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

Abstract

Disclosed herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, 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 methoxyl 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-wherein R8 represents a fluorine atom or a (C1-C3) alkyl group; # imgabs0 # represents a single bond or a double bond; x represents-CH =,-N = or-CR ''= wherein R'' represents a (C1-C3) alkyl or halogen atom such as fluorine or chlorine atom, cyano, 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 a trifluoromethyl group; and R6 represents an optionally substituted monocyclic or bicyclic ring selected from the group consisting of phenyl, a 5-or 6-membered monocyclic heteroaryl group, and a 7-membered, 8-membered, 9-membered or 10-membered bicyclic heterocyclic group. Further disclosed are processes for preparing the same, pharmaceutical compositions comprising the same and the compounds of formula (I) for use as inhibitors and degrading agents of estrogen receptors, in particular in the treatment of ovulation dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation. # imgabs1 #

Description

[0001] Disclosed herein are novel substituted 2-carbonyl-benzothiophene-6-carboxylic acid derivatives, methods for their preparation, and their therapeutic uses, particularly as anticancer agents via selective antagonism and degradation of estrogen receptors.

[0002] Estrogen receptor (ER) belongs to the steroid / nuclear receptor superfamily involved in regulating eukaryotic gene expression, cell proliferation and target tissues. ER is in two forms: estrogen receptor α (ERα) and estrogen receptor β (ERβ) encoded by ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors, which are activated by the hormone estrogen (the most potent estrogen produced in vivo is 17β-estradiol). In the absence of hormones, ER is mainly located in the cytosol of cells. When the hormone estrogen binds to ER, ER migrates from the cytosol of cells to the nucleus, forms a dimer, and then binds to a specific genomic sequence called an estrogen response element (ERE). DNA / ER complexes interact with co-regulators to regulate the transcription of target genes.

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

[0004] ERα is expressed in no more than 10% of normal breast epithelium, but is expressed in approximately 50%-80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is established, and regulation of ERα signaling remains an important approach to breast cancer treatment for most ERα-positive breast tumors. Currently, there are several strategies for inhibiting the estrogen axis in breast cancer, including: 1-Blocking estrogen synthesis through aromatase inhibitors for the treatment of early and late ERα-positive breast cancer patients; 2-Antagonizing estrogen ligand binding to ERα through tamoxifen for the treatment of ERα-positive breast cancer patients in both premenopausal and postmenopausal situations; 3-Antagonizing and downregulating ERα levels through Fulvestrant for the treatment of breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have greatly contributed to the reduction of breast cancer development, about more than one-third of ERα-positive patients show resistance to such existing therapies from the beginning or develop resistance over time. Several mechanisms have been described to explain resistance to such hormone therapies. For example, in the treatment with aromatase inhibitors, ERα is hypersensitive to low estrogen levels, and in tamoxifen treatment, the tamoxifen effect is switched from an antagonist effect to an agonist effect or a variety of growth factor receptor signaling pathways. ERα acquired mutations that occur after hormone therapy is initiated can also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand binding domain (LBD), lead to the ability to bind to DNA in the absence of a ligand and confer hormone independence in cells with such mutant receptors.

[0006] Most of the identified mechanisms of resistance to endocrine therapy rely on ERα-dependent activity. One of the new strategies to combat this resistance is to shut down ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data suggest that a number of resistance pathways can be circumvented by using SERDs.

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

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives that can be used as SERDs.

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

[0010] Described herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0011]

[0012] in:

[0013] - R1 and R2 independently represent a hydrogen atom or a deuterium atom;

[0014] - R3′ and R3″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group;

[0015] -R4 represents a hydrogen atom or a fluorine atom;

[0016] - R5 and R5' independently represent a hydrogen atom or a fluorine atom;

[0017] -Y represents -CH2-, -CH=, -CR8=, -O- or -NH-, wherein R8 represents a fluorine atom or a (C1-C3) alkyl group;

[0018] - represents a single or double bond;

[0019] -p is 0 or 1;

[0020] -X represents -CH=, -N= or -CR"=, wherein 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 a trifluoromethyl group;

[0021] - 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 a trifluoromethyl group;

[0022] -n is 0, 1, or 2; and

[0023] -R6 represents a monocyclic or bicyclic ring selected from the following:

[0024] o Phenyl,

[0025] o a 5-membered or 6-membered monocyclic heteroaryl group, and

[0026] o a 7-membered, 8-membered, 9-membered or 10-membered bicyclic heterocyclic group,

[0027] The monocyclic or bicyclic ring is optionally substituted by 1, 2, 3 or 4 groups selected from the following: halogen atoms, hydroxyl groups, (C1-C6) alkyl groups optionally substituted by cyano groups or -OH groups, (C3-C6) cycloalkyl groups, (C1-C6) fluoroalkyl groups, -CN groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, trifluoromethylsulfonyl groups, (C1-C4) alkylthio groups, (C1-C4) fluoroalkylthio groups and (C1-C4) alkylsulfonyl groups.

