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

Abstract

Provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof: (wherein 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 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; R6 represents a phenyl group, a fused phenyl group, a bicyclic group containing 5 to 12 carbon atoms, a heteroaryl group containing 2 to 9 carbon atoms and 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 -CH2-, -O- or -NH-; R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R8 represents a hydrogen atom, or a (C1-C3) alkyl group or a cyclopropyl group; n is 0, 1 or 2; m is 0 or 1; p is 0 or 1). Further disclosed are processes for the preparation of the compounds of formula (I), or pharma- ceutically acceptable salts thereof, pharmaceutical compositions containing them, and the use of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, in particular for the treatment of ovulation failure, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation. [Formula 1] TIFF2025513853000144.tif32170

Description

[Technical field]

[0001] Disclosed herein are novel substituted fluorinated N-propyl-pyrrolidine and N-propyl-azetidine derivatives, processes for their preparation and their therapeutic use, inter alia, as anti-cancer agents via selective antagonism and degradation of the estrogen receptor. [Background technology]

[0002] Estrogen receptors (ER) belong to the steroid / nuclear receptor superfamily, which are involved in the regulation of eukaryotic gene expression, cell growth and differentiation 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 is located mostly in the cytosol of cells. When the hormone estrogen binds to ER, ER translocates from the cytosol of cells to the nucleus, forms dimers, and subsequently 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 uterus, ovary, breast, bone and white adipose tissue. Aberrant ERα signaling leads to the development of various diseases such as cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases and osteoporosis.

[0004] ERα is expressed in less than 10% of normal breast epithelium, but approximately 50-80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The pathogenetic role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, 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; 3-antagonizing and downregulating ERα levels by fulvestrant, which is used to treat breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have contributed greatly to the reduction of breast cancer incidence, approximately one-third or more of ERα-positive patients show new resistance or develop resistance to such existing therapies over time. Several mechanisms have been described to explain resistance to such hormone therapy, such as high sensitivity of ERα to low estrogen levels in treatment with aromatase inhibitors, switching of tamoxifen effect from antagonistic to agonistic effects in tamoxifen treatment, or multiple growth factor receptor signaling pathways. Acquired mutations in ERα that occur after the initiation of hormone therapy may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), result in the ability to bind DNA in the absence of ligand, conferring hormone independence in cells with such mutant receptors.

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

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

[0008] The documents WO 2017 / 140669, WO 2018 / 091153 and the article by Youssef El-Ahmad et al. (J. Med. Chem., 2020, 63, 512-528) disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. Such compounds have an O-pyrrolidine side chain at the para position and are the (S) stereoisomers. However, the article by James S. Scott et al. (J. Med. Chem., 2023, 66, 2918-2945) on SERD compounds with a tricyclic scaffold and a basic amine-containing side chain shows that changing the side chain from the para position to the meta position has an effect on the biological profile of the compound. Summary of the Invention [Means for solving the problem]

[0009] The present inventors have now discovered novel compounds that can selectively antagonize and degrade estrogen receptors (SERD compounds) for use in the treatment of cancer.

[0010] As used herein, there is provided 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 represents a hydrogen atom or a fluorine atom; - R5 and R5' independently represent a hydrogen atom or a fluorine atom; - R6, ■ a phenyl group (the phenyl group is optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted by a cyano group or an -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)cycloalkyls (the (C3-C6)cycloalkyl rings optionally contain unsaturation) (the fused phenyl groups are 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, such as pyridyl, pyridone or pyrrolyl groups, containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and containing at least 5 atoms including carbon atoms and heteroatoms (said heteroaryl groups are 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 (the cycloalkyl groups 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 groups and phenyl groups, said (C3-C6)cycloalkyl groups or phenyl groups being optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups. and 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 a tetrahydropyranyl group or a tetrahydrofuranyl group (said heterocycloalkyl groups are saturated or partially saturated and are 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 groups 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 ■ Phenyl(C1-C2)alkyl group (the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and a -OH group). represents a group selected from: - X represents -CH2-, -O- or -S-; - Y represents -CH2-, -O- or -NH-; - R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; - R8 represents a hydrogen atom or a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; - m is 0 or 1; and - p is 0 or 1.

[0011] As used herein, there is provided 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 represents a hydrogen atom or a fluorine atom; - R5 and R5' independently represent a hydrogen atom or a fluorine atom; - R6, ■ a phenyl group (the phenyl group is optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted by a cyano group or an -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)cycloalkyls (the (C3-C6)cycloalkyl rings optionally contain unsaturation) (the fused phenyl groups are 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, such as pyridyl, pyridone or pyrrolyl groups, containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and containing at least 5 atoms including carbon atoms and heteroatoms (said heteroaryl groups are 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 (the cycloalkyl groups 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 groups and phenyl groups, said (C3-C6)cycloalkyl groups or phenyl groups being optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups. and 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 a tetrahydropyranyl group or a tetrahydrofuranyl group (said heterocycloalkyl groups are saturated or partially saturated and are 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 groups 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 ■ Phenyl(C1-C2)alkyl group (the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and a -OH group). represents a group selected from - X represents -CH2-, -O- or -S-; - Y represents -CH2-, -O- or -NH-; - R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; - R8 represents a hydrogen atom, a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; - m is 0 or 1; and - p is 0 or 1; Also disclosed are those in which when Y represents -O- or -NH- and p is 1, the asymmetric carbon of pyrrolidine linked to Y is of the (R) configuration.

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

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

[0014] The compounds of formula (I) can exist in the form of a base, an acid, a zwitterion, or an addition salt with an acid or a base. Accordingly, there is provided herein a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0015] 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.

[0016] Among suitable salts of the compounds of formula (I), mention may be made of the hydrochloride salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] 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 stated, a linear or branched saturated hydrocarbon-based aliphatic group containing 1 to 6 carbons (written as "(C1-C6) alkyl"). Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, etc.; - cycloalkyl group: unless otherwise stated, a monocyclic alkyl group containing 3 to 7 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted. Examples may include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, such as, in particular, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, or cyclohexenyl; - cycloalkylalkyl group: an alkyl group substituted with a cyclic alkyl group as defined above, which may include, but is not limited to: cyclobutylmethyl; - heterocycloalkyl group: a saturated or partially unsaturated 4- to 7-membered cycloalkyl group containing 1 to 2 heteroatoms, in particular oxygen or nitrogen, independently selected from oxygen, nitrogen and sulfur. Examples may include, but are not limited to: morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl and tetrahydrothiopyranyl. Heterocycloalkyl is advantageously tetrahydrofuranyl or tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above, wherein the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. Examples may include -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be called a perfluoroalkyl group. Examples may include a trifluoromethyl group or a trifluoroethyl group, etc.; - alkoxy group: -O-alkyl group, the alkyl group being as previously defined. Examples may include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; - Fluoroalkoxy group: -O-alkyl group, where the alkyl group is as defined above and the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. Examples may include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group may be called a perfluoroalkoxy group. Examples may include a trifluoromethoxy group, etc.; - (C1-C4) alkylthio groups, also called (C1-C4) alkylsulfanyl groups: -S-alkyl groups, where the alkyl group is as defined above. Examples may include, but are not limited to: methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.; - (C1-C4) alkylsulfonyl group: -SO2-alkyl group, where the alkyl group is as defined above. Examples can include, but are not limited to, -SO2CH3, -SO2CH2CH3, and the like. - (C1-C4)fluoroalkylthio group, also called (C1-C4)fluoroalkylsulfanyl group: -S-fluoroalkyl group, where fluoroalkyl group is as defined above. Examples may include, but are not limited to: fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - Fused phenyl group: a bicyclic group containing 7-10 carbon atoms and containing 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. The fused phenyl group may be attached to the rest of the molecule by its phenyl moiety. It may be substituted. Examples include, 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 atom may be replaced by an oxygen atom to form a -NO bond. Such -NO group may be present in the form of N-oxide (-N+-O-). Said heteroaryl group may be monocyclic or bicyclic. Examples of heteroaryl groups may 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. The heteroaryl groups are advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine, pyridone and pyrrole; - bicyclic radicals, which generally contain from 5 to 12 carbon atoms, are hydrocarbon radicals selected from the groups containing two rings linked through: A single shared atom: a "spiro-bicyclic ring". Such spiro-bicyclic alkyls generally contain 5-11 carbon atoms and are called "spiro (C5-C 11 )bicyclic ring". The ring may be saturated or partially unsaturated. Such spiro bicyclic rings may be unsubstituted or may be 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 11 Examples of spiro(C5-C6) bicyclic rings may include, but are not limited to, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.3]heptene, spiro[2.5]octane, and 7-azaspiro[3.5]nonane. 11 ) the bicyclic ring is advantageously still a spiro[3.3]heptane or spiro[3.3]heptene with respect to the R6 group; 2 shared atoms: in which case the bicyclic group contains 7 to 12 carbon atoms and optionally contains 1 to 2 unsaturations. Examples of such bicyclic groups may include, but are not limited to, cis-1,3a,4,5,6,6a-hexahydropentalenyl groups, bicyclic [3.1.0]hexan-1-yl, bicyclic [4.1.0]heptanyl and octahydropentalenyl. Three or more shared atoms: In that case, the bicyclic group contains 6 to 10 carbon atoms, and such a bicyclic group is not 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 can 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 carries positive and negative charges and has acidic and basic groups.

