Novel substituted vinyl fluoride-N-propyl-pyrrolidine compounds, processes for preparing same and therapeutic uses thereof

Abstract

A compound of formula (I) or a pharma- ceutically acceptable salt thereof [Formula 1] TIFF2025513063000111.tif53170 (wherein R1 and R2 represent hydrogen or deuterium; R3 represents hydrogen, -COOH or -OH; R3' and R3" represent hydrogen, methyl, methoxy, chlorine, fluorine or cyano; R4 and R4' represent hydrogen or fluorine; R5 represents hydrogen, fluorine or (C1-C3)alkyl; R6 represents phenyl, fused phenyl, a bicyclic group containing 5 to 12 carbon atoms, a heteroaryl group containing 2 to 9 carbon atoms and 1 to 3 heteroatoms, a cycloalkyl group containing 3 to 7 carbon atoms, a (C3-C6)cycloalkyl(C1-C3)alkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms, a (C1-C6)alkyl group and a phenyl(C1-C2)alkyl group; X represents Y represents -CH2-, -O- or -S-; Y represents -CH=, -N= or -CR"=, where R" represents (C1-C3)alkyl, halogen, cyano or (C1-C3)fluoroalkyl; R7 represents (C1-C3)alkyl, halogen, cyano or (C1-C3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C3)alkyl or cyclopropyl; n is 0, 1 or 2; and m is 0 or 1. Further disclosed herein are processes for preparing same, pharmaceutical compositions containing same, and said compounds of formula (I) for use as inhibitors and decomposers of estrogen receptors, especially in the treatment of ovulation dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

Description

[Technical field]

[0001] Disclosed herein are novel fluorinated vinyl-N-propyl-pyrrolidine derivatives, processes for their preparation and their therapeutic use, particularly as anti-cancer agents via selective antagonism and degradation of estrogen receptors. [Background technology]

[0002] Estrogen receptors (ER) belong to the steroid / nuclear receptor superfamily that are involved in the regulation of eukaryotic gene expression, cell growth and differentiation in target tissues. There are two forms of ER, 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 that are activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormone, ER is located primarily in the cytosol of cells. When the hormone estrogen binds to ER, ER translocates from the cytosol to the cell nucleus, forms dimers, and then binds to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to modulate the transcription of target genes.

[0003] ERα is mainly expressed in reproductive tissues such as the uterus, ovaries, and breasts, as well as in bone and white adipose tissue. Abnormalities in ERα signaling lead to the development of a variety of diseases, including cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and osteoporosis.

[0004] ERα is expressed in less than 10% of normal breast epithelium, but 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 axis in breast cancer, including: 1-blockade of estrogen synthesis by aromatase inhibitors, used to treat patients with early and advanced ERα-positive breast cancer; 2-antagonism of estrogen ligands binding to ERα by tamoxifen, used to treat patients with ERα-positive breast cancer in both pre- and postmenopausal settings; 3-antagonism and downregulation of ERα levels by fulvestrant, used to treat breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

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

[0006] The majority of identified endocrine therapy resistance mechanisms rely on ERα-dependent activity. One novel strategy to combat such resistance is to shut down 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 prevented by using SERDs.

[0007] There remains a need to provide a SERD with good decomposition efficiency.

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

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

[0010] A compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] (In the formula: - R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a -COOH group or a -OH group; - 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 and R4' independently represent a hydrogen atom or a fluorine atom; - R5 represents a hydrogen atom, a fluorine atom or a (C1-C3) alkyl group; R6 is a group selected from: ■ a phenyl group which is optionally substituted by 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group optionally substituted by a cyano group or a -OH group; a (C1-C6) fluoroalkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy group; a (C1-C6) fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4) alkylthio group; a (C1-C4) fluoroalkylthio group; a (C1-C4) alkylsulfonyl group and a -OH group; ■ a fused phenyl group selected from a phenyl group fused with a (C3-C6) cycloalkyl, wherein the (C3-C6) cycloalkyl optionally contains unsaturation, and the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3) alkyl group, a hydroxy group, a halogen atom, a (C1-C6) fluoroalkyl group, and a (C1-C3) alkoxy group; ■ A bicyclic group containing 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; and optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, an -OH group, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and an oxo group: ■ A heteroaryl group (e.g., a pyridyl group) containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and at least 5 atoms (including carbon atoms and heteroatoms), which is optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group, a (C1-C6) fluoroalkyl group, a (C1-C6) alkoxy group, a (C1-C6) fluoroalkoxy group, a cyano group, a carbamoyl group, and a -OH group; ■ A cycloalkyl group having 3 to 7 carbon atoms, which is saturated or partially saturated and optionally substituted with 1 to 4 substituents independently selected from the following: ○Fluorine atom, -OH group, (C1-C3) alkyl group, (C1-C3) fluoroalkyl group, (C1-C3) alkoxy group, (C1-C3) fluoroalkoxy group, oxo group, (C3-C6)cycloalkyl and phenyl groups, said (C3-C6)cycloalkyl or phenyl groups being optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; ■ a (C3-C6)cycloalkyl(C1-C3)alkyl group, optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from a fluorine atom, an -OH group, a (C1-C4)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, and an oxo group; ■ a 4- to 7-membered heterocycloalkyl group (e.g., a tetrahydropyranyl group) containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, which is saturated or partially saturated and optionally substituted with one to three substituents independently selected from a fluorine atom, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) fluoroalkoxy group, an oxo group, a (C1-C3) alkoxy group, and a -OH group; ■ (C1-C6) alkyl groups such as isobutyl, methyl or ethyl groups, which are optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group and an -OH group; and ■ a phenyl(C1-C2)alkyl group, wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and a -OH group; represents; - X represents -CH2-, -O- or -S-; - Y represents -CH=, -N= or -CR"=, where R" represents a (C1-C3) alkyl group, a halogen atom such as a fluorine atom or a chlorine atom, a cyano group or a (C1-C3) fluoroalkyl group (e.g. trifluoromethyl); - R7 independently represents a (C1-C3) alkyl group such as methyl, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R8 represents a hydrogen atom or a fluorine atom; - R9 represents a hydrogen atom, a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; - m is 0 or 1) are disclosed herein.

