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

Abstract

A compound of formula (I) or a pharma- ceutically acceptable salt thereof (wherein R1 and R2 represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a -COOH group or a -OH group; R3' and R3" represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom or a cyano group; R4 and R5 represent a hydrogen atom, a halogen atom, a -NH2 group, a (C1-C3) alkyl group, a (C1-C3) alkoxy group or a -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form a =NOCH3 group or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group, a -OH group or a fluorine atom; R6 represents a phenyl group, a fused phenyl group, a bicyclic group containing 5 to 12 carbon atoms, a cyclic group containing 2 to 9 carbon atoms, , a heteroaryl group containing 1 to 3 heteroatoms, a cycloalkyl group containing 3 to 7 carbon atoms, a (C3-C6)cycloalkyl(C1-C3)alkyl group, a 4- to 7-membered heterocycloalkyl group, a (C1-C6)alkyl group, or a phenyl(C1-C2)alkyl group; X represents -CH2-, -O-, or -S-; Y represents -CH=, -N=, or -CR"=; R8 represents a (C1-C3)alkyl group, a halogen atom, a cyano group, or a (C1-C3)fluoroalkyl group; R9 represents a hydrogen atom or a fluorine atom; R10 and R10' represent a hydrogen atom or a fluorine atom; R11 represents a hydrogen atom, a (C1-C3)alkyl group, or a cyclopropyl group; n is 0, 1, or 2, and m is 0 or 1). Further disclosed are compounds of formula (I) as well as processes for preparing same, pharmaceutical compositions containing them for use as inhibitors and degraders of estrogen receptors, particularly for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation. [Formula 1] TIFF2025513852000142.tif44170

Description

[Technical field]

[0001] Disclosed herein are novel substituted 6,7-dihydro-5H-benzo[7]annulene derivatives, processes for their preparation, and their therapeutic uses, particularly as anti-cancer agents through selective antagonism and degradation of estrogen receptors. [Background technology]

[0002] Estrogen receptors (ER) belong to the steroid / nuclear receptor superfamily that are involved in the regulation of eukaryotic gene expression, cell proliferation, and in target tissues. ER exists in two forms, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors that are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ER resides primarily in the cytosol of cells. When the hormone estrogen binds to ER, ER translocates from the cytosol to the cell nucleus, forms dimers, and then binds to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to regulate the transcription of target genes.

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

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

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

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

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

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

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

[0010] A compound of formula (I) or a pharma- ceutically acceptable salt thereof [ka] [In the formula, - R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a -COOH group or a -OH group; - R3' and R3" independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; - R4 and R5 independently represent a hydrogen atom, a fluorine atom, an -NH2 group, a (C1-C3) alkyl group such as a methyl group, a (C1-C3) alkoxy group such as a methoxy group or an ethoxy group, or a -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form, with the carbon atom to which they are attached, a =NOCH3 group or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group, an -OH group or a fluorine atom; or alternatively, R4 and R7 together form a cyclopropyl group via the bond to which they are attached, thereby providing an adjacent azetidine group, azaspiro[2.3]hexane; - R6, ■ a phenyl group optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with a cyano group or an -OH group; a (C1-C6) alkylene 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 an -OH group; ■ fused phenyl groups selected from phenyl groups fused with (C3-C6)cycloalkyl, in which the (C3-C6)cycloalkyl ring optionally contains unsaturation and is optionally substituted with 1 to 3 substituents independently selected from (C1-C3)alkyl groups, hydroxy groups, halogen atoms, (C1-C6)fluoroalkyl groups and (C1-C3)alkoxy groups; ■ a phenyl group fused with a hetero(C4-C6)cycloalkyl, wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation and 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 containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as a pyridyl group, a pyridone group or a pyrrolyl group, optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) fluoroalkyl groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, cyano groups, carbamoyl groups and -OH groups; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated, ○ a fluorine atom, an -OH group, a (C1-C3) alkyl group optionally substituted with an -OH group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, and (C3-C6)cycloalkyl groups and phenyl groups, optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; a cycloalkyl group optionally substituted with 1 to 4 substituents independently selected from: ■ a (C3-C6)cycloalkyl(C1-C3)alkyl group, optionally substituted on the cycloalkyl by 1 to 4 substituents independently selected from a fluorine atom, an —OH group, a (C1-C4)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group and an oxo group; ■ 4-7 membered heterocycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group or a tetrahydrofuranyl group, which are saturated or partially saturated and optionally substituted with one to three substituents independently selected from a fluorine atom, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) fluoroalkoxy group, an oxo group, a (C1-C3) alkoxy group and a -OH group; ■ (C1-C6) alkyl groups, such as an isobutyl group, a propyl group, or an ethylbutyl group, optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and a -OH group; and ■ A phenyl(C1-C2)alkyl group optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and a -OH group. represents a group selected from - X represents -CH2-, -O- or -S-; - Y represents -CH=, -N= or -CR"= (wherein R" represents a (C1-C3) alkyl group, a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl); - R8 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R9 represents a hydrogen atom or a fluorine atom; - R10 and R10' independently represent a hydrogen atom or a fluorine atom; - R11 represents a hydrogen atom, a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; - m is 0 or 1] are disclosed herein.

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

[0012] Compounds of formula (I) may exist in tautomeric forms as well.

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

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

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

[0016] As used herein, the following terms have the following definitions unless otherwise stated throughout the specification. halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; - Oxo: the "=O" group; - alkyl group: unless otherwise specified, a linear or branched saturated hydrocarbon-based aliphatic group (described as "(C1-C6) alkyl") containing 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups; - alkylene group: unless otherwise specified, a straight or branched chain hydrocarbon-based aliphatic group containing 1-6 carbon atoms and at least one unsaturation (referred to as "(C1-C6) alkylene"). Examples include, but are not limited to, vinyl groups; - cycloalkyl group: unless otherwise stated, a monocyclic alkyl group containing 3 to 7 carbon atoms, saturated or partially unsaturated, unsubstituted or substituted, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl or cyclohexenyl; - cycloalkylalkyl group: an alkyl group substituted with a cyclic alkyl group as defined above, including but not limited to cyclobutylmethyl; - Heterocycloalkyl group: a saturated or partially unsaturated 4- to 7-membered cycloalkyl group, in particular a 4- to 6-membered cycloalkyl group, containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen. Examples include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl and tetrahydrothiopyranyl. Advantageously, the heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above, in which the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Examples include -CH2F, -CHF2, CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkyl group may also be called a perfluoroalkyl group. Examples include trifluoromethyl group or trifluoroethyl group; - alkoxy group: -O-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; - Fluoroalkoxy group: -O-alkyl group, where the alkyl group is as defined above, and the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkoxy group may also be called a perfluoroalkoxy group. Examples include a trifluoromethoxy group, etc.; - (C1-C4) alkylthio group, also called (C1-C4) alkylsulfanyl group: -S-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.; - (C1-C4) alkylsulfonyl group: -SO2-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; - (C1-C4) fluoroalkylthio group, also called (C1-C4) fluoroalkylsulfanyl group: -S-fluoroalkyl group, in which the fluoroalkyl group is as defined above. Examples include, but are not limited to, fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - Fused phenyl group: a bicyclic group containing 7-10 carbon atoms and including a phenyl moiety. The phenyl moiety may be fused to a (C3-C6) cycloalkyl group, i.e. the phenyl moiety may share a bond with the (C3-C6) cycloalkyl group. The fused phenyl group may be bonded to the rest of the molecule by its phenyl moiety. The fused phenyl group may be substituted. Examples are, but are not limited to, indanyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, tetrahydronaphthalenyl, etc.; - Phenyl group fused to hetero(C4-C6)cycloalkyl: a bicyclic group containing 7-10 carbon atoms and including a phenyl moiety. The phenyl moiety may be fused to a hetero(C4-C6)cycloalkyl, 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. The fused phenyl group may be substituted. Examples include, but are not limited to, a chromanyl group, in particular a chroman-8-yl group; - Heteroaryl group: a cyclic 5-10 membered aromatic group containing 2-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. Such nitrogen atoms may be substituted with oxygen atoms to form -NO bonds. Such -NO bonds can also be expressed as N-oxides (-N + -O -) form. The heteroaryl group may be monocyclic or bicyclic. Examples of heteroaryl groups include, but are not limited to, thiophene, furan, thiadiazole, thiazole, imidazole, pyridazine, triazine, pyrazine, oxadiazole, pyrazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine, benzotriazole, benzoxazole, pyrrolo[2,3-b]pyridine, benzimidazole, benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridone groups, etc. Advantageously, the heteroaryl group is pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine, pyridone and pyrrole; bicyclic groups, which are hydrocarbon groups generally containing from 5 to 12 carbon atoms and selected from groups containing two rings linked via: A single common atom: a "spiro-bicyclic ring". Such spiro-bicyclic alkyls generally contain 5-11 carbon atoms and are called "spiro (C5-C 11 The ring may be saturated or partially unsaturated. Such spiro bicyclic rings may be unsubstituted or substituted, in particular by at least one (C1-C3) alkyl group such as methyl or fluorine. Spiro (C5-C6) with respect to the definition of R6 is referred to as a "spiro bicyclic ring". 11 Examples of spiro(C5-C6) bicyclic rings include, but are not limited to, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.3]heptene, spiro[2.5]octane, and 7-azaspiro[3.5]nonane. 11 Advantageously, the bicyclic ring is a spiro[3.3]heptane or spiro[3.3]heptene, also for the R6 group. 2 common atoms, in which case the bicyclic group contains 7 to 12 carbon atoms and optionally 1 to 2 unsaturations. Examples of such bicyclic groups include, but are not limited to, cis-1,3a,4,5,6,6a-hexahydropentalenyl, bicyclo[3.1.0]hexan-1-yl, bicyclo[4.1.0]heptanyl, and octahydropentalenyl. 3 or more common atoms. In this case, the bicyclic group contains 6 to 10 carbon atoms, and such a bicyclic group is called a “bridged (C6-C 10 (cycloalkyl) groups, where the rings share three or more atoms and the bridge contains at least one atom, e.g., 1, 2 or 3 atoms, and preferentially 1 atom. Examples of such bridged cycloalkyl groups include, but are not limited to, bicyclo[3.2.1]octan-3-yl and bicyclo[2.2.1]heptan-2-yl. - Zwitterion refers to an overall neutral molecule that has positive and negative charges and has acidic and basic groups.