[0028] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0029]

[0030] in:

[0031] - R1 and R2 independently represent a hydrogen atom or a deuterium atom;

[0032] - R3′ and R3″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group;

[0033] -R4 represents a hydrogen atom or a fluorine atom;

[0034] - R5 and R5' independently represent a hydrogen atom or a fluorine atom;

[0035] -Y represents -CH2-, -CH=, -CR8=, -O- or -NH-, wherein R8 represents a fluorine atom or a (C1-C3) alkyl group;

[0036] - represents a single bond or a double bond;

[0037] -p is 0 or 1;

[0038] -X represents -CH=, -N= or -CR"=, wherein 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 a trifluoromethyl group;

[0039] - 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 a trifluoromethyl group;

[0040] -n is 0, 1, or 2; and

[0041] -R6 represents a monocyclic or bicyclic ring selected from the following:

[0042] o Phenyl,

[0043] o a 5-membered or 6-membered monocyclic heteroaryl group, and

[0044] o a 7-membered, 8-membered, 9-membered or 10-membered bicyclic heterocyclic group,

[0045] The monocyclic or bicyclic ring is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of halogen atoms, hydroxyl groups, (C1-C6)alkyl groups optionally substituted by cyano or -OH groups, (C3-C6)cycloalkyl groups, (C1-C6)fluoroalkyl groups, -CN groups, (C1-C6)alkoxy groups, (C1-C6)fluoroalkoxy groups, trifluoromethylsulfonyl groups, (C1-C4)alkylthio groups, (C1-C4)fluoroalkylthio groups and (C1-C4)alkylsulfonyl groups,

[0046] The proviso is that compounds where p=1 and Y is -O- are excluded.

[0047] The compounds of formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in the form of enantiomers.

[0048] The compounds of formula (I) may also exist in tautomeric forms.

[0049] The compound of formula (I) may exist in the form of a base, an acid, a zwitterion or an addition salt with an acid or a base. Accordingly, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0050] These salts may be prepared with pharmaceutically acceptable acids or bases, although salts of other acids or bases useful, for example, in the purification or isolation of compounds of formula (I) are also provided.

[0051] Among suitable salts of the compounds of formula (I), hydrochlorides may be cited.

[0052] As used herein, unless otherwise mentioned throughout this specification, the following terms have the following definitions:

[0053] - halogen atoms: fluorine, chlorine, bromine or iodine atoms, and in particular fluorine and chlorine atoms;

[0054] -Alkyl: a straight-chain or branched saturated hydrocarbon aliphatic group, which, unless otherwise mentioned, contains from 1 to 6 carbon atoms (indicated as "(C1-C6)-alkyl"). By way of example, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc. may be mentioned;

[0055] - Cycloalkyl: saturated or partially unsaturated and unsubstituted or substituted monocyclic alkyl, which, unless otherwise mentioned, contains from 3 to 7 carbon atoms. By way of example, but not limited to, there may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, etc., in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, or cyclohexenyl;

[0056] - Heterocycloalkyl: saturated or partially unsaturated 4- to 7-membered cycloalkyl containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen;

[0057] -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. The 3- or 4-membered ring may contain 1 heteroatom selected from the group consisting of O, N and S. The 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. The 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;

[0058] -7-, 8-, 9- or 10-membered bicyclic heterocyclic groups: 7- to 10-membered bicyclic groups in which a monocyclic heterocycloalkyl group is fused to 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 heterocyclic ring may be attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained within the monocyclic or bicyclic heterocyclic portion of the bicyclic ring system;

[0059] -Fluoroalkyl: an alkyl group as defined previously, wherein the alkyl group is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, CH2F, CHF2, CH2CHF2, -CH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be named as a perfluoroalkyl group. By way of example, trifluoromethyl or trifluoroethyl, etc. may be mentioned;

[0060] - Alkoxy: -O-alkyl, wherein alkyl is as defined previously. By way of example, but not limited to, there may be mentioned: methoxy; ethoxy; propoxy; isopropoxy; linear butoxy, sec-butoxy or tert-butoxy; isobutoxy; pentyloxy; or hexyloxy, etc.;

[0061] -Fluoroalkoxy: -O-alkyl, wherein alkyl is as defined previously and wherein alkyl is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl is replaced by a fluorine atom. By way of example, -OCH2F, -OCHF2, -OCH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl are replaced by fluorine atoms, the fluoroalkoxy may be named as perfluoroalkoxy. By way of example, trifluoromethoxy, etc. may be mentioned;

[0062] -(C1-C4)alkylthio, which is also named (C1-C4)alkylsulfanyl: -S-alkyl, wherein alkyl is as defined previously. By way of example, but not limited to, there may be mentioned: methylthio; ethylthio; propylthio; isopropylthio; linear butylthio, sec-butylthio or tert-butylthio; isobutylthio, etc.;

[0063] -(C1-C4)alkylsulfonyl: -SO2-alkyl, wherein alkyl is as defined above. For example, -SO2CH3, -SO2CH2CH3, etc. may be mentioned but are not limited thereto;

[0064] -(C1-C4)fluoroalkylthio, which is also named (C1-C4)fluoroalkylsulfanyl: -S-fluoroalkyl, wherein the fluoroalkyl group is as defined above. For example, there can be mentioned but are not limited to: fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.;

[0065] -5- or 6-membered monocyclic heteroaryl: a cyclic 5- or 6-membered aromatic group. The 5-membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6-membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5- or 6-membered heteroaryl is attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained within the heteroaryl.

[0066] In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0067] In another embodiment, in the compounds of formula (I) as defined above, R3′ and R3″ both represent a hydrogen atom.

[0068] In another embodiment, in the compounds of formula (I) as defined above, R4 is a hydrogen atom.

[0069] In another embodiment, in the compounds of formula (I) as defined above, R5 and R5' both represent a hydrogen atom.

[0070] In another embodiment, in the compounds of formula (I) as defined above, p is 0. In another embodiment, in the compounds of formula (I) as defined above, p is 1.

[0071] In another embodiment, in the compound of formula (I) as defined above, Y is -CH2-, -CH=, -O- or -NH-.

[0072] In another embodiment, In another embodiment, Represents a double bond.

[0073] In another embodiment, in the compounds of formula (I) as defined above, n is 0.

[0074] In another embodiment, in the compounds of formula (I) as defined above, n is 0. In another embodiment, in the compounds of formula (I) as defined above, n is 1. In another embodiment, in the compounds of formula (I) as defined above, n is 2.

