Substituted 6,7-dihydro-5H-benzo[7]annulene derivatives, processes for their preparation and therapeutic uses thereof

Abstract

The present invention relates to a compound of formula (I), or a pharma- ceutically acceptable salt thereof: (wherein R1 and R2 represent hydrogen or deuterium; R3 represents hydrogen, -COOH or -OH; R3' and R3" represent hydrogen, methyl, methoxy, chlorine, fluorine or cyano; R4 and R4' represent hydrogen or fluorine; R5 represents hydrogen, fluorine or (C1-C3)alkyl; R6 represents phenyl, fused phenyl, a bicyclic group containing 5 to 12 carbon atoms, a heteroaryl group containing 2 to 9 carbon atoms and 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 containing 1 or 2 heteroatoms, a (C1-C6)alkyl, and a phenyl(C1-C2)alkyl group; X is - Y represents -CH2-, -O- or -S-; Y represents -CH=, -N= or -CR"=, where R" represents (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R7 represents (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C3)alkyl or cyclopropyl; n is 0, 1 or 2; and m is 0 or 1. Further disclosed 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] TIFF2025513065000152.tif40170

Description

[Technical field]

[0001] Disclosed herein are novel substituted 6,7-dihydro-5H-benzo[7]annulene 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] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. Summary of the Invention [Means for solving the problem]

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

[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 and R4' independently represent a hydrogen atom or a fluorine atom; - R5 represents a hydrogen atom, a fluorine atom or a (C1-C3) alkyl group; - R6, ■ 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)cycloalkyls 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 phenyl group fused to a hetero(C4-C6)cycloalkyl (wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation) (wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group, and a (C1-C3)alkoxy group); ■ a bicyclic group containing 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; 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 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- to 7-membered heterocycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group (the heterocycloalkyl group is saturated or partially saturated and is optionally substituted with one to three substituents independently selected from a fluorine atom, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) fluoroalkoxy group, an oxo group, a (C1-C3) alkoxy group, and a -OH group); ■ (C1-C6) alkyl groups such as isobutyl, methyl or ethyl groups, said alkyl groups being optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, (C1-C3) alkoxy groups, (C1-C3) fluoroalkoxy groups and -OH groups; 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 -CH=, -N= or -CR" (wherein R" represents a (C1-C3) alkyl group, a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl); - R7 independently represents a (C1-C3) alkyl group such as methyl, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R8 represents a hydrogen atom or a fluorine atom; - R9 represents a hydrogen atom, a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; and - m is 0 or 1.

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

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

[0013] The compounds of formula (I) can exist in the form of 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.

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

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

[0016] As used herein, the following terms have the following definitions unless otherwise stated throughout the specification: halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; - Oxo: the "=O" group; - alkyl group: unless otherwise 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 and cycloheptenyl groups, such as, in particular, cyclopentyl, cyclohexyl 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: saturated or partially unsaturated 4- to 7-membered cycloalkyl group or in particular 4- to 6-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 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 a fluorine atom, the fluoroalkyl group may be called a perfluoroalkyl group. Examples may include trifluoromethyl group or trifluoroethyl group, in particular trifluoromethyl group. - 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: -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 may include, but are not limited to: -SO2CH3, -SO2CH2CH3, etc.; - (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 8-10 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.; - Phenyl group fused with hetero(C4-C6)cycloalkyl: a bicyclic group containing 7-10 carbon atoms and containing a phenyl moiety. The phenyl moiety may be fused to a hetero(C4-C6)cycloalkyl group, i.e. the phenyl moiety may share a bond with the hetero(C4-C6)cycloalkyl group. The fused phenyl group may be linked to the rest of the molecule by its phenyl moiety. It may be substituted. Examples include, but are not limited to, chromanyl groups, in particular chroman-8-yl groups; - Heteroaryl group: a 5-10 membered cyclic aromatic group containing 2-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. Such 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. Heteroaryl is advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine; - bicyclic radicals, which generally contain from 5 to 12 carbon atoms, are hydrocarbon radicals selected from the 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[2.3]hexane, 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; 3 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.

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

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

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

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

[0021] In another embodiment, in the compounds of formula (I) as defined above, R4 and R4' represent a hydrogen atom.

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

[0023] In another embodiment, in the compounds of formula (I) as defined above, R5 represents a hydrogen atom, a -NH2 group, a methyl group, a methoxy group, an ethoxy group.

[0024] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, which is optionally substituted with 1 to 3 substituents independently selected from chlorine, fluorine, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy, trifluoromethoxy, 1,1-difluoroethyl, difluoromethyl, difluoromethoxy, fluoromethyl and cyano.

[0025] In another embodiment, in the compound of formula (I) as defined above, R6 represents a fused phenyl group selected from a bicyclo[4.2.0]octatrienyl group, an indanyl group or a tetrahydronaphthalenyl group, optionally substituted with one or two fluorine atoms, or R6 represents a chromanyl group.

[0026] In another embodiment, in the compound of formula (I) as defined above, R6 represents a bicyclic group selected from bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl and bicyclo[3.2.1]octan-3-yl, optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, -OH groups, (C1-C3)alkyl groups, (C1-C3)fluoroalkyl groups, (C1-C3)alkoxy groups, (C1-C3)fluoroalkoxy groups and oxo groups; advantageously, said bicyclic group is unsubstituted.

[0027] In another embodiment, in the compound of formula (I) as defined above, R6 represents a cycloalkyl selected from a cyclohexyl or cyclopropyl group, said cycloalkyl being ○ Fluorine atom, -OH group, (C1-C3) alkyl group, (C1-C3) fluoroalkyl group, (C1-C3) alkoxy group, (C1-C3) fluoroalkoxy group, oxo group optionally substituted with 1 to 4 substituents independently selected from a (C3-C6)cycloalkyl group and a phenyl group, said (C3-C6)cycloalkyl group or phenyl group being optionally substituted with 1 or 2 halogen atoms or a (C1-C3)alkyl group, Said cycloalkyl is advantageously Methyl, phenyl and Cyclohexyl groups substituted by two halogen atoms, in particular fluorine atoms is substituted with 1 or 2 substituents independently selected from:

[0028] In another embodiment, in the compound of formula (I) as defined above, R 7 independently represents a methyl group, a cyano group, a trifluoromethyl group or a fluorine atom; and n is 0, 1 or 2.

[0029] In another embodiment, in the compound of formula (I) as defined above, Y represents -CH=, -N= or -CR"=, and R" represents a fluorine atom, a cyano group, or a trifluoromethyl group.

[0030] In another embodiment, in the compound of formula (I) as defined above, m is 1.

[0031] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group fused to a hetero(C4-C6)cycloalkyl, the hetero(C4-C6)cycloalkyl ring optionally containing unsaturation, the fused phenyl optionally being substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group, and a (C1-C3)alkoxy group.

[0032] 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 halogen atoms; (C1-C6) alkyl groups optionally substituted with cyano or -OH groups; (C1-C6) fluoroalkyl groups; (C3-C6) cycloalkyl groups; (C1-C6) alkoxy groups; (C1-C6) fluoroalkoxy groups; cyano groups; trifluoromethylsulfonyl groups; (C1-C4) alkylthio groups; (C1-C4) fluoroalkylthio groups; (C1-C4) alkylsulfonyl groups and -OH groups; said phenyl being substituted by at least one trifluoromethoxy group, at least one 1,1-difluoroethyl group, at least one difluoromethyl group, at least one difluoromethoxy group or at least one fluoromethyl group.

