Novel substituted fluorinated N-propyl-pyrrolidine compounds, processes for their preparation and their therapeutic uses - Patents.com

Abstract

A compound of formula (I) or a pharma- ceutically acceptable salt thereof (wherein R1 and R2 represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a -COOH group or a -OH group; R3' and R3" represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom or a cyano group; R4 and R5 represent a hydrogen atom, a halogen atom, a -NH2 group, a (C1-C3) alkyl group, a (C1-C3) alkoxy group or a -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form a =NOCH3 group or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group, a -OH group or a fluorine atom; R6 represents a phenyl group, a fused phenyl group, a bicyclic group containing 5 to 12 carbon atoms, a cyclic group containing 2 to 9 carbon atoms, , a heteroaryl group containing 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, a (C1-C6)alkyl group, or a phenyl(C1-C2)alkyl group; X represents -CH2-, -O-, or -S-; Y represents -CH=, -N=, or -CR"=; R8 represents a (C1-C3)alkyl group, a halogen atom, a cyano group, or a (C1-C3)fluoroalkyl group; R9 represents a hydrogen atom or a fluorine atom; R10 and R10' represent a hydrogen atom or a fluorine atom; R11 represents a hydrogen atom, a (C1-C3)alkyl group, or a cyclopropyl group; n is 0, 1, or 2, and m is 0 or 1). Further disclosed are compounds of formula (I) as well as processes for preparing same, pharmaceutical compositions containing them for use as inhibitors and degraders of estrogen receptors, particularly for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation. [Formula 1] TIFF2025513044000155.tif39170

Description

[Technical field]

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

[0002] Estrogen receptors (ER) belong to the steroid / nuclear receptor superfamily that are involved in the regulation of eukaryotic gene expression, cell proliferation, and in target tissues. ER exists in two forms, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors that are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ER resides 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 regulate the transcription of target genes.

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

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

[0005] Although these endocrine therapies have made a great contribution to reducing the incidence of breast cancer, approximately one-third or more of ERα-positive patients show new resistance to such existing therapies or develop resistance over time. Several mechanisms have been described to elucidate resistance to such hormone therapies, such as hypersensitivity of ERα to low estrogen levels in aromatase inhibitor treatment, conversion of tamoxifen effect from antagonistic to agonistic effect in tamoxifen treatment, or signaling pathways of multiple growth factor receptors. In addition, acquired mutations in ERα that occur after the initiation of hormone therapy may also play a role in treatment failure and cancer progression. Certain mutations in ERα, especially those identified in the ligand-binding domain (LBD), give rise to the ability to bind DNA in the absence of ligand, conferring hormone independence to cells with such mutant receptors.

[0006] The majority of identified endocrine therapy resistance mechanisms are due to ERα-dependent activity. One novel strategy to combat such resistance is to block ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data have shown that it is possible to circumvent a significant number of resistance pathways by using SERDs.

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

[0008] WO 2017 / 140669 and WO 2018 / 091153 disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. However, as detailed below, such compounds do not exhibit an optimized pharmacological profile, particularly with regard to limiting CYP3A4 induction.

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

[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 R5 independently represent a hydrogen atom, a fluorine atom, an -NH2 group, a (C1-C3) alkyl group such as a methyl group, a (C1-C3) alkoxy group such as a methoxy group or an ethoxy group, or a -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form, with the carbon atom to which they are attached, a =NOCH3 group or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group, an -OH group or a fluorine atom; or alternatively, R4 and R7 together form a cyclopropyl group via the bond to which they are attached, thereby giving rise to adjacent pyrrolidine groups, azaspiro[2.4]heptane; - R6, ■ a phenyl group optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with 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; ■ fused phenyl groups selected from phenyl groups fused with (C3-C6)cycloalkyl, in which the (C3-C6)cycloalkyl ring optionally contains unsaturation and is optionally substituted with 1 to 3 substituents independently selected from (C1-C3)alkyl groups, hydroxy groups, halogen atoms, (C1-C6)fluoroalkyl groups, and (C1-C3)alkoxy groups; ■ a bicyclic group containing 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, -OH groups, (C1-C3) alkyl groups, (C1-C3) fluoro alkyl groups, (C1-C3) alkoxy groups, (C1-C3) fluoro alkoxy groups and oxo groups; ■ heteroaryl 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, such as a pyridyl group, a pyridone group or a pyrrolyl group, optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) fluoroalkyl groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, cyano groups, carbamoyl groups and -OH groups; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated, ○ 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, an oxo group, (C3-C6)cycloalkyl and phenyl groups, optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; a cycloalkyl group optionally substituted with 1 to 4 substituents independently selected from: ■ a (C3-C6)cycloalkyl(C1-C3)alkyl group, optionally substituted on the cycloalkyl by 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; ■ 4-7 membered heterocycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as tetrahydropyranyl or tetrahydrofuranyl, which are 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 an isobutyl group or an ethylbutyl group, the alkyl group being optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and a -OH group; and ■ A phenyl(C1-C2)alkyl group, wherein the phenyl 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 a group selected from - X represents -CH2-, -O-, or -S-; - Y represents -CH=, -N= or -CR"= (wherein R" represents a (C1-C3) alkyl group, a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl); - R8 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R9 represents a hydrogen atom or a fluorine atom; - R10 and R10' independently represent a hydrogen atom or a fluorine atom; - R11 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] Compounds of formula (I) may exist in tautomeric forms as well.

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

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

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

[0016] As used herein, the following terms have the following definitions unless otherwise stated throughout the specification. halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; - Oxo: the "=O" group; - alkyl group: unless otherwise specified, a linear or branched saturated hydrocarbon-based aliphatic group (described as "(C1-C6) alkyl") containing 1 to 6 carbon atoms. 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, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl 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. Advantageously, the heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above, in which the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Examples include -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkyl group may also be called a perfluoroalkyl group. Examples include trifluoromethyl group or trifluoroethyl group; - alkoxy group: -O-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; - Fluoroalkoxy group: -O-alkyl 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 substituted with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkoxy group may also be called a perfluoroalkoxy group. Examples include trifluoromethoxy group, etc.; - (C1-C4) alkylthio group, also called (C1-C4) alkylsulfanyl group: -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 called (C1-C4) fluoroalkylsulfanyl group: -S-fluoroalkyl group, in which the fluoroalkyl group is as defined above. Examples include, but are not limited to, fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - Fused phenyl: a bicyclic group containing 7-10 carbon atoms and including a phenyl moiety. The phenyl moiety may be fused to 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 cyclic 5-10 membered aromatic group containing 2-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. Such nitrogen atoms may be substituted with oxygen atoms to form -NO bonds. Such -NO bonds can also be expressed as N-oxides (-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 groups, etc. Advantageously, the heteroaryl group is pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine, pyridone and pyrrole; bicyclic groups, which are hydrocarbon groups generally containing from 5 to 12 carbon atoms and selected from groups containing two rings linked via: A single common atom: a "spiro-bicyclic ring". Such spiro-bicyclic alkyls generally contain 5-11 carbon atoms and are called "spiro (C5-C 11 The ring may be saturated or partially unsaturated. Such spiro bicyclic rings may be unsubstituted or substituted, in particular by at least one (C1-C3) alkyl group such as methyl or fluorine. Spiro (C5-C6) with respect to the definition of R6 is referred to as a "spiro bicyclic ring". 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 Advantageously, the bicyclic ring is a spiro[3.3]heptane or spiro[3.3]heptene, also for the R6 group. 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 and bicyclo[4.1.0]heptanyl. 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, and 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 or a -OH group, more particularly, R3 is a -COOH group.

[0019] In another embodiment, in the compounds of formula (I) as defined above, when m is 1, X represents -CH2- or -O-.

[0020] In another embodiment, in the compound of formula (I) as defined above, X represents -CH2- or -O-, in particular, X represents -CH2-.

[0021] In another embodiment, in a compound of formula (I) as defined above, R4 and R5 independently represent a hydrogen atom or a fluorine atom, more particularly, R4 and R5 both represent a hydrogen atom or R4 and R5 both represent a fluorine atom.

[0022] In another embodiment, in a compound of formula (I) as defined above, both R4 and R5 represent a hydrogen atom.

[0023] In another embodiment, in a compound of formula (I) as defined above, R7 represents a hydrogen or fluorine atom, more particularly a hydrogen atom.

[0024] In another embodiment, in the compound of formula (I) as defined above, - R4 and R5 independently represent a hydrogen atom, an -NH2 group, a (C1-C3) alkyl group such as a methyl group, a (C1-C3) alkoxy group such as a methoxy group or an ethoxy group, or a -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form, with the carbon atom to which they are attached, a =NOCH3 group or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group or an -OH group; Or alternatively, R4 and R7 together form a cyclopropyl group via the bond to which they are attached, thereby giving rise to an adjacent pyrrolidine group, an azaspiro[2.4]heptane.

[0025] In another embodiment, in the compound of formula (I) as defined above, R6 is - a phenyl group optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with 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; - heteroaryl 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, such as a pyridyl group, a pyridone group or a pyrrolyl group, optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) fluoroalkyl groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, cyano groups, carbamoyl groups and -OH groups; and - a cycloalkyl group containing 3 to 7 carbon atoms, which is saturated or partially saturated 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 (C3-C6) cycloalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, and a phenyl group optionally substituted with a halogen atom or a (C1-C3) alkyl group; represents a group selected from

[0026] In another embodiment, in the 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 fluorine atoms, chlorine 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.

[0027] In another embodiment, in the compound of formula (I) as defined above, R6 represents a pyridyl group, said pyridyl group being optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkoxy groups, more particularly methoxy groups.

[0028] In another embodiment, in the compound of formula (I) as defined above, R6 represents a saturated or partially saturated cyclohexyl group, more particularly a cyclohexyl group or a cyclohexenyl group, said saturated or partially saturated cyclohexyl group being optionally substituted with 1 to 4 substituents independently selected from (C1-C3) alkyl groups, more particularly 1 to 4 methyl groups.

[0029] In another embodiment, in a compound of formula (I) as defined above, both R3' and R3" represent a hydrogen atom.

[0030] In another embodiment, in the compounds of formula (I) as defined above, n is 0.

[0031] In another embodiment, in a compound of formula (I) as defined above, Y represents -CH=.

[0032] In another embodiment, in a compound of formula (I) as defined above, R9 represents a hydrogen atom.