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

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

[0019] In another embodiment, in a compound of formula (I) as defined above, X represents -CH2-.

[0020] In another embodiment, in the compound of formula (I) as defined above, R4 and R5, independently of each other, represent a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a -NH2 group or a -OH group; or R4 and R5 together form an oxo group, a =NOCH3 group or a cyclopropyl group with the carbon atom to which they are attached, or alternatively, R4 and R7 together form a cyclopropyl group with the bond to which they are attached, in particular, R4 and R5 both represent a hydrogen atom or a fluorine atom, or one of R4 and R5 represents a hydrogen atom and another fluorine atom or a -OH group, or one of R4 and R5 represents a methyl group and the other represents a hydroxyl group or a fluorine atom, more particularly, R4 and R5 both represent a hydrogen atom.

[0021] In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 represent a hydrogen atom, a -NH2 group, a methyl group, a methoxy group, an ethoxy group.

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

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

[0024] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from chlorine, fluorine, hydroxy, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, hydroxymethyl, 2-hydroxyethyl, fluoromethyl, difluoromethyl, 2,2-difluoroethyl, methoxy, ethoxy, cyano, vinyl, cyanomethyl, trifluoromethylsulfonyl, methylsulfanyl, difluoromethylsulfanyl, methylsulfonyl, trifluoromethoxy, cyclopropyl, and difluoromethoxy.

[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]octa-trienyl group, a tetrahydronaphthalenyl group and an indanyl group, optionally substituted with one or two fluorine atoms, or represents a chromanyl group.

[0026] In another embodiment, in the compound of formula (I) as defined above, R6 represents a cycloalkyl group selected from cyclobutyl, cyclohexyl, cyclopentyl, cycloheptyl, cycloheptenyl and cyclohexenyl, said cycloalkyl group being ○ a fluorine atom, an -OH group, a (C1-C3) alkyl group optionally substituted with an -OH group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, (C3-C6)cycloalkyl and phenyl groups, optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; and wherein the cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from ○ Fluorine atom, methyl group, and Cyclohexyl group substituted with two halogen atoms, especially fluoro atoms is substituted with 1 to 2 substituents independently selected from

[0027] In another embodiment, in a compound of formula (I) as defined above, R6 represents a (C1-C6) alkyl group selected from ethyl, isobutyl and ethylbutyl, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, (C1-C3) alkoxy groups, (C1-C3) fluoroalkoxy groups and -OH groups, in particular optionally substituted with 1 or 3 fluorine atoms or -OH groups.

[0028] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3" represent a hydrogen atom.

[0029] In another embodiment, in the compounds of formula (I) as defined above, R 8 independently represents a methyl group or a fluorine atom; and n is 0, 1 or 2.

[0030] In another embodiment, in a compound of formula (I) as defined above, Y represents -CH=, -C(CH3)=, -CF= or -N=, in particular -CH= or -N=.

[0031] In another embodiment, in a compound of formula (I) as defined above, R9 represents a hydrogen atom.

[0032] In another embodiment, in the compounds of formula (I) as defined above, R10 and R10' represent a hydrogen atom.

[0033] In another embodiment, in a compound of formula (I) as defined above, R11 represents a hydrogen atom.

[0034] In another embodiment, in the compounds of formula (I) as defined above, m is 1.

[0035] In another embodiment, in the compound of formula (I) as defined above, R6 is ■ a phenyl group which is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with a cyano group or a -OH group; a (C1-C6) alkylene 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, and which is at least substituted with a (C1-C6) alkylene group, particularly a vinyl group; ■ a phenyl group fused to a hetero(C4-C6)cycloalkyl, wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation and 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; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated, ○ a fluorine atom, an -OH group, a (C1-C3) alkyl group optionally substituted with an -OH group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, and (C3-C6)cycloalkyl groups and phenyl groups, optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; and optionally substituted with 1 to 4 substituents independently selected from It represents a cycloalkyl group substituted at least with a (C1-C3) alkyl group optionally substituted with an -OH group.

[0036] In another embodiment, in the compound of formula (I) as defined above, R6 is - a phenyl group, optionally substituted with 1 to 3 substituents independently selected from halogen atoms; a (C1-C6) alkyl group optionally substituted with a cyano group or an -OH group; a (C1-C6) alkylene 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, wherein the phenyl is substituted by at least one hydroxy group, by at least a vinyl group, by at least a trifluoromethoxy group, by at least a cyclopropyl group, or by at least a 1,1-difluoroethyl group; - tetrahydronaphthalenyl group; - a cyclobutyl group; or - represents a hydroxypropyl group.

[0037] In another embodiment, in the compound of formula (I), R3 is a COOH group, R6 is a phenyl group containing 2 or 3 substituents independently selected from phenyl groups, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from chlorine atoms, fluorine atoms, hydroxyl groups, methyl groups, ethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethyl groups, 1,1-difluoroethyl groups, hydroxymethyl groups, 2-hydroxyethyl groups, fluoromethyl groups, difluoromethyl groups, 2,2-difluoroethyl groups, methoxy groups, ethoxy groups, cyano groups, vinyl groups, cyanomethyl groups, trifluoromethylsulfonyl groups, methylsulfanyl groups, difluoromethylsulfanyl groups, methylsulfonyl groups, trifluoromethoxy groups, cyclopropyl groups, and difluoromethoxy groups, said phenyl group being at least substituted with a (C1-C6) alkylene group, in particular a vinyl group. In such embodiments, R3' and R3" are, in particular, hydrogen atoms. Note that in such embodiments, R1, R2, R4, R5, R7, R9, R10, R10' and R11 are hydrogen atoms. In such embodiments, Y is a -CH= group and n is equal to 0. Note that in such embodiments, X is a -CH2- group. Note that in such embodiments, m is 1.

[0038] Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or their pharma- ceutically acceptable salts, in particular their hydrochlorides: - 8-(2-(difluoromethoxy)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(5,6,7,8-tetrahydronaphthalen-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - 8-(3-chloro-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(2-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - 8-(chroman-8-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) - 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-carboxylic acid, (13) - 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid, (15) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (16) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (17) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (19) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(5-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (20) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (22) - 8-(2-(difluoromethyl)-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - 8-(2-(difluoromethyl)-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (25) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (28) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) - 8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) - 8-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (32) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (34) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(5-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) - 8-(3-fluoro-2-vinylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) - 8-(2-ethyl-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) - 8-(3-chloro-2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) - 8-(2,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) - 8-(2-chloro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (40) - 8-(2-fluoro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (41) - 8-(4-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (42) - 8-(2-fluoro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) - 8-(2-chloro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (44) - 8-(2-fluoro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) - 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) - 8-(2,4-difluoro-3-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (48) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (49) - 8-(2-chloro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) - 8-(2,6-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (51) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) - 8-(2-chloro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) - 8-(2-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (54) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxy-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) - 8-(3-fluoro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) - 8-(3-chloro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) - 8-(2,3-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) - 8-(2-(difluoromethyl)-5-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (60) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (61) - 8-(2-(1,1-difluoroethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (62) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) - 8-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (64) - 8-(3-fluoro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (65) - 8-(2-(difluoromethyl)-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (66) - 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) - 8-(3-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) - 8-(2-ethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (69) - 8-(4-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (70) - 8-(3,4-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (71) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-4,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) - 8-(3-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73).