[0033] In another embodiment, in the compound of formula (I) as defined above, R3 is a COOH group and R6 is a phenyl group, the phenyl group being optionally substituted with 1 to 3 substituents independently selected from chlorine, fluorine, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy, trifluoromethoxy, 1,1-difluoroethyl, difluoromethyl, difluoromethoxy, fluoromethyl and cyano, the phenyl being substituted with at least one trifluoromethoxy group, at least one 1,1-difluoroethyl group, at least one difluoromethyl group, at least one difluoromethoxy group or at least one fluoromethyl group. In such embodiments, R3' and R3" are, in particular, hydrogen atoms. Further, in such embodiments, R1, R2, R4, R4', R5, R8 and R9 are hydrogen atoms. In such embodiments, Y is a -CH= group, m is equal to 1 and n is equal to 0. Further, in such embodiments, X is a -CH2- group.

[0034] 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: - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 8-(3,4-difluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - 8-(3-fluoro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(3-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - 8-(2-fluoro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-mesityl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) - 8-(2-chloro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - 8-(3-fluoro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) - 8-(3-chloro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - 8-(2-(1,1-difluoroethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) - 8-(2-chloro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) - 8-(2-chloro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - 8-(4-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) - 8-(2-fluoro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) - 8-(2-chloro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) - 8-(2-fluoro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) - 8-(2-chloro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) - 8-(2-ethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) - 8-(2-fluoro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) - 8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) - 8-(4-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) - 8-(4-(difluoromethyl)-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) - 8-(2-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) - 8-(4-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) - 8-(2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) - 8-(2-(difluoromethoxy)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) - 8-(3-chloro-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (35) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (36) - 8-(2-(difluoromethyl)-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) - 8-(3-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) - 8-(2-ethyl-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) - 8-(3-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, (42) - 8-(2-(difluoromethyl)-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) - 8-(4-(difluoromethyl)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (44) - 8-(2-(difluoromethyl)-5-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) - 8-(3-chloro-2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) - 8-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) - 8-(3-chloro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (49) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) - 8-(4-(difluoromethyl)-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) - 8-(4-(difluoromethyl)-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (54) - 8-(4-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(trans-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) - 8-(2-(difluoromethyl)-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) - 8-(2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) - 8-(2-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (60) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(cis-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (61) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (62) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) - 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (64) - 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (65) - 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (66) - 8-(chroman-8-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) - 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (69) - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (70) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4,6-bis(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (71) - 8-(2,4-dimethyl-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) - 8-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73) - 8-(2,6-diethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (74) - 8-(3-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (75) - 8-(2-fluoro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (76) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-6-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (77) - 8-(2,5-dimethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (78) - 8-(2,3-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (79) - 8-(2,6-diethyl-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (80) - 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (81) - 8-(3,4-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (82) - 8-(4-chloro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (83) - 8-(2,6-dimethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (84).

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The compounds of formula (I) may be prepared by the following process.

[0042] 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.

[0043] 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.

[0044] The following abbreviations and empirical formulas are used: MeCN Acetonitrile NH4Cl Ammonium chloride BuLi Butyl lithium CO Carbon monoxide Cs2CO3 Cesium carbonate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane Et2O Diethyl ether DIEA Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOH Ethanol EtOAc Ethyl acetate h time H2 Hydrogen HCl Hydrochloric acid HPLC High Performance Liquid Chromatography LiOH Lithium hydroxide LiHMDS Lithium hexamethyldisilazane MeOH Methanol MgSO4 Magnesium Sulfate MTBE Methyl tert-butyl ether MeTHF 2-Methyltetrahydrofuran min n-BuLi n-Butyl lithium P2O5 Diphosphorus pentoxide Pd / C Palladium Carbon KOAc Potassium Acetate K2CO3 Potassium Carbonate KHMDS Potassium hexamethyldisilazane KOH Potassium hydroxide NaBH4 Sodium borohydride NaHCO3 Sodium bicarbonate NaH Sodium hydride NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NaHSO3 Sodium hydrogen sulfate SCX Strong cation exchange Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PhOK Potassium phenolate SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran PPh3 Triphenylphosphine RT room temperature Ar Argon DABCO 1,4-diazabicyclo[2.2.2]octane

[0045] Scheme 1a-part-1: Preparation of compounds of formula (I) - General process [ka] Scheme 1a - Part 2 [ka] According to scheme 1a-part-1 and part-2, R3a is H or a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, R9 is a hydrogen atom, R1, R2, R3, R3', R3'', R4, R4', R5, R6, R7, R8, X, m, n and Y are as defined above, compound 1A can be converted to compound 1B in step 1 by treatment with an aryl or heteroaryl bromide or iodide in 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 by heating to reflux of the solvent in the presence of a base such as K2CO3 or Cs2CO3. An alternative method for preparing compound 1B (R6 can be any of the groups defined above for R6 in formula (I)) is described in Scheme 1e below.

[0046] Compound 1B can be converted to compound 1C in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or KaH, or KHMDS at −50° C. in a solvent such as MeTHF.

[0047] Compound 1C can be converted to compound 1E in step 4 by treatment with bis(pinacolato)diboron and 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 a base, for example, KOPh, by heating the solvent to reflux.

[0048] Compound 1K can be prepared in a Suzuki coupling reaction between compounds 1C and 1D in step 3 or between compounds 1E and 1F in step 5 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.

[0049] Alternatively, compound 1E can be converted to compound 1H in a Suzuki coupling reaction with compound 1G in step 6 using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), DCM complex as a catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux. Compound 1H can be converted to compound 1I in step 7 by treatment with TFA in solution in DCM or HCl in solution in dioxane. Compound 1I can be converted to compound 1K in step 8 by treatment with compound 1J (W is Br, I, or OSOR, R = CH3, PhMe, CF3, or CF2CF2CF2CF3) in the presence of a base, such as potassium carbonate in DMF at 70 °C, or in the presence of sodium hydroxide or potassium hydroxide in THF at room temperature, or in the presence of aqueous sodium hydroxide in DCM at room temperature.

[0050] When R3a is a protected OH such as COOMe, COOEt, or O-pivaloyl, compound 1K can be deprotected to compound I in step 9 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, the sodium salt of compound I can be obtained by extraction of the compound. The neutral form can be obtained by acidification to pH 6-7 with an aqueous solution of HCl 2N. The hydrochloride salt can be obtained by acidification to pH 1-2 with an aqueous solution of HCl 2N. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0051] Scheme 1b - Part 1: Preparation of Compounds of Formula (I) - General Process [ka] Scheme 1b - Part 2 [ka] According to scheme 1b-part-1 and part-2, R3a is H, carboxylic acid ester such as COOMe, COOEt, or protected OH such as O-pivaloyl, R1, R2, R3, R3', R3'', R4, R4', R6, R7, R8, R9, X, n, m and Y are as defined above, compound 1L can be converted to compound 1N in Suzuki coupling reaction with compound 1M using e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM as catalyst in the presence of a base such as cesium carbonate (Cs2CO3) in a mixture of dioxane and water by heating the solvent to reflux in step 1.

[0052] Compound 1N can be converted to compound 1O in step 2 by treatment with sodium nitrite followed by sodium iodide in a solvent such as a mixture of water and acetonitrile.

[0053] Compound 1O can be converted to compound 1P in step 3, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature. Compound 1P can be converted to compound 1R in step 4 in a Heck coupling reaction with compound 1Q using, for example, palladium(II) acetate as a catalyst in a solvent such as DMF.

[0054] Compound 1R can be converted to compound 1S in step 5 by treatment with TFA in solution in DCM or HCl in solution in dioxane.

[0055] Compound 1S can be converted to compound 1T in step 6 by treatment with compound 1J (W is Cl, Br, or I, or OSO2R, R = CH3, PhMe, CF3, or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate in DMF at 70 °C, or in the presence of sodium hydroxide or potassium hydroxide in THF at room temperature, or in the presence of aqueous sodium hydroxide in DCM at room temperature.

[0056] Compound 1T can be converted to compound 1U in step 7 by treatment with bis(pinacolato)diboron and 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 a base, for example, KOPh, by heating the solvent to reflux.