[0033] In another embodiment, in the compounds of formula (I) as defined above, R10 and R10' both represent a hydrogen atom; or one of R10 and R10' represents a hydrogen atom and the other represents a fluorine atom.

[0034] In another embodiment, in the compounds of formula (I) as defined above, both R10 and R10' represent a hydrogen atom.

[0035] In another embodiment, in a compound of formula (I) as defined above, R11 represents a hydrogen atom or a methyl group, more particularly a hydrogen atom.

[0036] In another embodiment, in the compounds of formula (I) as defined above, m is 1.

[0037] 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 substituents independently selected from chlorine, fluorine, chlorine, methyl and trifluoromethyl, at least one of which contains a halogen atom. In such an embodiment, R3' and R3" are in particular hydrogen atoms. Note that in such an embodiment, R1, R2, R4, R5, R7, R9 and R11 are hydrogen atoms. In such an embodiment, R10 and R10' are both hydrogen atoms; or one of R10 and R10' is a hydrogen atom and the other is a fluorine atom. Note that in such an embodiment, Y is -CH=, m is equal to 1 and n is equal to 0. Note that in such an embodiment, X is a -CH2- group.

[0038] Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or their pharma- ceutically acceptable salts, in particular their hydrochlorides: - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S) isomer (1), - 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1(2), - 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (3), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (4), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (5), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (6), - 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride, isomer 1 (7), - 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride, isomer 2(8), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (9), - 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (10), - 8-(4,4-dimethylcyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (11), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (12), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (13), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (14), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (15), - 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (16), - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (17), - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (18), - 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (19), - 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (20), - 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (21), - 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid, isomer 2 (22), - 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid, isomer 1 (23), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (R) isomer (24), - 3-(2,4-dichlorophenyl)-4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid hydrochloride, isomer 1 (25), - 8-(2,4-dichlorophenyl)-9-(4-(difluoro(1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (26), - 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (27), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (28), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride, isomer 1 (29), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (30), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride, isomer 1 (31), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-fluoro-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (32), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (33), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (34), - 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (35), - 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, isomer 1 (36), - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (37), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (38), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (39), - 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (40), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (41), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (42), - 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 (43), - 4-(2-chlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 (44).

[0039] Another embodiment is a compound selected from the above list, or a pharma- ceutically acceptable salt thereof, for use in therapy, particularly as an inhibitor and degrader of the estrogen receptor.

[0040] Another embodiment is a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, in particular breast cancer.

[0041] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0042] 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 list above, or a pharma- ceutically acceptable salt thereof.

[0043] Another embodiment is a method of treating cancer comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0044] Another embodiment is a pharmaceutical composition comprising an effective dose of a compound selected from the above list, or a pharma- ceutically acceptable salt thereof, as an active ingredient, and at least one pharma- ceutically acceptable excipient.

[0045] The inventors have surprisingly found that the compounds of formula (I) exhibit an improved pharmacological profile, in particular as non-inducers of CYP3A4, in other words by minimizing CYP3A4 induction. This is unpredictable from the prior art, in particular in view of WO 2017 / 140669 and WO 2018 / 091153. The following illustrative part highlights this unexpected property in relation to a number of compounds of formula (I) of the present invention, as well as in relation to compounds representative of the prior art.

[0046] Cytochrome P450 isoform 3A4 (CYP3A4) is responsible for the metabolism of approximately 30% of clinically used drugs from almost all therapeutic categories. Therefore, assessing CYP3A4 induction potential is important to predict drug-drug interactions due to CYP3A4 overexpression. More precisely, low CYP3A4 induction indicates limited undesirable drug interactions. In particular, measuring a compound's CYP3A4 induction potential is part of its overall ADME (absorption, distribution, metabolism, excretion) evaluation.

[0047] Thus, another embodiment is a compound selected from the above list, or a pharma- ceutically acceptable salt thereof, for use in therapy, in particular as an estrogen receptor inhibitor and degrader, which at the same time exhibits an improved pharmacological profile, in particular no or only weak or moderate CYP3A4 induction.

[0048] As used herein, the term "no CYP3A4 induction or weak or moderate CYP3A4 induction" in reference to a compound relates to the degree of no CYP3A4 induction or the degree of weak or moderate CYP3A4 induction, respectively, and is typically calculated from the results of a test entitled "CYP3A4 induction potential to assess ADME profile" in comparison with the reference compound rifampicin, and is expressed as a "%E maxSuch a test is based on the quantification of the induction of CYP3A4 mRNA, which is carried out, for example, by RT-PCR analysis. max can be calculated based on the following formula, as detailed in the exemplary part:

number

[0049] Typically, E max Compounds with an E of 20% or less can be considered to be compounds that exhibit low or no CYP3A4 induction (low risk of drug-drug interactions), max Compounds with a CYP3A4 concentration between 20% and 45% can be considered to exhibit moderate CYP3A4 induction (limited risk of drug-drug interactions).

[0050] Another embodiment is a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, in particular breast cancer, which at the same time exhibits an improved pharmacological profile, typically exhibiting a low or limited risk of drug-drug interactions, and in particular exhibiting no or weak or moderate CYP3A4 induction.

[0051] Another embodiment is a method of inhibiting and degrading estrogen receptors comprising administering to a subject, particularly a human, a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, which exhibits an improved pharmacological profile, typically exhibiting a low or limited risk of drug interactions, and in particular exhibiting no or weak or moderate CYP3A4 induction.

[0052] 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, a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, which exhibits an improved pharmacological profile, typically exhibiting a low or limited risk of drug interactions, and in particular exhibiting no or weak or moderate CYP3A4 induction.

[0053] Another embodiment is a method of treating cancer comprising administering to a subject, particularly a human, a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, which exhibits an improved pharmacological profile, typically exhibiting a low or limited risk of drug interactions, and in particular exhibiting no or weak or moderate CYP3A4 induction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] The compounds of formula (I) may be prepared by the following process.

[0055] Compounds of formula (I) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0056] Described below are the following general methods for preparing compounds of formula (I), optionally modified by using appropriate reagents and conditions to introduce the various moieties found in formula (I).

[0057] The following abbreviations and empirical formulas are used: ADME Absorption, Distribution, Metabolism and Excretion AIBN Azobisisobutyronitrile MeCN Acetonitrile NH4Cl Ammonium chloride CO Carbon monoxide DDI Drug-Drug Interactions BAST Deoxofluor CS2CO3 Cesium carbonate CYP3A4 Cytochrome P450 (CYP) 3A4 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 H2 Hydrogen HCl Hydrochloric acid IsoPrOH Isopropanol LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate MeTHF 2-Methyltetrahydrofuran Pd / C Palladium Carbon KOAc Potassium Acetate KHMDS Potassium bis(trimethylsilyl)amide K2CO3 Potassium Carbonate NaBH4 Sodium borohydride NaHCO3 Sodium Bicarbonate NaH Sodium hydride NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NaHSO3 Sodium bisulfate SCX Strong Cation Exchange PCR Polymerase Chain Reaction 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 phenoxide SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran PPh3 Triphenylphosphine RT room temperature RT-PCR Reverse Transcriptase PCR

[0058] Scheme 1a - Parts 1 and 2: Preparation of Compounds of Formula (I) - General Process Scheme 1a - Part 1: [ka] Scheme 1a - Part 2: [ka] According to Scheme 1a-part 1 and part 2, where R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, and R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined above, compound 1A (prepared according to WO2017140669 when X=C) can be converted to compound 1C in step 1 by treatment with compound 1B in the presence of a palladium catalyst, e.g. bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), and a phosphine, such as triphenylphosphine, in toluene solution by heating the solvent to reflux in the presence of a base, such as KOPh.

[0059] Compound 1C can be converted to compound 1E in step 2 by treatment with compound 1D in a Suzuki coupling reaction using, for example, DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as catalyst in the presence of a base, for example cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0060] Alternatively, in step 1', compound 1E can be obtained by Suzuki coupling of compound 1A with compound 1D' using, for example, DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as catalyst in the presence of a base, for example cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0061] Compound 1E can be converted to compound 1F in step 3 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0062] The bromo derivative intermediate 1F can then be subjected to a second Suzuki coupling in step 4 with a suitable boron reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, using, for example, Pd(dppf)Cl2DCM complex as catalyst, in the presence of a base, for example Cs2CO3, in a mixture of dioxane and water as solvent at room temperature or by heating to reflux, to give compound 1G. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced, for example, by hydrogenation with a catalyst such as Pd / C under about 5 bar hydrogen pressure (H2) at a temperature of up to 70°C to give the corresponding saturated compound 1G.

[0063] Alternatively, compound 1F can be subjected to a photocatalytic coupling reaction with R6Br (wherein R6 is an alkyl group, cycloalkyl, or spiro-bicyclic alkyl group as defined above) using a catalyst such as (Ir[dF(CF3)ppy]2(dtbpy))PF6 and nickel(II) chloride ethylene glycol dimethyl ether complex in the presence of tris(trimethylsilyl)silane and a base such as 4,4'-di-tert-butyl-2,2'-bipyridine and sodium carbonate to give the corresponding compound 1G.

[0064] Compound 1G can be converted to a compound of formula (I) in step 5 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution.

[0065] Compound 1F can be converted to compound 1Fa in step 6 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution.

[0066] This compound 1Fa can be converted to compound I in step 7 via Suzuki conditions using a suitable boron reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, for example using Pd(dppf)Cl2DCM complex as catalyst in the presence of a base such as Cs2CO3 in a mixture of dioxane as solvent and water at room temperature or by heating the solvent to reflux. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced, for example by hydrogenation with a catalyst such as Pd / C under about 5 bar hydrogen (H2) pressure at a temperature of up to 70°C to give the corresponding saturated compound I.

[0067] If R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, deprotection can be achieved in step 5 by treatment with aqueous sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in MeOH. If R3 is COOH, the product can be extracted to give the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0068] Scheme 1b: Alternative preparation of compounds of formula (1E) [ka] Compound 1E' can be prepared in a Suzuki coupling reaction between either compound 1C of step 1 and 1Da or compound 1A of step 1 and 1Da' in the presence of a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex in the presence of a base, such as cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux according to scheme 1b, where R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, including for example O-pivaloyl, and R1, R2, R3, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined above.