[0075] In another embodiment, in the compounds of formula (I) as defined above, X represents -CH=.

[0076] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a phenyl group, which is optionally substituted by 1, 2, 3 or 4 groups selected from halogen atoms, and (C1-C6) alkyl groups, more particularly optionally substituted by 2, 3 or 4 groups selected from halogen, such as fluorine atoms, and methyl groups, and even more particularly substituted by one fluorine atom and by two methyl groups.

[0077] In another embodiment, Y is -CH2-, -CH=, or -CR8=.

[0078] In one embodiment, X represents a carbon atom (ie, a =CH- group) in a compound of formula (I). Thus, compounds of formula (II) are described herein:

[0079]

[0080] Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, Y, n and p are as defined above in formula (II).

[0081] The embodiments as described above for the compounds of formula (I) also apply to the compounds of formula (II).

[0082] In another embodiment, in the compounds of formula (II) as defined above, R represents a phenyl group, which is optionally substituted by 1, 2, 3 or 4 groups selected from halogen atoms, and (C1-C6) alkyl groups, more particularly optionally substituted by 2, 3 or 4 groups selected from halogen, such as fluorine atoms, and methyl groups, and even more particularly substituted by one fluorine atom and by two methyl groups. Among the compounds of formula (I) described herein, the following compounds or pharmaceutically acceptable salts thereof, in particular their hydrochlorides, may be mentioned:

[0083] -2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid (1),

[0084] -2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid (2),

[0085] -2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid (3),

[0086] -2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid (4),

[0087] -(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

[0088] -(S)-2-(4-Fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid (6).

[0089] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use in therapy, especially as an inhibitor and degrader of estrogen receptors.

[0090] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, especially breast cancer.

[0091] Another embodiment is a method of inhibiting and degrading estrogen receptors, which comprises administering a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof to a subject, especially a human, in need thereof.

[0092] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy 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.

[0093] 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.

[0094] 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 also at least one pharmaceutically acceptable excipient.

[0095] The compound of formula (I) can be prepared by the following method.

[0096] Compounds of formula (I) and other related compounds with different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0097] The following general methods for preparing compounds of formula (I), optionally modified by use of appropriate reagents, and conditions for introducing the various moieties found in formula (I) are described below.

[0098] The following abbreviations and empirical formulas are used:

[0099] MeCN Acetonitrile

[0100] Cs2CO3 Cesium carbonate

[0101] DCM Dichloromethane

[0102] Et2O Ether

[0103] DMF N,N-Dimethylformamide

[0104] DMSO Dimethyl sulfoxide

[0105] EtOAc Ethyl acetate

[0106] H2 Hydrogen

[0107] HCl

[0108] HPLC High Performance Liquid Chromatography

[0109] LiOH Lithium Hydroxide

[0110] MeOH Methanol

[0111] MgSO4 Magnesium sulfate

[0112] N2 Nitrogen

[0113] Pd / C Palladium / Carbon

[0114] Pd(OH)2 Palladium Hydroxide

[0115] K2CO3 Potassium carbonate

[0116] K3PO4 Potassium Phosphate

[0117] NaHCO3 Sodium bicarbonate

[0118] NaH Sodium hydride

[0119] NaOH Sodium hydroxide

[0120] Na2SO4 Sodium sulfate

[0121] SNAr Aromatic Nucleophilic Substitution

[0122] TFA Trifluoroacetic acid

[0123] THF Tetrahydrofuran

[0124] Et3N Triethylamine

[0125] H2O water

[0126] RT Room temperature

[0127] Option 1a : Preparation of compounds of formula (I) - General method

[0128]

[0129] According to Scheme 1a, wherein R3a is a carboxylate such as COOMe, COOEt, R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are defined as described above, and compound 1A (prepared according to US20130231484) can be converted to compound 1B in step 1 by treatment with a solution of R6MgBr in THF.

[0130] Compound 1B can be converted to compound 1D in step 2 by treating with compound 1C in a SNAr reaction in a solvent such as DMF in the presence of a base such as cesium carbonate (Cs2CO3) by heating to reflux of the solvent.

[0131] Alternatively, compound 1D can be obtained by treating compound 1B with compound 1E in a SNAr reaction in a solvent such as DMF in the presence of a base such as sodium hydride (NaH) in step 3, followed by a coupling reaction between the obtained compound 1F and one of the compounds 1G under coupling reaction conditions in step 4.

[0132] Compound 1D can be converted to Compound I in step 5 by treatment with aqueous sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product can give the sodium or lithium salt of Compound I. Acidification with aqueous HCl to pH 6-7 can give the neutral form of Compound I. Acidification with aqueous HCl to pH 1-2 can give the hydrochloride salt of Compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of Compound I.

[0133] When Y=-CH=, compound I can be reduced by hydrogenation in step 6 with a catalyst such as Pd / C or Pd(OH)2 / C under hydrogen (H2) pressure to give the corresponding saturated compound I'.

[0134] Option 1b : Alternative Method for the Preparation of Compound 1D - General Methods

[0135]

[0136] According to Scheme 1b, wherein R3a is a carboxylate such as COOMe, COOEt, R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined above. Compound 1F can be converted to compound 1H in step 1 by coupling reaction with one of compounds 1G' under coupling reaction conditions.

[0137] Alternatively, compound 1H can be obtained by treating compound 1B with compound 1C' in a SNAr reaction in a solvent such as DMF in the presence of a base such as cesium carbonate (Cs2CO3) by heating to reflux of the solvent in step 2.

[0138] Compound 1H can be converted to compound 1J in step 3 by treatment with TFA or HCl.

[0139] Compound 1J can be converted to compound 1D by treatment with compound 1K (wherein 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 solvent.