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

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

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

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

[0015] A suitable salt of the compound of formula (I) may include the hydrochloride salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] As used herein, the following terms have the following definitions unless stated otherwise throughout the specification. a halogen atom: a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom; - Oxo: the "=O" group; - alkyl group: unless otherwise stated, a linear or branched saturated hydrocarbon-based aliphatic group containing 1 to 6 carbon atoms (referred to as "(C1-C6) alkyl"). Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups; - cycloalkyl group: unless otherwise stated, a monocyclic alkyl group containing 3 to 7 carbon atoms, saturated or partially unsaturated, unsubstituted or substituted, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cycloheptenyl, in particular cyclopentyl, cyclohexyl or cyclohexenyl; - cycloalkylalkyl group: an alkyl group substituted with a cyclic alkyl group as defined above, including, but not limited to, cyclobutylmethyl; - Heterocycloalkyl group: a saturated or partially unsaturated 4-7 membered cycloalkyl group containing 1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen. Examples include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl and tetrahydrothiopyranyl. Heterocycloalkyl is advantageously tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above, wherein 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 by a fluorine atom. Examples include -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. If all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl group. Examples include trifluoromethyl group or trifluoroethyl group, especially trifluoromethyl group. - alkoxy group: -O-alkyl group, where the alkyl group is as defined above, examples of which may include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexyloxy groups; - Fluoroalkoxy group: -O-alkyl group, 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 by a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group can be named as perfluoroalkoxy group. Examples include trifluoromethoxy, etc.; - (C1-C4) alkylthio group, also named (C1-C4) alkylsulfanyl: -S-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.; - (C1-C4) alkylsulfonyl group: -SO2-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; - (C1-C4)fluoroalkylthio group, also named (C1-C4)fluoroalkylsulfanyl group: -S-fluoroalkyl group, where the fluoroalkyl group is as defined above. Examples include, but are not limited to, fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - Fused phenyl: a bicyclic radical containing 7-10 carbon atoms and containing a phenyl moiety. The phenyl moiety may be fused with a (C3-C6) cycloalkyl group, i.e. the phenyl moiety may share a bond with the (C3-C6) cycloalkyl group. The fused phenyl group may be bonded to the rest of the molecule by its phenyl moiety. The fused phenyl group may be substituted. Examples are, but are not limited to, indanyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, tetrahydronaphthalenyl, etc.; Heteroaryl group: a 5-10 membered cyclic aromatic group containing 2-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. Such a nitrogen atom may be substituted with an oxygen atom to form an -NO bond. Such an -NO bond can be converted to an N-oxide (-N + -O -) form. The heteroaryl group may be monocyclic or bicyclic. Examples of heteroaryl groups include, but are not limited to, thiophene, furan, thiadiazole, thiazole, imidazole, pyridazine, triazine, pyrazine, oxadiazole, pyrazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine, benzotriazole, benzoxazole, pyrrolo[2,3-b]pyridine, benzimidazole, benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridone, etc. Heteroaryl is advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine; - bicyclic radicals, which generally contain from 5 to 12 carbon atoms, are hydrocarbon radicals selected from the radicals containing two rings linked via: A single common atom: a "spiro-bicyclic ring". Such spiro-bicyclic alkyls are generally referred to as "spiro (C5-C 11 The spiro (C5-C6) bicyclic rings contain 5 to 11 carbon atoms. The ring may be saturated or partially unsaturated. Such spiro bicyclic rings may be unsubstituted or substituted (especially by at least one (C1-C3) alkyl group such as methyl or fluorine). With respect to the definition of R6, ... 11 Examples of spiro(C5-C6) bicyclic rings include, but are not limited to, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.3]heptene, spiro[2.5]octane, and 7-azaspiro[3.5]nonane. 11 ) the bicyclic ring is, continuing with respect to the R6 group, advantageously a spiro[2.3]hexane, spiro[3.3]heptane or spiro[3.3]heptene; 2 common atoms: in this case the bicyclic group contains 7 to 12 carbon atoms and optionally contains 1 to 2 unsaturations. Examples of such bicyclic groups include, but are not limited to, cis-1,3a,4,5,6,6a-hexahydropentalenyl, bicyclo[3.1.0]hexan-1-yl, bicyclo[4.1.0]heptanyl and octahydropentalenyl; Three or more common atoms: In this case, the bicyclic group contains 6 to 10 carbon atoms, and such a bicyclic group is called a "bridged (C6-C 10 (cycloalkyl) groups, where the rings share three or more atoms and the bridge contains at least one atom, e.g., 1, 2 or 3 atoms, preferentially 1 atom. Examples of such bridged cycloalkyl groups include, but are not limited to, bicyclo[3.2.1]octan-3-yl and bicyclo[2.2.1]heptan-2-yl. - Zwitterion refers to an overall neutral molecule that has positive and negative charges and has acidic and basic groups.

[0017] In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0018] In another embodiment, in the compounds of formula (I) as defined above, R3 is a -COOH group.

[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 a compound of formula (I) as defined above, X represents --CH.sub.2--.

[0021] In another embodiment, in a compound of formula (I) as defined above, R4 and R4' both represent a hydrogen atom, or one of R4 and R4' represents a hydrogen atom and the other represents a fluorine atom.

[0022] In another embodiment, in a compound of formula (I) as defined above, R5 represents a hydrogen atom.

[0023] In another embodiment, in a compound of formula (I) as defined above, R6 represents a phenyl group, said phenyl group being optionally substituted with one to three substituents independently selected from halogen atoms, (C1-C6) alkyl groups and (C1-C6) fluoroalkyl groups, more particularly selected from chlorine atoms, fluorine atoms, methyl groups and trifluoromethyl groups. In such an embodiment, in particular, at least one of the substituents of said phenyl group comprises a halogen atom.

[0024] In another embodiment, in the compounds of formula (I) as defined above, n is 0 or 1 and R7 is a fluorine atom.

[0025] In another embodiment, in the compounds of formula (I) as defined above, n is 0.

[0026] In another embodiment, in a compound of formula (I) as defined above, Y represents -CH=.

[0027] In another embodiment, in the compounds of formula (I) as defined above, m is 1.

[0028] In another embodiment, in the compounds of formula (I) as defined above, m is 0.

[0029] In another embodiment, in the compound of formula (I) as defined above, R3 is a -COOH group and R6 is a phenyl group containing one, two or three substitutions, more particularly two substitutions, independently selected from a chlorine atom, a fluorine atom, a trifluoromethyl group and a methyl group, at least one of the substitutions containing a halogen atom. In such an embodiment, R3' and R3" are in particular hydrogen atoms. In further such an embodiment, R1, R2, R5, R8 and R9 are hydrogen atoms. In such an embodiment, both R4 and R4' are hydrogen atoms or one of R4 and R4' is a hydrogen atom and the other is a fluorine atom. In further such an embodiment, Y is a -CH= group, m is equal to 1 and n is equal to 0. In further such an embodiment, X is a -CH2- group.

[0030] Among the compounds of formula (I) described herein, particular mention may be made of the following compounds or their pharma- ceutically acceptable salts, in particular their hydrochlorides: - (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (1), - (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (2), - (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride (3), - Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (4), - (Z)-8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (5), - (Z)-8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (6), - (Z)-3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)-1-(3-fluoropropyl)pyrrolidine (7), - (Z)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (8), - (Z)-8-(2,4-difluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic (9), - (Z)-8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (10), - (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (11), - (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (12), - (Z)-8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (13), - (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (14), - (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (15), - (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride (16), - (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride (17), - (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (18), - (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (19), - (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,6-dimethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (20), - (Z)-8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (21), - (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (22), - (Z)-8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (23), - (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride (24), - (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (25), - (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (26), - (Z)-8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (27), - (Z)-8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (28), - (Z)-8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (29), - (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol (30).

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

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

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

[0034] 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 pharma- ceutically acceptable salt thereof.

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

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

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

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

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

[0040] The following abbreviations and empirical formulas are used: MeCN Acetonitrile NH4Cl Ammonium chloride CO Carbon monoxide CO2 Carbon Dioxide Cs2CO3 Cesium carbonate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane Et2O Diethyl ether DIEA Diisopropylethylamine DMF N,N-Dimethylformamide DMAP Dimethylaminopyridine DMSO Dimethyl sulfoxide BOC2O Di-tert-butyl dicarbonate EtOH Ethanol EtOAc Ethyl acetate HCl Hydrochloric acid LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate MTBE Methyl tert-butyl ether MeTHF 2-Methyltetrahydrofuran n-BuLi n-Butyl lithium KOAc Potassium Acetate KHMDS Potassium bis(trimethylsilyl)amide K2CO3 Potassium Carbonate KOH Potassium hydroxide NaBH4 Sodium borohydride NaHCO3 Sodium bicarbonate NaH Sodium hydride NaOH Sodium hydroxide Na2SO4 Sodium Sulfate SCX Strong cation exchange Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(Pph3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PhOK Potassium carbonate SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran PPh3 Triphenylphosphine RT room temperature XANTPHOS (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane).

[0041] Scheme 1a-part-1: Preparation of compounds of formula (I) - General process [ka] Scheme 1a-Part-2 [ka] According to scheme 1a-part-1 and part-2, where R3a is a hydrogen atom or a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, R6 is a phenyl group or a heteroaryl group; and R1, R2, R3, R3', R3'', R4, R4', R5, R7, R8, R9 X, m, n and Y are as defined above, compound 1A can be converted to compound 1B in step 1 by treatment with an aryl or heteroaryl bromide or iodide in solution in toluene or xylene in the presence of a palladium catalyst, for example, tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and a phosphine such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (XANTPHOS), in the presence of a base such as K2CO3 or Cs2CO3, by heating the solvent to reflux. An alternative method for preparing compound 1B, where R6 can be any of the groups defined above for R6 of formula (I), is described below in Scheme 1e.