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

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

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

[0042] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

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

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

[0045] The compounds of formula (I) may be prepared by the following process.

[0046] Compounds of formula (I) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0047] The following methods, which are general for preparing compounds of formula (I), are optionally modified by using appropriate reagents and conditions to introduce the various moieties found in formula (I) as described below.

[0048] The following abbreviations and empirical formulas are used: MeCN Acetonitrile NH4Cl Ammonium chloride NH4OH Ammonium hydroxide 9-BBN 9-Borabicyclo[3.3.1]nonane CO Carbon monoxide CS2CO3 Cesium carbonate DCM Dichloromethane DIEA Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOH Ethanol EtOAc Ethyl acetate H2 Hydrogen HCl Hydrochloric acid HPLC High Performance Liquid Chromatography LiAlH4 Lithium Aluminum Hydride LiHMDS Lithium hexamethyldisilazane MeOH Methanol MgSO4 Magnesium Sulfate m-CPBA metachloroperbenzoic acid MTBE Methyl tert-butyl ether n-BuLi n-Butyl lithium Pd / C Palladium Carbon K2CO3 Potassium Carbonate KHMDS Potassium hexamethyldisilazane KOH Potassium hydroxide NaBH4 Sodium borohydride NaCl Sodium chloride NaHCO3 Sodium Bicarbonate NaH Sodium hydride NaHMDS Sodium hexamethyldisilazane NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NaHSO3 Sodium bisulfate SCX Strong Cation Exchange Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride PhOK Potassium phenoxide 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

[0049] Scheme 1a - Part 1: Preparation of compounds of formula (I) - General process [ka] Scheme 1a - Part 2: [ka] According to Scheme 1a-part 1 and part 2, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, for example O-pivaloyl, and R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X and Y are defined as above, compound 1A (prepared according to WO2017140669 when X=C) can be converted to compound 1C in step 1 by treatment with compound 1B in the presence of a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2, and a phosphine, such as triphenylphosphine, in a toluene solution by heating the solvent to reflux in the presence of a base, such as KOPh.

[0050] Compound 1C can be converted to compound 1E in step 2 by treatment with compound 1D in a Suzuki coupling reaction using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0051] Alternatively, in step 1', compound 1E can be obtained by Suzuki coupling of compound 1A with compound 1D' 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.

[0052] Compound 1E can be converted to compound 1F in step 3 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0053] The bromo derivative intermediate 1F can then be subjected to a second Suzuki coupling in step 4 with a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) in the presence of a base such as Cs2CO3 in a mixture of dioxane and water as solvent at room temperature or by heating to reflux, for example using Pd(dppf)Cl2DCM complex as catalyst, to give compound 1G. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced, for example by hydrogenation with a catalyst such as Pd / C under about 5 bar hydrogen pressure (H2) at a temperature of up to 70°C, to give the corresponding saturated compound 1G.

[0054] Alternatively, compound 1F can be subjected to a photocatalytic coupling reaction with R6Br (wherein R6 is an alkyl group, cycloalkyl, or spiro-bicyclic alkyl group as defined above) using a catalyst such as (Ir[dF(CF3)ppy]2(dtbpy))PF6 and nickel(II) chloride ethylene glycol dimethyl ether complex in the presence of tris(trimethylsilyl)silane and a base such as 4,4'-di-tert-butyl-2,2'-bipyridine and sodium carbonate to give the corresponding compound 1G.

[0055] Compound 1G can be converted to a compound of formula (I) in step 5 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution.

[0056] Intermediate 1F can be converted to compound 1Fa in Step 6 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution.

[0057] This compound 1Fa can be converted to compound I in step 7 via Suzuki conditions using a suitable boron reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, for example using Pd(dppf)Cl2DCM complex as catalyst in the presence of a base such as Cs2CO3 in a mixture of dioxane as solvent and water at room temperature or by heating the solvent to reflux. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced, for example by hydrogenation with a catalyst such as Pd / C under about 5 bar hydrogen (H2) pressure at a temperature of up to 70°C to give the corresponding saturated compound I.

[0058] If R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, deprotection can be achieved in step 5 by treatment with aqueous sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in MeOH. If R3 is COOH, the product can be extracted to give the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0059] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1G [ka] (wherein R1, R2, R3', R3", R4, R5, R6, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl) is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, said step optionally preceding a step to obtain compound 1G, a compound of formula 1F [ka] (wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, and R3a is as defined above) is subjected to Suzuki coupling with a boron reagent R6-B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0060] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1G [ka] (In the formula, R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, R6 is, ■ a phenyl group which is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with a cyano group or a -OH group; a (C1-C6) alkylene 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, and which is at least substituted with a (C1-C6) alkylene group, particularly a vinyl group; ■ a phenyl group fused with a hetero(C4-C6)cycloalkyl, wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation and 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; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated, ○ a fluorine atom, an -OH group, a (C1-C3) alkyl group optionally substituted with an -OH group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, and (C3-C6)cycloalkyl groups and phenyl groups, optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; and optionally substituted with 1 to 4 substituents independently selected from represents a cycloalkyl group substituted at least with a (C1-C3) alkyl group optionally substituted with an -OH group, R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, which is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, said step optionally preceding a step to obtain a compound 1G, a compound of formula 1F [ka] (wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, and R3a is as defined above) is subjected to Suzuki coupling with a boron reagent R6-B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above.

[0061] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1Fa [ka] wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, are subjected to Suzuki coupling with a boron reagent R6-B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, which step may optionally precede a step to obtain compound 1Fa, to obtain compound 1Fa of formula 1F. [ka] (wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, and R3a is as defined above) is converted to compound 1Fa in the presence of a hydroxide ion source, such as NaOH, in a methanol solution.

[0062] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1Fa [ka] where R1, R2, R3, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, can be reacted with a boron reagent R6-B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is ■ a phenyl group which is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with a cyano group or a -OH group; a (C1-C6) alkylene 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, and which is at least substituted with a (C1-C6) alkylene group, particularly a vinyl group; ■ a phenyl group fused with a hetero(C4-C6)cycloalkyl, wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation and 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; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated, ○ a fluorine atom, an -OH group, a (C1-C3) alkyl group optionally substituted with an -OH group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, and (C3-C6)cycloalkyl groups and phenyl groups, 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 cycloalkyl group, optionally substituted with a (C1-C3) alkyl group, optionally substituted with a -OH group, said step optionally preceding a step for obtaining compound 1Fa, [ka] (wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, and R3a is as defined above) is converted to compound 1Fa in the presence of a hydroxide ion source, such as NaOH, in a methanol solution.

[0063] Also, an intermediate compound selected from any of the compounds of formula 1E, 1F and 1Fa, or a pharma- ceutically acceptable salt thereof. [ka] (wherein R1, R2, R3, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl), as described herein.

[0064] In addition, intermediate compound 1G [ka] (wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, and R6 is ■ a phenyl group which is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with a cyano group or a -OH group; a (C1-C6) alkylene 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, and which is at least substituted with a (C1-C6) alkylene group, particularly a vinyl group; ■ a phenyl group fused with a hetero(C4-C6)cycloalkyl, wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation and 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; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated, ○ a fluorine atom, an -OH group, a (C1-C3) alkyl group optionally substituted with an -OH group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, an oxo group, and (C3-C6)cycloalkyl groups and phenyl groups, optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups; and optionally substituted with 1 to 4 substituents independently selected from Provided herein are cycloalkyl groups substituted at least with a (C1-C3) alkyl group, which is optionally substituted with an -OH group.

[0065] Additionally, any of the intermediate compounds of formula 1D and 1D', or pharma- ceutically acceptable salts thereof, [ka] (wherein R1, R2, R4, R5, R7, R8, R9, R10, R10', n, and Y are as defined above) are described herein.

[0066] In another aspect, there is also provided herein a process for preparing a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula IG as defined above, optionally followed by a purification step.

[0067] Said purification step may for example consist of an acidification step, for example with aqueous hydrochloric acid, as shown in step 2 of Example 6 herein below.

[0068] 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, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, R6 is an aryl or heteroaryl group, R11 is a hydrogen atom, and R1, R2, R3, R3', R3", R4, R5, R7, R8, R9, R10, R10', n, m, X and Y are as defined above, in step 1, compound 1I can be converted to compound 1J by treatment with an aryl or heteroaryl bromide or iodide in the presence of a palladium catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) in toluene solution, in the presence of a base such as K2CO3 or Cs2CO3, by heating the solvent to reflux. An alternative method for preparing compound 1J, where R6 can be any of the groups defined above for R6 in formula (I), is described below in Scheme 1f.

[0069] Compound 1J can be converted to compound 1K in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or NaH or KHMDS at −50° C. in a solvent such as MeTHF.