[0140] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1D

[0141]

[0142] --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined above, and R3a is a carboxylate such as COOMe or COOEt - is converted to a compound of formula (I) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, said step optionally being preceded by a step to obtain compound 1D, wherein a compound of formula 1F is

[0143]

[0144] -- wherein R3', R3", R6, R7, n, and X are as defined above, and R3a is a carboxylate such as COOMe or COOEt -- is subjected to a coupling step with one of the compounds 1G

[0145] wherein R1, R2, R4, R5, R5' and p are as defined above.

[0146]

[0147] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1D

[0148]

[0149] --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined above, and R3a is a carboxylate such as COOMe or COOEt - is converted to a compound of formula (I) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, optionally preceded by a step to obtain compound 1D, wherein a compound of formula 1B is

[0150]

[0151] -- wherein R3', R3" and R6 are as defined above, and R3a is a carboxylate such as COOMe or COOEt -- in a solvent such as DMF, subjected to a SNAr reaction with compound 1C in the presence of a base

[0152]

[0153] Where R1, R2, R4, R5, R5', p, n, R7, X, and Y are as defined above.

[0154] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1D

[0155]

[0156] --wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X, and Y are as defined above, and R3a is a carboxylate 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, said step optionally being preceded by a step to obtain compound 1D, wherein a compound of formula 1J

[0157]

[0158] --wherein R3', R3", Y, p, X, R7, n and R6 are as defined above, and R3a is a carboxylate such as COOMe or COOEt - converted with compound 1K in the presence of a base

[0159]

[0160] Wherein W is Cl, Br or I or OSO2R, wherein R=CH3, PhMe, CF3 or CF2CF2CF2CF3.

[0161] Also provided herein is an intermediate compound selected from the compounds of Formula 1D, 1F, 1H, 1J or any pharmaceutically acceptable salt thereof,

[0162]

[0163]

[0164] Wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined above, and R3a is a carboxylate such as COOMe or COOEt.

[0165] 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.

[0166] The purification step may, for example, include an acidification step (eg with aqueous hydrochloric acid) as described in step 2 of Example 1 herein below.

[0167] At 400 and 500MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, with chemical shifts (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0168] Liquid chromatography / mass spectrometry (LC / MS) was obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and fast Acquity UPLC CSH C18 1.7 μm, size 2.1×30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H, light scattering detector Sedere and SQD Waters mass spectrometer.

[0169] Tables 1a and 1b below contain specific compounds (names and structures) of formula (I) according to the present disclosure and their characterizations ( 1 H NMR and LC / MS / MS).

[0170] Table 1a : (the first column "Example" corresponds to the compound and example number)

[0171]

[0172]

[0173]

[0174] Table 1b :

[0175]

[0176]

[0177]

[0178] The following examples describe the preparation of some of the compounds of formula (I) described herein. The quantities of the compounds exemplified below match those given in Tables 1a and 1b above. Unless otherwise stated, all reactions were carried out under an inert atmosphere.

[0179] In the following examples, when the origin of the starting product is not specified, it is understood that the product is a known compound.

[0180] Examples

[0181] Intermediates:

[0182] Intermediate 1: 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylic acid methyl ester

[0183]

[0184] Step 1: (4-Fluoro-2,6-dimethyl-phenyl)magnesium bromide

[0185]

[0186] To a suspension of magnesium turnings (0.19 g, 7.83 mmol) in THF (7.61 ml) was added 2-bromo-5-fluoro-1,3-dimethylbenzene (1.50 g, 7.39 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was used directly in the next step without further workup (considered quantitative).

[0187] Step 2: 3-Chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylic acid methyl ester

[0188]

[0189] At 0 ° C, to 3-chloro-2-(chlorocarbonyl)benzo[b]thiophene-6-carboxylic acid methyl ester (prepared according to US 20130231484) (2.5g, 8.65mmol) in THF (12.5ml) solution was added dropwise (4-fluoro-2,6-dimethyl-phenyl) magnesium bromide (11.3ml, 11.3mmol). The reaction mixture was stirred at room temperature for 12h. At 0 ° C, the reaction mixture was acidified with 1M HCl aqueous solution (10ml) (pH adjusted to 2 to 2.5) and extracted with EtOAc (30ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc from 100 / 00 to 85 / 15 to give 1.95 g (60%) of methyl 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate.

[0190] LC / MS(m / z,MH+):377

[0191] Intermediate 2: 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylic acid methyl ester

[0192]

[0193] 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 60% NaH (0.41 g, 10.35 mmol) in mineral oil at room temperature. The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature and then aqueous NaOH (1 N) (10 ml) was added. The mixture was extracted with EtOAc (3 x 30 ml). The organic layer was washed with water (30 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the obtained residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc from 100 / 00 to 90 / 10 to give 945 mg (53%) of methyl 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylate as a yellow solid.

[0194] LC / MS(m / z,MH+):514

[0195] Intermediate 3: (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol

[0196]

[0197] Step 1: (R)-1-(3-fluoropropyl)pyrrolidin-3-ol

[0198]

[0199] 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 KCO (8.68 g, 62.2 mmol) in MeCN (20 ml) was stirred at 50 ° C for 18 hours. The reaction mixture was cooled to room temperature and the suspension was filtered through diatomaceous earth. The filtrate was evaporated under reduced pressure and dissolved 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, dissolved with a saturated aqueous solution of NaHCO (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.

[0200] LC / MS(m / z,MH+):148

[0201] Step 2: (S)-3-(4-(Benzyloxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine

[0202]

[0203] 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-tert-butyl azodicarboxylate (2.70 g, 11.7 mmol). The mixture was stirred at 80 ° C for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was acidified with aqueous HCl solution (1 M) (until pH = 2-3) and extracted with DCM (3×10 ml). The aqueous phase was alkalized with aqueous NaOH solution (3 M) (until pH = 14) and extracted with DCM (3×10 ml). The collected organic layers were combined and washed with brine (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM / isopropanol from 99 / 01 to 80 / 20 to give 1.03 g (40%) of (S)-3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)pyrrolidine as a brown viscous oil.