[0042] Compound 1B can be converted to compound 1C in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or NaH or KHMDS at −50° C. in a solvent such as MeTHF.

[0043] Compound 1C can be converted to compound 1E in step 4 by treatment with, for example, bis(pinacolato)diboron, a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) and a phosphine, such as triphenylphosphine, in a solution in toluene in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0044] Compound 1K can be prepared in a Suzuki coupling reaction between either compounds 1C and 1D in step 3 or between compounds 1E and 1F in step 5 in a mixture of dioxane and water in the presence of a base, such as cesium carbonate (Cs2CO3), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst by heating the solvent to reflux.

[0045] Alternatively, compound 1E can be converted to compound 1H in step 6 in a Suzuki coupling reaction with compound 1G by heating the solvent to reflux in a mixture of dioxane and water in the presence of a base, such as cesium carbonate (Cs2CO3), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst. Compound 1H can be converted to compound 1I in step 7 by treatment with TFA in solution in DCM or HCl in solution in dioxane. Compound 1I can be converted to compound 1K in step 8 by treatment with compound 1J (wherein W is Br, I, or OSOR (R = CH3, PhMe, CF3, or CF2CF2CF2CF3)) in the presence of a base, such as potassium carbonate in DMF at 70°C, or in the presence of sodium hydroxide or potassium hydroxide in THF at room temperature, or in the presence of aqueous sodium hydroxide in DCM at room temperature.

[0046] When R3a is a protected OH such as COOMe, COOEt, or O-pivaloyl, compound 1K can be deprotected to compound I in step 9 by treatment with aqueous sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, the compound can be extracted to obtain the sodium salt of compound I. The neutral form can be obtained by acidifying to pH 6-7 with aqueous 2N HCl. The hydrochloride salt can be obtained by acidifying to pH 1-2 with aqueous 2N HCl. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0047] Scheme 1b - Part-1 and Part-2: Alternative Process for Preparing Compounds of Formula (I) - General Process Scheme 1b-part-1: [ka] Scheme 1b-part-2: [ka] According to scheme 1b-part-1 and part-2, where R3a is hydrogen atom, carboxylic acid ester such as COOMe, COOEt or protected OH such as O-pivaloyl, R1, R2, R3, R3', R3'', R4, R4', R6, R7, R8, R9, X, n, m and Y are as defined above and R5 is hydrogen atom, compound 1L can be converted to compound 1N in step 1 in Suzuki coupling reaction with compound 1M in a mixture of dioxane and water in the presence of a base such as Cs2CO3 using, for example, DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as catalyst by heating the solvent to reflux.

[0048] Compound 1N can be converted to compound 1O in step 2, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0049] Compound 1O can be converted to compound 1P in step 3 by treatment with sulfuric acid in aqueous solution.

[0050] Compound 1P can be converted to compound 1Q in step 4 by treatment with, for example, bis(pinacolato)diboron, a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) and a phosphine, such as triphenylphosphine, in a solution in toluene in the presence of a base, such as KOPh or AcOK, by heating the solvent to reflux.

[0051] Compound 1K can be prepared in a Suzuki coupling reaction between either compound 1P and R6B(OR')2 or R6BF3K (where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in step 5 or compound 1Q and R6Br or R6I in step 6 in a mixture of dioxane and water in the presence of a base, such as cesium carbonate (Cs2CO3), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, by heating the solvent to reflux.

[0052] An alternative method for preparing compounds 1K, where R5 can be any of the groups defined above for R5 of formula (I), is described below in Scheme 1f.

[0053] Compound 1K can be converted to a compound of formula (I) in step 7 in the presence of a hydroxide ion source such as NaOH or LiOH in solution in MeOH.

[0054] Compound 1P can be converted to compound 1Pa in step 8 in the presence of a hydroxide ion source such as NaOH or LiOH in solution in MeOH.

[0055] This compound 1Pa can be converted to compound I in step 9 by Suzuki conditions using a suitable boron reagent R6B(OR')2 or R6BF3K (where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in a mixture of dioxane and water as solvent, in the presence of a base, such as Cs2CO3, using, for example, Pd(dppf)Cl2 complexed with DCM as a catalyst, at room temperature or by heating the solvent to reflux.

[0056] If R3a is a protected OH such as COOMe, COOEt, or O-pivaloyl, deprotection can be achieved in step 7 by treatment with an aqueous solution of 2N NaOH or LiOH in MeOH. If R3 is COOH, the product can be extracted to obtain the sodium or lithium salt of compound I. The neutral form of compound I can be obtained by acidifying with an aqueous solution of 2N HCl to pH 6-7. The hydrochloride salt of compound I can be obtained by acidifying with an aqueous solution of 2N HCl to pH 1-2. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC with formic acid or trifluoroacetic acid in the eluent.

[0057] Scheme 1c: Alternative process for preparing compounds of formula (I) - General process [ka] According to scheme 1c, where R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, R1, R2, R3, R3', R3'', R4, R4', R6, R7, R8, R9, X, n, m, and Y are as defined above, and R5 is a hydrogen atom, compound 1C' can be converted to compound 1S in step 1 in a Suzuki coupling reaction with compound 1R by heating the solvent to reflux in a mixture of dioxane and water in the presence of a base, such as Cs2CO3, using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst.

[0058] Compound 1S can be converted to compound 1N in step 2 by treatment with NaBH4 in a solvent such as MeOH.

[0059] Compound 1N can be converted to compound 1O in step 3, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0060] Compound 1O can be converted to compound 1T in step 4 by Suzuki conditions using a suitable boron reagent R6B(OR')2 or R6BF3K (where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in a mixture of dioxane and water in the presence of a base, such as Cs2CO3, by heating the solvent to reflux using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst.

[0061] Compound 1T can be converted to compound I by treatment with a hydroxide ion source, such as NaOH or LiOH in solution in MeOH, followed by treatment with sulfuric acid.

[0062] Scheme 1d: Preparation of compounds of formula (1A) where R3a = CO2Me - General process [ka] According to scheme 1d, where X, m, R3', R3" and R9 are as defined above, compound 1A is commercially available or can be prepared as follows: compound 1U (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted to compound 1V in step 1 by treatment with trifluoromethanesulfonic anhydride in the presence of pyridine as a base in solution in DCM.

[0063] Compound 1V can be converted to compound 1A in step 2 by carbonylation with carbon monoxide in the presence of a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed to DCM in a solution of DMF and MeOH.

[0064] Scheme 1e: Alternative preparation of compounds of formula (1B) - General process [ka] According to scheme 1e, where R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, and R3', R3", R9, R6, X and m are as defined above, compound 1B can alternatively be prepared as follows: compound 1A can be converted to compound 1Aa in step 1, for example by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0065] Compound 1Aa can be converted to compound 1Ab in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0066] Compound 1Ac can be prepared in step 3 in a Suzuki coupling reaction between compound 1Ab and R6B(Or')2 or R6BF3K (where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in a mixture of toluene and water in the presence of a base, such as cesium carbonate (Cs2CO3), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, by heating the solvent to reflux.

[0067] Compound 1Ac can be converted to compound 1B in step 4 by hydrolysis with aqueous HCl, for example by heating in methanol and DCM.

[0068] Scheme 1f: Alternative preparation of compounds of formula (1K) - General process [ka] According to scheme 1f, where R3a is a hydrogen atom or a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, and R1, R2, R3, R3', R3'', R4, R4', R5, R6, R7, R8, R9 X, m, n and Y are as defined above, compound 1C can be converted to compound 1E in step 1 by treating in solution in toluene with, for example, bis(pinacolato)diboron, a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) and a phosphine, such as triphenylphosphine, in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0069] Compound 1W can be prepared in a Suzuki coupling reaction between either compound 1E and 1R' in step 2 or between compound 1C and 1R in step 3 in a mixture of dioxane and water in the presence of a base, such as cesium carbonate (CsCO), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) complexed with DCM as a catalyst by heating the solvent to reflux.