[0069] In step 2, compound 1E' can be converted to compound 1E in the presence of TFA after treatment with compound 1Ea (wherein W is Cl, Br, or I or OS2R (R = CH3, PhMe, CF3, or CF2CF2CF2CF3)) in the presence of a base such as potassium carbonate in DMF as a solvent.

[0070] Scheme 1c: Preparation of 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, for example O-pivaloyl; R11 is a hydrogen atom, and R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', n, m, X, and Y are as defined above, in step 1, compound 1F can be converted to compound 1H, for example, by treatment with compound 1B, for example, with a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), and a phosphine, for example triphenylphosphine, in toluene, in the presence of a base, for example KOPh, by heating the solvent to reflux.

[0071] Compound 1G, where R6 is phenyl or heteroaryl, can be prepared in step 2 in a Suzuki coupling reaction of compound 1H with either R6Br or R6I or R6OTf using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as a catalyst in the presence of a base, such as cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0072] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 3 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0073] Scheme 1d: Part 1: Preparation of compounds of formula (I) - General process [ka] Scheme 1d - Part 2 [ka] According to Scheme 1d-part 1 and part 2, where R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, R11 is a hydrogen atom, R6 is a phenyl or heteroaryl group, and R1, R2, R3, R3', R3", R4, R5, R7, R8, R9, R10, R10', n, m, X and Y are as defined above, in step 1, compound 1I can be converted to compound 1J by treatment with an aryl or heteroaryl bromide or iodide in the presence of a palladium catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) in toluene or xylene solution, in the presence of a base such as K2CO3 or Cs2CO3, by heating the solvent to reflux. An alternative method for preparing compound 1J, where R6 can be any of the groups defined above for R6 in formula (I), is described below in Scheme 1g.

[0074] Compound 1J can be converted to compound 1K 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.

[0075] Compound 1K can be converted to compound 1L in step 3, for example, by treatment with compound 1B with a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) and a phosphine, such as triphenylphosphine, in a toluene solution in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0076] Compound 1G can be prepared in step 4 by Suzuki coupling reaction of compound 1L with compound 1D using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0077] Alternatively, compound 1L can be converted to compound 1N in a Suzuki coupling reaction with compound 1M in step 6 using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as a catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0078] Compound 1N can be reduced to compound 1O in step 7, for example, by hydrogenation with a catalyst such as PtO2 under about 2 bar hydrogen (H2) pressure at room temperature.

[0079] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1G or 1O can be converted to a compound of formula (I) in step 5 or step 8 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0080] Scheme 1e: Preparation of compounds of formula (I) - 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, e.g., O-pivaloyl, and R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X, and Y are as defined above, in step 1, compound 1K can be converted to compound 1G by treatment with compound 1D' in the presence of a palladium catalyst, e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex in the presence of a base, e.g., cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0081] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 2 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0082] Scheme 1f: Preparation of compounds of formula (1A) where R3a = CO2Me - General process [ka] According to scheme 1f, where X, m, R3', R3" and R11 are as defined above, compound 1A can be commercially available or prepared as follows: Compound 1P (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted to compound 1Q in step 1 by treatment with trifluoromethanesulfonic anhydride in DCM solution in the presence of pyridine as a base.

[0083] Compound 1Q can be converted to compound 1I' in step 2 by carbonylation with carbon monoxide in DMF and MeOH solution in the presence of a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex.

[0084] Compound 1I' can be converted to compound 1A (wherein R3a = CO2Me) in step 3 by treatment with trifluoromethanesulfonic anhydride in DCM solution in the presence of pyridine as a base.

[0085] Scheme 1g: Alternative preparation of compounds of formula (1J) - general process [ka] According to scheme 1g, where R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, including for example O-pivaloyl, and R3', R3", R6, R11, X and m are as defined above, compound 1J can alternatively be prepared as follows: compound 1I can be converted to compound 1R in step 1, for example by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0086] Compound 1R can be converted to compound 1S in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0087] Compound 1T can be prepared in step 3 by Suzuki coupling reaction of compound 1S with R6B(OR')2 or R6BF3K (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex as catalyst in the presence of a base, such as cesium carbonate (Cs2CO3), in a mixture of toluene and water by heating the solvent to reflux.

[0088] Compound 1T can be converted to compound 1J in step 4 by hydrolysis with aqueous HCl, for example by heating in methanol and DCM.

[0089] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1G [ka] (wherein R1, R2, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, 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, e.g. O-pivaloyl) is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, which step may optionally precede a step to obtain a compound 1G, a compound of formula 1F [ka] where R1, R2, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, 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, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0090] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1Fa [ka] wherein R1, R2, R3, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined above, are subjected to Suzuki coupling with a boron reagent R6-B(OR')2, 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 1Fa, to obtain compound 1Fa of formula 1F. [ka] (wherein R1, R2, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined above, and R3a is as defined above) is converted to compound 1Fa in the presence of a hydroxide ion source, such as NaOH, in a methanol solution.

[0091] Also, an intermediate compound selected from any of the compounds of formula 1E, 1F, 1G, and 1Fa, or a pharma- ceutically acceptable salt thereof. [ka] (wherein R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, 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, e.g., O-pivaloyl), is provided herein.

[0092] Additionally, any of the intermediate compounds of formula 1D and 1D', or pharma- ceutically acceptable salts thereof, [ka] (wherein R1, R2, R4, R5, R7, R8, R9, R10, R10', n, and Y are as defined above) are provided herein.

[0093] In another aspect, there is also provided herein a process for preparing a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula 1G as defined above, followed by optionally a purification step.

[0094] Said purification step may for example consist of an acidification step, for example with aqueous hydrochloric acid, as shown in step 2 of Example 1 herein below.

[0095] Additionally, any of the intermediate compounds of formula 1L, or pharma- ceutically acceptable salts thereof [ka] (wherein R3a, R3', R3", X, m and R6 are as defined above, and R11 is a hydrogen atom) is provided herein.

[0096] At 400MHz and 500MHz 1H NMR spectra were performed on a Bruker Avance DRX-400 spectrometer and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (σ in ppm) in the solvent dimethylsulfoxide-d6 (D6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0097] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument, a light scattering detector Sedere and an SQD Waters mass spectrometer using a DAD (210-400 nm) for UV detection, a Flash Acquity UPLC CSH C18 1.7 μm (dimensions 2.1 × 30 mm), and a mobile phase of H2O + 0.1% HCOH / CH3CN + 0.1% HCOH.

[0098] The following Tables 1a and 1b respectively list certain compounds of formula (I) according to the present disclosure (names and structures), as well as their characterization ( 1 H NMR and liquid chromatography / mass spectrometry.

[0099] [Table 1]

[0100] [Table 2]

[0101] [Table 3]

[0102] [Table 4]

[0103] [Table 5]

[0104]

Table 6

[0105]

Table 7

[0106]

Table 8

[0107]

Table 9

[0108]

Table 10

[0109]

Table 11

[0110]

Table 12

[0111]

Table 13

[0112]

Table 14

[0113]

Table 15

[0114]

Table 16

[0115] [Table 17]

[0116] [Table 18]

[0117] The following examples illustrate the preparation of some compounds of formula (I) described herein. The compound numbers exemplified below correspond to those shown in Table 1 above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0118] In the following examples, unless the source of a starting product is specified, it is to be understood that said products are known compounds.

[0119] Intermediates: Intermediate 1: 3-(4-bromobenzyl)-1-(3-fluoropropyl)pyrrolidine, Isomer 1 and Isomer 2 [ka] Step 1: tert-Butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate, Isomer 1 and Isomer 2 [ka] To a solution of commercially available 3-(4-bromobenzyl)pyrrolidine (35.0 g, 145 mmol) and TEA (29.5 g, 292 mmol) in DCM (250 ml) were added DMAP (1.78 g, 14.57 mmol) and Boc2O (33.4 g, 153 mmol) at room temperature and the suspension was stirred at room temperature for 12 h. The reaction mixture was quenched by adding water (300 ml) and extracted with DCM (100 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 petroleum ether / ethyl acetate: 98 / 02 to 50 / 50 to give 37 g (73%) of tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate as a pale yellow oil.

[0120] A mixture of isomers of tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate (37 g, 107 mmol) was separated by preparative SFC (column: DAICEL CHIRALCEL OJ (250×50 mm, 10 μm); supercritical CO 80% / [0.1% NHOH EtOH] 20%) to give 17 g of tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate isomer 1 and 17 g of tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate isomer 2. LC / MS(m / z,MH+):340

[0121] Step 2: 3-(4-Bromobenzyl)pyrrolidine hydrochloride, isomer 1 [ka] To a solution of tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate isomer 1 (17.0 g, 50.0 mmol) in EtOAc (160 ml) was added a 4N solution of HCl in dioxane (50 ml, 200 mmol) and the mixture was stirred at room temperature for 2 hours. The solution was concentrated in vacuo to give 17 g (crude) of 3-(4-bromobenzyl)pyrrolidine hydrochloride, isomer 1 compound. LC / MS(m / z,MH+):240

[0122] Step 3: 3-(4-Bromobenzyl)-1-(3-fluoropropyl)pyrrolidine, isomer 1 [ka] To a mixture of 3-(4-bromobenzyl)pyrrolidine hydrochloride, isomer 1 (12 g, 43.4 mmol) and K2CO3 in DMF (84 ml) was added 1-fluoro-3-iodo-propane (8.56 g, 45.55 mmol) and the mixture was heated to 80° C. for 2 h. The reaction mixture was quenched by adding water (400 ml) and extracted twice with EtOAc (200 ml). The combined organic phases were washed with brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 90 / 10 to give 10 g (76%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)pyrrolidine, isomer 1. LC / MS(m / z,MH+):300

[0123] Step 2': 3-(4-bromobenzyl)pyrrolidine hydrochloride, isomer 2 [ka] Intermediate 1 isomer 2 step 2' was prepared from tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate isomer 2 following a similar procedure to intermediate 1 isomer 1 step 2 to afford 16 g (crude) of 3-(4-bromobenzyl)pyrrolidine hydrochloride, isomer 2. LC / MS(m / z,MH+):240

[0124] Step 3': 3-(4-bromobenzyl)-1-(3-fluoropropyl)pyrrolidine, isomer 2 [ka] Intermediate 1, isomer 2, step 3' was prepared from 3-(4-bromobenzyl)pyrrolidine hydrochloride, isomer 2 following a similar procedure to intermediate 1, isomer 1, step 3 to afford 9.95 g (55%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)pyrrolidine, isomer 2. LC / MS(m / z,MH+):300