[0204] LC / MS(m / z,MH+):330

[0205] Step 3: (S)-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenol

[0206]

[0207] 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 room temperature. The resulting mixture was purged three times with N2, then charged with H2 (1 bar) and stirred at 25°C for 24 hours. 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.

[0208] LC / MS(m / z,MH+):240

[0209] Intermediate 4: 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol

[0210]

[0211] Step 1: tert-Butyl 3-(4-(Benzyloxy)phenoxy)azetidine-1-carboxylate

[0212]

[0213] Cs2CO3 (14.4 g, 44.2 mmol) was added 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). The reaction mixture was stirred at 140 ° C for 3 h. After cooling to room temperature and adding water (100 ml) and EtOAc (100 ml), the organic phase was separated and washed with water (40 ml), brine (40 ml), dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash chromatography with a gradient elution of ring / EtOAc from 95 / 05 to 85 / 15 to give 4.1 g (78%) of tert-butyl 3-(4-(benzyloxy)phenoxy)azetidine-1-carboxylate as a beige solid.

[0214] LC / MS(m / z,MH+):356

[0215] Step 2: 3-(4-(Benzyloxy)phenoxy)azetidine

[0216]

[0217] At 0 ° C, TFA (6.50 ml, 87.0 mmol) was slowly added to a solution of tert-butyl 3-(4-(benzyloxy)phenoxy)azetidine-1-carboxylate (3.1 g, 8.72 mmol) in DCM (6.5 ml). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The solution was concentrated under reduced pressure, diluted with DCM (10 ml), and a saturated aqueous solution of NaHCO3 (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 Na2SO4, filtered and concentrated under reduced pressure to give 2.22 g (100%) of 3-(4-(benzyloxy)phenoxy)azetidine as a beige powder.

[0218] LC / MS(m / z,MH+):256

[0219] Step 3: 3-(4-(Benzyloxy)phenoxy)-1-(3-fluoropropyl)azetidine

[0220]

[0221] 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 KCO (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 room temperature, the suspension was filtered through a celite pad. The filtrate was evaporated under reduced pressure and dissolved 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 layer was dried over NaSO, filtered, and evaporated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM / isopropanol from 98 / 02 to 80 / 20 to give 416 mg (16%) of 3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)azetidine as a beige solid.

[0222] LC / MS(m / z,MH+):316

[0223] Step 4: 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol

[0224]

[0225] To a solution of 3-(4-(benzyloxy)phenoxy)-1-(3-fluoropropyl)azetidine (270 mg, 0.86 mmol) in MeOH (5 ml) was added Pd(OH)2 (540 mg, 0.77 mmol) at room temperature. The resulting mixture was purged three times with N2, then charged with H2 (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)azetidine-3-yl)oxy)phenol as a colorless oil.

[0226] LC / MS(m / z,MH+):226

[0227] Intermediate 5: 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenol

[0228]

[0229] Step 1: (E)-tert-butyl 3-((2-((4-methoxyphenyl)sulfonyl)hydrazono)methyl)azetidine-1-carboxylate

[0230]

[0231] 3-formylazetidine-1-carboxylic acid tert-butyl ester (8.75 g, 47.5 mmol) was added to a solution of 4-methoxybenzenesulfonylhydrazide (8.68 g, 43.0 mmol) in MeOH (86 ml). 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 Et2O (3 × 7 ml), and then dried to give 8.89 g (51%) of (E)-3-((2-((4-methoxyphenyl)sulfonyl)hydrazono)methyl)azetidine-1-carboxylic acid tert-butyl ester as a white solid.

[0232] LC / MS(m / z,MH+):370

[0233] Step 2: tert-Butyl 3-(4-(Benzyloxy)benzyl)azetidine-1-carboxylate

[0234]

[0235] To a solution of (E)-tert-butyl 3-((2-((4-methoxyphenyl)sulfonyl)hydrazono)methyl)azetidine-1-carboxylate (7.1 g, 19.1 mmol) in 1,4-dioxane (118 ml) was added 4-benzyloxyphenylboronic 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 room temperature. The mixture was diluted with EtOAc (50 ml) and with 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 residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc from 98 / 02 to 80 / 20 to give 0.98 g (15%) of tert-butyl 3-(4-(benzyloxy)benzyl)azetidine-1-carboxylate as a white solid.

[0236] LC / MS(m / z,MH+):354

[0237] Step 3: 3-(4-(Benzyloxy)benzyl)azetidine

[0238]

[0239] At 0 ° C, TFA (0.8 ml, 11.2 mmol) was slowly added to a solution of tert-butyl 3-(4-(benzyloxy)benzyl)azetidine-1-carboxylate (472 mg, 1.12 mmol) in DCM (1 ml). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure, diluted with DCM (2 ml), and a saturated aqueous solution of NaHCO3 (7 ml) was added. The aqueous layer was separated and extracted with DCM (3 × 5 ml). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 192 mg (68%) of 3-(4-(benzyloxy)benzyl)azetidine as a brown viscous oil.

[0240] LC / MS(m / z,MH+):254

[0241] Step 4: 3-(4-(Benzyloxy)benzyl)-1-(3-fluoropropyl)azetidine

[0242]

[0243] 1-Fluoro-3-iodopropane (153 mg, 0.82 mmol) and KCO (264 mg, 1.91 mmol) were added to a suspension of 3-(4-(benzyloxy)benzyl)azetidine (227 mg, 0.68 mmol) in DMF (2 ml). The reaction mixture was stirred at 50 ° C for 2 h. After cooling to room temperature, the suspension was filtered through a celite pad. The filtrate was evaporated under reduced pressure and dissolved 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 layer was dried over NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of DCM / isopropanol from 98 / 02 to 80 / 20 to give 107 mg (50%) of 3-(4-(benzyloxy)benzyl)-1-(3-fluoropropyl)azetidine as a yellow viscous oil.