[0070] Compound 1W can be converted to compound 1X in step 4 by treatment with an alkylmagnesium bromide in a solvent such as THF.

[0071] Compound 1X can be converted to compound 1K in step 5 by treatment with sulfuric acid in water.

[0072] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein the compound of formula 1K [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined above and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt or a protected OH such as O-pivaloyl) 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, said step being optionally preceded by a step to obtain a compound 1K, and a compound of formula 1P [ka] (In the formula, R1, R2, R3', R3", R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above.) is subjected to Suzuki coupling with a boron reagent R6-B(OR')2 or R6BF3K, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0073] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein the compound of formula 1Pa [ka] wherein R1, R2, R3a, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, are subjected to Suzuki coupling with a boron reagent R6B(OR')2 or R6BF3K, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, optionally preceded by a step to obtain compound 1Pa, to obtain a compound of formula 1P [ka] (In the formula, R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above.) is converted to compound 1Pa in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol.

[0074] Also provided herein is an intermediate compound selected from the compounds of formula 1P, 1K, and 1Pa, or any of their pharma- ceutically acceptable salts. [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl) is provided.

[0075] Further provided herein are intermediate compounds of formula 1F and 1D, or pharma- ceutically acceptable salts thereof. [ka] (wherein R1, R2, R4, R4', R5, R7, R8, Y and n are as defined above).

[0076] This application also relates to any of the intermediate compounds of formula 1E or pharma- ceutically acceptable salts thereof. [ka] (wherein R3a, R3', R3", X, m, R6 and R9 are as defined above) are described.

[0077] In another aspect, also provided herein is a process for preparing a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula 1K as defined above, optionally followed by a purification step.

[0078] Said purification step may for example consist of an acidification step (eg with an aqueous solution of hydrochloric acid) as illustrated in step 2 of Example 1 herein below.

[0079] At 400 and 500MHz 1 H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively, and chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) were referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0080] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity (Waters) instrument, a light scattering detector (Sedere) and a SQD (Waters) mass spectrometer 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% HCOH / CH3CN+0.1% HCOH.

[0081] Tables 1a and 1b below show specific compounds (names and structures) of formula (I) according to the present disclosure and their characterization ( 1 1 H NMR and liquid chromatography / mass), respectively.

[0082] [Table 1]

[0083] [Table 2]

[0084] [Table 3]

[0085] [Table 4]

[0086] [Table 5]

[0087] [Table 6]

[0088] [Table 7]

[0089] [Table 8]

[0090] [Table 9]

[0091] [Table 10]

[0092] [Table 11]

[0093] The following examples describe the preparation of some compounds of formula (I) described herein. The compound numbers exemplified below correspond to those shown in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0094] In the following examples, unless the source of a starting product is specified, it is to be understood that said product is a known compound. EXAMPLES

[0095] Intermediates: Intermediate 1: Methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (15 g, 42.82 mmol) (prepared according to WO2017140669), Pd(PPh3)2Cl2 (1.53 g, 2.14 mmol), PPh3 (673.87 mg, 2.57 mmol), bis(pinacolato)diboron (13.38 g, 52.67 mmol) and PhOK (8.04 g, 60.80 mmol) in toluene (150 ml) was heated to 75 °C for 1.5 h. The yellow suspension turns orange and then brown. After cooling to RT, DCM (150 mL) and water (150 mL) were added and decanted through a hydrophobic column. The organic phase was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / DCM: 85 / 15 to 20 / 80 to give 10.1 g (72%) of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid. LC / MS(m / z, MH+): 329

[0096] Intermediate 2: 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 2 was prepared from 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO 2020 / 049153) following a similar procedure to intermediate 1 to give 3.9 g (82%) of 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid. LC / MS(m / z, MH+): 473

[0097] Intermediate 3: 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate methyl [ka] Argon is bubbled through a mixture of 1-bromo-2,4-difluoro-benzene (6.63 g, 34.37 mmol), 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-methyl carboxylate (5 g, 22.91 mmol) and K2CO3 (12.67 g, 91.66 mmol) in toluene (40 ml) for 10 min. After addition of XANTPHOS (1.32 g, 2.29 mmol) and Pd2(dba)3 (1.05 g, 1.15 mmol), the reaction mixture is heated to reflux for 72 h. After cooling to RT, water (40 ml) and DCM (40 ml) are added. After decantation, the aqueous phase is washed 3 times with 40 ml of DCM. The combined organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAC 100 / 00 to 90 / 10 to give 2.55 g (34%) of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 331

[0098] Step 2: 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a suspension of NaH (545 mg, 13.62 mmol, 60 wt% purity) in Me-THF (22 ml) cooled at 5° C., DBU (277 mg, 0.27 ml, 1.82 mmol) was added, followed by a solution of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate (3 g, 9.08 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (4.2 g, 11.81 mmol) in THF (25 ml). The cooling bath was removed and the temperature was allowed to warm to RT. A mixture of acetic acid (0.4 ml) and water (32 ml) was added dropwise, followed by water (100 ml) and EtOAC (150 ml). After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with DCM / heptane 50 / 50 to give 2.77 g (66%) of methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 463

[0099] Step 3: 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 3 step 3 was prepared from 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a similar procedure as intermediate 1 to give 1.89 g (72%) of methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 441

[0100] Intermediate 4: 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate methyl [ka] Intermediate 4, step 1, was prepared from 1-bromo-2-methyl-4-fluoro-benzene following a procedure similar to intermediate 3, step 1, to give 700 mg (47%) of methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 327

[0101] Step 2: 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 4, step 2, was prepared from methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate following a procedure similar to intermediate 3, step 2 to give 7.86 g (82%) of methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 459

[0102] Step 3: 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 4, step 3, was prepared from methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a similar procedure as intermediate 1 to give 3.93 g (43%) of methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 437

[0103] Intermediate 5: (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol [ka] Step 1: (4-Bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid [ka] To a solution of commercially available tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate (20.3 g, 57.31 mmol) in DCM (100 ml) was added TFA (100 ml) dropwise and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with Et2O. The solid formed was filtered to give 17 g (81%) of (4-bromophenyl)-pyrrolidin-3-yl-methanone; 2,2,2-trifluoroacetic acid. LC / MS(m / z, MH+): 254

[0104] Step 2: (4-Bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone [ka] A mixture of (4-bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid (9.45 g, 25.67 mmol), K2CO3 (10.64 g, 77 mmol), 1-fluoro-3-iodopropane (5.07 g, 26.95 mmol) in MeCN (200 ml) was heated at 80° C. for 3 h. The reaction mixture was quenched by adding saturated NH4Cl solution (200 ml) and extracted with EtOAc (3×200 ml). The organic phase was washed with brine (200 ml), dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 50 / 50 to 90 / 10 to give 6.34 g (78%) of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone. LC / MS(m / z, MH+): 314

[0105] Step 3: (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol [ka] To a mixture of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone (6.31 g, 20.07 mmol) in MeOH (180 ml) was added NaBH4 (2.28 g, 60.21 mmol) and the mixture was stirred at RT for 2 h. A concentrated solution of NH4Cl (100 ml) and EtOAc (300 ml) were added. After decantation, the organic phase was washed with brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6.69 g (crude) of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol. LC / MS(m / z, MH+): 316

[0106] Intermediate 6: 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine cis isomer [ka] To a mixture of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol (intermediate 5) (5.16 g, 16.33 mmol) and water (10 ml) was added dropwise sulfuric acid (35 ml) at 0 °C. The cooling bath was removed and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into a mixture of ice and water (500 ml). Powdered NaHCO3 was added to bring the pH to 9. EtOAc (300 ml) was added, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / EtOAc: 100 / 00 to 00 / 100 to give 4.13 g (85%) of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine as a mixture of cis and trans isomers. A mixture of cis and trans isomers of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine was separated by preparative SFC using an IF 5×25 cm, 5 μm column (Daicel) and a 30% CO2 mobile phase with 0.1% TEA as co-solvent in MeOH solution. The temperature was set at 40° C. and the back pressure regulator was set at 100 bar to give 1145 mg of cis isomer (3Z)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine and 2584 mg of trans isomer (3E)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine. LC / MS(m / z, MH+): 298