[0018] In another embodiment, in the compound of formula (I) as defined above, the asymmetric carbon of pyrrolidine or azetidine linked to Y is of the (R) configuration.

[0019] In another embodiment, in the compound of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0020] In another embodiment, in the compound of formula (I) as defined above, R3 is a -COOH group.

[0021] In another embodiment, in the compound of formula (I) as defined above, R3 is a hydrogen atom.

[0022] In another embodiment, in the compound of formula (I) as defined above, R3 is a -OH group.

[0023] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3" represent a hydrogen atom.

[0024] In another embodiment, in a compound of formula (I) as defined above, R4 represents a hydrogen atom.

[0025] In another embodiment, in the compounds of formula (I) as defined above, X represents -O- or -CH2-, preferably X represents -CH2-.

[0026] In another embodiment, in the compound of formula (I) as defined above, X represents -CH2-.

[0027] In another embodiment, in the compounds of formula (I) as defined above, X represents -O-.

[0028] In another embodiment, in the compounds of formula (I) as defined above, R5 and R5' represent a hydrogen atom.

[0029] In another embodiment, in the compound of formula (I) as defined above, R6 is ■ a phenyl group (the phenyl group is optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted by a cyano group or an -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); or ■ Cycloalkyl groups containing 3 to 7 carbon atoms (the cycloalkyl groups 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 groups and phenyl groups, said (C3-C6)cycloalkyl groups or phenyl groups being optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups. and optionally substituted with 1 to 4 substituents independently selected from Represents.

[0030] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, said phenyl group being optionally substituted by 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.

[0031] 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 or two substituents independently selected from a chlorine atom, a fluorine atom, and a methyl group.

[0032] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a phenyl group.

[0033] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, said phenyl group being substituted with one or two substituents independently selected from a chlorine atom, a fluorine atom, and a methyl group.

[0034] In another embodiment, in the compound of formula (I) as defined above, R6 is a cycloalkyl group containing 3 to 7 carbon atoms, said cycloalkyl group being saturated or partially saturated and ○ 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 groups and phenyl groups, said (C3-C6)cycloalkyl groups or phenyl groups being optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups. and optionally substituted with 1 to 4 substituents independently selected from Represents.

[0035] In another embodiment, in the compound of formula (I) as defined above, R6 represents a cyclohexyl group, said cyclohexyl group being substituted with one or two substituents independently selected from a chlorine atom and a methyl group.

[0036] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cyclopentyl group.

[0037] In another embodiment, in the compounds of formula (I) as defined above, R 7 represents a methyl group or a fluorine atom and n is 0 or 1.

[0038] In another embodiment, in a compound of formula (I) as defined above, R8 represents a hydrogen atom or a methyl group.

[0039] In another embodiment, in the compounds of formula (I) as defined above, Y represents -O-.

[0040] In another embodiment, in the compound of formula (I) as defined above, Y represents -O-, and the asymmetric carbon of the pyrrolidine or azetidine linked to -O- is of the (R) configuration.

[0041] In another embodiment, in the compound of formula (I) as defined above, Y represents -O-, p is 1 and the asymmetric carbon of the pyrrolidine linked to -O- is of the (R) configuration.

[0042] In another embodiment, in the compound of formula (I) as defined above, Y represents -CH2-.

[0043] In another embodiment, in the compounds of formula (I) as defined above, Y represents -NH-.

[0044] In another embodiment, in the compound of formula (I) as defined above, Y represents -NH-, and the asymmetric carbon of the pyrrolidine or azetidine linked to -NH- is of the (R) configuration.

[0045] In another embodiment, in the compound of formula (I) as defined above, Y represents -NH-, p is 1 and the asymmetric carbon of the pyrrolidine linked to -NH- is of the (R) configuration.

[0046] In another embodiment, in the compounds of formula (I) as defined above, m is 1.

[0047] In another embodiment, in the compound of formula (I) as defined above, m is 0.

[0048] In another embodiment, in the compound of formula (I) as defined above, p is 1.

[0049] In another embodiment, in the compound of formula (I) as defined above, p is 0.

[0050] In another embodiment, in the compound of formula (I) as defined above, R3 is a -COOH group and R6 is a phenyl group, said phenyl group being optionally substituted with one or two substituents independently selected from a chlorine atom, a fluorine atom, and a methyl group. In such an embodiment, R3' and R3" are, in particular, hydrogen atoms. Furthermore, in such an embodiment, R1, R2, R4, R5, R5' and R8 are hydrogen atoms. In such an embodiment, Y is -O-, p is equal to 1, m is equal to 1 and n is equal to 0. Furthermore, in such an embodiment, X is a -CH2- group.

[0051] In another embodiment, in the compound of formula (I) as defined above, R3 is a -COOH group and R6 is a cyclohexyl group, said cyclohexyl group being substituted with one or two substituents independently selected from a chlorine atom and a methyl group. In such an embodiment, R3' and R3" are, in particular, hydrogen atoms. Furthermore, in such an embodiment, R1, R2, R4, R5, R5' and R8 are hydrogen atoms. In such an embodiment, Y is -O-, p is equal to 1, m is equal to 1 and n is equal to 0. Furthermore, in such an embodiment, X is a -CH2- group.

[0052] In another embodiment, in the compound of formula (I) as defined above, R3 is a -COOH group and R6 is a cyclopentyl group. In such an embodiment, R3' and R3" are, in particular, hydrogen atoms. Furthermore, in such an embodiment, R1, R2, R4, R5, R5' and R8 are hydrogen atoms. In such an embodiment, Y is -O-, p is equal to 1, m is equal to 1 and n is equal to 0. Furthermore, in such an embodiment, X is a -CH2- group.

[0053] 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: - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - (R)-8-(2-chlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - (R)-8-(2-chloro-4-methylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - (R)-8-(2-chloro-4-fluorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - (R)-8-(4-chloro-2-fluorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - (R)-8-(2-fluoro-4-methylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - (R)-8-(2,4-dimethylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - (R)-8-(2-chloro-3-fluorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (10) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (11) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (12) - (R)-8-(4,4-dimethylcyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (13) - (R)-8-Cyclopentyl-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) - (R)-8-(2-chlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) - (R)-8-(4-fluoro-2-methylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - (R)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (19) - (R)-8-(2-chlorophenyl)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (20) - (R)-8-(2,4-dichlorophenyl)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (21) - (R)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) - (R)-8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - (R)-8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) - (R)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (25) - (R)-8-(2-chlorophenyl)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (26) - (R)-8-(2,4-dichlorophenyl)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (27) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (28) - 8-(2-chlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (29) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (30) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (33) - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, (34) - (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate hydrochloride, (35) - 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (36) - 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (37) - (R)-3-(3-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine, (38) - (R)-3-(3-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine, (39) - (R)-6-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, (40), and - (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, (41).

[0054] Another embodiment is a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, for use in therapy, in particular as an inhibitor and degrader of the estrogen receptor.

[0055] 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.

[0056] 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.

[0057] Another embodiment is a method for treating ovulation failure, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0058] 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.

[0059] Another embodiment is a pharmaceutical composition comprising an active ingredient, an effective dose of a compound selected from the above list, or a pharma- ceutically acceptable salt thereof, and also at least one pharma- ceutically acceptable excipient.

[0060] The compounds of formula (I) may be prepared by the following process.

[0061] 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 shown below may be varied as deemed appropriate by those skilled in the art.

[0062] The general methods below for the preparation of compounds of formula (I) are optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in formula (I) as described below.