[0244] LC / MS(m / z,MH+):314

[0245] Step 5: 4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenol

[0246]

[0247] To a N2-purged suspension of 3-(4-(benzyloxy)benzyl)-1-(3-fluoropropyl)azetidine (132 mg, 0.34 mmol) in MeOH (3.5 ml) at 25°C was added Pd(OH)2 (66 mg, 0.10 mmol). The resulting mixture was purged with N2 three times, then charged with H2 (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)azetidine-3-yl)methyl)phenol as a colorless oil.

[0248] LC / MS(m / z,MH+):224

[0249] Intermediate 6: 1-(3-fluoropropyl)azetidine-3-amine

[0250]

[0251] Step 1: tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0252]

[0253] N- (azetidine -3- base) tert-butyl carbamate hydrochloride (5g, 23.48mmol), 1- fluoro-3- iodopropane (4.86g, 25.83mmol) and K2CO3 (8.19g, 58.7mmol) in THF (50ml) and water (0.21g, 0.21ml, 11.74mmol). The reaction mixture was stirred at 70 ° C for 5h. The reaction mixture was allowed to cool to room temperature. Water (20ml) and the reaction mixture was extracted with EtOAc (2 × 20ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, 7g (78%) of (1- (3- fluoropropyl) azetidine -3- base) tert-butyl carbamate.

[0254] LC / MS(m / z,MH+):233

[0255] Step 2: 1-(3-Fluoropropyl)azetidine-3-amine

[0256]

[0257] Tert-butyl (1- (3- fluoropropyl) azetidine -3- base) carbamate (700mg, 3.013mmol) is dissolved in DCM (3ml). Hydrochloric acid solution (2M) in Et2O (30ml, 60.3mmol) is added and the reaction mixture is stirred at room temperature for 18h. The reaction mixture is concentrated under reduced pressure. The crude product is ground with Et2O (5ml). The white solid is dissolved in MeOH (20ml), Amberlyst A26 (960mg) is added, and the mixture is stirred at room temperature for 12 hours. The resin is filtered, and the filtrate is concentrated under reduced pressure to give 400mg (100%) of 1- (3- fluoropropyl) azetidine -3- amine as a yellow oil.

[0258] LC / MS(m / z,MH+):133

[0259] Intermediate 7: (S)-1-(3-fluoropropyl)pyrrolidin-3-amine

[0260]

[0261] Step 1: (S)-tert-butyl (1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate

[0262]

[0263] Step 1 of Intermediate 7 was prepared following a procedure similar to that of Step 1 of Intermediate 6 from (S)-tert-butyl pyrrolidin-3-ylcarbamate and 1-fluoro-3-iodopropane to give 6.03 g (91%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate.

[0264] LC / MS(m / z,MH+):247

[0265] Step 2: (S)-1-(3-fluoropropyl)pyrrolidin-3-amine

[0266]

[0267] Step 2 of Intermediate 7 was prepared following a procedure similar to that of Step 2 of Intermediate 6 from tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate to give 237 mg (40%) of (S)-1-(3-fluoropropyl)pyrrolidin-3-amine.

[0268] LC / MS(m / z,MH+):147

[0269] Intermediate 8: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine

[0270]

[0271] Step 1: 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid

[0272]

[0273] 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 room temperature. 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.

[0274] LC / MS(m / z,MH+):196

[0275] Step 2: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine

[0276]

[0277] Step 2 of Intermediate 8 was prepared following a procedure similar to that of Step 3 of Intermediate 4 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane to give 1.05 g (60%) of 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine.

[0278] LC / MS(m / z,MH+):256

[0279] Intermediate 9: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid methyl ester

[0280]

[0281] Method 1

[0282] Step 1: tert-Butyl 3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-(methoxycarbonyl)benzo[b]thiophen-3-yl)oxy)benzylidene)azetidine-1-carboxylate

[0283]

[0284] To a solution of 3-(4-bromophenoxy)-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylic acid methyl ester (Intermediate 2) (800 mg, 1.56 mmol), tert-butyl 3-methyleneazetidine-1-carboxylate (791 mg, 4.67 mmol) and Et3N (0.43 mL, 3.12 mmol) in 1,4-dioxane (12 ml) was added tri-tert-butylphosphonium tetrafluoroborate (135.6 mg, 0.47 mmol) and tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.22 mmol). The reaction mixture was stirred at 50 ° C for 72 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of cyclohexane / DCM from 100:00 to 00:100 to give 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.

[0285] LC / MS(m / z,MH+):602

[0286] Step 2: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid methyl ester

[0287]

[0288] 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) was added TFA (0.33 ml, 4.39 mmol) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction was quenched with an aqueous solution of KCO (1.21 g, 8.80 mmol) in H0 (1.50 ml), and 1-fluoro-3-iodopropane (99 mg, 0.53 mmol) was added to the mixture and allowed to stir at room temperature for 4 h. The reactants were 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 DCM / isopropanol from 100 / 00 to 80 / 20 to give 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.

[0289] LC / MS(m / z,MH+):562

[0290] Method 2

[0291] 2-(4-Fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid methyl ester

[0292]

[0293] 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), K3PO4 (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-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine (Intermediate 8) (447 mg, 0.88 mmol) in THF (0.48 ml) and H2O (0.010 ml) was heated at 40°C for 18 h. After cooling to room temperature, MgSO4 was added. The crude mixture was diluted with EtOAc and then filtered off. The filtrate was evaporated under reduced pressure and then purified by flash chromatography eluting with DCM / isopropanol from 100 / 00 to 80 / 20 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.

