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

Abstract

The present invention relates to a compound of formula (I): [Formula 1] TIFF2023545552000386.tif6086 [wherein R1 and R2 represent hydrogen atoms or deuterium atoms; R3 represents a hydrogen atom, a -COOH group or a -OH group; R3' and R3'' represent hydrogen, methyl, methoxy, chlorine, fluorine or cyano; R4 and R4' represent hydrogen or fluorine; R5 represents hydrogen, fluorine or (C1-C3) alkyl; R6 represents phenyl, fused phenyl, a bicyclic group containing 5 to 12 carbon atoms, a heteroaryl group containing 2 to 9 carbon atoms and 1 to 3 heteroatoms, a cycloalkyl group containing 3 to 7 carbon atoms, a (C3-C6)cycloalkyl(C1-C3)alkyl group, a cycloalkyl group containing 1 or 2 heteroatoms, represents a 3-8 membered heterocycloalkyl group containing a cycloatom, a (C1-C6)alkyl, and a phenyl(C1-C2)alkyl group; X represents -CH2-, -O-, or -S-; Y represents -CH=, -N=, or -CR"=, and R" represents a (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R7 represents a (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C3)alkyl, or cyclopropyl; n is 0, 1, or 2; and m is 0 or 1, or a pharmaceutically acceptable salt thereof. Further disclosed are compounds of formula (I) as defined above, methods for their preparation, pharmaceutical compositions containing them and for use as inhibitors and degraders of estrogen receptors, particularly in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

Description

[Technical Field]

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

[0002] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily, which are involved in the regulation of eukaryotic gene expression, cell growth, and differentiation in target tissues. ERs exist in two forms: estrogen receptor α (ERα) and estrogen receptor β (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormone, ERs are primarily located in the cytosol of cells. When the hormone estrogen binds to ERs, they translocate from the cytosol to the cell's nucleus, form dimers, and then bind 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 primarily expressed in reproductive tissues such as the uterus, ovaries, breast, bone, and white adipose tissue. Aberrant ERα signaling contributes to the development of various diseases, such as cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and osteoporosis.

[0004] ERα expression is less than 10% in normal breast epithelium, but is expressed in approximately 50–80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive. The pathogenetic role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, several strategies exist to inhibit the estrogen system in breast cancer, including: 1) blocking estrogen synthesis with aromatase inhibitors, which are used to treat patients with early and advanced ERα-positive breast cancer; 2) antagonizing estrogen ligand binding to ERα with tamoxifen, which is used to treat patients with ERα-positive breast cancer before and after menopause; and 3) antagonizing and downregulating ERα levels with fulvestrant, which is used to treat breast cancer in patients whose disease progresses despite endocrine therapy such as tamoxifen or aromatase inhibitors.

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

[0006] The majority of identified endocrine therapy resistance mechanisms utilize ERα-dependent activity. One emerging strategy to counterforce such resistance is to use selective estrogen receptor degraders (SERDs) to abolish ERα signaling by removing ERα from tumor cells. Clinical and preclinical data have shown that a significant number of resistance pathways can be circumvented by the use of SERDs.

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

[0008] Patent Documents 1 and 2 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives that are useful as SERDs. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2017 / 140669 [Patent Document 2] WO2018 / 091153 Summary of the Invention [Problem to be solved by the invention]

[0010] The present inventors have now discovered novel compounds that are capable of selectively antagonizing and degrading estrogen receptors (SERDs compounds) for use in cancer therapy. [Means for solving the problem]