[0125] Intermediate 2: 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 (674.87 mg, 2.57 mmol), bis(pinacolato)diboron (144.08 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 became orange and then brown. After cooling to room temperature, 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 afford 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

[0126] Intermediate 3: Methyl 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 [ka] Intermediate 3 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO 2020 / 049153) according to a similar procedure to intermediate 2 to give 4.23 g (30% yield) of methyl 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

[0127] Intermediate 4: 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine Isomer 1 and Isomer 2 [ka] Step 1: tert-Butyl 3-(4-bromobenzoyl)-3-fluoro-pyrrolidine-1-carboxylate [ka] To a solution of commercially available tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate (130 g, 367 mmol) in THF (1.00 L) was added LiHMDS (1 M, 514 ml) at −70° C. The reaction mixture was stirred at −70° C. for 1 h. To the above mixture was added N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (150 g, 477 mmol) in THF (500 ml) at −70° C. The reaction mixture was stirred at -70 °C for 1 h, then poured into aqueous NH4Cl (500 ml), extracted with 900 ml (3 x 300 ml) of EtOAc, dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc 10 / 1 to 4 / 1 to give 130 g (95%) of tert-butyl 3-(4-bromobenzoyl)-3-fluoro-pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):372

[0128] Step 2: tert-Butyl 3-[(4-bromophenyl)-hydroxy-methyl]-3-fluoro-pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 3-(4-bromobenzoyl)-3-fluoro-pyrrolidine-1-carboxylate (130 g, 349 mmol) in MeOH (1 L) was added NaBH4 (19.8 g, 524 mmol) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by adding water (20 ml) at 0° C., then diluted with water (400 ml) and the organic phase was removed. The aqueous layer was extracted with EtOAc (3×400 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 130 g (crude) tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]-3-fluoro-pyrrolidine-1-carboxylate as a pale yellow oil. LC / MS(m / z,MH+):374

[0129] Step 3: tert-Butyl 3-[(4-bromophenyl)-methylsulfanylcarbothioyloxy-methyl]-3-fluoro-pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]-3-fluoro-pyrrolidine-1-carboxylate (86 g, 230 mmol) and imidazole (78.2 mg, 1.15 mmol) in THF (900 ml) was added NaH (13.8 g, 345 mmol, 60% purity) at 10° C. The reaction mixture was stirred at 10° C. for 30 minutes. Carbon disulfide (35 g, 460 mmol, 27.8 ml) was added to the mixture and the reaction mixture was stirred at 25° C. for 30 minutes. Methyl iodide (58.7 g, 414 mmol, 25.8 ml) was added to the above mixture and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into NH4Cl solution (200 ml). The organic phase was separated, washed with EtOAc (3×200 ml), dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc 90 / 10 to 70 / 30 to afford 102 g (96%) of tert-butyl 3-[(4-bromophenyl)-methylsulfanylcarbothioyloxymethyl]-3-fluoro-pyrrolidine-1-carboxylate as a pale yellow oil. LC / MS(m / z,MH+):374

[0130] Step 4: tert-Butyl 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 3-[(4-bromophenyl)-methylsulfanylcarbothioyloxy-methyl]-3-fluoro-pyrrolidine-1-carboxylate (25.5 g, 54.9 mmol) in toluene (250 ml) was added tributylstannane (29.6 g, 102 mmol, 26.9 ml) and AIBN (721 mg, 4.39 mmol). The reaction mixture was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction mixture was poured into water (1 L), extracted with EtOAc (3×100 ml), dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc 90 / 10 to 70 / 30 to give 17.25 g (88%) of tert-butyl 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine-1-carboxylate as a pale yellow solid. LC / MS(m / z,MH+):358

[0131] Step 5: 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine, hydrochloride [ka] Intermediate 4, step 5, was prepared from tert-butyl 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine-1-carboxylate following a similar procedure to intermediate 1, isomer 1, step 2 to afford 32 g (crude) of 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine, hydrochloride. LC / MS(m / z,MH+):240

[0132] Step 6: 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine [ka] To a solution of 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine, hydrochloride (32.0 g, 109 mmol) in THF (220 ml) was added NaOH (5 M, 109 ml) and 1-fluoro-3-iodo-propane (20.4 g, 109 mmol). The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was poured into water (100 ml), extracted with EtOAc (300 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 98 / 02 to 90 / 10 to give 28 g (crude), which was further purified by preparative HPLC (column: Agela DuraShell C18 250×70 mm, 10 μm; mobile phase: gradient of 43% to 67% MeCN (0.05% NH4OH+10 mM NH4HCO3) in water in 20 min) to give 12 g (35%) of 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine. LC / MS(m / z,MH+):318

[0133] Step 7: 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine isomer 1 and isomer 2 [ka] The mixture of isomers of 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine was separated by preparative SFC (column: DAICEL CHIRALPAK IG (250×30 mm, 10 μm); supercritical CO 75% / MeOH 25%) to give 5 g of 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine isomer 1 and 5 g of 3-[(4-bromophenyl)methyl]-3-fluoro-1-(3-fluoropropyl)pyrrolidine isomer 2. LC / MS(m / z,MH+):318

[0134] Intermediate 5: (4-Bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone, racemic mixture [ka] Step 1: (4-Bromophenyl)-pyrrolidin-3-yl-methanone, hydrochloride, racemic mixture [ka] Intermediate 5, step 1, was prepared from tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate, racemic mixture following a similar procedure to intermediate 1, isomer 1, step 2 to give 76 g (crude) of (4-bromophenyl)-pyrrolidin-3-yl-methanone hydrochloride, racemic mixture. LC / MS(m / z,MH+):254

[0135] Step 2: (4-Bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone, racemic mixture [ka] Intermediate 5, step 2, was prepared from (4-bromophenyl)-pyrrolidin-3-yl-methanone hydrochloride, racemic mixture following a similar procedure to intermediate 4, step 6 to give 28 g (93%) of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone, racemic mixture. LC / MS(m / z,MH+):314

[0136] Intermediate 6: 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine isomer 1 and isomer 2 [ka] Step 1: tert-Butyl 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine-1-carboxylate, racemic mixture [ka] To a solution of tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate, racemic mixture (20 g, 56.5 mmol) was added bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (100 ml). The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with NaHCO3 (1000 ml) and extracted with EtOAc (300 ml). The organic phase was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / ethyl acetate 98 / 02 to 00 / 100 to give 19 g (89%) of tert-butyl 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine-1-carboxylate, racemic mixture. LC / MS(m / z,MH+):376

[0137] Step 2: 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine hydrochloride, racemic mixture [ka] Intermediate 6, step 2, was prepared from tert-butyl 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine-1-carboxylate, racemic mixture following a similar procedure to intermediate 1, isomer 1, step 2 to give 20 g (99%) of 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine, hydrochloride, racemic mixture. LC / MS(m / z,MH+):276

[0138] Step 3: 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine, racemic mixture [ka] Intermediate 6, step 3, was prepared from 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine hydrochloride, racemic mixture following a similar procedure to intermediate 1, isomer 1, step 3 to give 15 g (62%) of 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine, racemic mixture. LC / MS(m / z,MH+):336

[0139] Step 4: 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine isomer 1 and isomer 2 [ka] The mixture of isomers of 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine was separated by preparative SFC (column: DAICEL CHIRALPAK AD (250×50 mm, 10 μm); supercritical CO 85% / [0.1% NH OH MeOH] 15%) to give 5.2 g (21%) of 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine isomer 1 and 5.2 g (21%) of 3-[(4-bromophenyl)-difluoro-methyl]-1-(3-fluoropropyl)pyrrolidine isomer 2. LC / MS(m / z,MH+):336

[0140] Intermediate 7: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 [ka] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 [ka] A mixture of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 2) (9.09 g, 27.7 mmol), 3-[(4-bromophenyl)methyl]-1-(3-fluoropropyl)pyrrolidine, Isomer 1 (Intermediate 1, Isomer 1) (7.55 g, 25.1 mmol) (15 g, 52.41 mmol), Pd(dppf)Cl2DCM complex (1.23 g, 1.51 mmol), Cs2CO3 (20.49 g, 62.89 mmol) in dioxane (75 ml) and water (30 ml) was heated to reflux for 4 hours. After cooling to room temperature, DCM (80 ml) and water (80 ml) were added and decanted through a hydrophobic column. The organic phase was 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 8.44 g (80%) of methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 as an orange viscous oil. LC / MS(m / z,MH+):422

[0141] Step 2: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] To a mixture of methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 (8.58 g, 20.4 mmol) in DCM (90 ml) was added pyridinium tribromide (8.46 g, 26.5 mmol). The reaction mixture was stirred at room temperature for 2 h. Water (100 ml) and DCM (150 ml) were added and the pH was adjusted to 10 with concentrated solutions of NaHCO3 and K2CO3. The aqueous phase was washed three times with DCM and the collected organic phases were dried over MgSO4, 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 6.1 g (60%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):500

[0142] Intermediate 8: 3-[(4-bromophenyl)methyl]-1-(3,3-difluoropropyl)pyrrolidine, isomer 1 [ka] Step 1: 3-[(4-bromophenyl)methyl]pyrrolidine, 2,2,2-trifluoroacetic acid, isomer 1 [ka] To a solution of tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate isomer 1 (2.11 g, 5.6 mmol) in DCM (50 ml) was added TFA (30 ml) and the mixture was stirred at room temperature for 4 h. The solution was concentrated under vacuum and the resulting residue was treated with Et2O. The solid formed was filtered and dried to give 1.98 g (90%) of 3-[(4-bromophenyl)methyl]pyrrolidine, 2,2,2-trifluoroacetic acid, isomer 1. LC / MS(m / z,MH+):240

[0143] Step 2: 3,3-Difluoropropyl 4-methylbenzenesulfonate [ka] To a solution of 3,3-difluoropropan-1-ol (500 mg, 5.2 mmol) in THF (10 ml) cooled at 0° C., NaH (229 mg, 5.72 mmol, 60% purity) was added and the mixture was stirred at 0° C. for 1 h. Then, 4-methylbenzenesulfonyl chloride (1.04 g, 5.46 mmol) was added. After stirring at room temperature for 1 h, a concentrated solution of NH4Cl (20 ml) was added and the mixture was extracted with EtOAc (3×50 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 DCM to give 1.03 g (79%) of 3,3-difluoropropyl 4-methylbenzenesulfonate. LC / MS(m / z,MH+):251