[0057] Compound 1K can be prepared in a Suzuki coupling reaction between compound 1T and R6B(OR')2 or R6BF3K in step 8 or between compound 1U and R6Br or R6I in step 9 using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), DCM complex as a catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0058] Compound 1K can be converted in step 12 to a compound of formula (I) in the presence of a source of hydroxide ions, such as NaOH in solution in methanol (MeOH).

[0059] Intermediate 1T can be converted to compound 1Ta in step 10 in the presence of a source of hydroxide ions, such as NaOH in solution in methanol (MeOH).

[0060] In step 11, this compound 1Ta can be converted to compound I through Suzuki conditions using a suitable boron reagent R6B(OR')2 or R6BF3K (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) using, for example, 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 by heating at room temperature or to reflux of the solvent.

[0061] When R3a is a protected OH such as COOMe, COOEt, or O-pivaloyl, compound 1K can be deprotected to compound I in step 12 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, the sodium salt of compound I can be obtained by extraction of the compound. The neutral form can be obtained by acidification to pH 6-7 with an aqueous solution of HCl 2N. The hydrochloride salt can be obtained by acidification to pH 1-2 with an aqueous solution of HCl 2N. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0062] Scheme 1c part-1: Alternative process for preparing intermediate 1T [ka] Scheme 1c-Part-2 [ka] According to scheme 1c-part-1 and part-2, R3a is H, carboxylic acid ester such as COOMe, COOEt, or protected OH such as O-pivaloyl, R1, R2, R3, R3', R3'', R4, R7, R8, R9, X, n, m and Y are as defined above, compound 1V can be converted to compound 1X in Suzuki coupling reaction with compound 1W using e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM as catalyst in the presence of a base such as cesium carbonate (Cs2CO3) in a mixture of dioxane and water by heating the solvent to reflux in step 1.

[0063] Compound 1X can be converted to compound 1Y in step 2, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0064] Compound 1Y can be converted to compound 1Z in step 3 by treatment with TFA in solution in DCM or HCl in solution in dioxane.

[0065] Compound 1Z can be converted to compound 1AA in step 4 by treatment with compound 1J (W is Cl, Br, or I, or OSO2R, where R = CH3, PhMe, CF3, or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate in DMF at 70 °C or in the presence of sodium hydroxide or potassium hydroxide in THF at room temperature.

[0066] Compound 1AA can be converted to compound 1AB in step 5 by treatment with sodium borohydride in solution in MeOH.

[0067] Compound 1AB can also be prepared from compound 1V by using Suzuki coupling reaction with compound 1AC in step 6 using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), DCM complex as 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, followed by bromine addition of the resulting compound 1AD in step 7 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0068] Compound 1AB can be converted to compound 1T in step 8 by treatment with trifluoromethanesulfonic anhydride and pyridine in DCM.

[0069] Scheme 1d: Preparation of compounds of formula (I) - General process [ka] According to scheme 1d, R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, R9 is a hydrogen atom, R1, R2, R3, R3', R3'', R4, R4', R5, R6, R7, R8, X, n, m and Y are as defined above, and compound 1E can be converted to compound 1AF in a Suzuki coupling reaction by treatment with compound 1AE in step 1 using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, in a mixture of dioxane and water in the presence of a base, for example, cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0070] Compound 1AF can be converted to compound 1AG in step 2 by treatment with an alkyl magnesium bromide in a solvent such as THF.

[0071] Compound 1AG can be converted to compound 1K in step 3 by treatment with sulfuric acid in water.

[0072] When R3a is a protected OH such as COOMe, COOEt, or O-pivaloyl, compound 1K can be deprotected to compound I in step 4 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, the sodium salt of compound I can be obtained by extraction of the compound. The neutral form can be obtained by acidification to pH 6-7 with an aqueous solution of HCl 2N. The hydrochloride salt can be obtained by acidification to pH 1-2 with an aqueous solution of HCl 2N. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0073] Scheme 1e: Alternative preparation of compounds of formula (1B) - General process [ka] According to scheme 1e, R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, and R3', R3", R9, X, and m are as defined above, compound 1B can alternatively be prepared as follows: compound 1A can be converted to compound 1Aa in step 1, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0074] Compound 1Aa can be converted to compound 1Ab in step 2 by deprotection with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0075] Compound 1Ac can be prepared in step 3 in a Suzuki coupling reaction between compound 1Ab and R6B(OR')2 or R6BF3K using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), DCM complex as a catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of toluene and water by heating the solvent to reflux. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, 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 hydrogen pressure (H2) to obtain the corresponding saturated compound 1Ac.

[0076] Compound 1Ac can be converted to compound 1B in step 4 by hydrolysis with, for example, aqueous HCl by heating in methanol and DCM.

[0077] Scheme 1f: Alternative process for preparing intermediate 1H (R5=H) [ka] According to scheme 1f, R3a is H or a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, R9 is a hydrogen atom, R3', R3'', R6, R7, R8, X, m, n and Y are as defined above, and compound 1R can be converted in step 1 to compound 1AH by treatment with bis(pinacolato)diboron and a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine, such as triphenylphosphine, in solution in toluene, for example by heating the solvent to reflux in the presence of a base, such as KOPh.

[0078] Compound 1AH can be converted in step 2 to compound 1H (R5 = H) in a Suzuki coupling reaction with an aryl or heteroaryl bromide or iodide 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.

[0079] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the steps of: [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined above and R3a is a carboxylic acid ester such as COOMe, COOEt or a protected OH such as O-pivaloyl) is converted to a compound of formula (I) in the presence of a source of hydroxide ions such as NaOH in a solution in methanol, said step being optionally preceded by a step to obtain compound 1K, and a compound of formula 1T [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above) This is subjected to Suzuki coupling with a boronic acid reagent R6B(OR')2 or R6BF3K, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0080] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the steps of: [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, and R6 represents a phenyl group fused with a hetero(C4-C6)cycloalkyl, the hetero(C4-C6)cycloalkyl ring optionally containing unsaturation, the fused phenyl being optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group, and a (C1-C3)alkoxy group) in the presence of a source of hydroxide ions, such as NaOH, in a solution in methanol, said step being optionally preceded by a step to obtain compound 1K, to give compound 1T [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above) This is subjected to Suzuki coupling with a boronic acid reagent R6B(OR')2 or R6BF3K, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0081] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the steps of: [ka] (wherein R1, R2, R3a, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above) is subjected to Suzuki coupling with a boronic acid reagent R6B(OR')2 or R6BF3K (wherein -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 1Ta, to obtain a compound of formula 1T [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above) It is converted to compound 1Ta in the presence of a source of hydroxide ions, such as NaOH in solution in methanol.

[0082] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the steps of: [ka] wherein R1, R2, R3a, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, are subjected to Suzuki coupling with a boronic acid reagent R6B(OR')2 or R6BF3K, wherein -B(OR')2 is a boronic acid or a pinacolato ester and R6 represents a phenyl group fused with a hetero(C4-C6)cycloalkyl, the hetero(C4-C6)cycloalkyl ring optionally containing unsaturation, the fused phenyl group being optionally substituted with 1-3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group and a (C1-C3)alkoxy group, optionally preceded by a step to obtain a compound 1Ta, a compound of formula 1T [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above) is converted to compound 1Ta in the presence of a source of hydroxide ions, such as NaOH, in solution in methanol.

[0083] As used herein, there is provided an intermediate compound selected from compounds of formula 1T and 1Ta, or any of their pharma- ceutically acceptable salts. [ka] [ka] (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl) is also described.

[0084] As used herein, intermediate compound 1K or any of its pharma- ceutically acceptable salts is [ka] (wherein R1, R2, R3, R3', R3", R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined above, and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl) is also described.

[0085] As used herein, intermediate compound 1K or any of its pharma- ceutically acceptable salts is [ka] (wherein R1, R2, R3, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH such as O-pivaloyl, and R6 represents a phenyl group fused with a hetero(C4-C6)cycloalkyl, the hetero(C4-C6)cycloalkyl ring optionally containing unsaturation, the fused phenyl group optionally being substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group, and a (C1-C3)alkoxy group) are also provided.