[0011] Formula (I): [ka] [In formula: R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; - R3' and R3'' independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; - R4 and R4' independently represent a hydrogen atom or a fluorine atom; - R5 represents a hydrogen atom, a fluorine atom or a (C1-C3) alkyl group; - R6 a phenyl group (the phenyl group is optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted with a cyano group or an —OH group; a (C1-C6) fluoroalkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy group; a (C1-C6) fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4) alkylthio group; a (C1-C4) fluoroalkylthio group; a (C1-C4) alkylsulfonyl group and an —OH group); fused phenyl groups selected from phenyl groups fused with (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl optionally contains unsaturation and the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group, and a (C1-C3)alkoxy group; a bicyclic group containing 5 to 12 carbon atoms and optionally containing one or two unsaturations; optionally substituted with one to four substituents independently selected from a fluorine atom, an —OH group, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and an oxo group; 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 groups, which heteroaryl groups are optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) fluoroalkyl groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, cyano groups, carbamoyl groups, and -OH groups; Cycloalkyl groups containing 3 to 7 carbon atoms, said cycloalkyl groups being saturated or partially saturated; ○ fluorine atom, -OH group, (C1-C3) alkyl group, (C1-C3) fluoroalkyl group, (C1-C3) alkoxy group, (C1-C3) fluoroalkoxy group, oxo group, (C3-C6)cycloalkyl and phenyl groups, wherein the (C3-C6)cycloalkyl or phenyl group is optionally substituted with one or two halogen atoms or a (C1-C3)alkyl group. optionally substituted with 1 to 4 substituents independently selected from: (C3-C6)cycloalkyl(C1-C3)alkyl groups optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from a fluorine atom, an —OH group, a (C1-C4)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, and an oxo group; 3-8 membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as tetrahydropyranyl groups, which heterocycloalkyl groups are saturated or partially saturated and optionally substituted with 1 to 3 substituents independently selected from fluorine atoms, (C1-C3) alkyl groups, (C1-C3) fluoroalkyl groups, (C1-C3) fluoroalkoxy groups, oxo groups, (C1-C3) alkoxy groups and -OH groups; a (C1-C6) alkyl group, such as an isobutyl group, a methyl group, or an ethyl group, the alkyl group being optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and an —OH group; and a phenyl(C1-C2)alkyl group, wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and an —OH group. represents a group selected from: - X represents -CH2-, -O- or -S-; Y represents -CH=, -N= or -CR"=, where R" represents a (C1-C3) alkyl group or a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R8 represents a hydrogen atom or a fluorine atom; R9 represents a hydrogen atom, a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; - m is 0 or 1, or a pharmaceutically acceptable salt thereof.

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

[0013] Compounds of formula (I) may likewise exist in tautomeric forms.

[0014] The compounds of formula (I) can exist in the form of bases, acids, zwitterions or addition salts with acids or bases. Accordingly, there are provided herein compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0015] Other acid or base salts useful, for example, for purifying or isolating compounds of formula (I), are also provided, but these salts can be prepared with pharmaceutically acceptable acids or bases.

[0016] Among the suitable salts of the compounds of formula (I), mention may be made especially of the hydrochloride salt.