[0063] The following abbreviations and empirical formulas are used: Ar Argon BOC2O Di-tert-butyl dicarbonate CO Carbon monoxide Cs2CO3 Cesium carbonate DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIEA Diisopropylethylamine DMF N,N-Dimethylformamide DMAP Dimethylaminopyridine DMSO Dimethyl sulfoxide Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol H2 Hydrogen HCl Hydrochloric acid HPLC High Performance Liquid Chromatography K2CO3 Potassium Carbonate KHMDS Potassium hexamethyldisilazane KOH Potassium hydroxide LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide MeCN Acetonitrile MeOH Methanol MeTHF 2-Methyltetrahydrofuran MgSO4 Magnesium Sulfate MTBE Methyl tert-butyl ether n-BuLi n-Butyl lithium Na2SO4 Sodium Sulfate NaH Sodium hydride NaHCO3 Sodium bicarbonate NaOH Sodium hydroxide NH4OH Ammonium hydroxide Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd / C Palladium Carbon Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2Palladium Acetate Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride PhOK Potassium phenolate PPh3 Triphenylphosphine RT room temperature SCX Strong cation exchange SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran XANTPHOS (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0064] Scheme 1a-part-1: Preparation of compounds of formula (I) - General process [ka] Scheme 1a - Part 2 [ka] According to scheme 1a, in part-1 and part-2, R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt, or a protected OH such as O-pivaloyl, for example, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, R8, X, m, n, p and Y are defined as described 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, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine such as triphenylphosphine in solution in toluene by heating to reflux of the solvent in the presence of a base such as KOPh.

[0065] Compound 1C can be converted to compound 1E in step 2 by treatment with compound 1D in a Suzuki coupling reaction using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complex with DCM as a catalyst in the presence of a base, for example, cesium carbonate (CsCO), in a mixture of dioxane and water by heating the solvent to reflux.

[0066] Alternatively, compound 1E can be obtained in step 1' by Suzuki coupling between compound 1A and compound 1D' using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM 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.

[0067] Compound 1E can be converted to compound 1F in step 3, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0068] Compound 1F can be converted to compound 1H in step 4 by treatment with compound 1B in the presence of a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine, such as triphenylphosphine, in solution in toluene, by heating the solvent to reflux in the presence of a base, such as KOPh or AcOK.

[0069] Compound 1G, where R6 is phenyl or heteroaryl, can be prepared in step 5 by Suzuki coupling reaction between compound 1H and R6Br or R6I or R6OTf using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM 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.

[0070] Compound 1G can also be prepared from compound 1F in step 6 in a Suzuki coupling reaction with a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) using, for example, Pd(dppf)Cl2, complex with DCM as a catalyst in the presence of a base, for example, Cs2CO3, in a mixture of dioxane and water as a solvent at room temperature or by heating to the reflux of the solvent. When R6 is a substituted cycloalkene, heterocycloalkene, it may be reduced, for example, by hydrogenation with a catalyst such as Pd / C at room temperature to 70°C under approximately 5 bar hydrogen pressure (H2) to give the corresponding saturated compound 1G.

[0071] Alternatively, compound 1F can be subjected to a photocatalytic coupling reaction with R6Br (wherein R6 is an alkyl group, cycloalkyl, or spiro-bicyclic alkyl 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.

[0072] Compound 1G can be converted in step 7 to a compound of formula (I) in the presence of a source of hydroxide ions, such as NaOH or LiOH, in solution in methanol (MeOH).

[0073] Intermediate 1F can be converted to compound 1Fa in Step 8 in the presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol (MeOH).

[0074] This compound 1Fa can be converted to a compound of formula (I) in step 9 through Suzuki conditions using a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in a mixture of dioxane and water as a solvent, for example, Pd(dppf)Cl2, complex with DCM as a catalyst in the presence of a base, for example, Cs2CO3, by heating at room temperature or to the reflux of the solvent. When R6 is a substituted cycloalkene, heterocycloalkene, it can be reduced, for example, by hydrogenation with a catalyst such as Pd / C at room temperature to 70°C under approximately 5 bar of hydrogen (H2) pressure to obtain the corresponding saturated compound of formula (I).

[0075] When R3a is a protected -OH such as -COOMe, -COOEt, or O-pivaloyl, deprotection can be carried out in step 7 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in methanol (MeOH). When R3 is -COOH, the sodium or lithium salt of the compound of formula (I) can be obtained by extraction of the product. The neutral form of the compound of formula (I) can be obtained by acidification to pH 6-7 with an aqueous solution of HCl 2N. The hydrochloride salt of the compound of formula (I) can be obtained by acidification to pH 1-2 with an aqueous solution of HCl 2N. The formate or trifluoroacetate salt of the compound of formula (I) can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0076] Scheme 1b: Alternative process for preparing compound 1E [ka]

[0077] According to scheme 1b, R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt, or a protected -OH such as O-pivaloyl, e.g. R1, R2, R3a, R3', R3'', R4, R5, R5', R7, R8, X, m, n, and Y are defined as above, and compound 1A (prepared according to WO2017140669 when X=C) can be converted in step 1 to compound 1J, e.g. by treatment with compound 1D'' using a palladium catalyst, e.g. bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, in the presence of a base, e.g. cesium carbonate (Cs2CO3), in a mixture of dioxane and water as solvent, at room temperature or by heating to reflux of the solvent.

[0078] Compound 1J can be converted to compound 1E (Y=-O-) in step 2 by reaction with compound 1K (A=-Br or -I) in the presence of a base such as cesium carbonate (CsCO) in DMF or MeCN when (A=-OH) using, for example, N,N,N',N'-tetramethylazodicarboxamide and triphenylphosphine as coupling agents in THF as solvent, or under Mitsunobu conditions.

[0079] Scheme 1c: Alternative process for preparing compound 1G [ka]

[0080] According to scheme 1c, R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt, or a protected OH such as O-pivaloyl, for example R1, R2, R3a, R3', R3'', R4, R5, R5', R7, R8, X, Y, m, n, and p are defined as above, and R6 is phenyl or heteroaryl, and compound 1L can be converted in step 1 to compound 1M by treatment with aryl and heteroaryl bromides or iodides in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3, and a phosphine such as (9.9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) in solution in toluene or xylene, by heating to reflux of the solvent in the presence of a base such as K2CO3 or Cs2CO3. An alternative method for preparing compound 1M (R6 can be any of the groups defined above for R6 in formula (I)) is described in Scheme 1f below.

[0081] Compound 1M can be converted to compound 1A' in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or KaH, or KHMDS at -50°C in a solvent such as MeTHF.

[0082] Compound 1A' can be converted to compound 1C' in step 3 by treatment with a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine, such as triphenylphosphine, in solution in toluene, in the presence of compound 1B and a base, such as KOPh, by heating the solvent to reflux.

[0083] Compound 1G can be prepared in a Suzuki coupling reaction between compounds 1C' and 1D in step 4 or between compounds 1A' and 1D' in step 5 using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM as a catalyst in the presence of a base, for example, Cs2CO3, in a mixture of dioxane and water by heating the solvent to reflux.

[0084] Scheme 1d: Preparation of compounds of formula (I) - General process [ka] According to scheme 1d, R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt, or a protected OH, e.g. O-pivaloyl, R1, R2, R3, R3', R3'', R4, R5, R5', R6, R7, R8, X, m, n, and p are defined as above, and Y is -NH-; compound 1A' can be converted to compound 1J' in step 1 by treatment with compound 1D'' using, e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, as catalyst in the presence of a base, e.g., Cs2CO3, in a mixture of dioxane and water, by heating to reflux of the solvent.

[0085] Compound 1J' can be converted to compound 1N in step 2 by treatment with trifluoromethanesulfonic anhydride in the presence of pyridine in DCM.

[0086] Compound 1N can be converted to compound 1P in step 3 under Buchwald coupling conditions with compound 1O in dioxane at 130° C. in a microwave using, for example, xanthophos and Pd(OAc) 2 as a catalytic system.

[0087] Compound 1P can be converted to compound 1Q in step 4 by treatment with TFA in DCM.

[0088] Compound 1Q can be converted to compound 1G in step 5 by treatment with compound 1R (W is Br, I or OSO2R, R = CH3, PhMe, CF3 or CF2CF2CF2CF3) in the presence of a base such as K2CO3 in DMF at 70°C or in the presence of NaOH or KOH in THF at room temperature or in the presence of aqueous NaOH in DCM at room temperature.