[0086] As used herein, any intermediate compound of formula 1F or a pharma- ceutically acceptable salt thereof is [ka] (wherein R1, R2, R4, R4', R5, R7, R8, Y and n are as defined above) are further described.

[0087] The present specification also relates to an intermediate compound of formula 1E, or any of its pharma- ceutically acceptable salts. [ka] (wherein R3a, R3', R3", X, m, R6 and R9 are as defined above) are also described.

[0088] 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 1K as defined above.

[0089] 400 and 500MHz 1H 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.

[0090] 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.

[0091] The following Tables 1a and 1b respectively list specific compounds (names and structures) of formula (I) according to the present disclosure together with their characteristics ( 1 H NMR and liquid chromatography / mass.

[0092] [Table 1]

[0093] [Table 2]

[0094] [Table 3]

[0095] [Table 4]

[0096] [Table 5]

[0097]

Table 6

[0098]

Table 7

[0099]

Table 8

[0100]

Table 9

[0101]

Table 10

[0102]

Table 11

[0103]

Table 12

[0104]

Table 13

[0105]

Table 14

[0106]

Table 15

[0107]

Table 16

[0108]

Table 17

[0109]

Table 18

[0110]

Table 19

[0111]

Table 20

[0112]

Table 21

[0113]

Table 22

[0114]

Table 23

[0115]

Table 24

[0116]

Table 25

[0117]

Table 26

[0118]

Table 27

[0119]

Table 28

[0120]

Table 29

[0121]

Table 30

[0122]

Table 31

[0123]

Table 32

[0124]

Table 33

[0125]

Table 34

[0126]

Table 35

[0127]

Table 36

[0128] [Table 37] EXAMPLES

[0129] 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.

[0130] In the following examples, unless the source of a starting product is specified, it is to be understood that said product is a known compound.

[0131] Intermediates: Intermediate 1: 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Step 1: tert-Butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate [ka] Method 1: To a solution of (4-bromobenzyl)triphenylphosphonium bromide (79.2 g, 155 mmol) in DMF (400 mL) was added NaH (6.18 g, 155 mmol, 60% purity by weight) at 0° C. The mixture was stirred at 0° C. for 15 min. To this reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (24.1 g, 141 mmol) in DMF (160 mL). The mixture was stirred at 20° C. for 9 h. The reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl (100 mL) at 0° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 60.0 g of (crude) tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a yellow solid. LC / MS(m / z,MH+):324

[0132] Method 2: A mixture of tert-butyl 3-methyleneazetidine-1-carboxylate (12.5 g, 73.9 mmol), 1-bromo-4-iodobenzene (23 g, 81.3 mmol), potassium carbonate (20.4 g, 148 mmol), tetrabutylammonium bromide (23.8 g, 73.9 mmol) and palladium(II) acetate (1.66 g, 7.39 mmol) in DMF (125 mL) was heated to 60° C. for 16 h. After cooling to room temperature, EtOAc (500 ml) and water (500 mL) were added. After decantation, the organic phase was washed twice with water (500 ml), dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with DCM to give 20.7 g (86%) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a beige solid. LC / MS(m / z,MH+):324

[0133] Step 2: 3-(4-bromobenzylidene)azetidine, 2,2,2-trifluoroacetic acid [ka] A mixture of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate (60 g, 185 mmol) and TFA (192 mL, 2.59 mol) in DCM (300 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (50 mL) and filtered to give 28 g (45%) of 3-(4-bromobenzylidene)azetidine, 2,2,2-trifluoroacetic acid. LC / MS(m / z,MH+):224

[0134] Step 3: 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine [ka] A mixture of 1-fluoro-3-iodopropane (11.5 g, 61.2 mmol), 3-[(4-bromophenyl)methylene]-azetidine, 2,2,2-trifluoroacetic acid (23.0 g, 68.0 mmol), KOH (5.72 g, 102 mmol) in DMF (100 ml) was stirred at room temperature for 10 h. The reaction mixture was quenched by addition of water (200 mL) followed by extraction with EtOAc (500 mL). After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 95 / 05 to give 8.9 g (47% yield) of 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS(m / z,MH+):284

[0135] Intermediate 2: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine [ka] A mixture of 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (2 g, 7.04 mmol), bis(pinacolato)diboron (2.5 g, 9.85 mmol), KOAc (1.73 g, 17.6 mmol) and Pd(dppf)Cl2 (257 mg, 0.35 mmol) in dioxane (40 mL) was degassed and purged with argon, and the mixture was then refluxed for 2.5 h. After cooling to room temperature, AcOEt (50 mL), Et2O (20 mL), water (30 mL) and brine (30 mL) were added under stirring. After decantation, the organic phase was washed twice with 30 mL of brine and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / AcOEt 100 / 0 to 0 / 100 followed by a gradient of DCM / MeOH 99 / 01 to 95 / 05 to give 1.2 g (51% yield) of 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine. LC / MS(m / z,MH+):332

[0136] Intermediate 3: 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 (144.08 g, 52.67 mmol) and PhOK (8.04 g, 60.80 mmol) in toluene (150 ml) was heated to 75 °C for 1.5 h. The yellow suspension 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

[0137] Intermediate 4: 8-Bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Method 1 Step 1: 9-(4-aminophenyl)-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 (20 g, 57.09 mmol) (prepared according to WO2017140669), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (13.13 g, 59.95 mmol), Cs2CO3 (37.21 g, 114.2 mmol), and Pd(dppf)Cl2, complex with DCM (1.25 g, 1.71 mmol) in dioxane (160 mL) and water (40 mL) was heated to 95° C. for 1 h. Water (200 mL) and EtOAc (500 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with cyclohexane / EtOAc: 85 / 15 to give 14.5 g (87%) of methyl 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):294

[0138] Step 2: 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of methyl 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (14.5 g, 49.4 mmol) in MeCN (270 mL) and 4N HCl (300 mL, 1200 mmol) cooled at 0° C., a solution of sodium nitrite (3.58 g, 51.9 mmol) in water (20 mL) was added slowly. After stirring the reaction mixture at 0° C. for 1 h, a solution of sodium iodide (14.8 g, 98.9 mmol) in water (40 mL) was added. The cold bath was removed and the temperature was allowed to warm to room temperature. After stirring at room temperature for 4 h, Et2O (500 mL) and a 2N solution of NaHSO3 (200 mL) were added. After decantation, the organic phase was washed twice with water (100 mL) followed by brine (100 mL), dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with cyclohexane / EtOAc: 95 / 05 to give 14.8 g (74%) of methyl 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):405

[0139] Step 3: 8-Bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of methyl 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (14.8 g, 36.6 mmol) in DCM (500 mL) was added pyridinium tribromide (12.9 g, 40.3 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with Et2O (500 mL) and pentane (500 mL) and washed twice with a 0.2 N solution of NaHSO3 (100 mL) and water (200 mL). After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 17.7 g (100%) of methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):484

[0140] Step 4: tert-Butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate [ka] A solution of tert-butyl 3-methyleneazetidine-1-carboxylate (7.44 g, 44 mmol) and methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (17.7 g, 36.6 mmol) in DMF (200 mL) was degassed and purged with Ar for 5 min. To this solution was added K2CO3 (10.1 g, 73.3 mmol), tetrabutylammonium bromide (11.8 g, 36.6 mmol) and palladium(II) acetate (0.83 g, 3.66 mmol) under stirring. The mixture was heated to 50° C. for 30 h and then cooled to room temperature. Et2O (300 mL) and water (300 mL) were added. After decantation, the aqueous phase was extracted with another 300 mL of EtO and the combined organic phases were washed twice with water (200 mL), dried over MgSO, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (95 / 05 to 80 / 20) to give 14.7 g (76%) of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate. LC / MS(m / z,MH+):525