[0070] Compound 1K can be converted to compound 1L in step 3 by treatment with, for example, bis(pinacolato)diboron (compound 1B) with a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2) and a phosphine, such as triphenylphosphine, in a toluene solution in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0071] Compound 1G can be prepared in step 4 by Suzuki coupling reaction of compound 1L with compound 1D using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0072] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 5 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0073] Alternatively, compound 1L can be converted to compound 1N in a Suzuki coupling reaction with compound 1M in step 4' 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.

[0074] Compound 1N can be reduced to compound 1O in step 5', for example, by hydrogenation with a catalyst such as PtO2 under about 2 bar hydrogen (H2) pressure at room temperature.

[0075] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1O can be converted to a compound of formula (I) in step 6' in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0076] Alternatively, steps 5' and 6' can be reversed to provide compound I.

[0077] Additionally, any of the intermediate compounds of formula 1L, or pharma- ceutically acceptable salts thereof [ka] (wherein R3a, R3', R3", X, m and R6 are as defined above, and R11 is a hydrogen atom) are described herein.

[0078] Scheme 1c: Preparation of compounds of formula (I) - general process [ka] According to Scheme 1c, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, R11 is a hydrogen atom, and R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X, and Y are as defined above, in step 1, Compound 1F can be converted to Compound 1H, for example, by treatment with bis(pinacolato)diboron (Compound 1B) with a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), and a phosphine, such as triphenylphosphine, in toluene, in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0079] Compound 1G, where R6 is phenyl or heteroaryl, can be prepared in step 2 in a Suzuki coupling reaction of compound 1H with either R6Br or R6I or R6OTf using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as a catalyst in the presence of a base, such as cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0080] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 3 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0081] Scheme 1d: Preparation of compounds of formula (1A) where R3a=CO2Me - General process [ka] According to scheme 1d, where X, m, R3', R3" and R11 are as defined above, compound 1A can be commercially available or prepared as follows: compound 1Aa (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted to compound 1Ab in step 1 by treatment with trifluoromethanesulfonic anhydride in DCM solution in the presence of pyridine as a base.

[0082] Compound 1Ab can be converted to compound 1Ac in step 2 by carbonylation with carbon monoxide in DMF and MeOH solution in the presence of a palladium catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex.

[0083] Compound 1Ac can be converted to compound 1A (wherein R3a = CO2Me) in step 3 by treatment with trifluoromethanesulfonic anhydride in DCM solution in the presence of pyridine as a base.

[0084] Scheme 1e: Preparation of compounds of formula (I) - General process [ka] According to scheme 1e, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, R11 is a hydrogen atom, and R1, R2, R3, R3', R3", R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X and Y are defined as defined above, in step 1, compound 1K can be converted to compound 1G by treatment with compound 1D' in the presence of a palladium catalyst, e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex in the presence of a base, e.g., cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0085] When R3a is COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 2 in the presence of a hydroxide ion source, such as NaOH in methanol (MeOH) solution. When R3 represents a -COOH group, the product can be extracted to obtain the sodium salt of compound I. The neutral form of compound I can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt of compound I can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. The formate or trifluoroacetate salt of compound I can be obtained by purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent.

[0086] Scheme 1f: Alternative preparation of compounds of formula (1J) - general process [ka] According to scheme 1f, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, and R3', R3", R11, X, and m are as defined above, compound 1J can alternatively be prepared as follows: compound 1I can be converted to compound 1Ia in step 1, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0087] Compound 1Ia can be converted to compound 1Ib in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0088] Compound 1Ic can be prepared in step 3 by Suzuki coupling reaction of compound 1Ib with R6B(OR')2 or R6BF3K using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2)DCM complex as catalyst in the presence of a base, such as cesium carbonate (Cs2CO3), in a mixture of toluene and water by heating the solvent to reflux.

[0089] Compound 1Ic can be converted to compound 1J in step 4 by hydrolysis with aqueous HCl, for example by heating in methanol and DCM.

[0090] Scheme 1g-Part 1: Alternative Process for Preparing Compounds of Formula (I) [ka] Scheme 1g - Part 2: [ka] According to part 1 of scheme 1g, where R3a is H or a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, and R1, R2, R3, R3', R3", R6, R8, R9, R10, R10', R11, n, m, X and Y are as defined above, in step 1, compound 1P can be prepared in a Suzuki coupling reaction of compound 1A with 1Da using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) DCM complex as catalyst in the presence of a base, e.g., cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0091] Compound 1P can be converted to compound 1Q under standard Sandmeyer reaction conditions such as sodium nitrite in acidic medium in step 2, followed by treatment with sodium iodide. The resulting compound 1Q can be brominated to compound 1R in step 3, for example with pyridinium tribromide in DCM or THF at room temperature. In step 4, compound 1T can be obtained by Heck coupling by heating compound 1R with compound 1S, catalyzed by, for example, palladium(II) acetate, in the presence of tetrabutylammonium bromide and a base such as K2CO3 in a solvent such as DMF.

[0092] Compound 1T can be converted to compound 1U in step 5 by treatment with a palladium catalyst, such as bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), and a phosphine, such as triphenylphosphine, in a toluene solution, for example with bis(pinacolato)diboron, in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0093] Compound 1U can be converted to compound 1V 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) DCM complex as catalyst in the presence of a base, for example, cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux in step 6.

[0094] According to part 2 of scheme 1g, compound 1V can be converted to compound 1W in step 7 by treatment with TFA in DCM or HCl in dioxane.

[0095] Compound 1W can be converted to compound 1Y in step 8 by treatment with compound 1X, where 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, or in the presence of DIEA in MeCN at room temperature.

[0096] Compound 1Y can be converted to compound 1Z in step 9, for example, by hydrogenation over a catalyst such as Pd / C under about 5 bar hydrogen pressure (H2).

[0097] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1Z can be deprotected to compound I in step 10 by treatment with aqueous sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is -COOH, the product can be extracted to give the sodium salt of compound I. The neutral form can be obtained by acidifying to pH 6-7 with 2N aqueous HCl. The hydrochloride salt can be obtained by acidifying to pH 1-2 with 2N aqueous HCl. Purification using HPLC can give the formate or trifluoroacetate salt.

[0098] Alternatively, steps 9 and 10 can be reversed to provide compound I.

[0099] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of: [ka] (wherein R1, R2, R3', R3", Y, R6, R8, R9, R10, R10', R11, n, m, X are as defined above and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl) is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, said step preceding a step to obtain compound 1Z, a compound of formula 1Y [ka] (wherein R1, R2, R3, R3', R3", R4, R5, R6, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl) is converted to compound 1Z by hydrogenation with a catalyst such as Pd / C under hydrogen pressure.

[0100] Scheme 1h: Alternative preparation of compounds of formula (1N) [ka] According to Scheme 1h, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g., O-pivaloyl, R11 is a hydrogen atom, and R1, R2, R3, R3', R3", R4, R6, R8, R9, R10, R10', n, m, X, and Y are as defined above, in step 1, compound 1L can be converted to compound 1VA by treatment with compound 1MA in the presence of a palladium catalyst, e.g., CataCXium A Pd G3 or tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) in toluene solution, in the presence of a base such as K2CO3 or Cs2CO3, by heating the solvent to reflux.

[0101] Compound 1VA can be converted to compound 1W in step 2 by treatment with TFA in DCM or HCl in dioxane.

[0102] Compound 1W can be converted to compound 1N in step 3 by treatment with compound 1X, where 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, or in the presence of DIEA in MeCN at room temperature.

[0103] At 400MHz and 500MHz 1 H NMR spectra were performed on a Bruker Avance DRX-400 spectrometer and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (σ in ppm) in the solvent dimethylsulfoxide-d6 (D6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0104] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument, a light scattering detector Sedere and an SQD Waters mass spectrometer using a DAD (210-400 nm) for UV detection, a Flash Acquity UPLC CSH C18 1.7 μm (dimensions 2.1 × 30 mm), and a mobile phase of H2O + 0.1% HCOH / CH3CN + 0.1% HCOH.

[0105] The following Tables 1a and 1b respectively list certain compounds of formula (I) according to the present disclosure (names and structures), as well as their characterization ( 1 H NMR and liquid chromatography / mass spectrometry.

[0106] [Table 1]

[0107] [Table 2]

[0108] [Table 3]

[0109] [Table 4]

[0110] [Table 5]

[0111] [Table 6]

[0112] [Table 7]

[0113]

Table 8

[0114]

Table 9

[0115]

Table 10

[0116]

Table 11

[0117]

Table 12

[0118]

Table 13

[0119]

Table 14

[0120]

Table 15

[0121]

Table 16

[0122]

Table 17

[0123]

Table 18

[0124]

Table 19

[0125]

Table 20

[0126]

Table 21

[0127]

Table 22

[0128]

Table 23

[0129]

Table 24

[0130]

Table 25

[0131]

Table 26

[0132]

Table 27

[0133]

Table 28

[0134] [Table 29]

[0135] [Table 30]

[0136] [Table 31]

[0137] The following examples illustrate the preparation of some compounds of formula (I) described herein. The compound numbers exemplified below correspond to those shown in Table 1a above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0138] In the following examples, unless the source of a starting product is specified, it is to be understood that said products are known compounds.