[0089] When R3a is a protected -OH such as -COOMe, -COOEt, or O-pivaloyl, deprotection can be carried out in step 6 by treatment with an aqueous solution of NaOH 2N or LiOH in MeOH. When R3 is -COOH, the sodium or lithium salt of the compound of formula (I) can be obtained by extraction of the product. The neutral form of the compound of formula (I) can be obtained by acidification to pH 6-7 with an aqueous solution of HCl 2N. The hydrochloride salt of the compound of formula (I) can be obtained by acidification to pH 1-2 with an aqueous solution of HCl 2N. The formate or trifluoroacetate salt of the compound of formula (I) can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0090] Scheme 1e: Preparation of compounds of formula (1A) where R3a = CO2Me - General process [ka] According to Scheme 1e, X, m, R3', R3" and R8 are defined as above, and compound 1A can be prepared as follows: Compound 1Aa (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted in step 1 to compound 1Ab by treatment with trifluoromethanesulfonic anhydride in solution in DCM in the presence of pyridine as a base.

[0091] Compound 1Ab can be converted to compound 1Ac in step 2 by carbonylation with carbon monoxide in a solution in DMF and MeOH in the presence of a palladium catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complexed with DCM.

[0092] Compound 1Ac can be converted to compound 1A (R3a = CO2Me) in step 3 by treatment with trifluoromethanesulfonic anhydride in solution in DCM in the presence of pyridine as a base.

[0093] Scheme 1f: Alternative preparation of compounds of formula (1M) - General process [ka] According to scheme 1f, R3a is a hydrogen atom, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, and R3', R3", R8, R6, X, and m are defined as above, compound 1M can alternatively be prepared as follows: compound 1L can be converted to compound 1La in step 1, e.g. by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0094] Compound 1La can be converted to compound 1Lb in step 2 by deprotection with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0095] Compound 1Lc can be prepared in step 3 by Suzuki coupling reaction between compound 1Lb and R6B(OR')2 or R6BF3K using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM as a catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of toluene and water by heating the solvent to reflux.

[0096] Compound 1Lc can be converted to compound 1M in step 4 by hydrolysis with aqueous HCl by heating in, for example, methanol and DCM.

[0097] 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, R5', R6, R7, R8, m, n, p, X and Y are as defined above and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt or a protected OH such as, for example, O-pivaloyl, is converted to a compound of formula (I) in the presence of a source of hydroxide ions such as NaOH or LiOH in solution in methanol, said step being optionally preceded by a step to obtain compound 1G, a compound of formula 1F: [ka] (wherein R1, R2, R3', R3", R4, R5, R5', R7, R8, m, n, p, X and Y are as defined above, and R3a is as defined above) This is subjected to Suzuki coupling with a boronic acid reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0098] 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, R5', R7, R8, m, n, p, X and Y are as defined above, are subjected to Suzuki coupling with a boronic acid reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, said step being optionally preceded by a step to obtain compound 1Fa, a compound of formula 1F: [ka] (wherein R1, R2, R3', R3", R4, R5, R5', R7, R8, m, n, p, X and Y are as defined above, and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe or -COOEt, or a protected -OH such as O-pivaloyl) is It is converted to compound 1Fa in the presence of a source of hydroxide ions such as NaOH or LiOH in solution in methanol.

[0099] Provided herein is 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, R5', R6, R7, R8, m, n, p, X and Y are as defined above, and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt, or a protected -OH such as O-pivaloyl) is also provided.

[0100] Provided herein is an intermediate compound of formula 1D', or any of its pharma- ceutically acceptable salts: [ka] Further provided is: (wherein R1, R2, R4, R5, R5', R7, Y, p and n are as defined above).

[0101] The present specification also relates to an intermediate compound of formula 1C', or any of its pharma- ceutically acceptable salts: [ka] (wherein R3a, R3', R3", X, m, R6 and R8 are as defined above) are also described.

[0102] In another aspect, also provided herein is a process for the preparation of 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 optionally by a purification step.

[0103] Said purification step may consist, for example, of an acidification step, for example with an aqueous solution of hydrochloric acid, as shown, for example, in step 2 of Example 1 hereinafter.

[0104] 400 and 500MHz 1 H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0105] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and a flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1x30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H, light scattering detector Sedere and a SQD Waters mass spectrometer.

[0106] [Table 1]

[0107] [Table 2]

[0108] [Table 3]

[0109] [Table 4]

[0110] [Table 5]

[0111] [Table 6]

[0112] [Table 7]

[0113] [Table 8]

[0114] [Table 9]

[0115] [Table 10]

[0116] [Table 11]

[0117] [Table 12]

[0118] [Table 13]

[0119] [Table 14]

[0120] [Table 15]

[0121] [Table 16] EXAMPLES

[0122] The following examples describe the preparation of some compounds of formula (I) described herein. The number of compounds exemplified below corresponds to those given in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0123] In the following examples, unless the source of a starting product is specified, said products are to be understood as known compounds.

[0124] Intermediates: Intermediate 1: (R)-1-(3-fluoropropyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine [ka] Step 1: (R)-tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate [ka] To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.01 g, 4.50 mmol), (S)-1-N-boc-3-hydroxypyrrolidine (0.97 g, 5.08 mmol), and N,N,N',N'-tetramethylazodicarboxamide (1.25 g, 7.11 mmol) in THF (20 ml) was added PPh3 (1.84 g, 6.87 mmol). The reaction mixture was stirred at room temperature for 18 hours. Diisopropyl ether (50 ml) and water (30 ml) were added. The organic phase was washed with water (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue purified by flash chromatography eluting with heptane / EtOAc: 80 / 20 to give 1.36 g (78%) of tert-butyl (R)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):390

[0125] Step 2: (R)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine, hydrochloride [ka] To a solution of (R)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate tert-butyl (1.03, 2.65 mmol) in MeOH (10 ml) cooled at 5° C. was added HCl 4M in dioxane (5.2 ml, 20.80 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with diisopropyl ether. The solid was filtered and dried to give 0.76 g (99%) of (R)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine, hydrochloride salt. LC / MS(m / z,MH+):290

[0126] Step 3: (R)-1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine [ka] A mixture of (R)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine, hydrochloride (0.75 g, 2.62 mmol), K2CO3 (0.73 g, 5.24 mmol), 1-fluoro-3-iodo-propane (0.475 g, 2.48 mmol) in MeCN (7 ml) was heated at 70° C. for 2 h. After cooling to room temperature, DCM (20 ml) and water (10 ml) were added. The organic phase was washed with Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with DCM / MeOH:95 / 05 to give 0.4 g (44%) of (R)-1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine. LC / MS(m / z,MH+):350

[0127] Intermediate 2: (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (25 g, 71.37 mmol) (prepared according to WO2017140669), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (17.28 g, 78.50 mmol), Cs2CO3 (46.55 g, 142.73 mmol), Pd(dppf)Cl2DCM complex (4.70 g, 6.42 mmol) in dioxane (204 ml) and water (72 ml) was stirred at room temperature for 30 min. The reaction mixture was quenched by addition of water (500 mL) and extracted with EtOAc (2x500 ml). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue purified by flash chromatography eluting with heptane / EtOAc:80 / 20 to give 20.5 g (98%) of methyl 9-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):295

[0128] Step 2: (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka]

[0129] Method 1 To a mixture of methyl 9-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (0.5 g, 1.70 mmol), (S)-1-(3-fluoropropyl)pyrrolidin-3-ol (0.276 g, 1.88 mmol) (prepared according to WO2018091153), and N,N,N',N'-tetramethylazodicarboxamide (0.39 g, 2.23 mmol) in THF (5 ml) was added PPh3 (0.59 g, 2.21 mmol). The reaction mixture was stirred at room temperature for 18 hours. Diisopropyl ether (20 ml) and water (5 ml) were added. The organic phase was washed with water (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.86 g (crude) of methyl (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, which was used as is in the next step. LC / MS(m / z,MH+):424

[0130] Method 2 A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (0.72 g, 2.06 mmol) (prepared according to WO2017140669), (R)-1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine (Intermediate 1) (0.63 g, 1.79 mmol), Cs2CO3 (1.55 g, 4.66 mmol), Pd(dppf)Cl2 complex with DCM (91 mg, 0.1 mmol) in dioxane (8 ml) and water (2 ml) was stirred at room temperature for 20 min. The reaction mixture was quenched by the addition of water (5 ml) and DCM (10 ml) and extracted with a hydrophobic column. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue purified by flash chromatography eluting with DCM / MeOH:95 / 05 to give 0.75 g (99%) of methyl (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0131] Step 3: (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of (R)-methyl 9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (0.75 g, 1.77 mmol) in DCM (8 ml) was added pyridinium tribromide (0.69 g, 1.95 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched with a solution of concentrated NaHCO3 and extracted with a hydrophobic column. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM:MeOH:100 / 00 to 90 / 10 to give 0.48 g (54%) of methyl (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):502

