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid.

[0111] Example 3: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka]

[0112] Step 1: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylate [ka] Step 1 of Example 3 was prepared from methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 1) and 4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenol (Intermediate 5) according to a procedure similar to that of Step 1 of Example 2 to afford 58 mg (82%) of methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+):579

[0113] Step 2: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 2 of Example 3 was prepared from methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to that for Step 2 of Example 1 to afford 13 mg (23%) of 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid.

[0114] Example 5: (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka]

[0115] Step 1: Methyl (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate [ka] Step 1 of Example 5 was prepared from methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate (Intermediate 1) and (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol (Intermediate 3) according to a procedure similar to that of Step 1 of Example 2 to afford 181 mg (84%) of methyl (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate. LC / MS(m / z, MH+):579

[0116] Step 2: (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Step 2 of Example 5 was prepared from methyl (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate according to a procedure similar to that of Step 2 of Example 1 to afford 55 mg (33%) of (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid.

[0117] Method C: Example 4: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid [ka] Example 4 was prepared from methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylate (Intermediate 9) according to a procedure similar to that in Step 2 of Example 1 to afford 44 mg (38%) of 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid.

[0118] The compounds according to Table 1 above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0119] Test: Estrogen receptor degrading activity The test involves measuring the in vitro degradation activity of the compounds of Table 1a.

[0120] Degradation activity was measured using breast cancer cell ERα in a cell Western assay as described herein below.

[0121] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells per well in 30 μL of red phenol-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran-treated FBS. The following day, nine-point serial 1:5 dilutions of each compound, ranging from 0.3 to 0.0000018 μM (see Table 2), or fulvestrant (used as a positive control) at a final concentration of 0.1 μM, were added to the cells in 2.5 μL. Four hours after compound addition, cells were fixed for 10 minutes at room temperature by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton) and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 minutes at room temperature. The LI-COR blocking buffer was removed, and the cells were incubated overnight in a cold room 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.

[0122] 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

[0123] The % reduction in ERα levels was determined as follows: % inhibition = 100 * (1 - (sample - fulvestrant: DMSO - fulvestrant)).

[0124] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1a tested at 0.3 μM, demonstrating that the compounds have significant degrading activity against the estrogen receptor.

[0125] [Table 6]

[0126] Therefore, it is clear that the tested compounds have degradation activity for estrogen receptors with IC50 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.

[0127] Accordingly, also provided herein is a medicament comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0128] There is also provided herein a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0129] 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.

[0130] There is also provided herein a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation.

[0131] 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.

[0132] In some embodiments, the cancer is a hormone-dependent cancer.

[0133] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0134] 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.

[0135] In another embodiment, the metastasis is a brain metastasis.

[0136] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0137] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound of formula (I). These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0142] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the customary excipients known to those skilled in the art.

[0143] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, 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.

[0144] Suitable unit dosage forms include oral forms such as tablets, soft gel 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.

[0145] As an example, a unit dosage form of a compound of formula (I) in tablet form may include 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

[0146] There may be particular cases in which higher or lower dosages are appropriate. According to normal practice, the dosage that is 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. Formula (I): 【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-, where 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 represents -CH=, -N= or -CR"=, where 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 independently represents 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 a phenyl group, o 5- or 6-membered monocyclic heteroaryl groups, and o 7-, 8-, 9-, or 10-membered bicyclic heterocyclic group represents a monocyclic or bicyclic ring selected from The monocyclic or bicyclic ring is optionally substituted with a halogen atom, a hydroxyl group; a cyano group or an —OH group (C １ ~C ６ ) alkyl group; (C ３ ~C ６ ) a cycloalkyl group, (C １ ~C ６ ) fluoroalkyl group, —CN group, (C １ ~C ６ ) an alkoxy group, (C １ ~C ６ ) a fluoroalkoxy group, a trifluoromethylsulfonyl group, (C １ ~C ４ ) alkylthio group, (C １ ~C ４ ) fluoroalkylthio group and (C １ ~C ４ ) alkylsulfonyl groups, with the proviso that compounds where p=1 and Y is —O— are excluded. or a pharmaceutically acceptable salt thereof.