[0139] Intermediates: Intermediate 1: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine. [ka] Method 1: A suspension of 3-(4-bromobenzyl)azetidine, 2,2,2-trifluoroacetic acid (4.5 g, 13.23 mmol) in DMF (45 ml), K2CO3 (5.67 g, 41.01 mmol) and 1-fluoro-3-iodopropane (2.49 g, 13.32 mmol) was heated to 70 °C for 2 h. After cooling to room temperature, water (500 ml) was added and the reaction mixture was extracted three times with 200 ml of EtOAc. The organic phases were collected, washed with water (150 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 95 / 05 to give 2.3 g (61%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine as a viscous oil. LC / MS(m / z,MH+):286

[0140] Method 2: A mixture of 3-(4-bromobenzyl)azetidine, 2,2,2-trifluoroacetic acid (4 g, 11.76 mmol) in THF (20 ml), 1-fluoro-3-iodopropane (2.21 g, 11.76 mmol) and 5N NaOH (7.06 ml, 35.28 mmol) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (150 ml) and the reaction mixture was extracted three times with 150 ml EtOAc. The organic phases were collected, washed with water (150 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 95 / 05 to give 1.58 g (47%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine as a viscous oil.

[0141] Intermediate 2: Methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (15 g, 42.82 mmol) (prepared according to WO2017140669) in toluene (150 ml), 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) was heated to 75 °C for 1.5 h. The yellow suspension turned orange and then brown. After cooling to room temperature, DCM (150 ml) and water (150 ml) were added and decanted through a hydrophobic column. The organic phase was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / DCM: 85 / 15 to 20 / 80 to afford 10.1 g (72%) of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid. LC / MS(m / z,MH+):329

[0142] Intermediate 3: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 2) (17 g, 52.41 mmol), 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine (intermediate 1) (15 g, 52.41 mmol), Pd(dppf)Cl2DCM complex (2.42 g, 3.14 mmol), Cs2CO3 (43.56 g, 134 mmol) in dioxane (120 ml) and water (50 ml) was heated to reflux for 1 h. After cooling to room temperature, DCM (500 ml) and water (300 ml) were added and decanted through a hydrophobic column. The organic phase was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 98 / 02 to afford 16.19 g (90%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange viscous oil. LC / MS(m / z,MH+):408

[0143] Step 2: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (19 g, 46.62 mmol) in DCM (150 ml) was added pyridinium tribromide (21.54 g, 60.61 mmol). The reaction mixture was stirred at room temperature for 2 h. Water (100 mL) and DCM (150 mL) were added and the pH was adjusted to 8 with a concentrated solution of NaHCO3. The aqueous phase was washed three times with DCM and the collected organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 95 / 05 to give 7.48 g (33%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown viscous oil. LC / MS(m / z,MH+):486

[0144] Intermediate 4: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(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 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) (9.7 g, 20 mmol) in toluene (150 ml), Pd(PPh3)2Cl2 (1.5 g, 2 mmol), PPh3 (1 g, 4 mmol), bis(pinacolato)diboron (13 g, 50 mmol) and PhOK (7.9 g, 60 mmol) was heated to 100 °C for 3 h. After cooling to room temperature, a saturated solution of Na2CO3 (50 ml) was added. After decantation, the organic phase was washed with water (25 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 95 / 05 to give 8.2 g (75%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)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+):534

[0145] Intermediate 5: 2-(3-((benzyloxy)methyl)cyclobut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1: 3-((benzyloxy)methyl)cyclobut-1-en-1-yl trifluoromethanesulfonate [ka] A solution of 3.9 ml (6.3 mmol) of butyllithium 1.6N in heptane was added to a solution of diisopropylamine (638 mg, 6.3 mmol) in 5 ml of THF at 0° C. under argon. To this mixture, a solution of 3-((benzyloxy)methyl)cyclobutan-1-one (1 g, 5.26 mmol) in 10 ml of THF was slowly added at −78° C. under argon and the reaction mixture was stirred for 2 h. Then, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.06 g, 5.78 mmol) was added dropwise, the mixture was allowed to warm to room temperature in 15 min, and then poured into 50 ml of saturated aqueous NH4Cl and 50 ml of Et2O. The organic layer was washed with water and brine, 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 95 / 05, v / v) to afford 650 mg (39%) of 3-((benzyloxy)methyl)cyclobut-1-en-1-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):323.

[0146] Step 2: 2-(3-((benzyloxy)methyl)cyclobut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 3-((benzyloxy)methyl)cyclobut-1-en-1-yl trifluoromethanesulfonate (300 mg, 0.93 mmole), potassium acetate (274 mg, 2.79 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (354 mg, 1.4 mmol) in anhydrous DMF (10 ml) under argon was added PdCl2(dppf) (34 mg, 46 μmol). The mixture was stirred at 80° C. for 2 h and then poured into water and Et2O (50 ml). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was used as such in the next step.

[0147] Intermediate 6: tert-Butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)methoxy)silane [ka] Step 1: 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclopent-1-en-1-yl trifluoromethanesulfonate [ka] Intermediate 6, step 1, was prepared from 3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopentan-1-one (Tetrahedron Assymetry (2013) 449-456) following a similar procedure as Intermediate 5, step 1 to give 4 g (56%) of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclopent-1-en-1-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):361.

[0148] Step 2: tert-Butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)methoxy)silane [ka] Intermediate 6, step 2, was prepared from 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclopent-1-en-1-yl trifluoromethanesulfonate according to a similar procedure as intermediate 5, step 2 to give 1.26 g (67%) of tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)methoxy)silane after purification by flash chromatography eluting with a gradient of EtOAc in cyclohexane (100 / 0 to 95 / 05, v / v). LC / MS(m / z,MH+):339.

[0149] Intermediate 7: 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 [ka] Step 1: Methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] To a mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (9.42 g, 43.2 mmol) in DCM (400 mL) was added pyridinium tribromide (16.12 g, 45.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Water (500 ml) and 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

[0150] Step 2: Methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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) at -78 °C under Ar atmosphere was added LiHMDS (1 M, 27 mL). The mixture was stirred for 2 h, then treated with acetic anhydride (8.8 mL, 75 mmol) and 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

[0151] Step 3: Methyl 9-acetoxy-8-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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 following a procedure similar to that of example 6, 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

[0152] Step 4: Methyl 9-acetoxy-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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

[0153] Step 5: Methyl 6-(4,4-dimethylcyclohexyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [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 into 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), then dried over Na2SO4, filtered and concentrated 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

[0154] Step 6: Methyl 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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) at -55°C under Ar atmosphere was added KHMDS (1 M, 4.93 ml, 4.93 mmol). 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 a 5% aqueous solution of Na2CO3 (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

[0155] Step 7: 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 [ka] Intermediate 7, step 7, was prepared from methyl 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a similar procedure as intermediate 2 to give 1.08 g (73%) of 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. LC / MS(m / z,MH+):439

[0156] Intermediate 8: 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) under argon, palladium(II) acetate (420 mg, 1.87 mmol) was added and the mixture was heated to 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, after trituration in pentane, 3.06 g (55%) of tert-butyl 3-((6-chloro-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate. LC / MS(m / z,MH+):299

[0157] Intermediate 9: 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) at 0° C., trifluoromethanesulfonic anhydride (1.93 mL, 11.45 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 min. Ether and water were added. The aqueous layer was separated and extracted three times with ether. The combined organic layers were washed with a 10% aqueous solution of citric acid, then with water twice, 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.