[0132] Intermediate 3: (R)-8-bromo-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(2-fluoro-5-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 3 step 1 was prepared following a similar procedure as that of step 1 intermediate 2 from methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) and 2-fluoro-5-hydroxyphenylboronic acid to afford 1.52 g (85%) of methyl 9-(2-fluoro-5-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):313

[0133] Step 2: (R)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 3, step 2, was prepared from methyl 9-(2-fluoro-5-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (S)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) following a procedure similar to that of Intermediate 2, step 2, method 1 to give 0.7 g (99%) of methyl (R)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):442

[0134] Step 3: (R)-8-bromo-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 3, step 3 was prepared from methyl (R)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 2, step 3 to give 0.36 g (42%) of methyl (R)-8-bromo-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):520

[0135] Intermediate 4: (R)-8-bromo-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(5-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 4 step 1 was prepared from methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol following a similar procedure to that of step 1 intermediate 2 to give 1.43 g (81%) of methyl 9-(5-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):309

[0136] Step 2: (R)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 4, step 2, was prepared from methyl 9-(5-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (S)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) following a procedure similar to that of Intermediate 2, step 2, method 1 to give 0.7 g (99%) of methyl (R)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):438

[0137] Step 3: (R)-8-bromo-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 4, step 3, was prepared from methyl (R)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 2, step 3 to give 0.34 g (41%) of methyl (R)-8-bromo-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):516

[0138] Intermediate 5: (R)-8-bromo-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(2-fluoro-3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 5 step 1 was prepared following a similar procedure as that of step 1 intermediate 2 from methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) and 2-fluoro-3-hydroxyphenylboronic acid to afford 1.15 g (86%) of methyl 9-(2-fluoro-3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):313

[0139] Step 2: (R)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 5, step 2, was prepared from methyl 9-(2-fluoro-3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (S)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) following a procedure similar to that of Intermediate 2, step 2, method 1 to give 1.5 g (92%) of methyl (R)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):442

[0140] Step 3: (R)-8-bromo-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 5, step 3, was prepared from methyl (R)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 2, step 3 to give 0.4 g (23%) of (R)-8-bromo-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):520

[0141] Intermediate 6: (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 9-(3-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 6 step 1 was prepared from methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol following a similar procedure to that of step 1 intermediate 2 to afford 1.15 g (87%) of methyl 9-(3-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):309

[0142] Step 2: (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 6, step 2, was prepared from methyl 9-(5-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (S)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) following a procedure similar to that of Intermediate 2, step 2, method 1 to give 1.5 g (92%) of methyl (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):438

[0143] Step 3: (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 6, step 3, was prepared from methyl (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 2, step 3 to give 0.58 g (38%) of methyl (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):516

[0144] Intermediate 7: 8-Bromo-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate [ka] To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13 g, 59.07 mmol), 1-boc-3-iodoazetidine (25.86 g, 88.61 mmol) in DMF (150 ml) was added Cs2CO3 (38.53 g, 118.14 mmol). The reaction mixture was stirred at 65° C. for 20 h. After cooling to room temperature, the reaction mixture was poured into water (1500 ml) and EtOAc (500 ml). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was triturated with isopropyl ether. The solid was filtered and dried to give 10.6 g (48%) of tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate. LC / MS(m / z,MH+):376

[0145] Step 2: (R)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine, hydrochloride [ka] Intermediate 7, step 2, was prepared from tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate following a procedure similar to that of intermediate 1, step 2 to afford 9.1 g (crude) of tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate hydrochloride. LC / MS(m / z,MH+):276

[0146] Step 3: 1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine [ka] Intermediate 7, step 3, was prepared from tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate hydrochloride following a procedure similar to that of intermediate 1, step 3 to afford 1.53 g (16%) of 1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine. LC / MS(m / z,MH+):336

[0147] Step 4: 9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 4 of intermediate 7 was prepared according to a similar procedure to that of step 1 of intermediate 2 from methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) and 1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine to afford 0.57 g (94%) of methyl 9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):410

[0148] Step 5: 8-Bromo-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 7, step 5, was prepared from methyl 9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 2, step 3 to afford 0.56 g (82%) of methyl 8-bromo-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):488

[0149] Intermediate 8: Methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (15 g, 42.82 mmol) (prepared according to WO2017140669), Pd(PPh3)2Cl2 (1.53 g, 2.14 mmol), PPh3 (673.87 mg, 2.57 mmol), bis(pinacolato)diboron (13.38 g, 52.67 mmol) and PhOK (8.04 g, 60.80 mmol) in toluene (150 ml) was heated to 75 °C for 1.5 h. The yellow suspension turns orange and then brown. After cooling to room temperature, DCM (150 mL) and water (150 mL) were added and decantation was performed by 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

[0150] Intermediate 9: 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 9 was prepared from 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO 2020 / 049153) following a similar procedure to that of intermediate 8 to afford 3.9 g (82%) of 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid. LC / MS(m / z,MH+):473

[0151] Intermediate 10: 8-Bromo-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 3-(3-bromobenzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 10, step 1, was prepared from 3-(3-bromobenzyl)azetidine, 2,2,2-trifluoroacetic acid following a procedure similar to that of intermediate 1, step 3 to afford 1.4 g (33%) of 3-(3-bromobenzyl)-1-(3-fluoropropyl)azetidine. LC / MS(m / z,MH+):286

[0152] Step 2: 9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [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 (0.62 g, 1.89 mmol) (Intermediate 8), 3-(3-bromobenzyl)-1-(3-fluoropropyl)azetidine (0.59 g, 1.87 mmol), Cs2CO3 (1.83 g, 5.61 mmol), Pd(dppf)Cl2 complex with DCM (86 mg, 0.11 mmol) in dioxane (6 ml) and water (2.5 ml) was heated to 65° C. for 1 h. After cooling to room temperature, DCM (10 mL) and water (5 ml) were added. After decantation on a hydrophobic column, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with DCM / MeOH:95 / 05 to give 0.67 g (88%) of methyl 9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):408

[0153] Step 3: 8-Bromo-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 10, step 3, was prepared from methyl 9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 2, step 3 to give 0.66 g (83%) of methyl 8-bromo-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):488

[0154] Intermediate 11: 3-[(3-bromophenyl)methyl]-1-(3-fluoropropyl)pyrrolidine, isomer 1 [ka] Step 1: tert-Butyl 3-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate, Isomer 1 and Isomer 2 [ka] To a solution of 3-[(3-bromophenyl)methyl]pyrrolidine racemic mixture (58.0 g, 242 mmol) and TEA (48.9 g, 483 mmol) in DCM (420 ml) was added DMAP (2.95 g, 24.2 mmol) and BOC2O (55.4 g, 254 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched by addition of 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 / EtOAc 98 / 02 to 50 / 50 to give 45 g (51%) of tert-butyl 3-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate, racemic mixture. The racemic mixture of tert-butyl 3-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate was separated by preparative SFC (column: DAICEL CHIRALCEL OJ (250x50mm, 10μm); supercritical CO2 85% / EtOH [0.1% NH4OH] 15% to give 19g of tert-butyl 3-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate isomer 1 and 19g of tert-butyl 3-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate isomer 2. LC / MS(m / z,MH+):340

[0155] Step 2: 3-[(3-bromophenyl)methyl]pyrrolidine, hydrochloride isomer 1 [ka] Intermediate 11, step 2, was prepared from tert-butyl 3-[(3-bromophenyl)methyl]pyrrolidine-1-carboxylate isomer 1 following a procedure similar to that of Intermediate 1, step 2, to afford 17 g (crude) of 3-[(3-bromophenyl)methyl]pyrrolidine, hydrochloride salt isomer 1. LC / MS(m / z,MH+):240

[0156] Step 3: 3-[(3-bromophenyl)methyl]-1-(3-fluoropropyl)pyrrolidine, isomer 1 [ka] Intermediate 11, step 3, was prepared from 3-[(3-bromophenyl)methyl]pyrrolidine, hydrochloride isomer 1 following a procedure similar to that of Intermediate 1, step 3 to afford 10.1 g (74%) of 3-[(3-bromophenyl)methyl]-1-(3-fluoropropyl)pyrrolidine, isomer 1. LC / MS(m / z,MH+):300

[0157] Intermediate 12: 8-(2,4-dichlorophenyl)-9-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1: 8-(2,4-dichlorophenyl)-9-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 12, step 1, was prepared from 3-hydroxyphenylboronic acid and 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO 2020 / 049153) following a procedure similar to that of Intermediate 2, step 1 to give 2.29 g (86%) of 8-(2,4-dichlorophenyl)-9-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):439