[0144] Step 3: 3-[(4-bromophenyl)methyl]-1-(3,3-difluoropropyl)pyrrolidine, isomer 1 [ka] To a mixture of 3-[(4-bromophenyl)methyl]pyrrolidine, 2,2,2-trifluoroacetic acid isomer 1 (1.2 g, 3.39 mmol) and K2CO3 in MeCN (30 ml) was added 3,3-difluoropropyl 4-methylbenzenesulfonate (1.02 g, 4.07 mmol) and the mixture was heated at 80 °C for 2 h. The reaction mixture was quenched by adding a concentrated solution of NH4Cl (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by flash chromatography eluting with a gradient of DCM / EtOAc 100 / 00 to 00 / 100 to give 607 mg (56%) of 3-[(4-bromophenyl)methyl]-1-(3,3-difluoropropyl)pyrrolidine, isomer 1. LC / MS(m / z,MH+):318

[0145] Intermediate 9: 1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine, isomer 1 [ka] A mixture of 3-[(4-bromophenyl)methyl]-1-(3-fluoropropyl)pyrrolidine, isomer 1 (isomer 1 of intermediate 1) (640 mg, 2.13 mmol), Pd(PPh3)2Cl2 (109 mg, 0.15 mmol), bis(pinacolato)diboron (704 mg, 2.77 mmol) and AcOK (523 mg, 5.33 mmol) in dioxane (10 ml) was heated to reflux for 2 h. After cooling, the reaction mixture was filtered over dicalite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 90 / 10 to give 270 g (36%) of 1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine, isomer 1. LC / MS(m / z,MH+):348

[0146] Intermediate 10: 1-(3,3-difluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine, isomer 1 [ka] Intermediate 10 was prepared from 3-[(4-bromophenyl)methyl]-1-(3,3-difluoropropyl)pyrrolidine, isomer 1 (Intermediate 8) following a similar procedure as for Intermediate 9 to give 114.8 mg (87%) of 1-(3,3-difluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine, isomer 1. LC / MS(m / z,MH+):366

[0147] Intermediate 11: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Step 1: Methyl 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Intermediate 11, step 1, was prepared from 3-[(4-bromophenyl)methyl]-1-(3,3-difluoropropyl)pyrrolidine, isomer 1 (Intermediate 8) and methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 2) following a procedure similar to Intermediate 7, step 1, to give 252 mg (59%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):440

[0148] Step 2: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Intermediate 11, step 2, was prepared from methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 following a similar procedure to Intermediate 7, step 2 to give 212 mg (71%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):518

[0149] Intermediate 12: 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), Cs2CO3 (2.03 g, 10.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.304 g, 0.53 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.3 g, 0.53 mmol) in xylene (10 ml) was heated to reflux for 16 h. After cooling to room temperature, 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

[0150] 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 separated, 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

[0151] 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), potassium carbonate (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 room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography with 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

[0152] 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 H2O 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 with 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

[0153] Intermediate 13: Methyl 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [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 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):311

[0154] Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate [ka] To a solution of 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)Cl2DCM complex (1.10 g, 1.43 mmol). The suspension was degassed and purged with CO 3 times. The mixture was stirred at 75 °C under CO (5 bar) for 2 h. The reaction mixture was filtered through Celite. The filtrate was diluted with water (400 ml) and extracted 3 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

[0155] Step 3: Methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 13, step 3, was prepared from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate and 1-bromo-2,4-dichloro-benzene following a similar procedure to intermediate 12, 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

[0156] Step 4: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 13, step 4, was prepared from methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a similar procedure as Intermediate 12, step 4 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

[0157] Step 5: Methyl 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 13, 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 2 to give 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

[0158] Intermediate 14: Methyl 3-bromo-4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate [ka] Step 1: 4-Oxothiochroman-7-yl trifluoromethanesulfonate [ka] Intermediate 14, step 1, was prepared from 7-hydroxythiochroman-4-one (prepared according to WO2018091153) following a procedure similar to that of Intermediate 13, step 1, to give 1.14 g (33%) of 4-oxothiochroman-7-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):313

[0159] Step 2: Methyl 4-oxothiochroman-7-carboxylate [ka] Intermediate 14, step 2, was prepared from 4-oxothiochroman-7-yl trifluoromethanesulfonate following a similar procedure to intermediate 13, step 2 to give 0.61 g (76%) of methyl 4-oxothiochroman-7-carboxylate. LC / MS(m / z,MH+):223

[0160] Step 3: Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate [ka] Intermediate 14, step 3, was prepared from methyl 4-oxothiochroman-7-carboxylate following a similar procedure to intermediate 12, step 4 to afford 199 mg (41%) of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate. LC / MS(m / z,MH+):355

[0161] Step 4: Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-thiochromene-7-carboxylate [ka] Intermediate 14, step 4, was prepared from methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate following a similar procedure as intermediate 2 to give 1 g (35%) of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-thiochromene-7-carboxylate. LC / MS(m / z,MH+):333

[0162] Step 5: Methyl 4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate [ka] Intermediate 14, step 5, was prepared from methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-thiochromene-7-carboxylate and 3-[(4-bromophenyl)methyl]-1-(3-fluoropropyl)pyrrolidine, isomer 1 (Intermediate 1, isomer 1) following a similar procedure to Intermediate 7, step 1 to give 120 mg (47%) of methyl 4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate, isomer 1. LC / MS(m / z,MH+):426

[0163] Step 6: Methyl 3-bromo-4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate, isomer 1 [ka] Intermediate 14, step 6, was prepared from methyl 4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate following a similar procedure to Intermediate 7, step 2 to afford 140 mg (64%) of methyl 3-bromo-4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate, isomer 1. LC / MS(m / z,MH+):504

[0164] Intermediate 15: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate [ka] Step 1: Methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate [ka] Intermediate 15, step 1, was prepared from methyl 1-oxotetralin-6-carboxylate and 1-bromo-2,4-dichloro-benzene following a similar procedure to intermediate 12, step 1 to give 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

[0165] Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate [ka] Intermediate 15, step 2, was prepared from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate following a similar procedure to intermediate 12, 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

[0166] Intermediate 16: 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 [ka] Step 1: Methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 16, step 1, was prepared from methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate and 1-bromo-2,4-difluoro-benzene following a similar procedure to intermediate 12, step 1 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

[0167] Step 2: Methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a suspension of NaH (545 mg, 13.62 mmol, 60% purity by weight) 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 room temperature. 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, concentrated under reduced pressure and 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

[0168] Step 3: 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 [ka] Intermediate 16, step 3, was prepared from methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a similar procedure as intermediate 2 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

[0169] Intermediate 17: 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 [ka] Step 1: Methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 17, step 1, was prepared from 1-bromo-2-methyl-4-fluoro-benzene following a similar procedure as intermediate 12, 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

[0170] Step 2: Methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 17, step 2, was prepared from methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate following a similar procedure as Intermediate 16, 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

[0171] Step 3: 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 [ka] Intermediate 17, 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 2 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

[0172] Intermediate 18: tert-Butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-1-carboxylate, isomer 1 [ka] Intermediate 18 was prepared from tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate isomer 1 (step 1 of Intermediate 1) following a similar procedure to Intermediate 9 to give 2.53 g (74%) of tert-butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-1-carboxylate, isomer 1. LC / MS(m / z,MH+):388

[0173] Intermediate 19: 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, isomer 1 [ka] Step 1: Methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] To a mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (9.42 g, 43.2 mmol) in DCM (400 mL) was added pyridinium tribromide (16.12 g, 45.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Water (500 ml) and ether (1 L) were added. The organic phase was separated, washed twice with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z,MH+):297

[0174] Step 2: Methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate [ka] To a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (10 g, 33.66 mmol) in acetonitrile (100 mL) was added DABCO (7.4 mL, 67.32 mmol). The reaction mixture was heated to 55° C. under Ar for 2.5 h. Ether and 1N HCl were added. The organic phase was separated, washed twice with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane / EtOAc 85 / 15 to give 1.88 g (26%) of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z,MH+):217

[0175] Step 3: Methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, racemic mixture [ka] To a solution of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate (1.88 g, 8.6 mmol) in THF (30 mL) at 0° C. under Ar was added a 0.328 M solution of copper salt (35 mL, 11.5 mmol) (prepared by adding 15 mL of a 1.6 N solution of methyllithium in ether to a suspension of 2.5 g of CuI (13 mmol) in 25 mL of ether at 0° C. under Ar). The reaction mixture was stirred at 0° C. for 30 min. Ether (200 mL) and 1 N HCl (200 mL) were added. The organic phase was separated and the aqueous phase was extracted with ether. The combined organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane / EtOAc 95 / 5 to give 1.95 g (86%) of methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture. LC / MS(m / z,MH+):233

[0176] Step 4: Methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 19, step 4, was prepared from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a similar procedure as intermediate 12, step 4 to give 2.5 g (86%) of methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z,MH+):365

[0177] Step 5: tert-Butyl 3-(4-(3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1 [ka] Intermediate 19, step 5, was prepared from methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and tert-butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-1-carboxylate, isomer 1 (Intermediate 18) following a similar procedure to Intermediate 7, step 1 to give 1.02 g (76%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1. LC / MS(m / z,MH+):476

[0178] Step 6: Methyl 7-methyl-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid, isomer 1 [ka] Intermediate 19, step 6, was prepared from 3-(4-(3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1 following a similar procedure to Intermediate 8, step 1 to give 753 mg (100%) of methyl 7-methyl-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid, isomer 1. LC / MS(m / z,MH+):376

[0179] Step 7: Methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] To a solution of methyl 7-methyl-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid, isomer 1 (753 mg, 1.538 mmol) in DCM (15 ml) was added NaOH (0.5N, 7 ml) followed 5 min later by 1-fluoro-3-iodo-propane (0.166 ml, 1.692 mmol). The reaction mixture was stirred at room temperature overnight. 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 446 mg (67%) of methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):436

[0180] Step 8: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Intermediate 19, step 8, was prepared from methyl 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 following a similar procedure to Intermediate 7, step 2 to give 372 mg (71%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):514