[0017] As used herein, the following terms have the following definitions throughout the specification, unless otherwise stated. - halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; - oxo: "=O" group; - alkyl group: unless otherwise specified, a linear or branched saturated hydrocarbon-based aliphatic group containing 1 to 6 carbon atoms (denoted as "(C1-C6)-alkyl"). Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups; - cycloalkyl group: unless otherwise stated, a saturated or partially unsaturated and unsubstituted or substituted monocyclic alkyl group containing 3 to 7 carbon atoms, examples of which may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, in particular cyclopentyl, cyclohexyl, or cyclohexenyl; - cycloalkylalkyl group: an alkyl group substituted with a cyclic alkyl group as defined above, including but not limited to cyclobutylmethyl; - Heterocycloalkyl group: a saturated or partially unsaturated 3- to 8-membered cycloalkyl group containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, in particular oxygen or nitrogen. Examples include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl, and tetrahydrothiopyranyl. Heterocycloalkyl is advantageously tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above (wherein the alkyl group is substituted with at least one fluorine atom). In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include -CHF, -CHF, -CHCHF, -CHCHF, etc. When all hydrogen atoms of the alkyl group are replaced with fluorine atoms, the fluoroalkyl group can be named a perfluoroalkyl group. Examples include a trifluoromethyl group or a trifluoroethyl group, in particular a trifluoromethyl group; - alkoxy groups: -O-alkyl groups, where alkyl groups are as defined above. Examples that may be mentioned, 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 (wherein the alkyl group is as defined above, and the alkyl group is substituted with at least one fluorine atom). In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are replaced with fluorine atoms, the fluoroalkoxy group can be named a perfluoroalkoxy group. Examples include a trifluoromethoxy group, etc.; - (C1-C4) alkylthio groups, also named (C1-C4) alkylsulfanyl: -S-alkyl groups, wherein alkyl 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, wherein alkyl group is as defined above. Examples include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; - (C1-C4)fluoroalkylthio group, also named (C1-C4)fluoroalkylsulfanyl group: -S-fluoroalkyl group, wherein fluoroalkyl group is as defined above. Examples include, but are not limited to, fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - Fused phenyl: a bicyclic group containing 8 to 10 carbon atoms and containing a phenyl moiety. The phenyl moiety can be fused to a (C3-C6) cycloalkyl group, i.e., the phenyl moiety can share a bond with the (C3-C6) cycloalkyl group. The fused phenyl group can be bonded to the rest of the molecule through its phenyl moiety. It can be substituted. Examples include, but are not limited to, indanyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, tetrahydronaphthalenyl, etc.; Heteroaryl group: a 5- to 10-membered cyclic aromatic group containing 2 to 9 carbon atoms and 1 to 3 heteroatoms such as nitrogen, oxygen, or sulfur. Such nitrogen atoms can be substituted with oxygen atoms to form -NO bonds. Such -NO bonds can be substituted with 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. Heteroaryl is advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine; bicyclic groups, which generally contain from 5 to 12 carbon atoms, A hydrocarbon group selected from groups containing two rings connected by a single common atom: "spiro bicyclic rings." Such spiro bicyclic alkyls generally contain 5 to 11 carbon atoms and are referred to as "spiro (C5-C 11 These rings may be saturated or partially unsaturated. Such spiro bicyclic rings may be unsubstituted or substituted, in particular with at least one (C1-C3) alkyl group, such as methyl or fluorine. With respect to the definition of R6, spiro (C5-C 11 Examples of spiro(C5-C6) bicyclic rings include, but are not limited to, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.3]heptene, spiro[2.5]octane, and 7-azaspiro[3.5]nonane. 11) the bicyclic ring, in the case of a further R6 group, is advantageously spiro[2.3]hexane, spiro[3.3]heptane or spiro[3.3]heptene; two common atoms, in which case the bicyclic group contains 7 to 12 carbon atoms and optionally 1 or 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 which case the bicyclic group contains 6 to 10 carbon atoms, and such bicyclic group is not a "bridged (C6-C 10 (C)cycloalkyl" groups, where the rings share three or more atoms and the bridge contains at least one atom, e.g., one, two, or three atoms, and preferentially one 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 acidic and basic groups.

[0018] In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0019] In another embodiment, in the compounds of formula (I) as defined above, R3 is -COOH.

[0020] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3'' represent a hydrogen atom.

[0021] In another embodiment, in the compounds of formula (I) as defined above, X represents -CH2-.

[0022] In another embodiment, in the compounds of formula (I) as defined above, R4 and R4' represent a hydrogen atom.

[0023] In another embodiment, in the compounds of formula (I) as defined above, R5 represents a hydrogen atom.

[0024] In another embodiment, in the compounds of formula (I) as defined above, R5 represents a hydrogen atom, a -NH2 group, a methyl group, a methoxy group, an ethoxy group.

[0025] 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, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy and cyano.