[0141] Step 5: 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl, 2,2,2-trifluoroacetic acid [ka] Intermediate 4, step 5, was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzylidene)azetidine-1-carboxylate following a procedure similar to that of intermediate 1, step 2 to give 9.66 g (94%) of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid. LC / MS(m / z,MH+):425

[0142] Step 6: 8-Bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 1-fluoro-3-iodopropane (2.88 g, 15.3 mmol) and 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid (8.24 g, 15.3 mmol) in a mixture of NaOH 1N (46 mL, 46 mmol) and DCM (70 mL) was stirred at room temperature for 48 h. DCM (200 mL) and water (100 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc 100 / 00 to 00 / 100 to give 4.41 g (59% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):485

[0143] Method 2 Step 1: tert-Butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate [ka] To a solution of 1,4-dibromobenzene (290 g, 1.23 mol, 157 mL) in THF (1050 mL) was added n-BuLi (2.5 m, 491 mL) at -70 °C. The mixture was stirred for 30 min, and then tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (200 g, 819 mmol) in THF (420 mL) was added at -70 °C. The reaction mixture was stirred for 1.5 h. The solution was warmed to -25 °C and slowly quenched with an aqueous solution of saturated NH4Cl (2000 mL). The mixture was extracted twice with MTBE (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc 10 / 1 to 0 / 1 to afford 180 g (65%) of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate as a white solid. LC / MS(m / z,MH+):340

[0144] Step 2: tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate [ka] Intermediate 4, step 2 (method 2) was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 4, step 1 (method 1) to afford 8.5 g (99%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzoyl)azetidine-1-carboxylate. LC / MS(m / z,MH+):462

[0145] Step 3: tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate [ka] Intermediate 4, step 3 (method 2) was prepared from tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 4, step 3 (method 1) to afford 6.1 g (88%) of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate. LC / MS(m / z,MH+):540

[0146] Step 4: 9-(4-(azetidine-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl, 2,2,2-trifluoroacetic acid [ka] Intermediate 4, step 4 (method 2) was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzoyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2 to give 5 g (100%) of methyl 9-(4-(azetidine-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid. LC / MS(m / z,MH+):440

[0147] Step 5: 8-Bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 1-fluoro-3-iodopropane (4.27 g, 22.7 mmol), 9-(4-(azetidine-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid (5 g, 9.24 mmol), K2CO3 (4.71 g, 34 mmol) in MeCN (200 mL) was heated to 70° C. for 1 h. The reaction mixture was quenched by the addition of water (200 mL) followed by extraction with EtOAc (500 mL). After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc: 100 / 00 to 00 / 100 to give 3 g (53%) of methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):500

[0148] Step 6: 8-Bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (3 g, 6 mmol) in methanol (5 mL) cooled to 0° C. was added NaBH4 (340 mg, 9 mmol). The reaction mixture was stirred at 0° C. for 30 min. 10% aqueous citric acid (20 mL) and DCM (250 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 05 / 95 to give 3 g (99%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):502

[0149] Step 7: 8-Bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a mixture of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (3 g, 5.97 mmol) in DCM (200 mL) was added pyridine (945 mg, 11.94 mmol, 0.96 mL) and trifluoromethylsulfonyl trifluoromethanesulfonate (3.37 g, 11.94 mmol, 2 mL). The reaction mixture was stirred at room temperature for 18 h. DCM (400 mL) and a saturated aqueous solution of hydrogenocarbonate (300 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 05 / 95 to give 1.9 g (66%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):484

[0150] Alternative Method for Preparation of Intermediate 4, Step 6 (Method 2) Step 1: 3-Azetidinyl(4-bromophenyl)-methanone, 2,2,2-trifluoroacetic acid [ka] Step 1 was prepared from tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate following a similar procedure to that of step 2 of intermediate 1 to give 41.6 g (100%) of 3-azetidinyl(4-bromophenyl)-methanone, 2,2,2-trifluoroacetic acid. LC / MS(m / z,MH+):240

[0151] Step 2: (4-Bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone [ka] Step 2 was prepared following a similar procedure to that of step 3 of intermediate 1 from 3-azetidinyl(4-bromophenyl)-methanone, 2,2,2-trifluoroacetic acid to give 20 g (54%) of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone. LC / MS(m / z,MH+):300

[0152] Step 3: (4-Bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol [ka] To a solution of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone (20.0 g, 66.6 mmol) in MeOH (100 mL) was added NaBH4 (5.04 g, 133 mmol) at 0 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was slowly quenched with water (100 mL) and concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted three times with EtOAc (80 mL). After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM:MeOH 98 / 02 to 90 / 10 to give 16 g (77%) of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol as a mixture of two isomers. LC / MS(m / z,MH+):302

[0153] Step 4: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 4 was prepared from 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol following a procedure similar to that of Step 1 (Method 1) of Intermediate 4 to give 1.39 g (79%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):424

[0154] Step 5: 8-Bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 5 was prepared following a procedure similar to that of Step 3 (Method 1) of Intermediate 4 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.59 g (100%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):502

[0155] Intermediate 5: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) (605 mg, 1.25 mmol), Pd(PPh3)2Cl2 (35 mg, 50 μmol), PPh3 (26 mg, 100 μmol), bis(pinacolato)diboron (793 mg, 3.12 mmol), K2CO3 (38 mg, 0.27 mmol) and PhOK (413 mg, 3.12 mmol) in toluene (30 mL) was degassed and purged with Ar for 5 min, then heated to 75 °C for 6 h. After cooling to room temperature, Et2O (100 mL) and a 5% solution of Na2CO3 (50 mL) were added. After decantation, the organic phase was washed with water (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc: 100 / 00 to 00 / 100 to give 500 mg (75%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):532

[0156] Intermediate 6: 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Step 1: 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 6, step 1, was prepared according to a procedure similar to that of Intermediate 4, step 1 (Method 1) from 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (prepared according to WO2018091153) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to afford 376 mg (88%) of 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z,MH+):336

[0157] Step 2: 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 6, step 2, was prepared from 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate following a procedure similar to that of Intermediate 4, step 2 (Method 1) to afford 285 mg (57%) of 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z,MH+):447

[0158] Step 3: 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 6, step 3, was prepared from 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate following a procedure similar to that of Intermediate 4, step 3 (Method 1) to afford 340 mg (100%) of 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z,MH+):524

[0159] Step 4: tert-Butyl 3-(4-(8-bromo-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate [ka] Intermediate 6, step 4, was prepared from 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate and tert-butyl 3-methyleneazetidine-1-carboxylate following a procedure similar to that of Intermediate 4, step 4 (Method 1) to afford 233 mg (64%) of tert-butyl 3-(4-(8-bromo-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate. LC / MS(m / z,MH+):566

[0160] Step 5: 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate, 2,2,2-trifluoroacetic acid [ka] Intermediate 6, step 5, was prepared from tert-butyl 3-(4-(8-bromo-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2 (Method 1) to afford 250 mg (100%) of 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate, 2,2,2-trifluoroacetic acid. LC / MS(m / z,MH+):466

[0161] Step 6: 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 6, step 6 was prepared from 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate, 2,2,2-trifluoroacetic acid and 3,3-difluoropropyl trifluoromethanesulfonate (Intermediate 11) following a procedure similar to that of Intermediate 4, step 6 (Method 1) to give 38 mg (28%) of 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z,MH+):544

[0162] Intermediate 7: 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [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 ethyl ether (1 L) were added. After decantation, the organic phase was 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

[0163] Step 2: 9-Acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (7.4 g, 25 mmol) in THF (80 mL) was added LiHMDS (1 M, 27 mL) at −78° C. under Ar atmosphere. The mixture was stirred for 2 h, then treated with acetic anhydride (8.8 mL, 75 mmol) and the temperature was allowed to warm to 0° C. After pouring into diisopropyl ether and water, the aqueous layer was separated and extracted with diisopropyl ether. After decantation, the combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography with a 0-50% gradient of EtOAc in cyclohexane to give 6.97 g (83%) of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):339