[0158] Intermediate 10: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Method 1 Step 1: Methyl 9-(4-aminophenyl)-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 (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)Cl2DCM complex (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

[0159] Step 2: Methyl 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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 slowly added. The reaction mixture was stirred at 0° C. for 1 h, and then a solution of sodium iodide (14.8 g, 98.9 mmol) in water (40 mL) was added. The mixture was removed from the cooling bath and allowed to warm to room temperature. After stirring at room temperature for 4 h, a 2N solution of Et2O (500 mL) and NaHSO3 (200 mL) was added. After decantation, the organic phase was washed twice with water (100 mL), then with 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

[0160] Step 3: Methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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), washed with a 0.2 N solution of NaHSO3 (100 mL) and twice with 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

[0161] Step 4: tert-Butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-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 stirring 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). 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 further extracted with 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 (77%) 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

[0162] Step 5: Methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzylidene)azetidine-1-carboxylate (9.5 g, 18.1 mmol) in DCM (95 mL) was added TFA (24 mL, 0.33 mol) dropwise. The reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was taken up twice with DCM (30 ml) and concentrated under reduced pressure to give 10.4 g (100%) 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

[0163] Step 6: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of 1-fluoro-3-iodopropane (2.88 g, 15.3 mmol) and methyl 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 1N NaOH (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

[0164] 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 saturated aqueous 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 give 180 g (65%) of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate as a white solid. LC / MS(m / z,MH+):340

[0165] Step 2: tert-Butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate [ka] Intermediate 10 (Method 2), step 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 Intermediate 10 (Method 1), step 1, to give 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

[0166] 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 10 (Method 2), step 3, 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 Intermediate 10 (Method 1), step 3, to give 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

[0167] Step 4: Methyl 9-(4-(azetidine-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid [ka] Intermediate 10 (Method 2), step 4, 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 similar procedure to Intermediate 10 (Method 1), step 5 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

[0168] Step 5: Methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of 1-fluoro-3-iodopropane (4.27 g, 22.7 mmol), methyl 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 adding water (200 mL) and then extracted 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

[0169] Step 6: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [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 at 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

[0170] Step 7: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 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 bicarbonate (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

[0171] Intermediate 11: 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 [ka] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 10) (605 mg, 1.25 mmol) in toluene (30 mL), 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) 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 to give a residue which 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 EXAMPLES

[0172] Example: Compounds of formula (I) Method A: Example 6: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) (100 mg, 205.6 μmol), 4,4,5,5-tetramethyl-2-[2-methyl-3-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane (93 mg, 308.4 μmol), Cs2CO3 (141 mg, 432 μmol), and Pd(dppf)Cl2DCM complex (15 mg, 20.6 μmol) in dioxane (4 ml) and water (1 ml) was heated to reflux under microwave irradiation for 30 min. After cooling to room temperature, EtOAc (20 ml) and water (10 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 48 mg (40%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):582

[0173] Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] To a solution of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (48 mg, 82.5 μmol) in MeOH (5 ml) and water (1 ml) was added LiOH (8 mg, 330 μM) and the reaction mixture was stirred at room temperature for 18 h. Water (10 ml), EtOAc (20 ml) and ethyl ether (20 ml) were added and the pH was adjusted to 7 with 0.1 N HCl. After decantation, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 80 / 20, v / v) to afford 46 mg (98%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0174] Example 46: 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: Methyl 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 46 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and 2,3-dimethoxyphenylboronic acid following a procedure similar to that of Step 1 of Example 6 to give 194 mg (87%) of methyl 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):544

[0175] Step 2: 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Example 46, step 2, was prepared from methyl 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to example 6 for step 2 to give 85.5 mg (45%) of 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0176] Method B: Example 14: 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: Methyl 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 14 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) and 1-bromo-3-(difluoromethoxy)-2-methyl-benzene according to a procedure similar to that of Step 1 of Example 6 to give 99 mg (62%) of methyl 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):564

[0177] Step 2: 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 14 was prepared from methyl 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to step 2 of Example 6 to give 53 mg (55%) of 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0178] Method C: Example 15: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid [ka] Step 1: Methyl (E)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxyprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 15 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol according to a procedure similar to step 1 of Example 6 to give 140 mg (98%) of methyl (E)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxyprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):464.

[0179] Step 2: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Methyl (E)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxyprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (100 mg, 215.7 μmol), Pd / C 10% (20 mg, 187 μmol) in DCM (10 ml) and MeOH (10 ml) was hydrogenated at room temperature and 4.5 bar H2 for 5 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give 99 mg (99%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):466

[0180] Step 3: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid [ka] Example 15, step 3 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to example 6, step 2 to give 25 mg (21%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid.

[0181] Method D: Example 21: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: Methyl 8-(3-((benzyloxy)methyl)cyclobut-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 21 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and 2-(3-((benzyloxy)methyl)cyclobut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 5) according to a procedure similar to that of Step 1 of Example 6 to give 278 mg (71%) of methyl 8-(3-((benzyloxy)methyl)cyclobut-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):580.

[0182] Step 2: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Methyl 8-(3-((benzyloxy)methyl)cyclobut-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (278 mg, 105 μmol), Pd / C 10% (250 mg, 235 μmol) in MeOH (20 ml) and DCM (20 ml) was hydrogenated at room temperature and 4 bar H2 for 20 h. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 97 / 03, v / v) to give 88 mg (37%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):492

[0183] Step 3: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 3 of Example 21 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to step 2 of Example 6 to give 57 mg (67%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0184] Method E: Example 3: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: Methyl 8-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopent-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 3 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl)methoxy)silane (Intermediate 6) according to a procedure similar to that of Step 1 of Example 6 to give 770 mg (99%) of methyl 8-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopent-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):618.

[0185] Step 2: Methyl 8-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopentyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopent-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (760 mg, 1.23 mmol), Pd / C 10% (80 mg, 75 μmol) in MeOH (15 ml) and DCM (15 ml) was hydrogenated at room temperature and 4 bar H2 for 7 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give 760 mg (99%) of methyl 8-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopentyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):620

[0186] Step 3: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclopentyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (760 mg, 1.23 mmol) in 20 ml of acetonitrile and 20 ml of 1N aqueous HCl was stirred at room temperature for 2 h. The reaction mixture was neutralized with saturated aqueous NaHCO3, extracted with EtOAc (2 x 150 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 450 mg (73%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):506

[0187] Step 4: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 4 of Example 3 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to step 2 of Example 6 to give 16 mg (29%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0188] Method F: Example 10: 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)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 8) (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 7) (700 mg, 1.6 mmol), CsCO (1.56 g, 4.79 mmol) in 40 mL of toluene and 10 mL of water in a screw-cap tube was degassed with argon 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 of 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 give 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

[0189] Step 2: 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 [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.

[0190] Step 3: 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 [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 After semi-concentration under reduced pressure, this was directly purified by flash chromatography eluting with a gradient of AcOEt / MeOH mixture in cyclohexane:80 / 20 (100 / 0 to 0 / 100, v / v) to give 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

[0191] Step 4: Methyl 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture 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 (60 mg, 112 μmol), Pd / C 10% (60 mg, 56 μmol) in MeOH (10 ml) and AcOEt (5 ml) was hydrogenated at room temperature and 3 bar H2 for 11 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give 30 mg (50%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z,MH+):537

[0192] Step 5: 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 5 of Example 10 was prepared from methyl 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to step 2 of Example 6 to give 22 mg (75%) of 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0193] Example 13: 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-carboxylic acid [ka] Step 1: Methyl 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-carboxylate [ka] Step 1 of Example 13 was prepared from 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 and 3,3-difluoropropyl trifluoromethanesulfonate (Intermediate 9) according to a procedure similar to Step 3 of Example 10 to give 174 mg (46%) of methyl 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-carboxylate. LC / MS(m / z,MH+):553

[0194] 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] Step 2 of Example 13 was prepared from methyl 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-carboxylate following a procedure similar to step 2 of Example 6 to give 64 mg (33%) 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. LC / MS(m / z,MH+):539

[0195] Step 3: 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-carboxylic acid [ka] Step 3 of Example 13 was prepared from 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 following a procedure similar to step 4 of Example 10 to give 47 mg (46%) 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.

[0196] Method G: Example 67: 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 1: 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 [ka] A mixture 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 (Intermediate 11) (200 mg, 338 μmol), 1-bromo-2-ethyl-3-(trifluoromethyl)benzene (129 mg, 508 μmol), Cs2CO3 (232 mg, 711 μmol) and Pd(dppf)Cl2DCM complex (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

[0197] 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 67, 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 example 6, 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.

[0198] Step 3: 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] A mixture 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 (20 mg, 35.5 μmol), Pd / C 10% (10 mg, 94 μmol) in DCM (5 ml) and MeOH (10 ml) was hydrogenated at room temperature and 5 bar H2 for 3 h. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure and triturated with diethyl ether / pentane, then the solid was filtered and dried under vacuum to give 12 mg (60%) of 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0199] The compounds listed in Table 1a above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0200] Test: Estrogen receptor degrading activity Said test is directed to determining the in vitro degradation activity of the compounds of Table 1a.

[0201] Measurement of degradation activity was performed using breast cancer cell ERα in a cell Western assay as described below.

[0202] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells / 30 μL per well in red phenol-free MEMα medium (invitrogen) containing 5% charcoal dextran-treated FBS. The next day, 9-point serial 1:5 dilutions of each compound were added to the cells in 2.5 μL at final concentrations ranging from 0.3 to 0.0000018 μM (Table 2), or fulvestrant at 0.1 μM (used as a positive control). At 4 h after compound addition, cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton) for 10 min at room temperature, then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added and plated for 30 min at room temperature. The LI-COR blocking buffer was removed and the cells were incubated overnight in a refrigerator with 50 μL of anti-ER rabbit monoclonal antibody (Thermo Scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells treated with blocking buffer but no antibody were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated for 60 min at 37°C in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 DNA dye (final concentration of 2 μM). The cells were then washed three times with PBS and scanned with an ACUMEN explorer (TTP-LabTech). The integrated intensity in green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0203] In this test, the degradation activity of estrogen receptors was determined by the concentration at which 50% of the estrogen receptors were degraded (i.e., IC 50 ) in nM.