[0158] Step 2: 8-(2,4-dichlorophenyl)-9-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of methyl 8-(2,4-dichlorophenyl)-9-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (0.32 g, 0.73 mol) and pyridine (0.12 g, 1.46 mmol) in DCM (5 ml) cooled to 5° C., trifluoromethanesulfonic anhydride (0.42 g, 1.49 mmol) was added. The reaction mixture was stirred at 5° C. for 1 h. After addition of chilled water (5 ml) and decantation on a hydrophobic column, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.48 g (crude) of methyl 8-(2,4-dichlorophenyl)-9-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):571

[0159] Intermediate 13: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Step 1: 6-(2,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 1-bromo-2,4-dichloro-benzene (890 mg, 3.94 mmol), 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (500 mg, 2.63 mmol), 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

[0160] Step 2: 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 6-(2,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (470 mg, 1.23 mmol) and aluminum chloride (395 mg, 2.96 mmol) in toluene (8 ml) was heated at 90° C. for 2 h. After cooling to room temperature, water (20 ml) and EtOAc (50 ml) were added. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc 100 / 00 to 80 / 20 to give 165 mg (42%) of 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z,MH+):321

[0161] Step 3: 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate [ka] A mixture of 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (163 mg, 0.51 mmol), K2CO3 (77 mg, 0.56 mmol) and pivaloyl chloride (67 mg, 0.56 mmol) in acetone (5 ml) was heated at 40° C. for 1 h. After cooling to 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

[0162] 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 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (173 mg, 0.49 mmol) was added to the resulting mixture. The reaction mixture was slowly warmed to 20° C. and stirred for 90 min. The reaction mixture was quenched with saturated aqueous citric acid solution, followed by dilution with water and extraction 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

[0163] Intermediate 14: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate methyl [ka] Step 1: 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate [ka] To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO2018091153) and pyridine (2.82 g, 2.89 ml, 35.36 mmol) in DCM (120 ml) cooled to -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 a saturated aqueous solution of NaHCO3 (50 ml). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 7.40 g (crude) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):311

[0164] Step 2: 5-Oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate methyl [ka] To a solution of the compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate (7.4 g, 23.85 mmol) in DMF (30 ml) and MeOH (15 ml) were 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 three times. The mixture was stirred at 75° C. under CO (5 bar) for 2 h. The reaction was filtered through Celite. The filtrate was diluted with water (400 ml) and extracted three times with EtOAc (300 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 85 / 15 to 80 / 20 to give 4.6 g (88%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z,MH+):221

[0165] Step 3: 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate methyl [ka] Intermediate 14, step 3, was prepared from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of intermediate 13, step 1 to afford 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

[0166] Step 4: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate methyl [ka] Intermediate 14, step 4, was prepared from methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of intermediate 13, step 4 to afford 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

[0167] Intermediate 15: 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate methyl [ka] Step 1: 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate methyl [ka] Intermediate 15, step 1, was prepared from methyl 1-oxotetralin-6-carboxylate following a procedure similar to that of intermediate 13, step 1 to afford 459 mg (19%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z,MH+):349

[0168] Step 2: 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate methyl [ka] Intermediate 15, step 2, was prepared from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate following a procedure similar to that of intermediate 13, step 4 to afford 0.48 g (31%) of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z,MH+):481

[0169] Intermediate 16: (R)-3-(3-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] Step 1: 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate [ka] To a mixture of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.02 g, 6.37 mmol) and pyridine (0.765 g, 0.78 ml, 9.68 mmol) in DCM (30 ml) cooled to 0° C., trifluoromethanesulfonic anhydride (3.61 g, 2.15 ml, 12.8 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 24 h. Water (30 ml) was added. The organic phase was separated and washed with a saturated aqueous solution of NaHCO3 (50 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 1.18 g (63%) of 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):293

[0170] Step 2: (R)-3-(3-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] Intermediate 16, step 2, was prepared from (R)-1-(3-fluoropropyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (Intermediate 1) and 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 2, step 1, to give 0.34 g (46%) of (R)-3-(3-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. LC / MS(m / z,MH+):366

[0171] Step 3: (R)-3-(3-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] Intermediate 16, step 3, was prepared from (R)-3-(3-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine following a procedure similar to that of Intermediate 2, step 3 to give 0.41 g (97%) of (R)-3-(3-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. LC / MS(m / z,MH+):444

[0172] Intermediate 17: Methyl 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka] Step 1: 6-Bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate methyl [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) in small portions. 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

[0173] Step 2: 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate methyl [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, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was 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

[0174] 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) was added 0.328 M copper salt solution (35 mL, 11.5 mmol) prepared by addition of a 1.6 N solution of methyllithium in 15 mL of 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 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

[0175] Step 4: Methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 17, step 4, was prepared from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of intermediate 16, step 1 to afford 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

[0176] Step 5: Methyl 9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, equimolar mixture of stereoisomers [ka] Intermediate 17, step 5, was prepared from (R)-1-(3-fluoropropyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (Intermediate 1) and 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 2, step 1 to afford 0.306 g (48%) of 9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an equimolar mixture of stereoisomers. LC / MS(m / z,MH+):438

[0177] Step 6: 8-bromo-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, equimolar mixture of stereoisomers [ka] Intermediate 17, step 6, was prepared from methyl 9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an equimolar mixture of stereoisomers following a procedure similar to that of intermediate 2, step 3 to give 0.48 g (31%) of (R)-3-(3-(6,7-dihydro-5H-benzo[7]annulene-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine and 0.294 g (81%) of 8-bromo-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, an equimolar mixture of stereoisomers. LC / MS(m / z,MH+):516

[0178] Step 7: Methyl 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka] A mixture of methyl 8-bromo-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, equimolar mixture of stereoisomers (294 mg, 0.57 mmol), 3-chlorophenylboronic acid (98 mg, 0.63 mmol), Cs2CO3 (464 mg, 1.42 mmol), complex with Pd(dppf)Cl2DCM (28 mg, 34 μmol) in dioxane (7.6 ml) and water (3.2 ml) was heated at 80° C. for 1 h. After cooling to room temperature, DCM (10 ml) and water (2 ml) were added and the mixture was separated on a hydrophobic column. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 95 / 05 to afford 238 mg (76%) of methyl 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an equimolar mixture of stereoisomers. The mixture of methyl 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was purified by chiral chromatography (column: I-amylose-3 (250x30mm, 5μm); heptane 90% / EtOH [0.1% TEA] 10%) to give 88 mg of methyl 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 and 88 mg of methyl 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2. LC / MS(m / z,MH+):548

[0179] Intermediate 18: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Step 1: (R)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Intermediate 18 step 1 was prepared from 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate (prepared according to WO2018091153) and (R)-1-(3-fluoropropyl)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (Intermediate 1) following a procedure similar to that of Intermediate 2 Method 2 to afford 160 mg (77%) of (R)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate. LC / MS(m / z,MH+):484

[0180] Step 2: (R)-4-bromo-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Intermediate 18, step 2, was prepared from (R)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate following a procedure similar to that of Intermediate 2, step 3 to afford 114 mg (62%) of (R)-4-bromo-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate. LC / MS(m / z,MH+):562

[0181] Method A: Example 1: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-methyl carboxylate (Intermediate 2) (100 mg, 0.20 mmol), 2,4-dichlorophenylboronic acid (43 mg, 0.22 mmol), Cs2CO3 (207 mg, 0.62 mmol), Pd(dppf)Cl2 complex with DCM (11 mg, 12.7 μmol) in dioxane (1 ml) and water (0.4 ml) was heated to 80° C. under microwave irradiation for 30 min. After cooling to room temperature, DCM (10 ml) and water (2 ml) were added and the mixture was separated on a hydrophobic column. The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 95 / 05 to give 72 mg (63%) of methyl (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):568

[0182] Step 2: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] To a mixture of (R)-methyl 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (72 mg, 0.13 mmol) in MeOH (3 ml) was added NaOH 2M (185 μl, 0.37 mmol) and the reaction mixture was stirred at reflux for 3 h. After cooling to room temperature, water (3 ml), DCM (3 ml) and HCl 1N were added to obtain a pH of 6-7. After separation on a hydrophobic column, the organic phase 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 47 mg (66%) of (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0183] Method B: Example 10: (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] Step 1: (R)-8-(4,4-difluorocyclohex-1-en-1-yl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1 of Example 10 was prepared from (R)-8-bromo-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-methyl carboxylate (Intermediate 2) and (4,4-difluorocyclohex-1-en-1-yl)boronic acid according to a procedure similar to that of Step 1 of Example 1 to give 130 mg (61%) of (R)-8-(4,4-difluorocyclohex-1-en-1-yl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-methyl carboxylate. LC / MS(m / z,MH+):540.