[0294] LC / MS(m / z,MH+):562

[0295] Examples

[0296] Method A:

[0297] Example 1 :2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0298]

[0299] Step 1: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate

[0300]

[0301] A mixture of 1-(3-fluoropropyl)azetidine-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), Cs2CO3 (661 mg, 2.02 mmol), BrettPhos (87 mg, 0.16 mmol) and BrettPhos Pd G3 (73 mg, 0.081 mmol) in dioxane (7 ml) was stirred at 100°C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / isopropanol from 100 / 00 to 90 / 10 to give 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.

[0302] LC / MS(m / z,MH+):565

[0303] Step 2: 2-(4-Fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0304]

[0305] 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.H2O (85 mg, 2.04 mmol). The mixture was stirred at 60°C for 10 hours. The mixture was acidified with aqueous HCl (1 N) (2 ml) until pH = 2. The mixture was extracted with EtOAc (3 x 10 mL). The organic layer was washed with water (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the obtained residue was purified by HPLC (C18, Interchim, IR-50SI-F0012, water / MeCN from 98 / 2 to 0 / 100) to give 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.

[0306] 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

[0307]

[0308] Step 1: (S)-methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate

[0309]

[0310] Step 1 of Example 6 was prepared according to a procedure similar to that of Step 1 of Example 1 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) to give 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.

[0311] LC / MS(m / z,MH+):579

[0312] 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

[0313]

[0314] Step 2 of Example 6 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from (S)-methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenoxy)benzo[b]thiophene-6-carboxylate to give 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.

[0315] Method B:

[0316] Example 2 :2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0317]

[0318] Step 1: Methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate

[0319]

[0320] To a solution of 3-chloro-2-(4-fluoro-2,6-dimethylbenzoyl)benzo[b]thiophene-6-carboxylic acid methyl ester (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 Cs2CO3 (251 mg, 0.77 mmol). The reaction was stirred at 100 ° C for 2 h. The solution was cooled to room temperature 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 Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with a gradient of DCM / isopropanol from 98 / 02 to 80 / 20 to give 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.

[0321] LC / MS(m / z,MH+):566

[0322] Step 2: 2-(4-Fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0323]

[0324] Step 2 of Example 2 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate to give 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.

[0325] Example 3 :2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0326]

[0327] Step 1: 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid methyl ester

[0328]

[0329] Step 1 of Example 3 was prepared according to a procedure similar to that of Step 1 of Example 2 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) to give 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.

[0330] LC / MS(m / z,MH+):579

[0331] Step 2: 2-(4-Fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0332]

[0333] Step 2 of Example 3 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenoxy)benzo[b]thiophene-6-carboxylate to give 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.

[0334] 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

[0335]

[0336] Step 1: (S)-methyl 2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylate

[0337]

[0338] Step 1 of Example 5 was prepared according to a procedure similar to that of Step 1 of Preparative Example 2 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) to give 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.

[0339] LC / MS(m / z,MH+):579

[0340] 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

[0341]

[0342] Step 2 of Example 5 was prepared according to a procedure similar to that of Step 2 of Preparative Example 1 from (S)-2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenoxy)benzo[b]thiophene-6-carboxylic acid methyl ester to give 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.

[0343] Method C:

[0344] Example 4 :2-(4-fluoro-2,6-dimethylbenzoyl)-3-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenoxy)benzo[b]thiophene-6-carboxylic acid

[0345]

[0346] 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) following a procedure similar to that of Step 2 of Preparative Example 1 to give 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.

[0347] The compounds according to Table 1 above were subjected to pharmacological testing for determining their degradation effect on estrogen receptors.

[0348] Test: Estrogen receptor degradation activity

[0349] The test involves measuring the in vitro degradation activity of the compounds of Table 1a.

[0350] Degradation activity of ERα was measured using breast cancer cells in a cellular Western blot assay as described below.

[0351] MCF7 cells (ATCC) were seeded in red phenol-free MEMα medium (Invitrogen) containing 5% charcoal dextran-treated FBS at a concentration of 10,000 cells / 30 μL / well in 384-well microplates (collagen coated). The next day, 9 points of each compound were added to the cells in a final concentration ranging from 0.3-0.0000018 μM (Table 2) or 0.1 μM of Fulvestrant (used as a positive control) in 2.5 μL cells: 1:5 dilutions were added to the cells. 4 hours after compound addition, cells were fixed by adding 25 μL of formalin (5% formalin with a final concentration of 0.1% triton) for 10 minutes at room temperature, 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. LI-COR blocking buffer was removed and 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 were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated at 37°C for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa488 (1:1000) and Syto-64a DNA dye (2 μM final concentration). The cells were then washed 3 times in PBS and scanned in an ACUMEN detector (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0352] In this test, the degradation activity of estrogen receptor is determined by the concentration that degrades 50% of the estrogen receptor (or IC 50 ) is given in nM.

[0353] The % reduction in ERa levels was determined as follows: % inhibition = 100*(1 - (sample-fulvestrant:DMSO-fulvestrant)).

[0354] The following Table 2 shows the estrogen receptor degradation activity results of the compounds of Table 1a tested at 0.3 μM, and demonstrates that the compounds have significant degradation activity on the estrogen receptor.

[0355] Table 2 :

[0356]

[0357] Therefore, it is obvious that the test compound has degradation activity on estrogen receptor, with IC50 less than 1 μM and degradation level greater than 50%. Therefore, the compound of formula (I) can be used for the preparation of drugs, especially drugs as degraders of estrogen receptor.