[0107] Intermediate 7: (4-Bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanol [ka] Step 1: 3,3-difluoropropyl 4-methylbenzenesulfonate [ka] To a solution of 3,3-difluoropropan-1-ol (500 mg, 5.20 mmol) in THF (10 ml) cooled at 0° C. was added NaH (229 mg, 5.72 mmol, 60% by weight). After stirring at 0° C. for 1 h, 4-methylbenzenesulfonyl chloride (1.03 g, 4.13 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched by adding a saturated solution of NH4Cl (20 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine (20 ml), dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with DCM to give 1.03 g (79%) of 3,3-difluoropropyl 4-methylbenzenesulfonate. LC / MS(m / z, MH+): 251

[0108] Step 2: (4-Bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanone [ka] Intermediate 7, step 2, was prepared from (4-bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid and 3,3-difluoropropyl 4-methylbenzenesulfonate following a similar procedure to intermediate 5, step 2 to give 6.29 g (70%) of (4-bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanone. LC / MS(m / z, MH+): 332

[0109] Step 3: (4-Bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanol [ka] Intermediate 7, step 3, was prepared from (4-bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanone following a procedure similar to intermediate 5, step 3, to give 5.53 g (crude) of (4-bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanol. LC / MS(m / z, MH+): 334

[0110] Intermediate 8: 3-[(4-bromophenyl)methylene]-1-(3,3-difluoropropyl)pyrrolidine cis isomer [ka] Intermediate 8 was prepared from (4-bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanol (Intermediate 7) following a similar procedure as Intermediate 6 to give 2.71 g (64%) of 3-[(4-bromophenyl)methylene]-1-(3,3-difluoropropyl)pyrrolidine as a mixture of cis and trans isomers. The mixture of cis and trans isomers of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine was separated by preparative SFC using an IG 5×25 cm, 5 μm column (Daicel) and a mobile phase containing 30% CO2 with 0.1% TEA as co-solvent in MeOH. The temperature was set to 40° C. and the back pressure regulator was set to 100 bar to give 158 mg of the cis isomer (3Z)-3-[(4-bromophenyl)methylene]-1-(3,3-difluoropropyl)pyrrolidine and 299 mg of the trans isomer (3E)-3-[(4-bromophenyl)methylene]-1-(3,3-difluoropropyl)pyrrolidine. LC / MS(m / z, MH+): 316

[0111] Intermediate 9: (Z)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 1) (3.42, 10.44 mmol), (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol (intermediate 5) (3 g, 9.49 mmol), Cs2CO3 (8.04 g, 24.67 mmol), and Pd(dppf)Cl2 complexed with DCM (466 mg, 0.57 mmol) in dioxane (24 ml) and water (6 ml) was heated to reflux for 1 h. The reaction mixture was quenched by adding saturated NH4Cl solution (50 ml) and extracted with EtOAc (3 x 50 ml). The organic phase was washed with brine (50 ml), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 80 / 20 to give 2.59 g (62%) of methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 438

[0112] Step 2: 8-Bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (2.60 g, 5.94 mmol) in DCM (100 ml) was added pyridinium tribromide (2.66 g, 8.31 mmol). The reaction mixture was stirred at RT for 18 h. The reaction was quenched with a concentrated solution of NaHCO3 (100 ml) and DCM (150 ml). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 80 / 20 to give 1.53 g (50%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):516

[0113] Step 3: (Z)-8-Bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (1.53 g, 2.97 mmol) and water (2 ml) was added sulfuric acid (7 ml) dropwise at 0° C. The cooling bath was removed and the reaction mixture was stirred at RT for 30 min. The reaction mixture was poured into a mixture of ice and water (150 ml). Powdered NaHCO3 was added to bring the pH to 9. EtOAc (100 ml) was added, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / EtOAc: 100 / 00 to 00 / 100 to give 1.04 g (69%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a mixture of cis and trans isomers. A mixture of cis and trans isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by preparative SFC using an IB-N5 5 × 25 cm, 5 μm column (Daicel) and a mobile phase containing 23% CO2 as co-solvent in 0.1% TEA in MeOH. The temperature was set to 40° C. and the back pressure regulator was set to 100 bar to give 170 mg of the cis isomer (Z)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 388 mg of the trans isomer (E)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 498

[0114] Intermediate 10: (Z)-8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 10, step 1, was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 1) and (4-bromophenyl)-[1-(3,3-difluoropropyl)pyrrolidin-3-yl]methanol (Intermediate 7) following a procedure similar to that of intermediate 9, step 1, to give 5.98 g (80%) of methyl 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 456

[0115] Step 2: 8-Bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 10, step 2, was prepared from methyl 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to intermediate 9, step 2, to give 3.93 g (56%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 534

[0116] Step 3: (Z)-8-Bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 10, step 3, was prepared from methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to intermediate 9, step 3, to afford 2.46 g (65%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a mixture of cis and trans isomers. Chiral chromatography of a mixture of cis and trans isomers of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate eluted with heptane / EtOH / TEA: 50 / 50 / 0.1: Chiralpak AD Separation by 20 μm (250×4.6 mm) gave 562 mg of the cis isomer (Z)-8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 986 mg of the trans isomer (E)-8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):516

[0117] Intermediate 11: 2-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 6-(2-chlorophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] Intermediate 11, step 1, was prepared from 1-bromo-2-chloro-benzene and 6,7,8,9-tetrahydrobenzo[7]annulen-5-one following a procedure similar to intermediate 3, step 1 to give 580 mg (16%) of 6-(2-chlorophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+): 271

[0118] Step 2: 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate [ka] Intermediate 11, step 2, was prepared from 6-(2-chlorophenyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to intermediate 3, step 2 to afford 608 mg (71%) of 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 403

[0119] Step 3: 2-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Intermediate 11, step 3, was prepared from 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate following a similar procedure as intermediate 1 to afford 430 mg (84%) of 2-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LC / MS(m / z, MH+): 381

[0120] Intermediate 12: 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate methyl [ka] Step 1: 5-Oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate [ka] To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO2018091153) and pyridine (2.82 g, 2.89 ml, 35.36 mmol) in DCM (120 ml) cooled at -20°C, trifluoromethanesulfonic anhydride (8.14 g, 6 ml, 28.28 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 min. Water (50 ml) was added. The organic phase was separated and washed with saturated aqueous NaHCO3 (50 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 7.40 g (crude) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 311

[0121] Step 2: 5-Oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate methyl [ka] To a solution of the compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate (7.4 g, 23.85 mmol) in DMF (30 ml) and MeOH (15 ml) was added DIEA (3.15 g, 4.16 ml, 23.85 mmol) and Pd(dppf)Cl2 complexed with DCM (1.10 g, 1.43 mmol), the suspension was degassed and purged with CO three times. The mixture was stirred under CO (5 bar) at 75° C. for 2 h. The reaction was filtered through Celite. The filtrate was diluted with water (400 ml) and extracted three times with EtOAc (300 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 85 / 15 to 80 / 20 to give 4.6 g (88%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 221

[0122] Step 3: 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate methyl [ka] Intermediate 12, step 3, was prepared from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to intermediate 3, step 1 to give 1.13 g (67%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 365

[0123] Step 4: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate methyl [ka] Intermediate 12, step 4, was prepared from methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to intermediate 3, step 2 to give 0.48 g (31%) of methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 496

[0124] Step 5: 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate methyl [ka] Intermediate 12, step 5, was prepared from methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate following a similar procedure as intermediate 1 to afford 260 mg (61%) of methyl 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 271

[0125] Intermediate 13: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Step 1: 6-(2,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 1-bromo-2,4-dichloro-benzene (890 mg, 3.94 mmol), 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (500 mg; 2.63 mmol), XANTPHOS (0.304 g, 0.53 mmol) and Pd2(dba)3 (0.3 g, 0.53 mmol) in xylene (10 ml) was heated to reflux for 16 h. After cooling to RT, water (50 ml) and Et2O (50 ml) were added. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc 100 / 00 to 95 / 05 to give 470 mg (42%) of 6-(2,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+): 335