[0181] Intermediate 20: 4-Bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 [ka] Step 1: tert-Butyl 3-(4-(8-(pivaloyloxy)-2,3-dihydrobenzo[b]thiepin-5-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1 [ka] Intermediate 20, step 1, was prepared from 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate (prepared according to WO2018091153) and tert-butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-1-carboxylate, isomer 1 (Intermediate 18) following a procedure similar to Intermediate 7, step 1, to give 810 mg (86%) of tert-butyl 3-(4-(8-(pivaloyloxy)-2,3-dihydrobenzo[b]thiepin-5-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1. LC / MS(m / z,MH+):522

[0182] Step 2: 5-(4-(pyrrolidin-3-ylmethyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, 2,2,2-trifluoroacetic acid, isomer 1 [ka] Intermediate 20, step 2, was prepared from tert-butyl 3-(4-(8-(pivaloyloxy)-2,3-dihydrobenzo[b]thiepin-5-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1 following a similar procedure to Intermediate 8, step 1 to give 1.1 g (crude) of 5-(4-(pyrrolidin-3-ylmethyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate, 2,2,2-trifluoroacetic acid, isomer 1. LC / MS(m / z,MH+):422

[0183] Step 3: 5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, isomer 1 [ka] Intermediate 20, step 3, was prepared from 5-(4-(pyrrolidin-3-ylmethyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, 2,2,2-trifluoroacetic acid, isomer 1 following a similar procedure to Intermediate 1, step 3 to afford 490 mg (66%) of 5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, isomer 1. LC / MS(m / z,MH+):482

[0184] Step 4: 4-Bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, isomer 1 [ka] Intermediate 20, step 4, was prepared from 5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, isomer 1 following a similar procedure to Intermediate 7, step 2 to afford 360 mg (63%) of 4-bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, isomer 1. LC / MS(m / z,MH+):560

[0185] Step 5: 4-Bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 [ka] A mixture of 4-bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, isomer 1 (360 mg, 0.64 mmol) in MeOH (7 ml) and 1N NaOH (2 ml, 2 mmol) was stirred at room temperature for 30 min. After addition of 1N HCl (2 ml), the reaction mixture was concentrated under reduced pressure. To the resulting residue were added DCM (60 ml) and water (20 ml). After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 360 ​​mg (crude) 4-bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1. LC / MS(m / z,MH+):476 EXAMPLES

[0186] Method A: Example 1: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S) isomer [ka] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] A mixture of methyl 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 3) (101 mg, 214.75 μmol), 3-(4-bromobenzyl)-1-(3-fluoropropyl)pyrrolidine, isomer 1 (isomer 1 of intermediate 1) (65.8 mg, 219.14 μmol), Cs2CO3 (178.5 mg, 536.9 μmol), and Pd(dppf)Cl2DCM complex (18 mg, 21 μmol) in dioxane (1 ml) and water (0.4 ml) was heated to reflux for 1 h. Water (2 ml) and DCM (5 ml) were added. After decantation through a hydrophobic column, the organic phase was concentrated under reduced pressure and the residue was applied to an SCX column. The resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 94 mg (77%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):566

[0187] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S) isomer [ka] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 (94 mg, 165.8 μmol) in MeOH (0.50 ml) and THF (0.5 ml) was added 1N NaOH solution (0.5 ml) and the reaction mixture was heated to reflux for 1 h. After cooling, water (5 ml) and DCM (5 ml) were added and the pH was adjusted to 2 with 1N HCl. After decantation through a hydrophobic column, the organic phase was concentrated under reduced pressure and the residue was purified by SFC (Flash DCPAK B 5 μm; 250 × 30 mm; supercritical CO2 75% / MeOH 25% / TEA 0.1%, 120 ml / min) to give 65.46 mg (71%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S)-isomer.

[0188] Method B: Example 2: 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 [ka] Step 1: Methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 (intermediate 7) (98 mg, 195.8 μmol), (2-chloro-4-fluoro-phenyl)boronic acid (35 mg, 203 μmol), Cs2CO3 (175 mg, 537 μmol), and Pd(dppf)Cl2DCM complex (16 mg, 19 μmol) in dioxane (1 ml) and water (0.4 ml) was heated at 70° C. for 1 h. After cooling to room temperature, water (2 ml) and DCM (5 ml) were added. After decantation through a hydrophobic column, the organic phase was concentrated under reduced pressure and the residue was subjected to SCX column to give 85 mg (79%) of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):550

[0189] Step 2: 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 [ka] To a solution of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 (85 mg, 154.5 μmol) in MeOH (1 ml) and THF (1 ml) was added 1N NaOH (15 mg, 465 μmol) and the reaction mixture was heated to reflux for 40 min. After cooling, water (5 ml) and DCM (5 ml) were added and the pH was adjusted to 2 with 1N HCl. After decantation through a hydrophobic column, the organic phase was concentrated under reduced pressure and the residue was purified by SFC (Flash DCPAK B 5 μm; 250 × 30 mm; supercritical CO2 70% / MeOH 30% / TEA 0.1%, 120 ml / min) to give 26.47 mg (30%) of 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1.

[0190] Method C: Example 36: 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, isomer 1 [ka] Step 1: Methyl 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate, isomer 1 [ka] A mixture of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate (Intermediate 15) (177 mg, 367 μmol), 1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine, isomer 1 (Intermediate 9) (98 mg, 282 μmol), Cs2CO3 (230 mg, 705 μmol), and Pd(dppf)Cl2DCM complex (14 mg, 17 μmol) in dioxane (2 ml) and water (0.8 ml) was heated at 50° C. for 40 min. Water (2 ml) and DCM (4 ml) were added. After separation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a solution of MeOH in DCM (95 / 05, v / v) to give 33 mg (21%) of methyl 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate, isomer 1. LC / MS(m / z,MH+):552

[0191] Step 2: 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, isomer 1 [ka] Step 2 of Example 36 was prepared from methyl 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate isomer 1 following a procedure similar to Step 2 of Example 2 to give 34 mg (100%) of 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate hydrochloride, isomer 1.

[0192] Method D: Example 3: 8-(4,4-Dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 [ka] Step 1: Methyl 8-(4,4-dimethylcyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Example 3, step 1, was prepared from 2-(4,4-dimethyl-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to a procedure similar to example 2, step 1, to give 99 mg (22%) of methyl 8-(4,4-dimethylcyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):530.

[0193] Step 2: Methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] A mixture of methyl 8-(4,4-dimethylcyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 (99 mg, 187 μmol), Pd / C 10% (21 mg, 200 μmol) in EtOH (6.5 ml) and EtOAc (4 ml) was hydrogenated at 50° C. and 5 bar H2 for 20 h. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (Amylose-1 5 μM; 250 × 30 mm; heptane / IsoPrOH / TEA 95 / 05 / 0.1) to give 35 mg (35%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1. LC / MS(m / z,MH+):532

[0194] Step 3: 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 [ka] Step 3 of Example 3 was prepared from methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 following a procedure similar to that of Step 2 of Example 2 to give 35 mg (97%) of 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrochloride, isomer 1.

[0195] Method E: Example 43: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 [ka] Example 43 was prepared from 4-bromo-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 (Intermediate 20) and 2,4-dichlorophenylboronic acid according to a procedure similar to that of Example 2, step 1 to give 120 mg (70%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1.

[0196] The compounds listed in Table 1 above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0197] Test: Estrogen receptor degrading activity Said test is directed to determining the in vitro degradation activity of the compounds of Table 1a.

[0198] Measurement of degradation activity was performed using breast cancer cell ERα in a cell Western assay as described below.

[0199] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells / 30 μL per well in red phenol-free MEMα medium (invitrogen) containing 5% charcoal dextran-treated FBS. The next day, 9-point serial 1:5 dilutions of each compound were added to the cells in 2.5 μL at final concentrations ranging from 0.3 to 0.0000018 μM (Table 2), or fulvestrant at 0.1 μM (used as a positive control). At 4 h after compound addition, cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton) for 10 min at room temperature, then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added and plated 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 no antibody were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated for 60 min at 37°C in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 DNA dye (final concentration of 2 μM). The cells were then washed three times with 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.

[0200] In this test, the degradation activity of estrogen receptors was determined by the concentration at which 50% of the estrogen receptors were degraded (i.e., IC 50 ) in nM.

[0201] The percentage of decrease in ERα levels was determined as follows: % inhibition=100*(1-(sample-fulvestrant:DMSO-fulvestrant)).

[0202] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1a tested at 0.3 μM, demonstrating that said compounds have significant degrading activity on the estrogen receptor.

[0203] [Table 19]

[0204] [Table 20]

[0205] Therefore, the test compounds have IC50 less than 1 μM, and degradation levels of more than 40%, particularly more than 45% or 50%, and most of the compounds are more than 60% or 80%, clearly showing that they have estrogen receptor degradation activity.Therefore, the compounds of formula (I) can be used to prepare medicines, particularly medicines that are estrogen receptor degraders.

[0206] Testing: CYP3A4 induction potential to assess ADME profile The study evaluates the potential inductive effect of test compounds on CYP3A4 gene expression in primary cultures of human hepatocytes from one or two donors with a confirmed concentration-dependent response to the reference inducer rifampicin.

[0207] Materials and Methods Compounds and Chemicals: Rifampicin and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich (St. Louis, Mo.) All other chemicals and reagents used were obtained from regular commercial sources and were of the highest grade commercially available.

[0208] Cell culture medium for cryopreserved human hepatocytes Thawing medium (UCRM™) and plating medium (UPCM™) were purchased from In Vitro ADMET Laboratories (Bethesda, MD). Culture medium consisted of Williams' medium E containing 2 mM Glutamax, 0.1 μM dexamethasone, 1% ITS (10 μg / mL insulin, 5.5 μg / mL transferrin, 6.7 ng / mL sodium selenite, 50 μg / mL gentamicin (all purchased from Sigma-Aldrich).

[0209] Thawing procedure for cryopreserved human hepatocytes Briefly, vials containing cryopreserved cells were removed from liquid nitrogen storage and thawed in a 37°C water bath (75-90 seconds), then quickly poured into 50 mL pre-warmed UCRM™, centrifuged at 100g for 10 minutes, and rediluted in UPCM™ (IVAL), the so-called plating medium.