[0358] Therefore, also provided herein is a medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0359] Also provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0360] Also provided herein are compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, particularly as inhibitors and degraders of estrogen receptors.

[0361] Also provided herein is 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, benign prostatic hypertrophy or inflammation.

[0362] A particular aspect is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0363] In embodiments, the cancer is a hormone-dependent cancer.

[0364] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular the cancer is an estrogen receptor alpha dependent cancer.

[0365] 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.

[0366] In another embodiment, the metastasis is a brain metastasis.

[0367] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0368] In another embodiment, the cancer is resistant to anti-hormone therapy.

[0369] In further embodiments, the compounds of Formula (I) are used as single agents or in combination with other agents such as CDK4 / 6, mTOR or PI3K inhibitors.

[0370] According to another aspect, provided herein is a method of treating the above indicated 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 an embodiment of this method of treatment, the subject is a human.

[0371] 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 for the treatment of any of the above indicated pathological conditions, more particularly useful for the treatment of cancer.

[0372] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. 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.

[0373] The excipients are selected from the customary excipients known to those skilled in the art, depending on the desired pharmaceutical form and method of administration.

[0374] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I) or its base, acid, zwitterion or salt thereof can be administered to animals and humans in a unit administration form, as a mixture with conventional pharmaceutical excipients for the treatment of the above disorders or diseases.

[0375] Suitable unit administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the compounds of formula (I) can be used in creams, gels, ointments or lotions.

[0376] As an example, a unit administration form of a compound of formula (I) in the form of a tablet may comprise the following components:

[0377]

[0378] There may be specific cases where higher or lower doses are appropriate. According to routine practice, the appropriate dose for the patient is determined by the physician according to the mode of administration and the weight and response of each patient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: - 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-, wherein R8 represents a fluorine atom or a (C1-C3) alkyl group; - represents a single bond or a double bond; -p is 0 or 1; -X represents -CH=, -N= or -CR"=, wherein 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 a trifluoromethyl group; - 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 a trifluoromethyl group; -n is 0, 1, or 2; and -R6 represents a monocyclic or bicyclic ring selected from the following: o Phenyl, o a 5-membered or 6-membered monocyclic heteroaryl group, and o a 7-membered, 8-membered, 9-membered or 10-membered bicyclic heterocyclic group, The monocyclic or bicyclic ring is optionally substituted by 1, 2, 3 or 4 groups selected from the group consisting of halogen atoms, hydroxyl groups, (C1-C6)alkyl groups optionally substituted by cyano or -OH groups, (C3-C6)cycloalkyl groups, (C1-C6)fluoroalkyl groups, -CN groups, (C1-C6)alkoxy groups, (C1-C6)fluoroalkoxy groups, trifluoromethylsulfonyl groups, (C1-C4)alkylthio groups, (C1-C4)fluoroalkylthio groups and (C1-C4)alkylsulfonyl groups, The proviso is that compounds where p=1 and Y is -O- are excluded.

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

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

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

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

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Y is -CH2-, -CH=, -O- or -NH-, in particular Y is -CH2-, -CH- or -CR8=.

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

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

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: R6 represents a phenyl group, which is optionally substituted by 1, 2, 3 or 4 groups selected from halogen atoms, and (C1-C6) alkyl groups, more particularly optionally substituted by 2, 3 or 4 groups selected from halogen, such as fluorine atoms, and methyl groups, and even more particularly substituted by one fluorine atom and by two methyl groups.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular a hydrochloride thereof, according to any one of claims 1 to 9, characterized in that: The compound is selected from the following compounds: -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).

11. A method for preparing a compound of formula (I) according to any one of claims 1 to 10, wherein The compound of formula 1D --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined in any one of claims 1 to 9, and R3a is a carboxylate such as COOMe or COOEt - is converted to a compound of formula (I) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, said step optionally being preceded by a step to obtain compound 1D, wherein a compound of formula 1F is -- wherein R3', R3", R6, R7, n, and X are as defined above, and R3a is a carboxylate such as COOMe or COOEt -- is subjected to a coupling step with one of the compounds 1G wherein R1, R2, R4, R5, R5' and p are as defined above.

12. A method for preparing a compound of formula (I) according to any one of claims 1 to 10, wherein The compound of formula 1D --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined in any one of claims 1 to 9, and R3a is a carboxylate such as COOMe, COOEt - is converted to a compound of formula (I) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, said step optionally being preceded by a step to obtain compound 1D, wherein a compound of formula 1B is -- wherein R3', R3" and R6 are as defined above, and R3a is a carboxylate such as COOMe or COOEt -- in a solvent such as DMF, subjected to a SNAr reaction with compound 1C in the presence of a base Where R1, R2, R4, R5, R5', p, n, R7, X, and Y are as defined above.

13. A method for preparing a compound of formula (I) according to any one of claims 1 to 10, wherein The compound of formula 1D --Among which R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined in any one of claims 1 to 9, and R3a is a carboxylate such as COOMe or COOEt - is converted to a compound of formula (I) in solution in methanol or THF in the presence of a hydroxide ion source such as NaOH or LiOH, optionally preceded by a step to obtain compound 1D, wherein a compound of formula 1J --wherein R3', R3", Y, p, X, R7, n and R6 are as defined above, and R3a is a carboxylate such as COOMe or COOEt - converted with compound 1K in the presence of a base Wherein W is Cl, Br or I or OSO2R, wherein R is CH3, PhMe, CF3 or CF2CF2CF2CF3.

14. A compound selected from the group consisting of compounds of formula 1D, 1F, 1H and 1L, Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, n, p, X and Y are as defined in any one of claims 1 to 9, and R3a is a carboxylate such as COOMe or COOEt.

15. A drug, characterized in that The medicament comprises a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises 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) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for use as an inhibitor and degrader of estrogen receptors.

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

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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