[0164] Step 3: 9-Acetoxy-8-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 7, step 3, was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to a procedure similar to that of example 3, step 1 to give 1.55 g (65%) of methyl 9-acetoxy-8-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):369

[0165] Step 4: 9-Acetoxy-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of methyl 9-acetoxy-8-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (2.08 g, 5.65 mmol) and Pd / C 10% (400 mg) in EtOAc (50 ml) was hydrogenated at room temperature and 2.5 bar H2 for 5 h. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure to give 1.96 g (94%) of methyl 9-acetoxy-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):371

[0166] Step 5: 6-(4,4-dimethylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate methyl [ka] To a solution of methyl 9-acetoxy-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (1.96 g, 5.29 mmol) in MeOH (32 mL) and DCM (16 mL) was added a 12N solution of HCl (5.29 mL, 63.5 mmol). The resulting reaction mixture was stirred at room temperature overnight. After pouring onto diethyl ether (20 ml), EtOAc (30 ml) and water (50 ml), the organic layer was separated and washed with water (50 ml), a 5% aqueous solution of Na2CO3 (50 ml) and water (50 ml), followed by drying over Na2SO4, filtration and concentration under reduced pressure. The resulting residue was purified by flash chromatography with a 0-20% gradient of ethyl acetate in cyclohexane to give 1.59 g (87%) of methyl 6-(4,4-dimethylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z,MH+):329

[0167] Step 6: 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] To a solution of methyl 6-(4,4-dimethylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (1.35 g, 4.11 mmol) in THF (30 mL) was added KHMDS (1 M, 4.93 ml, 4.93 mmol) under Ar atmosphere at −55° C. After stirring for 30 min at −55° C., N,N-bis(trifluoromethylsulfonyl)aniline (1.51 g, 4.23 mmol) was added. The reaction mixture was stirred for 30 min. Diethyl ether (50 ml) and an aqueous solution of Na2CO3 (5%) (30 ml) were added. After decantation, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with cyclohexane / EtOAc (95 / 05) to give 1.75 g (93%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):461

[0168] Intermediate 8: 8-(trans-4-methylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 8-(cis-4-methylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1: 9-acetoxy-8-(4-methylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 8, step 1, was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (4-methylcyclohexen-1-yl)boronic acid following a procedure similar to that of step 1, example 3, to give 4.12 g (95%) of methyl 9-acetoxy-8-(4-methylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):355

[0169] Step 2: 6-(4-methylcyclohexylidene)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate methyl [ka] Intermediate 8, step 2, was prepared from methyl 9-acetoxy-8-(4-methylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of intermediate 7, step 5 to give 3.8 g (100%) of methyl 6-(4-methylcyclohexylidene)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z,MH+):313

[0170] Step 3: 6-(cis-4-methylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate and 6-(trans-4-methylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 8, step 3, was prepared from methyl 6-(4-methylcyclohexylidene)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of intermediate 7, step 4 to give 1.97 g (65%) of a 70 / 30 mixture of methyl 6-(cis-4-methylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate and methyl 6-(trans-4-methylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z,MH+):315

[0171] Step 4: 8-(cis-4-methylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl and 8-(trans-4-methylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 8, step 4, was prepared from a mixture of methyl 6-(trans-4-methylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate and methyl 6-(cis-4-methylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a similar procedure as that for step 6 of intermediate 7 to give 1.04 g (37%) of a 70 / 30 mixture of methyl 8-(cis-4-methylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and methyl 8-(trans-4-methylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):447

[0172] Intermediate 9: tert-Butyl 3-((6-chloro-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate [ka] To a mixture of 2-chloro-3-fluoro-5-iodopyridine (4.82 g, 18.7 mmol), tert-butyl 3-methyleneazetidine-1-carboxylate (3.17 g, 18.7 mmol), K2CO3 (5.18 g, 37.4 mmol) and t-butylammonium bromide (6 g, 18.7 mmol) in anhydrous DMF (100 ml) was added palladium(II) acetate (420 mg, 1.87 mmol) under argon and the mixture was heated at 55° C. for 16 h and then cooled to room temperature. After dilution with Et2O (500 ml), the mixture was washed with water (3×500 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in cyclohexane (100 / 0 to 0 / 100, v / v) to give 3.06 g (55%) of tert-butyl 3-((6-chloro-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate after trituration in pentane. LC / MS(m / z,MH+):299

[0173] Intermediate 10: 8-(4,4-dimethylcyclohexyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 10 was prepared from 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) following a procedure similar to that of Intermediate 3 to give 1.08 g (73%) of 8-(4,4-dimethylcyclohexyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):439

[0174] Intermediate 11: 3,3-Difluoropropyl trifluoromethanesulfonate [ka] To a solution of 3,3-difluoropropan-1-ol (1 g, 10.41 mmol) and 2,6-lutidine (2.66 mL, 22.9 mmol) in DCM (20 mL) cooled to 0° C., trifluoromethanesulfonic anhydride (1.93 mL, 11.45 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. Et2O and water were added. The aqueous phase was separated and extracted three times with ether. The combined organic phase was washed twice with 10% aqueous citric acid, followed by water, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.06 g (86%) of 3,3-difluoropropyl trifluoromethanesulfonate, which was used in the next step without further purification.

[0175] Intermediate 12: 2,3-Difluoropropyl trifluoromethanesulfonate [ka] Intermediate 12 was prepared according to a similar procedure as that of Intermediate 11 from 2,3-difluoropropan-1-ol to give 0.96 g (93%) of 2,3-difluoropropyl trifluoromethanesulfonate, which was used in the next step without further purification.

[0176] Intermediate 13: 8-Bromo-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Intermediate 13 was synthesized by the reaction of 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid (Intermediate 4, Method 1, Step 5). Prepared from 2,3-difluoropropyl trifluoromethanesulfonate (Intermediate 12) following a procedure similar to that of Intermediate 4, step 6 (Method 1) by direct purification by flash chromatography without decanting the reaction mixture and concentrating the crude under reduced pressure to give 272 mg (17%) of methyl 8-bromo-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):502

[0177] Example: Compounds of formula (I) Method A: Example 3: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) (200 mg, 413 μmol), (2-methoxy-3-methyl-phenyl)boronic acid (137 mg, 826 μmol), Cs2CO3 (283 mg, 867 μmol), and Pd(dppf)Cl2, complex with DCM (30 mg, 41 μmol) in dioxane (8 mL) and water (2 mL) was heated to 90° C. for 30 min. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (100 / 0 to 0 / 100, v / v) to give 153 mg (70%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):526

[0178] Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] To a solution of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (153 mg, 291.1 μmol) in MeOH (40 mL) and water (8 mL), LiOH (28 mg, 1.16 mmol) was added and the reaction mixture was stirred at room temperature overnight. Water (50 mL), EtOAc (100 mL) and Et2O (100 mL) were added and the pH was adjusted to 7 with HCl 0.1 N. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 80 / 20, v / v) to give 148 mg (99%) of 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a white solid.

[0179] Method B: Example 5: 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) (200 mg, 338 μmol), 1-bromo-2-ethyl-3-(trifluoromethyl)benzene (129 mg, 508 μmol), Cs2CO3 (232 mg, 711 μmol), and Pd(dppf)Cl2, complex with DCM (25 mg, 34 μmol) in dioxane (8 mL) and water (2 mL) was heated to 90° C. for 1 h. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (100 / 0 to 0 / 100, v / v) to give 113 mg (58%) of methyl 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):578

[0180] Step 2: 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Example 5, step 2 was prepared from methyl 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Example 3, step 2 to give 71 mg (64%) of 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0181] Method C: Examples 35 and 36: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 and isomer 2 [ka] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka] A mixture of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) (250 mg, 516 μmol), potassium trifluoro(spiro[2.3]hexan-1-yl)borate (194 mg, 1032 μmol), Cs2CO3 (336 mg, 1032 μmol), and Pd(dppf)Cl2, complex with DCM (37 mg, 52 μmol) in toluene (6 mL) and water (2 mL) was heated to 90° C. for 4 h in a sealed tube. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (100 / 0 to 0 / 100, v / v) and reversed-phase preparative HPLC on a RP-18 column with a gradient of ACN in water (30 / 70 to 100 / 0, v / v) to give 76 mg (30%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture of isomer 1 and isomer 2. LC / MS(m / z,MH+):486

[0182] The racemic mixture of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral SFC (CHIRALPAK IJ column, supercritical CO2 80% / MeOH 20% / TEA 0.1%) to give 28 mg of isomer 1 and 29 mg of isomer 2.