[0184] Step 2: (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of (R)-8-(4,4-difluorocyclohex-1-en-1-yl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (127 mg, 235 μmol), Pd / C 10% (12 mg, 117 μmol) in EtOH (9 ml) and EtOAc (5 ml) was hydrogenated at 65° C. and 7 bar of H2 for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 135 mg (crude) of (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, which was used as such in the next step. LC / MS(m / z,MH+):542

[0185] Step 3: (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 [ka] Step 3 of Example 10 was prepared from methyl (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate according to a procedure similar to that of Step 2 of Example 1 to give 100 mg (73.9%) of (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1.

[0186] Method C Example 28: 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 [ka] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Step 1 of Example 28 was prepared from 3-(3-bromobenzyl)-1-(3-fluoropropyl)pyrrolidine isomer 1 (Intermediate 11) and 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 9) according to a procedure similar to that of Step 1 of Example 1 to give 100 mg (82%) of 8-(2,4-dichlorophenyl)-9-(3-((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: Methyl 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Example 28, step 2, was prepared from methyl 8-(2,4-dichlorophenyl)-9-(3-((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 Example 1, step 2 to give 55 mg (56%) of 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1.

[0188] Method D Example 32: 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: tert-butyl 3-((3-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)azetidine-1-carboxylate [ka] A mixture of 8-(2,4-dichlorophenyl)-9-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 12) (0.42 g, 0.73 mol), tert-butyl 3-aminoazetidine-1-carboxylate (0.26 g, 1.48 mmol), Cs2CO3 (0.74 g, 2,22 mmol), Pd(OAc)2 (18 mg, 0.075 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg, 0.10 μmol) in dioxane (5 ml) was heated to 130° C. for 1 h under microwave irradiation. After cooling to room temperature, DCM (5 ml) and water (1 ml) were added. After separation on a hydrophobic column, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a petroleum DCM / MeOH gradient from 100 / 00 to 98 / 02 to give 0.26 g (60%) of tert-butyl 3-((3-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)azetidine-1-carboxylate. LC / MS(m / z,MH+):593

[0189] Step 2: 9-(3-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a solution of tert-butyl 3-((3-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)azetidine-1-carboxylate (0.26 g, 0.438 mmol) in DCM (3 ml) was added TFA (0.35 ml, 4.52 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified on an SCX-2 column to give 0.17 g (81%) of methyl 9-(3-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):493.

[0190] Step 3: 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Example 32, step 3, was prepared from methyl 9-(3-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 1, step 3 to afford 63 mg (33%) of methyl 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):554

[0191] Step 4: 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 4 of Example 32 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of step 2 of Example 1 to afford 45.6 mg (74%) of 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0192] Example 33: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] Step 1: (R)-3-((3-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate tert-butyl [ka] Step 1 of Example 33 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 12) and (R)-1-BOC-3-aminopyrrolidine following a procedure similar to that of Step 1 of Example 32 to afford 160 mg (13%) of tert-butyl (R)-3-((3-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):607

[0193] Step 2: (R)-8-(2,4-dichlorophenyl)-9-(3-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 2 of Example 33 was prepared from tert-butyl (R)-3-((3-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)pyrrolidine-1-carboxylate following a procedure similar to that of Step 2 of Example 32 to afford 120 mg (90%) of methyl (R)-8-(2,4-dichlorophenyl)-9-(3-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):507.

[0194] Step 3: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Example 33, step 3 was prepared from (R)-8-(2,4-dichlorophenyl)-9-(3-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-methyl carboxylate following a procedure similar to that of intermediate 1, step 3 to give 114 mg (44%) of (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-methyl carboxylate. LC / MS(m / z,MH+):567

[0195] Step 4: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] Step 4 of Example 33 was prepared from methyl (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 1 to give 98 mg (83%) of (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride.

[0196] Method E Example 35: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride [ka] Step 1: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate methyl [ka] Intermediate 35, step 1, was prepared from (R)-1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine (Intermediate 1) and 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate (Intermediate 14) following a procedure similar to that of Example 1, step 1 to afford 57 mg (33%) of (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z,MH+):570

[0197] Step 2: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride [ka] Step 2 of Example 28 was prepared from methyl (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of Step 2 of Example 1 to afford 49 mg (83%) of (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate hydrochloride.

[0198] Method F Example 34: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] Step 1: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 34, step 1, was prepared from (R)-1-(3-fluoropropyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine (Intermediate 1) and 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (Intermediate 13) following a procedure similar to that of Example 1, step 1, to give 105 mg (42%) of (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z,MH+):610

[0199] Step 2: (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] Step 2 of Example 34 was prepared from (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate following a procedure similar to that of Step 2 of Example 1 to give 55 mg (56%) of (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol.

[0200] Example 41: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol [ka] Step 1: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate [ka] Intermediate 41, step 1, was prepared from (R)-4-bromo-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate (intermediate 18) and 2,4-dichlorophenylboronic acid following a procedure similar to that of example 1, step 1 to afford 67 mg (69%) of (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate. LC / MS(m / z,MH+):628

[0201] Step 2: (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol [ka] Example 41, step 2, was prepared from (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate following a procedure similar to that of example 1, step 2 to give 23 mg (40%) of (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol.

[0202] Method G Example 36: 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 [ka] Example 36 was prepared from 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, methyl isomer 1 following a procedure similar to that in step 2 of Example 1 to afford 51 mg (59%) of 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1.

[0203] Working Example: Compounds according to Table 1a above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0204] Test: Estrogen receptor degrading activity Said test involves measuring the in vitro degradation activity of the compounds of Table 1a.

[0205] Measurement of degradation activity was done using breast cancer cell ERα in a cell Western assay as described herein.

[0206] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells / 30 μL per well in phenol-red-free MEM alpha medium (invitrogen) containing 5% charcoal-dextran-striped FBS. The next day, nine-point serial 1:5 dilutions of each compound were added to the cells in 2.5 μL at a final concentration ranging from 0.3 to 0.0000018 μM (Table 2), or 0.1 μM for fulvestrant (used as a positive control). Four hours after compound addition, cells were fixed for 10 min at room temperature by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton), followed by two washes with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plates for 30 min at room temperature. The LI-COR blocking buffer was removed and the cells were incubated overnight in the cold with 50 μL of anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells treated with blocking buffer but without antibody were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 μM final concentration). The cells were then washed three times in PBS and scanned in an ACUMEN explorer (TTP-Labtech). The integrated intensity in green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0207] The degradative activity of estrogen receptors in this test is expressed as the concentration required to degrade 50% of the estrogen receptor (or IC 50)

[0208] The % reduction in ERα levels was determined as follows: % inhibition=100*(1-(sample-fulvestrant:DMSO-fulvestrant)).

[0209] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1a tested at 0.3 μM, demonstrating that the compounds of the present invention have significant degrading activity against the estrogen receptor.

[0210] [Table 17]

[0211] [Table 18]

[0212] Therefore, it is clear that the tested compound according to the present invention has degrading activity on estrogen receptor with IC50 less than 1 μM and degrading level greater than 50%.Therefore, the compound of formula (I) can be used to prepare a drug, in particular a drug that is a degrading drug of estrogen receptor.

[0213] Furthermore, comparative compounds 1a and 2a, which have an -O-pyrrolidine side chain in the meta position and are both (S) stereoisomers, are apparently inactive.

[0214] Compound 1a can be compared to compound No. 51 of WO 2017 / 140669 A1 and compound No. 43d of Youssef El-Ahmad et al. (J. Med. Chem., 2020, 63, 512-528). Compound 2a can be compared to compound No. 217 of WO 2017 / 140669 A1. The three compounds of the prior art have an O-pyrrolidine side chain in the para position, are (S) stereoisomers, and have degrading activity against the estrogen receptor.

[0215] Thus, the data indicate that alteration of the side chain resulted in loss of biological activity when simply moving the side chain from the para to meta position.

[0216] Surprisingly, activity was retained only after the stereochemistry was changed from (S) to (R).

[0217] Thus, there is also provided herein a medicament comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0218] 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.

[0219] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above for use in therapy, in particular as an estrogen receptor inhibitor and degrader.