[0204] The percentage of decrease in ERα levels was determined as follows: % inhibition=100*(1-(sample-fulvestrant:DMSO-fulvestrant)).

[0205] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1a tested at 0.3 μM, demonstrating that said compounds have significant degrading activity on the estrogen receptor.

[0206] [Table 32]

[0207] [Table 33]

[0208] Therefore, the tested compounds have IC50 less than 1 μM and degradation level more than 50%, which shows that they have degradation activity against estrogen receptor.Therefore, the compounds of formula (I) can be used to prepare medicines, especially medicines that are degraders of estrogen receptor.

[0209] Accordingly, also provided herein is a pharmaceutical agent comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0210] 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.

[0211] There is also provided herein a compound of formula (I), as defined above, or a pharma- ceutically acceptable salt thereof, for use in therapy, particularly as an estrogen receptor inhibitor and degrader.

[0212] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as hereinbefore defined, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0213] 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.

[0214] In one embodiment, the cancer is a hormone-dependent cancer.

[0215] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular an estrogen receptor alpha dependent cancer.

[0216] 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.

[0217] In another embodiment, the metastasis is a brain metastasis.

[0218] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0219] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0220] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6 inhibitors, mTOR inhibitors or PI3K inhibitors.

[0221] According to another aspect, there is provided herein a method of treating a pathological condition as set forth above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0222] Also provided herein is the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament useful for treating any of the pathological conditions set out above, more particularly useful for treating cancer.

[0223] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0224] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the conventional excipients known to those skilled in the art.

[0225] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or a base, acid, zwitterion or salt thereof, may be administered in unit dosage form in admixture with conventional pharmaceutical excipients to animals and humans for treating the above disorders or diseases.

[0226] 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.

[0227] 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

[0228] There may be specific cases in which higher or lower doses are appropriate. According to usual practice, the dose appropriate for each patient is determined by the physician according to the method of administration, as well as the weight and response of said patient.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 [In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3' and R3" each independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R5 are independently a hydrogen atom, a fluorine atom, or —NH ２ group, methyl group, etc. １ ~C ３ ) an alkyl group, a methoxy group, or an ethoxy group, etc. １ ~C ３ ) an alkoxy group, or an —OH group; or R4 and R5 together form an oxo group, or R4 and R5 together represent, by the carbon atom to which they are attached, =NOCH ３ Group or (C ３ ~C ５ ) forming a cycloalkyl group; R7 represents a hydrogen atom, a methyl group, an —OH group or a fluorine atom; or alternatively, R4 and R7 together form a cyclopropyl group via the bond to which they are attached, thereby providing an adjacent azetidine group, azaspiro[2.3]hexane; - R6 is phenyl group, optionally substituted with a halogen atom; a cyano group or an -OH group (C １ ~C ６ ) alkyl group; １ ~C ６ ) an alkylene group, (C １ ~C ６ ) fluoroalkyl group; ３ ~C ６ ) a cycloalkyl group; １ ~C ６ ) an alkoxy group; １ ~C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ ~C ４ ) an alkylthio group; １ ~C ４ ) a fluoroalkylthio group; １ ~C ４ ) an alkylsulfonyl group; and a phenyl group, optionally substituted with 1 to 3 substituents independently selected from -OH groups; ■ (C ３ ~C ６ ) a phenyl group fused to a cycloalkyl, ３ ~C ６ ) the cycloalkyl ring optionally contains unsaturation, (C １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a fused phenyl group optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Hetero (C ４ ~C ６ ) a phenyl group fused to a cycloalkyl; ４ ~C ６ ) the cycloalkyl ring optionally contains unsaturation, (C １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a fused phenyl group optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Bicyclic groups containing 5 to 12 carbon atoms, optionally containing 1 to 2 unsaturations; １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a bicyclic group optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; Heteroaryl groups containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as pyridyl, pyridone or pyrrolyl groups, which are not limited to halogen atoms, (C １ ~C ６ ) alkyl group, (C １ ~C ６ ) a fluoroalkyl group, １ ~C ６ ) an alkoxy group, (C １ ~C ６ ) a heteroaryl group optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group, a cyano group, a carbamoyl group, and an —OH group; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated; ○ Fluorine atom, —OH group, optionally substituted with —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, and ○ (C ３ ~C ６ ) cycloalkyl groups, and phenyl groups containing one or two halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group; ３ ~C ６ ) a cycloalkyl group or a phenyl group a cycloalkyl group optionally substituted with 1 to 4 substituents independently selected from: ■ (C ３ ~C ６ ) Cycloalkyl(C １ ~C ３ ) alkyl group, which is selected from the group consisting of a fluorine atom, an —OH group, a (C １ ~C ４ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) optionally substituted on said cycloalkyl by 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; ３ ~C ６ ) Cycloalkyl(C １ ~C ３ ) alkyl group; ■ A 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group or a tetrahydrofuranyl group, which is saturated or partially saturated and contains a fluorine atom, (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) a fluoroalkoxy group, an oxo group, (C １ ~C ３ ) a heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from an alkoxy group and an —OH group; (C) such as isobutyl, propyl or ethylbutyl groups １ ~C ６ ) an alkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) an alkyl group, optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and —OH groups; and ■ Phenyl (C １ ~C ２ ) an alkyl group which is a halogen atom; １ ~C ３ ) alkyl group; １ ~C ３ ) fluoroalkyl group; １ ~C ３ ) an alkoxy group; １ ~C ３ ) a phenyl group optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group; a cyano group; and an —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 atom or a chlorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R8 is independently a (C １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine atom, a cyano group, or a trifluoromethyl group, etc. １ ~C ３ ) represents a fluoroalkyl group; R9 represents a hydrogen atom or a fluorine atom; R10 and R10' independently represent a hydrogen atom or a fluorine atom; R11 is a hydrogen atom or (C １ ~C ３ ) an alkyl group or a cyclopropyl group; n is 0, 1 or 2, - m is 0 or 1.

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

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

4. X is -CH ２ -, or a pharma- ceutically acceptable salt thereof.

5. R4 and R5 each independently represent a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, or -NH ２ or -OH; or R4 and R5 together, together with the carbon atom to which they are attached, represent an oxo group, =NOCH ３ or alternatively, R4 and R7 together form a cyclopropyl group or a cyclopropyl group by the bond to which they are attached, and in particular R4 and R5 both represent a hydrogen atom or a fluorine atom, or one of R4 and R5 represents a hydrogen atom and the other a fluorine atom or an -OH group, or one of R4 and R5 represents a methyl group and the other a hydroxy group or a fluorine atom, and more particularly R4 and R5 both represent a hydrogen atom, or a pharma- ceutically acceptable salt thereof.

6. A compound of formula (I) according to any one of claims 1 to 5, characterized in that R7 represents a hydrogen atom, an -OH group, a methyl group or a fluorine atom, more particularly a hydrogen atom, or a pharma- ceutically acceptable salt thereof.

7. The compound of formula (I) according to any one of claims 1 to 6, characterized in that R6 represents a phenyl group, and the phenyl group is optionally substituted with 1 to 3 substituents independently selected from chlorine atoms, fluorine atoms, hydroxyl groups, methyl groups, ethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethyl groups, 1,1-difluoroethyl groups, hydroxymethyl groups, 2-hydroxyethyl groups, fluoromethyl groups, difluoromethyl groups, 2,2-difluoroethyl groups, methoxy groups, ethoxy groups, cyano groups, vinyl groups, cyanomethyl groups, trifluoromethylsulfonyl groups, methylsulfanyl groups, difluoromethylsulfanyl groups, methylsulfonyl groups, trifluoromethoxy groups, cyclopropyl groups, and difluoromethoxy groups. Or a pharma- ceutically acceptable salt thereof.

8. A compound of formula (I) according to any one of claims 1 to 6, characterized in that R6 represents a fused phenyl group selected from a bicyclo[4.2.0]octa-trienyl group, a tetrahydronaphthalenyl group and an indanyl group, optionally substituted with one or two fluorine atoms, or represents a chromanyl group, or a pharma- ceutically acceptable salt thereof.