[0183] Example 35, Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 [ka] Example 35, step 2, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 following a procedure similar to that of example 3, step 2, to give 12 mg (44%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1.

[0184] Example 36, Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 [ka] Example 36, step 2, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 following a procedure similar to that of example 3, step 2, to give 16 mg (57%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2.

[0185] Method D Example 68: 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (162 mg, 350 μmol), 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine (Intermediate 2) (140 mg, 420 μmol), Pd(dppf)Cl2DCM complex (26 mg, 40 μmol), Cs2CO3 (229 mg, 0.7 mmol) in dioxane (6 ml) and water (1.5 ml) was heated to 95° C. for 1 h. After cooling to room temperature, water (50 mL), EtOAc (100 mL) and Et2O (100 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (100 / 0 to 0 / 100, v / v) to give 120 mg (66%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):516

[0186] Step 2: 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Example 68, step 2, was prepared from methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of example 3, step 2 to give 110 mg (94%) of 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0187] Method E: Example 64: 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: tert-butyl 3-(4-(3-(methoxycarbonyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate [ka] Example 64, step 1, was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate (Intermediate 4, Method 1, step 4) following a procedure similar to that of Intermediate 5 to give 1.37 g (63%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate. LC / MS(m / z,MH+):516

[0188] Step 2: tert-butyl 3-(4-(8-(chroman-5-yl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate [ka] Example 64, step 2 was prepared from tert-butyl 3-(4-(3-(methoxycarbonyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate and 5-bromochroman following a procedure similar to that of example 5, step 1 to give 120 mg (59%) of tert-butyl 3-(4-(8-(chroman-5-yl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate. LC / MS(m / z,MH+):578

[0189] Step 3: 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(chroman-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 3 of Example 64 was prepared from tert-butyl 3-(4-(8-(chroman-5-yl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzylidene)azetidine-1-carboxylate following a procedure similar to that of Step 2 of Intermediate 1, including an additional quench with saturated aqueous NaHCO to afford 100 mg (100%) of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(chroman-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):478

[0190] Step 4: 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 4 of Example 64 was prepared from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(chroman-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of step 5 (method 2) of intermediate 4 to give 35 mg (31%) of methyl 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):538

[0191] Step 5: 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 5 of Example 64 was prepared from methyl 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 3 to give 31 mg (91%) of 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0192] Method F: Example 65: 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: tert-butyl 3-((6-(8-(4,4-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate [ka] A mixture of tert-butyl 3-((6-chloro-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate (Intermediate 9) (715 mg, 2.4 mmol), methyl 8-(4,4-dimethylcyclohexyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 10) (700 mg, 1.6 mmol), CsCO (1.56 g, 4.79 mmol) in 40 ml toluene and 10 ml water in a sealed tube was degassed for 5 min. CataCXium A Pd G3 ((di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, CAS number 1651823-59-4) (116 mg, 0.16 mmol) was added. The tube was sealed and the reaction mixture was stirred at 90 °C for 18 h. Water (10 ml) and Et2O (30 ml) were added and the organic layer was washed with 10 ml water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in cyclohexane (100 / 0 to 50 / 50, v / v) to afford 560 mg (60%) of tert-butyl 3-((6-(8-(4,4-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate. LC / MS(m / z,MH+):575

[0193] Step 2: 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl, 2,2,2-trifluoroacetic acid [ka] A mixture of tert-butyl 3-((6-(8-(4,4-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate (640 mg, 1.11 mmol) in DCM (4 ml) and trifluoroacetic acid (4 ml) was stirred at room temperature for 1 h and then concentrated under reduced pressure to give 1.3 g of crude methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid, which was used directly in the next step. LC / MS(m / z,MH+):475.

[0194] Step 3: 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] A mixture of crude methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid (370 mg, 0.47 mmole), 1-fluoro-3-iodopropane (97 mg, 0.52 mmole) and DIEA (244 mg, 1.89 mmol) in acetonitrile (10 ml) was stirred at room temperature for 20 h, then concentrated to half its original volume under reduced pressure and the mixture was dissolved in cyclohexane. Direct purification by flash chromatography eluting with a gradient of AcOEt / MeOH:80 / 20 (100 / 0 to 0 / 100, v / v) afforded 100 mg (40%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):535

[0195] Step 4: 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 5 of Example 65 was prepared from methyl 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 3 to give 51 mg (35%) of 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0196] Example 66: 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: 9-(5-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate methyl [ka] Step 1 of Example 66 was prepared from methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid and 3,3-difluoropropyl trifluoromethanesulfonate (Intermediate 11) according to a procedure similar to that of Step 3 of Example 65 to give 174 mg (46%) of methyl 9-(5-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):555

[0197] Step 2: 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Example 66, step 2 was prepared from methyl 9-(5-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of example 3, step 2 to give 32 mg (16%) of 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0198] Method G: Example 42: 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] Step 1: 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Example 42, step 1, was prepared from 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (intermediate 6) and (3-chloro-2-methyl-phenyl)boronic acid following a procedure similar to that of example 3, step 1, to give 21 mg (61%) of 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z,MH+):590

[0199] Step 2: 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] Example 42, step 2, was prepared from 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate following a procedure similar to that of example 3, step 2 to give 12.5 mg (69%) of 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol.

[0200] Compounds according to Table 1a above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0201] Test: Estrogen receptor degrading activity Said test involves measuring the in vitro degradation activity of the compounds of Table 1a.

[0202] Measurement of degradation activity was done using breast cancer cell ERα in a cell Western assay as described below.

[0203] 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.

[0204] 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 )

[0205] The % reduction in ERα levels was determined as follows: % inhibition=100*(1-(sample-fulvestrant:DMSO-fulvestrant)).

[0206] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1a tested at 0.3 μM, demonstrating that said compounds have significant degrading activity against the estrogen receptor.

[0207] [Table 38]

[0208] [Table 39]

[0209] [Table 40]

[0210] Therefore, it is clear that the tested compounds have degrading activity on estrogen receptor with IC50 less than 1 μM and degrading level greater than 50%. Therefore, the compounds of formula (I) can be used to prepare drugs, particularly drugs that are degrading agents of estrogen receptor.

[0211] Thus, there is also provided herein a medicament comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] In some embodiments, the cancer is a hormone-dependent cancer.

[0217] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0218] 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.

[0219] In another embodiment, the metastasis is a cerebral metastasis.

[0220] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0221] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0222] 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.

[0223] 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.