[0210] Cell culture and treatment of human hepatocytes: Prior to seeding, cell viability was estimated by trypan blue dye exclusion test. Hepatocytes were seeded in collagen I-coated 96-well plates at a density of 70000 cells / well in 100 μL plating medium for at least 4 h at 37°C in a humidified atmosphere of CO2 / air (5% / 95%). After the cell attachment period, plating medium was removed and hepatocytes were treated daily for two consecutive days (approximately 48 h) with 100 μL fresh culture medium per well containing either solvent control (0.1% DMSO) or four concentrations of the investigated compounds, 0.3 μM, 1 μM, 3 μM, and 10 μM, or the reference inducer rifampicin at 10 μM. All incubations were performed in duplicate.

[0211] 10 mM stock solutions of the different compounds were diluted to obtain daughter solutions of 0.3 mM, 1 mM and 3 mM. On the day of the experiment, the stock solutions were diluted 1000-fold in incubation / culture medium to obtain final concentrations of 0.3 μM, 1 μM, 3 μM and 10 μM.

[0212] The quality of the hepatocyte cultures before incubation with the test compounds was evaluated by light microscopy. The shape of the cultured cells, as well as the attachment efficiency and confluence, were observed and recorded every day. Only monolayers with a minimum confluency of 80% were used for further evaluation.

[0213] Assessment of cytotoxicity of test compounds: Cytotoxicity of each test compound was evaluated during incubation by microscopic examination of the shape of hepatocytes. In addition, cytotoxicity assessment using a Resazurin Cell Viability Assay Kit (Abcam) was also performed to quantify the potential cytotoxic effect of compounds in each experiment.

[0214] Induction assay and measurement of gene expression: After a 48-hour incubation period with the test compounds, the cell culture medium was removed and the cells were lysed to release RNA for assessment of CYP3A4 gene expression. Quantification of CYP3A4 mRNA induction was performed by RT-PCR analysis.

[0215] Total RNA was extracted from hepatocytes using the King Fisher™ Flex Purification System with the MagMAX mirVana Total RNA Isolation Kit (Thermo Fisher Scientific, USA). RNA was quantified fluorometrically using the Quantifluor RNA System (Promega, USA) and cDNA was synthesized from 0.1 μg total RNA using Biorad's (France) iScript Reverse Transcription Supermix for RT-qPCR at 42° C. for 30 min. The cDNA samples were then diluted (1:5) with water and 5 μL of each sample was used for real-time PCR amplification by using the Biorad (France) SYBR Green kit. The following program was used: denaturation step at 95° C. for 30 s, 40 cycles of PCR (denaturation, 95° C., 10 s, and annealing and extension, 58° C., 1 min). In all cases, the quality of the PCR products was assessed by monitoring the fusion step at the end of the run. The human forward and reverse primer sequences used were 5'-CCT-GGC-ACC-CAG-CAC-AAT-3' and 5'-GGG-CCG GAC-TCG-TCA-TAC-3' for actin, and 5'-CAC-AAA-CG-GAG-GCC-TTT-TG-3' and 5'-ATC-CAT-GCT-GTA-GGC-CCC-AA-3' for CYP3A4.

[0216] For each individual well trace, a multivariate nonlinear regression model was used to determine Cq (quantification cycle) values, which were then used to calculate the optimal Cq value. The Cq value is inversely proportional to the amount of target nucleic acid in the sample (i.e., the lowest Cq level corresponds to the maximum amount of target nucleic acid in the sample). The Cq of a reference gene (human actin in this study) was also used as a positive control for quantitative PCR.

[0217] Calculations and Evaluation: The degree of induction caused by treatment with the test compound, i.e., E max The percentage of was calculated based on the following formula:

number

[0218] The fold induction of test compound relative to the level of mRNA expression of the solvent control can also be determined and is calculated based on the following formula: Fold induction (FI) relative to solvent control = E Compound / E Vehicle control and E Vehiclecontrol is set to 1 for mRNA expression.

[0219] The evaluation of test compounds to demonstrate induction was performed using the E max The results are shown in Table 3 below, based on percentages.

[0220] [Table 21]

[0221] Example A: Comparative biological activity of compound (C1) as disclosed in WO 2017 / 140669 and compound (C2) within the scope of WO 2018 / 091153 (C1) corresponds to the compound of Example 51 of WO 2017 / 140669, (C2) corresponds to a compound within the scope of WO 2018 / 091153, both compounds (C1) and (C2) being outside the scope of the present invention.

[0222] Compound (C1) has been synthesized according to Example 51 of WO 2017 / 140669. Compound (C1) shows an oxygen as a linker between the north phenyl moiety and the pyrrolidinyl moiety.

[0223] Compound (C2) is not specifically disclosed in WO 2018 / 091153, but is generally encompassed. This compound is synthesized according to Scheme 3a described in WO 2018 / 091153. Compound (C2) shows a nitrogen as a linker between the north phenyl moiety and the pyrrolidinyl moiety.

[0224] Example A.1: Preparation of compound (C2) Compound (C2): (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: Methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (23.8 g, 67.94 mmol) (prepared according to WO2017140669), (4-hydroxyphenyl)boronic acid (10.85 g, 74.73 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (4.48 g, 6.11 mmol) in dioxane (200 ml) and water (70 ml) was added Cs2CO3 (44.32 g, 135.88 mmol). The reaction mixture was stirred at room temperature for 30 min. Water (500 ml) and EtOAc (500 ml) were added. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of EtOAc and n-heptane (20 / 80; v / v) to give 17.36 g (87%) of methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):295

[0225] Step 2: Methyl 9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (5.02 g, 17.1 mmol) in DCM (100 mL) cooled at 0° C., pyridine (2.5 mL, 30.91 mmol) and trifluoromethanesulfonic anhydride (8.55 g, 30.32 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. DCM (50 mL) and cold water (100 mL) were added and decanted through a hydrophobic column. The organic phase was concentrated under reduced pressure to give 7.2 g (99%) of methyl 9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, which was used in the next step without further purification. LC / MS(m / z,MH+):427

[0226] Step 3: tert-Butyl (S)-3-((4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate [ka] A mixture of methyl 9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (2.81 g, 6.59 mmol), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (2.45 g, 13.18 mmol), palladium(II) acetate (148 mg, 0.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.53 g, 0.92 mmol) and Cs2CO3 (6.44 g, 19.77 mmol) in dioxane (27 mL) was heated to 140° C. for 2 h under microwave irradiation. After cooling to room temperature, dichloromethane and water were added and decanted through a hydrophobic column. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc (100 / 00 to 70 / 30) to give 0.8 g (26%) of tert-butyl (S)-3-((4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate.

[0227] Step 4: Methyl (S)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Compound (C2), step 4, was prepared from tert-butyl (S)-3-((4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)pyrrolidine-1-carboxylate following a similar procedure to step 2 of isomer 1 of intermediate 1 to give 1.64 g (71%) of methyl (S)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):363

[0228] Step 5: Methyl (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Compound (C2), step 5, was prepared from methyl (S)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a similar procedure to step 3 of isomer 1 of intermediate 1 to give 2.17 g (100%) of methyl (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0229] Step 6: Methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Compound (C2), step 6, was prepared from methyl (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 7, step 2, to give 1.51 g (56%) of methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):501

[0230] Step 7: Methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 7 was prepared from methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 2,4-dichlorophenylboronic acid according to a procedure similar to that of step 1 of example 2 to give 182 mg (100%) of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):567

[0231] Step 8: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (compound (C2)) Compound (C2) step 8 was prepared from methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to step 2 of example 1 to give 71 mg (100%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid. LC / MS(m / z,MH+):553. 1H NMR(400MHz,DMSO-d6)δppm 1.44-1.58(m,1H),1.70-1.90(m,2H),2.03-2.22(m,5H),2.29(dd,J=9,5Hz,1H),2.39-2.62(m,5H ),2.76(dd,J=9,7Hz,1H),2.84-2.94(m,2H),3.68-3.86(m,1H),4.47(dt,J=47,6Hz,2H),5.75(br d,J=6Hz,1H),6.29(d,J=9Hz,2H),6.52(d,J=9Hz,2H),6.92(d,J=8Hz,1H),7.19(d,J= 8Hz,1H),7.24-7.33(m,1H),7.58(d,J=2Hz,1H),7.74(dd,J=8,1.8Hz,1H),7.88(d,J= 2Hz, 1H).

[0232] Example A.2: Test: Estrogen receptor degrading activity of compound (C2) Preliminarily, the estrogen receptor degrading activity of compound (C2) was tested according to the same biological conditions as in "Test: Estrogen receptor degrading activity" described above.

[0233] [Table 22]

[0234] In Table 4, compound (C2) tested at 0.3 μM shows significant degrading activity towards the estrogen receptor.

[0235] In addition, as described in WO 2017 / 140669, compound (C1) also exhibits significant decomposition activity against the estrogen receptor (data not shown).

[0236] Example A.3: Test: CYP3A4 induction potential to assess the ADME profile of the compounds of Examples 1, (C1) and (C2) Table 5 below shows comparative data regarding CYP3A4 induction of a compound of the invention (Example 1) versus compounds (C1) and (C2) in the test described above.

[0237] [Table 23]

[0238] The compounds of Example 1, (C1) and (C2) are structurally similar, since they represent the same south moiety related to the annulene ring and the same north moiety in the fluoropropyl-pyrrolidine side chain, and differ only in the nature of the linker between the north phenyl moiety and the pyrrolidinyl moiety. However, as shown in Table 5, the compound of Example 1 of the present invention does not show CYP3A4 induction, in other words, it has no CYP3A4 induction effect, and therefore shows an improved ADME profile compared to compounds (C1) and (C2). Thus, surprisingly, Example 1 of the present invention shows an improved pharmacological profile with a lower risk of inducing drug-drug interactions compared to compounds (C1) and (C2) of the prior art. Such a result was not predictable from the prior art.

[0239] Example B: CYP3A4 Induction Potential of Other Compounds of the Invention Other compounds of the invention listed in Table 1a above were evaluated in the test "CYP3A4 induction potential"; the results are shown in Table 6.

[0240] [Table 24]

[0241] The CYP3A4 induction potential results in Table 6 demonstrate that various compounds of the present invention have no CYP3A4 induction or only weak or moderate CYP3A4 induction. Thus, various examples of the present invention exhibit improved pharmacological profiles with much lower risk of drug-drug interactions compared to compounds (C1) and (C2).

[0242] Accordingly, also provided herein is a pharmaceutical agent comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0243] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above, for use as a medicament.