9. R6 represents a cycloalkyl group selected from a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, a cycloheptyl group, a cycloheptenyl group, and a cyclohexenyl group, said cycloalkyl group being ○ Fluorine atom, —OH group, optionally substituted with —OH group (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) a fluoroalkyl group, １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a fluoroalkoxy group, an oxo group, ○ (C ３ ~C ６ ) cycloalkyl groups and phenyl groups containing one or two halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group; ３ ~C ６ ) a cycloalkyl group or a phenyl group and wherein the cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from ○ Fluorine atom, methyl group, and a cyclohexyl group substituted with two halogen atoms, in particular fluoro atoms The compound of formula (I) according to any one of claims 1 to 6, characterized in that it is substituted with 1 to 2 substituents independently selected from:

10. R6 is selected from ethyl, isobutyl and ethylbutyl (C １ ~C ６ ) alkyl group, the alkyl group being selected from the group consisting of a fluorine atom, (C １ ~C ３ ) an alkoxy group, (C １ ~C ３ 7. A compound of formula (I) according to any one of claims 1 to 6, characterized in that it is optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and -OH groups, in particular with 1 or 3 fluorine atoms or -OH groups, or a pharma- ceutically acceptable salt thereof.

11. A compound of formula (I) according to any one of claims 1 to 10, characterized in that R3' and R3" represent a hydrogen atom, or a pharma- ceutically acceptable salt thereof.

12. A compound of formula (I) according to any one of claims 1 to 11, characterized in that R8 independently represents a methyl group or a fluorine atom and n is 0, 1 or 2, or a pharma- ceutically acceptable salt thereof.

13. Y is -CH=, -C(CH ３ 13. A compound of formula (I) according to any one of claims 1 to 12, wherein -CH=, -CF= or -N=, in particular -CH= or -N=, 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 R9 represents a hydrogen atom.

15. A compound of formula (I) according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein R10 and R10' represent a hydrogen atom.

16. A compound of formula (I) according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein R11 represents a hydrogen atom.

17. 17. A compound of formula (I) according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

18. R6, phenyl group, optionally substituted with a halogen atom; a cyano group or an -OH group (C １ ~C ６ ) alkyl group; １ ~C ６ ) an alkylene group, (C １ ~C ６ ) fluoroalkyl group; ３ ~C ６ ) a cycloalkyl group; １ ~C ６ ) an alkoxy group; １ ~C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ ~C ４ ) an alkylthio group; １ ~C ４ ) a fluoroalkylthio group; １ ~C ４ ) an alkylsulfonyl group; and an —OH group; １ ~C ６ ) a phenyl group, at least substituted with an alkylene group, in particular a vinyl group; ■ Hetero (C ４ ~C ６ ) a phenyl group fused to a cycloalkyl; ４ ~C ６ ) the cycloalkyl ring optionally contains unsaturation, (C １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a fused phenyl group optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated; ○ Fluorine atom, —OH group, optionally substituted with —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, and ○ (C ３ ~C ６ ) cycloalkyl groups, and phenyl groups containing one or two halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group; ３ ~C ６ ) a cycloalkyl group or a phenyl group and optionally substituted with 1 to 4 substituents independently selected from Optionally substituted with —OH groups (C １ ~C ３ 18. A compound of formula (I) according to any one of claims 1 to 6 and 11 to 17, or a pharma- ceutically acceptable salt thereof, wherein R represents a cycloalkyl group at least substituted with an alkyl group.

19. R6, a phenyl group, optionally substituted with a halogen atom; a cyano group or an —OH group (C １ ~C ６ ) alkyl group; １ ~C ６ ) an alkylene 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 ) alkylsulfonyl groups; and -OH groups, wherein the phenyl is substituted by at least one hydroxy group, at least one vinyl group, at least one trifluoromethoxy group, at least one cyclopropyl group, or at least one 1,1-difluoroethyl group; - tetrahydronaphthalenyl group; - a cyclobutyl group; or A compound of formula (I) according to any one of claims 1 to 6 and 11 to 17, or a pharma- ceutically acceptable salt thereof, which represents a hydroxypropyl group.

20. A compound of formula (I) according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, in particular the hydrochloride thereof, said compound being selected from the group consisting of the following compounds: - 8-(2-(difluoromethoxy)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(5,6,7,8-tetrahydronaphthalen-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclopentyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - 8-(3-chloro-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(2-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - 8-(chroman-8-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) 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-carboxylic acid, (13) - 8-(3-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxypropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 2,2,2-trifluoroacetic acid, (15) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (16) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (17) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (19) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(5-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (20) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)cyclobutyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (22) - 8-(2-(difluoromethyl)-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - 8-(2-(difluoromethyl)-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (25) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (28) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) - 8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (32) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (34) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(5-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) - 8-(3-fluoro-2-vinylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) - 8-(2-ethyl-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) - 8-(3-chloro-2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) - 8-(2,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) 8-(2-chloro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (40) 8-(2-fluoro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (41) 8-(4-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (42) - 8-(2-fluoro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) - 8-(2-chloro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (44) - 8-(2-fluoro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) - 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) - 8-(2,4-difluoro-3-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (48) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (49) - 8-(2-chloro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(2,6-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (51) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) - 8-(2-chloro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) 8-(2-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (54) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxy-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) - 8-(3-fluoro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) - 8-(3-chloro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) - 8-(2,3-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) 8-(2-(difluoromethyl)-5-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (60) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-hydroxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (61) - 8-(2-(1,1-difluoroethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (62) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) - 8-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride, (64) - 8-(3-fluoro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (65) - 8-(2-(difluoromethyl)-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (66) - 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) - 8-(3-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) - 8-(2-ethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (69) - 8-(4-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (70) - 8-(3,4-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (71) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-4,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) 8-(3-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73).

21. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 20, comprising the step of: 【Chemistry 2】 wherein R1, R2, R3', R3", R4, R5, R6, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined in any one of claims 1 to 19 and R3a is a carboxylic acid ester such as COOMe, COOEt or a protected OH, e.g. O-pivaloyl, is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, said step optionally preceding a step to obtain compound 1G, and a compound of formula 1F 【Chemistry 3】 (wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined in any one of claims 1 to 19, and R3a is as defined above), Boron Reagent R6B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester, and R6 is as defined in any one of claims 1 or 7-10 or 18 or 19,

22. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 20, comprising the steps of: 【Chemistry 4】 (wherein R1, R2, R3, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined in any one of claims 1 to 19), is a boron reagent R6B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester and R6 is as defined in any one of claims 1 or 7 to 10 or 18 or 19, said step optionally preceding a step to obtain compound 1Fa, 【Chemistry 5】 wherein R1, R2, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined in any one of claims 1 to 19, and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, in the presence of a hydroxide ion source such as NaOH in a methanol solution is converted to compound 1Fa.

23. A compound of formula 1G, or any of its pharma- ceutically acceptable salts: 【Chemistry 6】 (wherein R1, R2, R3, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined in any one of claims 1 to 19, R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, and R6 is phenyl group, optionally substituted with a halogen atom; a cyano group or an -OH group (C １ ~C ６ ) alkyl group; １ ~C ６ ) an alkylene group, (C １ ~C ６ ) fluoroalkyl group; ３ ~C ６ ) a cycloalkyl group; １ ~C ６ ) an alkoxy group; １ ~C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ ~C ４ ) an alkylthio group; １ ~C ４ ) a fluoroalkylthio group; １ ~C ４ ) an alkylsulfonyl group; and an —OH group; １ ~C ６ ) a phenyl group, at least substituted with an alkylene group, in particular a vinyl group; ■ Hetero (C ４ ~C ６ ) a phenyl group fused to a cycloalkyl; ４ ~C ６ ) the cycloalkyl ring optionally contains unsaturation, (C １ ~C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a fused phenyl group optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Cycloalkyl groups containing 3 to 7 carbon atoms, which are saturated or partially saturated; ○ Fluorine atom, —OH group, optionally substituted with —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, and ○ (C ３ ~C ６ ) cycloalkyl groups, and phenyl groups containing one or two halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group; ３ ~C ６ ) a cycloalkyl group or a phenyl group and optionally substituted with 1 to 4 substituents independently selected from Optionally substituted with —OH groups (C １ ~C ３ ) represents a cycloalkyl group substituted with at least one alkyl group.

24. A process for preparing a compound of formula (I) as defined in any one of claims 1 to 20, comprising the step of: 【Chemistry 7】 wherein R1, R2, R3', R3", Y, R6, R8, R9, R10, R10', R11, n, m, X are as defined in any one of claims 1 to 19 and R3a is a carboxylic acid ester such as COOMe, COOEt or a protected OH, e.g. O-pivaloyl, is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in a methanolic solution, said step preceding a step to obtain compound 1Z, a compound of formula 1Y 【Chemistry 8】 wherein R1, R2, R3, R3', R3", R4, R5, R6, Y, R8, R9, R10, R10', R11, n, m, X are as defined in any one of claims 1 to 19 and R3a is a carboxylic acid ester such as COOMe, COOEt, or a protected OH, e.g. O-pivaloyl, is converted to compound 1Z by hydrogenation with a catalyst such as Pd / C under hydrogen pressure.

25. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

27. A compound of formula (I) as defined in any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, for use as an estrogen receptor inhibitor and degrader.

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

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

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