[0220] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above for use in the treatment of ovulatory failure, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation.

[0221] 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.

[0222] In some embodiments, the cancer is a hormone-dependent cancer.

[0223] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0224] 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.

[0225] In another embodiment, the metastasis is a cerebral metastasis.

[0226] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0227] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0228] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR or PI3K inhibitors.

[0229] According to another aspect, provided herein is a method of treating the pathological conditions 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 some embodiments of this method of treatment, the subject is a human.

[0230] 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 in treating any of the pathological conditions set out above, more particularly useful in treating cancer.

[0231] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions also contain an effective dose of at least one compound of formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0232] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the usual excipients known to those skilled in the art.

[0233] 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, in a mixture with conventional pharmaceutical excipients, may be administered in unit dosage form to animals and humans for the treatment of the above disorders or diseases.

[0234] 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.

[0235] 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

[0236] There may be specific cases in which higher or lower dosages are appropriate. According to normal practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. A compound of formula (I) or a 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″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; - R6 is A phenyl group (the phenyl group is optionally substituted with a halogen atom; a cyano group or an —OH group (C １ ~C ６ ) alkyl group; 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 ) optionally substituted with 1 to 3 substituents independently selected from alkylsulfonyl groups and —OH groups; ■ (C ３ ~C ６ ) cycloalkyl ((C ３ ~C ６ ) the cycloalkyl ring is optionally unsaturated) and a fused phenyl group selected from the group consisting of (C １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ containing 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; 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 bicyclic group optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; Heteroaryl groups, such as pyridyl, pyridone or pyrrolyl groups, containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and containing at least 5 atoms including carbon atoms and heteroatoms (the heteroaryl groups 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 ) optionally substituted with 1 to 3 substituents independently selected from fluoroalkoxy, cyano, carbamoyl, and —OH groups; Cycloalkyl groups containing 3 to 7 carbon atoms, said cycloalkyl groups being 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 (see above (C ３ ~C ６ ) The cycloalkyl group or the phenyl group is substituted with one or two halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group optionally substituted with 1 to 4 substituents independently selected from: ■ Fluorine atom, —OH group, (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; ■ 4- to 7-membered heterocycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as tetrahydropyranyl or tetrahydrofuranyl groups (the heterocycloalkyl groups are saturated or partially saturated and may contain fluorine atoms, (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 ) optionally substituted with 1 to 3 substituents independently selected from alkoxy groups, and —OH groups; (C) such as isobutyl or ethylbutyl groups １ ~C ６ ) an alkyl group (the alkyl group is 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; and ■ Phenyl (C １ ~C ２ ) an alkyl group (the phenyl group is a halogen atom; (C １ ~C ３ ) alkyl group; １ ~C ３ ) fluoroalkyl group; １ ~C ３ ) an alkoxy group; １ ~C ３ ) optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group; a cyano group; and a -OH group. represents a group selected from - X is -CH ２ represents -, -O- or -S-; - Y is -CH ２ represents -, -O- or -NH-; R7 is independently a (C １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R8 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; and - p is 0 or 1; With the proviso that when Y represents --O-- or --NH-- and p is 1, the asymmetric carbon of the pyrrolidine linked to Y is of the (R) configuration.

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 group.

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

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

6. X is -O- or -CH ２ -, preferably X is -CH ２ -, 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 R5 and R5' represent a hydrogen atom.

8. A compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a phenyl group, said phenyl group being optionally substituted with one or two substituents independently selected from a chlorine atom, a fluorine atom and a methyl group, or a pharma- ceutically acceptable salt thereof.

9. A compound of formula (I) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, characterized in that R6 represents a cyclohexyl group, said cyclohexyl group being substituted with one or two substituents independently selected from a chlorine atom and a methyl group.

10. A compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a cyclopentyl group, or a pharma- ceutically acceptable salt thereof.

11. A compound of formula (I) according to any one of claims 1 to 10, characterized in that R7 represents a methyl group or a fluorine atom and n is 0 or 1, or a pharma- ceutically acceptable salt thereof.

12. A compound of formula (I) according to any one of claims 1 to 11, characterized in that R8 represents a hydrogen atom or a methyl group, or a pharma- ceutically acceptable salt thereof.

13. A compound of formula (I) according to any one of claims 1 to 12, wherein Y represents -O-, or a pharma- ceutically acceptable salt thereof.

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

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

16. The compound is the following compound: - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - (R)-8-(2-chlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - (R)-8-(2-chloro-4-methylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - (R)-8-(2-chloro-4-fluorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - (R)-8-(4-chloro-2-fluorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - (R)-8-(2-fluoro-4-methylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - (R)-8-(2,4-dimethylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - (R)-8-(2-chloro-3-fluorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - (R)-8-(4,4-difluorocyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (10) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (11) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (12) - (R)-8-(4,4-dimethylcyclohexyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (13) - (R)-8-cyclopentyl-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - (R)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) - (R)-8-(2-chlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) - (R)-8-(4-fluoro-2-methylphenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - (R)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (19) - (R)-8-(2-chlorophenyl)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (20) - (R)-8-(2,4-dichlorophenyl)-9-(2-fluoro-3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (21) - (R)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) - (R)-8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - (R)-8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) - (R)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (25) - (R)-8-(2-chlorophenyl)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (26) - (R)-8-(2,4-dichlorophenyl)-9-(2-fluoro-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (27) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (28) - 8-(2-chlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (29) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (30) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) - 8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (33) - (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, (34) - (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride, (35) - 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (36) - 8-(3-chlorophenyl)-9-(3-(((R)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (37) - (R)-3-(3-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine, (38) - (R)-3-(3-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine, (39) (R)-6-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, (40), and - (R)-4-(2,4-dichlorophenyl)-5-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, (41) Compounds of formula (I) according to any one of claims 1 to 15, characterized in that they are selected from: or a pharma- ceutically acceptable salt thereof, in particular the hydrochloride thereof.

17. Compound of formula 1G: 【Chemistry 2】 wherein R1, R2, R3′, R3″, R4, R5, R5′, R6, R7, R8, m, n, p, X and Y are as defined in any of claims 1 to 15 and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt or a protected OH such as, for example, O-pivaloyl, is converted to a compound of formula (I) in the presence of a source of hydroxide ions such as NaOH or LiOH in solution in methanol, said step being optionally preceded by a step to obtain compound 1G, a compound of formula 1F: 【Chemistry 3】 wherein R1, R2, R3', R3", R4, R5, R5', R7, R8, m, n, p, X and Y are as defined in any one of claims 1 to 15, and R3a is as defined above, Boronic acid reagent R6B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester and R6 is as defined in any of claims 1 or 8 to 10), which is subjected to Suzuki coupling with

18. Compound of formula 1Fa: 【Chemistry 4】 wherein R1, R2, R3, R3', R3", R4, R5, R5', R7, R8, m, n, p, X and Y are as defined in any one of claims 1 to 15, are reacted with a boronic acid reagent R6B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester and R6 is as defined in any of claims 1 or 8 to 10), said step being optionally preceded by a step to obtain compound 1Fa, to obtain a compound of formula 1F: 【Chemistry 5】 (wherein R1, R2, R3', R3", R4, R5, R5', R7, R8, m, n, p, X and Y are as defined in any one of claims 1 to 15, and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe, -COOEt, or a protected -OH such as O-pivaloyl), A process for preparing a compound of formula (I) as claimed in any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, which is converted to compound 1Fa in the presence of a source of hydroxide ions such as NaOH or LiOH in a solution in methanol.

19. An intermediate compound selected from compounds of formula 1E, 1F, 1G, and 1Fa, or any of its pharma- ceutically acceptable salts: 【Chemistry 6】 (In the formula, R1, R2, R3, R3', R3", R4, R5, R5', R6, R7, R8, m, n, p, X and Y are as defined in any one of claims 1 to 15, and R3a is a hydrogen atom or a carboxylic acid ester such as -COOMe or -COOEt, or a protected -OH such as O-pivaloyl.)

20. An intermediate compound of formula 1D', or any of its pharma- ceutically acceptable salts: 【Chemistry 7】 (wherein R1, R2, R4, R5, R5', R7, Y, p and n are as defined in any one of claims 1 to 15).

21. A medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof.

22. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

23. A compound of formula (I) as defined in any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

24. A compound of formula (I) as defined in any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ovulatory failure, cancer, endometriosis, osteoporosis, prostatic hyperplasia or inflammation.

25. 25. A compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use according to claim 24, for use in the treatment of cancer.

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