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

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. Y is -CH ２ -, -CH=, -O- or -NH-, in particular when Y is -CH ２ A compound of formula (I) according to any one of claims 1 to 5, characterized in that -, -CH= or -CR8=, or a pharmaceutically acceptable salt thereof.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that n is 0.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that X represents -CH=.

9. R6 is a phenyl group optionally substituted by 1, 2, 3 or 4 groups selected from halogen atoms, and more particularly by 2, 3 or 4 groups selected from halogen, e.g., fluorine atoms, and methyl groups, even more particularly by one fluorine atom and two methyl groups, (C １ ~C ６ 9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that:

10. The compound is the following compound: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid (1), 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (2), 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid (3), 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid (4), (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (5), and (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid (6) 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:

11. A process for preparing a compound of formula (I) according to any one of claims 1 to 10, comprising the steps of: 【Chemistry 3】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 4】 , n, p, X and Y are as defined in any of claims 1 to 9, and R3a is a carboxylic acid ester such as COOMe or COOEt, is converted to a compound of formula (I) in the presence of a source of hydroxide ions, such as NaOH or LiOH, in solution in methanol or THF, optionally preceded by a step to obtain compound 1D, in which step 【Chemistry 5】 wherein R3′, R3″, R6, R7, n, and X are defined above, and R3a is a carboxylic acid ester such as COOMe or COOEt, is compound 1G. 【Chemistry 6】 wherein R1, R2, R4, R5, R5′ and p are as defined above. a coupling step with one of

12. A process for preparing a compound of formula (I) according to any one of claims 1 to 10, comprising the steps of: 【Chemistry 7】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 8】 n, p, X and Y are as defined in any one of claims 1 to 9, and R3a is a carboxylic acid ester such as COOMe, COOEt, etc., is converted to a compound of formula (I) in the presence of a source of hydroxide ions, such as NaOH or LiOH, in solution in methanol or THF, optionally preceded by a step to obtain compound 1D, in which step a compound of formula 1B 【Chemistry 9】 wherein R3′, R3″ and R6 are as defined above and R3a is a carboxylic acid ester such as COOMe or COOEt, is reacted in a solvent such as DMF in the presence of a base to give compound 1C 【Chemistry 10】 (In the formula, R1, R2, R4, R5, R5', p, n, R7, X, 【Chemistry 11】 and Y is as defined above),

13. A process for preparing a compound of formula (I) according to any one of claims 1 to 10, comprising the steps of: 【Chemistry 12】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 13】 , n, p, X and Y are as defined in any of claims 1 to 9, and R3a is a carboxylic acid ester such as COOMe or COOEt, is converted to a compound of formula (I) in the presence of a source of hydroxide ions, such as NaOH or LiOH, in solution in methanol or THF, optionally preceded by a step to obtain compound 1D, in which step 【Chemistry 14】 (In the formula, R3', R3'', Y, p, 【Chemistry 15】 , X, R7, n and R6 are as defined above, and R3a is a carboxylic acid ester such as COOMe or COOEt, is reacted with compound 1K in the presence of a base. 【Chemistry 16】 wherein W is Cl, Br, or I, or R is CH ３ , PhMe, CF ３ Or CF ２ CF ２ CF ２ CF ３ OSO ２ R), the process.

14. Formulas 1D, 1F, 1H and 1L 【Chemistry 17】 【Chemistry 18】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, 【Chemistry 19】 , n, p, X and Y are as defined in any one of claims 1 to 9, and R3a is a carboxylic acid ester such as COOMe or COOEt. A compound selected from the compounds of

15. A medicament comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

17. A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

18. A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

19. 19. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use according to claim 18 for use in the treatment of cancer.

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