[0224] There is also provided herein the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions set out above, more particularly useful in treating cancer.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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

[0230] 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" each independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R4' independently represent a hydrogen atom or a fluorine atom; R5 is a hydrogen atom, a fluorine atom or (C １ ~C ３ ) represents an alkyl group; - R6 is A 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; (C １ ~C ６ ) fluoroalkyl group; ３ ~C ６ ) a cycloalkyl group; １ ~C ６ ) an alkoxy group; １ ~C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ ~C ４ ) an alkylthio group; １ ~C ４ ) a fluoroalkylthio group; １ ~C ４ ) optionally substituted with 1 to 3 substituents independently selected from alkylsulfonyl groups and —OH groups; ■ (C ３ ~C ６ ) cycloalkyl (as defined above in (C ３ ~C ６ ) cycloalkyl is a fused phenyl group selected from a phenyl group fused with (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; ■ Hetero (C ４ ~C ６ ) cycloalkyl(hetero(C ４ ~C ６ ) a cycloalkyl ring is a phenyl group fused to a cycloalkyl group, which optionally contains unsaturation; 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; ■ Contains 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a bicyclic group optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; Heteroaryl groups, such as pyridyl 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 a tetrahydropyranyl group (the heterocycloalkyl group is saturated or partially saturated, and is not limited to a fluorine atom, (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) a fluoroalkoxy group, an oxo group, (C １ ~C ３ ) optionally substituted with 1 to 3 substituents independently selected from alkoxy groups, and —OH groups; (C) such as isobutyl, methyl or ethyl 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=, -N= or -CR" (wherein R" is (C １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine or chlorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R7 is independently (C) such as methyl. １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R8 represents a hydrogen atom or a fluorine atom; R9 is a hydrogen atom, (C １ ~C ３ ) an alkyl group or a cyclopropyl group; - n is 0, 1 or 2; and m is 0 or 1).

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

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

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, characterized in that R4 and R4' represent a hydrogen atom, or a pharma- ceutically acceptable salt thereof.

6. 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 represents a hydrogen atom.

8. The 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 1 to 3 substituents independently selected from chlorine atoms, fluorine atoms, methyl groups, ethyl groups, trifluoromethyl groups, cyclopropyl groups, methoxy groups, trifluoromethoxy groups, 1,1-difluoroethyl groups, difluoromethyl groups, difluoromethoxy groups, fluoromethyl groups and cyano groups, or a pharma- ceutically acceptable salt thereof.

9. A compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a fused phenyl group selected from a bicyclo[4.2.0]octatrienyl group, an indanyl group or a tetrahydronaphthalenyl group, optionally substituted with one or two fluorine atoms, or R6 represents a chromanyl group, or a pharma- ceutically acceptable salt thereof.

10. R6 is a fluorine atom, an —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 8. Compounds of formula (I) according to any one of claims 1 to 7, or pharma- ceutically acceptable salts thereof, characterized in that: 1) represents a bicyclic group selected from bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl and bicyclo[3.2.1]octan-3-yl, optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; advantageously, said bicyclic group is unsubstituted.

11. R6 represents a cycloalkyl selected from a cyclohexyl or cyclopropyl group, said cycloalkyl being ○ 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 alkyl groups; Said cycloalkyl is advantageously Methyl, phenyl and a cyclohexyl group substituted by two halogen atoms, in particular by fluorine atoms; A compound of formula (I) according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, characterized in that it is substituted with one or two substituents independently selected from:

12. A compound of formula (I) according to any one of claims 1 to 11, characterized in that R7 independently represents a methyl group, a cyano group, a trifluoromethyl group or a fluorine atom, and n is 0, 1 or 2, 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 -CH=, -N= or -CR"=, and R" represents a fluorine atom, a cyano group, or a trifluoromethyl group, 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. R6 is hetero (C ４ ~C ６ ) cycloalkyl(hetero(C ４ ~C ６ ) a cycloalkyl ring is a phenyl group fused to a cycloalkyl group, which optionally contains unsaturation; １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ 15. A compound of formula (I) according to any one of claims 1 to 7 or 12 to 14, or a pharma- ceutically acceptable salt thereof, which represents:

16. R6 is a phenyl group, the phenyl group being 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 15. The compound of formula (I) according to any one of claims 1 to 7 or 12 to 14, wherein: R 1 is optionally substituted by 1 to 3 substituents independently selected from alkylsulfonyl groups and -OH groups; and said phenyl is substituted by at least one trifluoromethoxy group, at least one 1,1-difluoroethyl group, at least one difluoromethyl group, at least one difluoromethoxy group or at least one fluoromethyl group; or a pharma- ceutically acceptable salt thereof.

17. The compound is the following compound: - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 8-(3,4-difluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - 8-(3-fluoro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(3-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - 8-(2-fluoro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-mesityl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) - 8-(2-chloro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - 8-(3-fluoro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) - 8-(3-chloro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - 8-(2-(1,1-difluoroethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) - 8-(2-chloro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) - 8-(2-chloro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - 8-(4-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) - 8-(2-fluoro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) - 8-(2-chloro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) - 8-(2-fluoro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) - 8-(2-chloro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) - 8-(2-ethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) - 8-(2-fluoro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) - 8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) - 8-(4-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) - 8-(4-(difluoromethyl)-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) - 8-(2-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) - 8-(4-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) - 8-(2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) - 8-(2-(difluoromethoxy)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) - 8-(3-chloro-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1, (35) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (36) - 8-(2-(difluoromethyl)-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) - 8-(3-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) - 8-(2-ethyl-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) - 8-(3-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, (42) - 8-(2-(difluoromethyl)-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) - 8-(4-(difluoromethyl)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (44) - 8-(2-(difluoromethyl)-5-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) - 8-(3-chloro-2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) - 8-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) - 8-(3-chloro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (49) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) - 8-(4-(difluoromethyl)-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) - 8-(4-(difluoromethyl)-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (54) - 8-(4-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(trans-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) - 8-(2-(difluoromethyl)-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) - 8-(2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) - 8-(2-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (60) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(cis-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (61) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (62) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) - 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (64) - 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (65) - 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (66) - 8-(chroman-8-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) - 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (69) - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2, (70) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4,6-bis(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (71) - 8-(2,4-dimethyl-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) - 8-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73) - 8-(2,6-diethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (74) - 8-(3-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (75) - 8-(2-fluoro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (76) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-6-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (77) - 8-(2,5-dimethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (78) - 8-(2,3-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (79) - 8-(2,6-diethyl-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (80) - 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (81) - 8-(3,4-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (82) - 8-(4-chloro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (83) - 8-(2,6-dimethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (84) Compounds of formula (I) according to any one of claims 1 to 16, characterized in that they are selected from: or a pharma- ceutically acceptable salt thereof, in particular the hydrochloride thereof.

18. Compound of Formula 1K 【Chemistry 2】 wherein R1, R2, R3', R3", R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 16 and R3a is a carboxylic acid ester such as COOMe, COOEt or a protected OH such as O-pivaloyl, is converted to a compound of formula (I) in the presence of a source of hydroxide ions such as NaOH in solution in methanol, said step being optionally preceded by a step to obtain compound 1K, and a compound of formula 1T 【Chemistry 3】 wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 16, and R3a is as defined above; Boronic acid reagent R6B(OR') ２ Or R6BF ３ K (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 11).

19. Compound of Formula 1Ta 【Chemistry 4】 (wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 16, and R3a is as defined in any one of claims 1 to 18), is reacted with a boronic acid reagent R6B(OR') ２ Or R6BF ３ K (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 11), said step being optionally preceded by a step to obtain compound 1Ta, and a compound of formula 1T is subjected to Suzuki coupling with 【Chemistry 5】 wherein R1, R2, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 16, and R3a is as defined above; is converted to compound 1Ta in the presence of a source of hydroxide ions, such as NaOH, in solution in methanol; A process for preparing a compound of formula (I) according to any one of claims 1 to 17.

20. Any of the compounds of formula 1K or a pharma- ceutically acceptable salt thereof 【Chemistry 6】 (wherein R1, R2, R3, R3', R3", R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 16, R3a is a carboxylic acid ester such as COOMe, COOEt or a protected OH such as O-pivaloyl, R6 is a hetero(C ４ ~C ６ ) cycloalkyl(hetero(C ４ ~C ６ ) a cycloalkyl ring is a phenyl group fused to a cycloalkyl group, which optionally contains unsaturation; 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).

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

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

23. A compound of formula (I) as defined in any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

24. 20. A compound of formula (I) as defined in any one of claims 1 to 17, 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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