[0126] Step 2: 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 6-(2,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (470 mg, 1.23 mmol) and aluminum chloride (395 mg, 2.96 mmol) in toluene (8 ml) was heated at 90° C. for 2 h. After cooling to room temperature, water (20 ml) and EtOAc (50 ml) were added. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc 100 / 00 to 80 / 20 to give 165 mg (42%) of 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+): 321

[0127] Step 3: 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate [ka] A mixture of 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (163 mg, 0.51 mmol), K2CO3 (77 mg, 0.56 mmol) and pivaloyl chloride (67 mg, 0.56 mmol) in acetone (5 ml) was heated at 40 °C for 1 h. After cooling to RT, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography using a gradient of cyclohexane / EtOAc 100 / 00 to 90 / 10 to give 205 mg (96%) of 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate. LC / MS(m / z, MH+): 405

[0128] Step 4: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] To a solution of 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate (197 mg, 0.48 mmol) in THF (5 ml) was added KHMDS (1 M, 0.58 ml, 0.58 mmol) at -50°C under Ar atmosphere. The mixture was stirred for 30 min and to the resulting mixture was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (173 mg, 0.49 mmol). The reaction mixture was slowly warmed to 20°C and stirred for 90 min. The reaction mixture was quenched with saturated aqueous citric acid, then diluted with water and extracted twice with Et2O. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a gradient of cyclohexane / EtOAc 100 / 00 to 90 / 10 to give 160 mg (61%) of 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z, MH+): 537

[0129] Intermediate 14: (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine [ka] A mixture of (3Z)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine (Intermediate 6) (200 mg, 0.67 mmol) in dioxane (4 ml), Pd(PPh3)2Cl2 (38 mg, 0.07 mmol), bis(pinacolato)diboron (221 mg, 0.87 mmol) and AcOK (164 mg, 1.68 mmol) was heated at reflux for 2 h. After cooling, the reaction mixture was filtered through dicalite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of DCM / EtOAc / EtOH: 100 / 00 / 00 to 75 / 20 / 05 to give 160 mg (69%) of (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine. LC / MS(m / z, MH+): 346

[0130] Intermediate 15: (3Z)-1-(3,3-difluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine [ka] Intermediate 15 was prepared from (3Z)-3-[(4-bromophenyl)methylene]-1-(3,3-difluoropropyl)pyrrolidine (Intermediate 8) following a similar procedure to intermediate 14 to give 114.8 mg (87%) of (3Z)-1-(3,3-difluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine. LC / MS(m / z, MH+): 364

[0131] Intermediate 16: 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate methyl [ka] Step 1: 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate methyl [ka] Intermediate 16, step 1, was prepared from methyl 1-oxotetralin-6-carboxylate following a procedure similar to intermediate 3, step 1 to afford 459 mg (19%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 349

[0132] Step 2: 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate methyl [ka] Intermediate 16, step 2, was prepared from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate following a procedure similar to intermediate 3, step 2 to give 0.48 g (31%) of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z, MH+): 481

[0133] Intermediate 17: (Z)-3-(4-bromo-2-fluorobenzylidene)-1-(3-fluoropropyl)pyrrolidine [ka] Step 1: tert-Butyl 3-(4-bromo-2-fluorobenzoyl)pyrrolidine-1-carboxylate [ka] To a solution of 1,4-dibromo-2-fluoro-benzene (11.3 g, 44.52 mmol) in THF (60 ml) cooled at -78°C, 2.5 M n-BuLi (18 ml, 44.52 mmol) was added dropwise. After stirring at -78°C for 45 min, a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (10 g, 38.71 mmol) in THF (60 ml) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for 18 h. The reaction mixture was poured into a mixture of saturated aqueous NH4Cl (200 ml) and EtOAc (300 ml). After decantation, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a gradient of DCM / EtOAc 100 / 0 to 80 / 20 to give 2.27 g (13%) of tert-butyl 3-(4-bromo-2-fluorobenzoyl)pyrrolidine-1-carboxylate. LC / MS(m / z, MH+): 372

[0134] Step 2: (4-Bromo-2-fluorophenyl)(pyrrolidin-3-yl)methanone, 2,2,2-trifluoroacetic acid [ka] Intermediate 17, step 2, was prepared from tert-butyl 3-(4-bromo-2-fluorobenzoyl)pyrrolidine-1-carboxylate following a procedure similar to intermediate 5, step 1 to afford 1.96 g (84%) of (4-bromo-2-fluorophenyl)(pyrrolidin-3-yl)methanone, 2,2,2-trifluoroacetic acid. LC / MS(m / z, MH+): 272

[0135] Step 3: (4-bromo-2-fluorophenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)methanone [ka] Intermediate 17, step 3, was prepared from (4-bromo-2-fluorophenyl)(pyrrolidin-3-yl)methanone, 2,2,2-trifluoroacetic acid following a procedure similar to intermediate 5, step 2 to afford 1.13 g (67%) of (4-bromo-2-fluorophenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)methanone. LC / MS(m / z, MH+): 332

[0136] Step 4: (4-bromo-2-fluorophenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)methanol [ka] Intermediate 17, step 4, was prepared from (4-bromo-2-fluorophenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)methanone following a procedure similar to intermediate 5, step 3, to afford 2.1 g (97%) of (4-bromo-2-fluorophenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)methanol. LC / MS(m / z, MH+): 334

[0137] Step 5: (Z)-3-(4-bromo-2-fluorobenzylidene)-1-(3-fluoropropyl)pyrrolidine [ka] Intermediate 17 step 5 was prepared from (4-bromo-2-fluorophenyl)(1-(3-fluoropropyl)pyrrolidin-3-yl)methanol following a similar procedure to intermediate 6 to give 925 mg of 3-(4-bromo-2-fluorobenzylidene)-1-(3-fluoropropyl)pyrrolidine as a mixture of cis and trans isomers. The mixture of cis and trans isomers of 3-(4-bromo-2-fluorobenzylidene)-1-(3-fluoropropyl)pyrrolidine was separated by chiral chromatography: Chiralpak AD 20 μm (250×4.6 mm) eluting with heptane / EtOH / TEA: 95 / 05 / 0.1 to give 510 mg of the trans isomer (E)-3-(4-bromo-2-fluorobenzylidene)-1-(3-fluoropropyl)pyrrolidine and 248 mg of the cis isomer (Z)-3-(4-bromo-2-fluorobenzylidene)-1-(3-fluoropropyl)pyrrolidine. LC / MS(m / z, MH+): 316

[0138] Intermediate 18: [1-(3-fluoropropyl)pyrrolidin-3-yl]-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone [ka] Intermediate 18 was prepared from (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone (step 2 of intermediate 5) following a similar procedure to intermediate 14 to give 2.4 g (100%) of [1-(3-fluoropropyl)pyrrolidin-3-yl]-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone. LC / MS(m / z, MH+): 362

[0139] Method A: Example 1: (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride [ka] Step 1: (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 2) (261.8 mg, 0.23 mmol), (3Z)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine (intermediate 6) (150 mg, 0.50 mmol), Cs2CO3 (426 mg, 1.31 mmol), and Pd(dppf)Cl2 DCM complex (25.8 mg, 0.03 mmol) in dioxane (4 ml) and water (1 ml) was heated to reflux for 1 h. After cooling to RT, water (10 ml) and EtOAc (20 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with cyclohexane / EtOAc 50 / 50 to give 131 mg (46%) of methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):564

[0140] Step 2: (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride [ka] To a solution of (Z)-methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (131 mg, 0.22 mmol) in MeOH (2 ml), THF (1 ml), and water (0.5 ml) was added LiOH (53.86 mg, 2.25 mmol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (and 1N HCl until pH 1-2). The solid that formed was filtered, washed with EtO, and dried in an oven to give 81.5 mg (62%) of (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride.