[0244] In particular, there is also provided herein compounds of formula (I) as defined above, or pharma- ceutically acceptable salts thereof, for use in therapy, in particular as inhibitors and degraders of the estrogen receptor, which exhibit an improved pharmacological profile, typically with a low or limited risk of drug interactions, and in particular no or only weak or moderate CYP3A4 induction.

[0245] 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.

[0246] 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.

[0247] In one embodiment, the cancer is a hormone-dependent cancer.

[0248] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular an estrogen receptor alpha dependent cancer.

[0249] 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.

[0250] In another embodiment, the metastasis is a brain metastasis.

[0251] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0252] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0253] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6 inhibitors, mTOR inhibitors or PI3K inhibitors.

[0254] According to another aspect, there is provided herein a method of treating a pathological condition as set forth above, 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.

[0255] Also provided herein is the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament useful for treating any of the pathological conditions set out above, more particularly useful for treating cancer.

[0256] 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 at least one pharma- ceutically acceptable excipient.

[0257] 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.

[0258] 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 treating the above disorders or diseases.

[0259] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, 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.

[0260] As an example, a unit dosage form of a compound of formula (I) in tablet form may contain the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Cornstarch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0261] There may be specific cases in which higher or lower doses are appropriate. According to usual practice, the dose appropriate for each patient is determined by the physician according to the method of administration, as well as 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 R5 are independently a hydrogen atom, a fluorine atom, or —NH ２ group, methyl group, etc. １ ~C ３ ) an alkyl group, a methoxy group, or an ethoxy group, etc. １ ~C ３ ) an alkoxy group, or an —OH group; or R4 and R5 together form an oxo group, or R4 and R5 together represent, by the carbon atom to which they are attached, =NOCH ３ Group or (C ３ ~C ５ ) forming a cycloalkyl group; R7 represents a hydrogen atom, a methyl group, an —OH group or a fluorine atom; or alternatively, R4 and R7 together form a cyclopropyl group via the bond to which they are attached, thereby providing an adjacent pyrrolidine group, azaspiro[2.4]heptane; - R6 is 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 ) an alkylsulfonyl group; and a phenyl group, optionally substituted with 1 to 3 substituents independently selected from -OH groups; ■ (C ３ ~C ６ ) a phenyl group fused to a cycloalkyl, ３ ~C ６ ) the cycloalkyl ring optionally contains unsaturation, (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 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 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, such as pyridyl, pyridone or pyrrolyl groups, which are not limited to 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 ) a 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; ○ 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 ) cycloalkyl groups, and phenyl groups containing one or two halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group; ３ ~C ６ ) a cycloalkyl group or a phenyl group a cycloalkyl group optionally substituted with 1 to 4 substituents independently selected from: ■ (C ３ ~C ６ ) Cycloalkyl(C １ ~C ３ ) alkyl group, which is selected from the group consisting of a fluorine atom, an —OH group, a (C １ ~C ４ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) optionally substituted on the cycloalkyl by 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 containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group or a tetrahydrofuranyl group, which is saturated or partially saturated and contains 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 ) a heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from an alkoxy group and an —OH group; (C) such as isobutyl or ethylbutyl groups １ ~C ６ ) alkyl group, wherein the alkyl group is selected from the group consisting of a fluorine atom, (C １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and —OH groups; １ ~C ６ ) alkyl groups; and ■ Phenyl (C １ ~C ２ ) an alkyl group, wherein the phenyl is 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 a group selected from - X is -CH ２ represents -, -O-, or -S-; - Y is -CH=, -N= or -CR"= (wherein 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 a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R8 is independently a methyl group or the like. 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; R9 represents a hydrogen atom or a fluorine atom; R10 and R10' independently represent a hydrogen atom or a fluorine atom; R11 is a hydrogen atom or (C １ ~C ３ ) an alkyl group or a cyclopropyl group; n is 0, 1 or 2, - m is 0 or 1.

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

4. When m is 1, X is -CH ２ A compound of formula (I) according to any one of claims 1 to 3, characterised in that it represents - or -O-, or a pharma- ceutically acceptable salt thereof.

5. X is -CH ２ - or -O-, in particular, X is -CH ２ -, or a pharma- ceutically acceptable salt thereof.

6. A compound of formula (I) according to any one of claims 1 to 5, characterized in that R4 and R5 independently represent a hydrogen atom or a fluorine atom, in particular R4 and R5 both represent a hydrogen atom or R4 and R5 both represent a fluorine atom, or a pharma- ceutically acceptable salt thereof.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, characterized in that R7 represents a hydrogen atom or a fluorine atom, more particularly a hydrogen atom.

8. A compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, R4 and R5 are independently a hydrogen atom, —NH ２ group, methyl group, etc. １ ~C ３ ) an alkyl group, a methoxy group, or an ethoxy group, etc. １ ~C ３ ) an alkoxy group, or an —OH group; or R4 and R5 together form an oxo group, or R4 and R5 together represent, by the carbon atom to which they are attached, =NOCH ３ Group or (C ３ ~C ５ ) forming a cycloalkyl group; R7 represents a hydrogen atom, a methyl group or an —OH group; Or alternatively, compounds in which R4 and R7 together form a cyclopropyl group via the bond to which they are attached, thereby giving rise to adjacent pyrrolidine groups, azaspiro[2.4]heptane.

9. R6 represents a phenyl group, and the phenyl group is selected from the group consisting of a halogen atom, (C １ ~C ６ ) alkyl group and (C １ ~C ６ 9. Compounds of formula (I) according to any one of claims 1 to 8, characterized in that they are independently selected from the group consisting of fluoroalkyl groups; and are optionally substituted with one to three substituents selected in particular from fluorine atoms, chlorine atoms, methyl groups and trifluoromethyl groups, or pharma- ceutically acceptable salts thereof.

10. R6 represents a pyridyl group, and the pyridyl group is １ ~C ６ 10. A compound of formula (I) according to any one of claims 1 to 9, characterized in that it is optionally substituted with 1 to 3 substituents independently selected from alkoxy groups, more particularly methoxy groups, or a pharma- ceutically acceptable salt thereof.

11. R6 represents a saturated or partially saturated cyclohexyl group, and the saturated or partially saturated cyclohexyl group is １ ~C ３ 10. A compound of formula (I) according to any one of claims 1 to 9, characterized in that it is optionally substituted with 1 to 4 substituents independently selected from alkyl groups, more particularly 1 to 4 methyl groups, or a pharma- ceutically acceptable salt thereof.

12. A compound of formula (I) according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, characterized in that R3' and R3" both represent a hydrogen atom.

13. A compound of formula (I) according to any one of claims 1 to 12, characterized in that n is 0, or a pharma- ceutically acceptable salt thereof.

14. A compound of formula (I) according to any one of claims 1 to 13, wherein Y represents -CH=, or a pharma- ceutically acceptable salt thereof.

15. A compound of formula (I) according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein R9 represents a hydrogen atom.

16. A compound of formula (I) according to any one of claims 1 to 15, wherein R10 and R10' both represent a hydrogen atom; or one of R10 and R10' represents a hydrogen atom and the other represents a fluorine atom, or a pharma- ceutically acceptable salt thereof.

17. A compound of formula (I) according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein R11 represents a hydrogen atom or a methyl group, more particularly a hydrogen atom.

18. 18. A compound of formula (I) according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

19. A compound of formula (I) according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, in particular the hydrochloride thereof, said compound being selected from the group consisting of the following compounds: - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S) isomer (1), - 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (2), - 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (3), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (4), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (5), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (6), - 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride, isomer 1 (7), - 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride, isomer 2 (8), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (9), - 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (10), - 8-(4,4-dimethylcyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (11), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (12), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (13), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (14), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (15), - 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (16), - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (17), - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (18), - 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (19), - 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (20), - 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (21), - 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid, isomer 2 (22), - 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid, isomer 1 (23), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (R) isomer (24), - 3-(2,4-dichlorophenyl)-4-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid hydrochloride, isomer 1 (25), - 8-(2,4-dichlorophenyl)-9-(4-(difluoro(1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (26), - 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (27), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (28), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride, isomer 1 (29), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (30), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol hydrochloride, isomer 1 (31), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-fluoro-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (32), 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (33), - 9-(4-((1-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (34), - 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (35), - 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, isomer 1 (36), - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (37), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (38), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (39), - 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, isomer 1 (40), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (41), - 9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (42), 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 (43), - 4-(2-chlorophenyl)-5-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, isomer 1 (44).

20. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, comprising the step of: 【Chemistry 2】 wherein R1, R2, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined in any one of claims 1 to 18 and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt or a protected OH, e.g. O-pivaloyl, is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, said step optionally preceding a step to obtain a compound 1G, a compound of formula 1F 【Chemistry 3】 wherein R1, R2, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined in any one of claims 1 to 18, and R3a is as defined above; Boron Reagent R6-B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester, and R6 is as defined in any one of claims 1 or 9-11,

21. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, comprising the step of: 【Chemistry 4】 wherein R1, R2, R3, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined in any one of claims 1 to 18, are reacted with a boron reagent R6-B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester, and R6 is as defined in any one of claims 1 or 9 to 11, said step optionally preceding a step for obtaining compound 1Fa, 【Chemistry 5】 wherein R1, R2, R3', R3", R4, R5, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined in any one of claims 1 to 18, and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt or a protected OH, e.g. O-pivaloyl, A process in the presence of a hydroxide ion source such as NaOH in a methanol solution to convert to compound 1Fa.

22. A compound selected from any of the compounds of formula 1E, 1F, 1G, and 1Fa, or a pharma- ceutically acceptable salt thereof: 【Chemistry 6】 (wherein R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X and Y are as defined in any one of claims 1 to 18, and R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl).

23. A compound of formula 1D or 1D', or any of their pharma- ceutically acceptable salts: 【Chemistry 7】 (wherein R1, R2, R4, R5, R7, R8, R9, R10, R10', n, and Y are as defined in any one of claims 1 to 18).

24. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

26. A compound of formula (I) as claimed in any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, for use as an inhibitor and degrader of the estrogen receptor, which exhibits an improved pharmacological profile, typically with a low or limited risk of drug-drug interactions, and in particular no or only weak or moderate CYP3A4 induction.

27. A compound of formula (I) as defined in any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

28. 28. A compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use according to claim 27 for use in the treatment of cancer.

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