[0141] Method B: Example 2: (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of (Z)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 9) (87 mg, 0.17 mmol), (2-chloro-4-fluoro-phenyl)boronic acid (36.5 mg, 0.21 mmol), Cs2CO3 (148 mg, 0.45 mmol), and Pd(dppf)Cl2 complex in DCM (8.55 mg, 0.01 mmol) in dioxane (4 ml) and water (1 ml) was heated at reflux for 1 h. After cooling to RT, the reaction mixture was quenched with saturated NH4Cl solution (5 ml) and EtOAc (20 ml). After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 80 / 20 to give 53 mg (55%) of methyl (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 548

[0142] Step 2: (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Example 2, step 2 was prepared from methyl (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Example 1, step 2 to give 33 mg (66%) of (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0143] Method C: Example 24: (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid, hydrochloride [ka] Step 1: (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate methyl [ka] A mixture of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate (Intermediate 16) (280 mg, 0.28 mmol), (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine (Intermediate 14) (151 mg, 0.44 mmol), Cs2CO3 (486 mg, 1.49 mmol), and Pd(dppf)Cl2 complexed with DCM (43 mg, 0.05 mmol) in dioxane (3 ml) and water (1.21 ml) was heated at reflux for 30 min. After cooling to RT, water (2 ml) and DCM (10 ml) were added. After decantation through a hydrophobic column, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 95 / 05 to give 123 mg (51%) of methyl (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z, MH+): 550

[0144] Step 2: (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid, hydrochloride [ka] Example 24, step 2, was prepared from methyl (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate following a procedure similar to that of example 1, step 2, to give 113 mg (88%) of (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid, hydrochloride.

[0145] Method D: Example 16: (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, hydrochloride [ka] Step 1: (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] A mixture of 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (Intermediate 13) (60 mg, 0.11 mmol), (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine (Intermediate 14) (40 mg, 0.11 mmol), Cs2CO3 (91 mg, 0.28 mmol), and Pd(dppf)Cl2 DCM complex (6 mg, 0.008 mmol) in dioxane (2 ml) and water (0.5 1 ml) was heated to reflux for 30 min. After cooling to RT, water (5 ml) and EtOAc (10 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc 90 / 10 to 80 / 20 to give 31 mg (46%) of (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z, MH+):607

[0146] Step 2: (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, hydrochloride [ka] To a solution of (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (31 mg, 0.04 mmol) in MeOH (2 ml), NaOH (6.8 mg, 0.17 mmol) was added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure. To the resulting residue, water (5 ml) and 1N HCl (to pH 1-2) were added followed by DCM (10 ml). After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 95 / 05 to give 5.6 mg (17%) of (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, hydrochloride.

[0147] Method E: Example 30: (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol [ka] Step 1: 5-(4-(1-(3-fluoropropyl)pyrrolidine-3-carbonyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Step 1 of Example 30 was prepared according to a procedure similar to Step 1 of Example 16 from 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate (prepared according to WO2018091153) and [1-(3-fluoropropyl)pyrrolidin-3-yl]-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone (Intermediate 18) to give 2.7 g (86%) of 5-(4-(1-(3-fluoropropyl)pyrrolidine-3-carbonyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate. LC / MS(m / z, MH+): 496

[0148] Step 2: 5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Example 30, step 2, was prepared from 5-(4-(1-(3-fluoropropyl)pyrrolidine-3-carbonyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate following a procedure similar to intermediate 5, step 3 to afford 980 mg (36%) of 5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate. LC / MS(m / z, MH+): 498

[0149] Step 3: 4-Bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Example 30, step 3, was prepared from 5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate following a procedure similar to intermediate 9, step 2, to afford 650 mg (56%) of 4-bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate. LC / MS(m / z, MH+): 576

[0150] Step 4: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Example 30, step 4, was prepared from 4-bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate following a procedure similar to example 2, step 1 to give 700 mg (97%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate. LC / MS(m / z, MH+):642

[0151] Step 5: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol [ka] To a solution of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate (724 mg, 1.09 mmol) in MeOH (5 ml) was added 5N NaOH (0.65 ml, 3.3 mmol) and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (5 ml) and 1N HCl (to pH 7) followed by DCM (20 ml). After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 90 / 10 to give 570 mg (91%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol. LC / MS(m / z, MH+): 558

[0152] Step 5: (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol [ka] To a mixture of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)(hydroxy)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol (560 mg, 1 mol) in water (1.3 ml) cooled at 0° C. was added sulfuric acid (11 ml, 207 mmol) dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for 18 h and at 50° C. for 1.5 h. The reaction mixture was poured into a mixture of ice and water (500 ml). Powdered NaHCO3 was added to bring the pH to 9 followed by EtOAc (300 ml), the organic phase was separated, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 95 / 05 to give 11 mg (2%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol as a mixture of (Z) and (E) isomers.

[0153] A mixture of the (Z) and (E) isomers of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol was eluted with heptane / EtOH / TEA (90 / 10 / 0.1) on column I-Cellulose 5 μm (Phenomenex Chiralpak IC equivalents (0.3 x 25 cm) to give 2.7 mg of the (Z)-isomer (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol and 4.1 mg of the (E)-isomer (E)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol.

[0154] Compounds according to Table 1a above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0155] Test: Estrogen receptor degrading activity Said test involves measuring the in vitro degradation activity of the compounds of Table 1a.

[0156] Measurement of degradation activity was performed using breast cancer cell ERα in a cell Western assay as described below.

[0157] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells / 30 μL per well in phenol red-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran striped FBS. The next day, 2.5 μL of 1:5 nine-step serial dilutions of each compound were added to the cells at final concentrations ranging from 0.3 to 0.0000018 μM (Table 2) or for fulvestrant (used as a positive control) at a final concentration of 0.1 μM. Four hours after compound addition, cells were fixed by adding 25 μL of formalin (5% final concentration of formalin containing 0.1% triton) for 10 min 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 plates for 30 min at room temperature. The LI-COR blocking buffer was removed and the cells were incubated overnight in a refrigerator 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 for 60 minutes at 37°C in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and DNA dye Syto-64 (final concentration 2 μM). The cells were then washed three times in PBS and scanned with an ACUMEN explorer (TTP-Labtech). The integrated intensity in green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0158] In this test, the decomposition activity against estrogen receptors was measured using the concentration that decomposes 50% of the estrogen receptor (i.e., IC 50 ) and are shown in nM.

[0159] The % decrease in ERα levels was determined as follows: % inhibition=100×(1−(sample-fulvestrant:DMSO-fulvestrant)).

[0160] Table 2 below shows the results of the estrogen receptor degrading activity of the compounds in Table 1a tested at 0.3 μM, demonstrating that said compounds have significant degrading activity towards the estrogen receptor.

[0161] [Table 12]

[0162] Therefore, it is clear that the tested compound has degrading activity against estrogen receptor, with IC50 less than 1 μM and degrading level more than 50%.Therefore, the compound of formula (I) can be used for preparing medicine, especially medicine that is degrading agent of estrogen receptor.

[0163] Thus, there is also provided herein a medicament comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0164] There is also provided herein a compound of formula (I) or a pharma- ceutically acceptable salt thereof as hereinbefore defined for use as a medicament.

[0165] There is also provided herein a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof for use in therapy, especially as an inhibitor and degrader of the estrogen receptor.

[0166] There is also provided herein a compound of formula (I) or a pharma- ceutically acceptable salt thereof as hereinbefore defined for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0167] A particular embodiment is a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined above for use in the treatment of cancer.

[0168] In one embodiment, the cancer is a hormone-dependent cancer.

[0169] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0170] 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.

[0171] In another embodiment, the metastasis is a brain metastasis.

[0172] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0173] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0174] 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.

[0175] According to another aspect, provided herein is a method of treating the above indicated conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0176] There is also provided herein the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament useful in the treatment of any of the above indicated conditions, more particularly useful in the treatment of cancer.

[0177] 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 pharma- ceutically acceptable salt thereof, and further at least one pharma- ceutically acceptable excipient.

[0178] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the conventional excipients known to those skilled in the art.

[0179] 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 a base, acid, zwitterion or salt thereof, may be administered in unit dosage form in admixture with conventional pharmaceutical excipients to animals and humans for the treatment of the above disorders or diseases.

[0180] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral liquids or suspensions, sublingual, buccal, intratracheal, ocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, the compounds of formula (I) can be used in creams, gels, ointments or lotions.

[0181] As an example, a unit dosage form of a compound of formula (I) in tablet form may contain the following ingredients: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Corn starch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0182] There may be specific cases in which higher or lower dosages are appropriate. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (In the formula: R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3' and R3" each independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R4' independently represent a hydrogen atom or a fluorine atom; R5 is a hydrogen atom, a fluorine atom or (C １ ~C ３ ) represents an alkyl group; R6 is a group selected from: A phenyl group optionally substituted with a halogen atom, a cyano group or an —OH group (C １ ~C ６ ) alkyl group; (C １ ~C ６ ) fluoroalkyl group; ３ ~C ６ ) a cycloalkyl group; １ ~C ６ ) an alkoxy group; １ ~C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ ~C ４ ) an alkylthio group; １ ~C ４ ) a fluoroalkylthio group; １ ~C ４ ) the phenyl group optionally substituted by 1 to 3 substituents independently selected from alkylsulfonyl groups and -OH groups; ■ (C ３ ~C ６ ) a phenyl group fused with a cycloalkyl; ３ ~C ６ ) cycloalkyl optionally contains unsaturation and said fused phenyl group is (C １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a fused phenyl group, optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Bicyclic groups containing 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a bicyclic group optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups: Heteroaryl groups (e.g., pyridyl groups) containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and at least 5 atoms (including carbon atoms and heteroatoms), including halogen atoms, (C １ ~C ６ ) alkyl group, (C １ ~C ６ ) a fluoroalkyl group, １ ~C ６ ) an alkoxy group, (C １ ~C ６ ) the heteroaryl group optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group, a cyano group, a carbamoyl group, and an —OH group; Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated and optionally substituted with 1 to 4 substituents independently selected from the following: ○Fluorine atom, —OH group, (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a fluoroalkoxy group, an oxo group, ○ (C ３ ~C ６ ) a cycloalkyl group and a phenyl group, ３ ~C ６ ) a cycloalkyl group or a phenyl group containing 1 or 2 halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group; ３ ~C ６ ) cycloalkyl groups and phenyl groups; ■ (C ３ ~C ６ ) Cycloalkyl(C １ ~C ３ ) alkyl group, wherein on the cycloalkyl, there is no fluorine atom, —OH group, (C １ ~C ４ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; ３ ~C ６ ) Cycloalkyl(C １ ~C ３ ) alkyl group; ■ A 4- to 7-membered heterocycloalkyl group (e.g., a tetrahydropyranyl group) containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, which is saturated or partially saturated and is not limited to a fluorine atom, (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) a fluoroalkoxy group, an oxo group, (C １ ~C ３ ) the heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from an alkoxy group and an —OH group; (C) groups such as isobutyl, methyl or ethyl groups １ ~C ６ ) an alkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) the alkyl group, optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and -OH groups; and ■ Phenyl (C １ ~C ２ ) an alkyl group, the phenyl group being selected from the group consisting of a halogen atom; １ ~C ３ ) alkyl group; (C １ ~C ３ ) fluoroalkyl group; １ ~C ３ ) an alkoxy group; １ ~C ３ phenyl (C) optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group; a cyano group; and an —OH group; １ ~C ２ ) alkyl group; represents; - X is -CH ２ represents -, -O- or -S-; - Y represents -CH=, -N= or -CR"=, where R" is (C １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or (C １ ~C ３ ) a fluoroalkyl group (e.g., trifluoromethyl); R7 is independently (C) such as methyl. １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R8 represents a hydrogen atom or a fluorine atom; R9 is a hydrogen atom, (C １ ~C ３ ) an alkyl group or a cyclopropyl group; - n is 0, 1 or 2; m is 0 or 1).

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

3. 3. A compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1 or 2, characterized in that R3 is a -COOH group.

4. A compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, characterised in that R3' and R3" both represent a hydrogen atom.

5. Compounds of formula (I) according to any one of claims 1 to 4, characterized in that R4 and R4' both represent a hydrogen atom; or one of R4 and R4' represents a hydrogen atom and the other represents a fluorine atom, or a pharma- ceutically acceptable salt thereof.

6. X is -CH ２ - or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 5, characterized in that: - represents a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

7. A compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 6, characterised in that R5 represents a hydrogen atom.

8. R6 represents a phenyl group, and the phenyl group is independently selected from the group consisting of a halogen atom, (C １ ~C ６ ) alkyl group and (C １ ~C ６ 8. The compound of formula (I) according to claim 1, wherein the compound is optionally substituted with 1 to 3 substituents selected from the group consisting of fluoroalkyl groups, more particularly chlorine atoms, fluorine atoms, methyl groups and trifluoromethyl groups, or a pharma- ceutically acceptable salt thereof.

9. A compound of formula (I) according to any one of claims 1 to 8, characterized in that n is 0 or 1, and R7 is a fluorine atom, or a pharma- ceutically acceptable salt thereof.

10. A compound of formula (I) according to any one of claims 1 to 9, wherein Y represents -CH= or a pharma- ceutically acceptable salt thereof.

11. A compound of formula (I) according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

12. Compounds of formula (I) according to any one of claims 1 to 11, characterized in that the compounds are selected from the following compounds or their pharma- ceutically acceptable salts, in particular their hydrochlorides: - (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (1), (Z)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (2), (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride (3), - Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (4), - (Z)-8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (5), (Z)-8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (6), (Z)-3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)-1-(3-fluoropropyl)pyrrolidine (7), - (Z)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (8), (Z)-8-(2,4-difluorophenyl)-9-(4-((1-(3,3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (9), (Z)-8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (10), (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (11), (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (12), (Z)-8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (13), (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (14), (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (15), - (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride (16), - (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride (17), (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (18), (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (19), (Z)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,6-dimethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (20), - (Z)-8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (21), (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (22), (Z)-8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (23), - (Z)-6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride (24), (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (25), (Z)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (26), (Z)-8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (27), (Z)-8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (28), - (Z)-8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (29), (Z)-4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol (30).

13. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemistry 2】 wherein R1, R2, R3', R3", R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 11 and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt or a protected OH such as O-pivaloyl, 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, said step being optionally preceded by a step to obtain compound 1K, and a compound of formula 1P 【Chemistry 3】 (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 11, and R3a is as defined above). is the boron reagent R6B(OR') ２ Or R6BF ３ K (where -B(OR') ２ is a boronic acid or pinacolato ester, and R6 is as defined in claim 1 or 8,

14. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemistry 4】 (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 11, and R3a is as defined in claim 13), ２ Or R6BF ３ K (where -B(OR') ２ is a boronic acid or pinacolato ester, and R6 is as defined in claim 1 or 8, said step being optionally preceded by a step to obtain compound 1Pa, 【Chemistry 5】 (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 11, and R3a is as defined above). is converted to compound 1Pa in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol.

15. A compound selected from the compounds of formula 1P, 1K, and 1Pa, or any of their pharma- ceutically acceptable salts. 【Chemistry 6】 wherein R1, R2, R3, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 11, and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl.

16. A compound of formula 1F or formula 1D, or a pharma- ceutically acceptable salt thereof: 【Chemistry 7】 (wherein R1, R2, R4, R4', R5, R7, R8, Y and n are as defined in any one of claims 1 to 11).

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

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

19. A compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 12 for use as an estrogen receptor inhibitor and degrader.

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

21. 21. The compound of formula (I) or a pharma- ceutically acceptable salt thereof for use according to claim 20 for use in the treatment of cancer.

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