[0026] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a fused phenyl group selected from a bicyclo[4.2.0]octa-trienyl group, an indanyl group or a tetrahydronaphthalenyl group optionally substituted with one or two fluorine atoms.

[0027] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a bicyclic group selected from bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl and bicyclo[3.2.1]octan-3-yl, optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, an —OH group, a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group and an oxo group; advantageously, said bicyclic group is unsubstituted.

[0028] In another embodiment, in the compound of formula (I) as defined above, R6 represents a pyridyl group, said pyridyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group, a (C1-C6) fluoroalkyl group and a (C1-C6) alkoxy group, more particularly selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a methoxy group.

[0029] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cycloalkyl selected from a cyclohexyl or cyclopropyl group, said cycloalkyl being ○ fluorine atom, -OH group, (C1-C3) alkyl group, (C1-C3) fluoroalkyl group, (C1-C3) alkoxy group, (C1-C3) fluoroalkoxy group, oxo group, (C1-C6)cycloalkyl and phenyl groups, wherein the (C3-C6)cycloalkyl or phenyl group is optionally substituted with one or two halogen atoms or a (C1-C3)alkyl group. and optionally substituted with 1 to 4 substituents independently selected from The cycloalkyl is Methyl, phenyl and a cyclohexyl group substituted by two halogen atoms, in particular by fluorine atoms Advantageously, it is substituted with 1 to 2 substituents independently selected from:

[0030] In another embodiment, in the compounds of formula (I) as defined above, R6 represents cyclobutylmethyl optionally substituted on the cycloalkyl with one to four 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; advantageously, said cyclobutylmethyl is unsubstituted.

[0031] In another embodiment, in the compound of formula (I) as defined above, R6 represents a tetrahydropyranyl group, said tetrahydropyranyl group being optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group and an —OH group; advantageously, said tetrahydropyranyl group is unsubstituted.

[0032] In another embodiment, in the compound of formula (I) as defined above, R6 represents an isobutyl group, said isobutyl group 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; advantageously, said isobutyl group is unsubstituted.

[0033] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a phenyl(C1-C2)alkyl group chosen in particular from phenylmethyl or phenylethyl.

[0034] In another embodiment, in the compounds of formula (I) as defined above, R 7 independently represents a methyl group, a cyano group, a trifluoromethyl group or a fluorine atom; and n is 0, 1 or 2.

[0035] In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH=, -N= or -CR"=, and R" represents a fluorine atom, a cyano group, or a trifluoromethyl group.

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

[0037] In another embodiment, in the compound of formula (I) defined above, R3 is a COOH group and R6 is a phenyl group containing two substituents independently selected from a chlorine atom, a fluorine atom, a trifluoromethyl group, and a methyl group, wherein at least one of the substitutions contains a halogen atom. In such an embodiment, R3' and R3" are, in particular, hydrogen atoms. In further such an embodiment, R1, R2, R4, R4', R5, R8, and R9 are hydrogen atoms. In such an embodiment, Y is a -CH= group, m is equal to 1, and n is equal to 0. In further such an embodiment, X is a -CH2- group.

[0038] In addition to the above embodiments, further embodiments are provided herein. A further embodiment is a compound of formula (I'): [ka] [In formula: - [ka] represents a double bond or a single bond, and if it is a double bond, then R4 b and R7 b does not exist; - R1 b and R2 b independently represent a hydrogen atom or a deuterium atom; - R3 b represents a hydrogen atom, a -COOH group, or a -OH group; - R3' b and R3'' b independently represent a hydrogen atom, a methyl, a chlorine atom, or a fluorine atom; - R4 b and R5 b independently represent a hydrogen atom, a halogen atom, an -NH2 group, a methyl group, or an -OH group; or R4 and R5 together form an oxo group; - R6 b teeth, a phenyl group (the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group, a (C1-C6) haloalkyl group, a (C1-C6) alkoxy group, a (C1-C6) haloalkoxy group, and an —OH group); heteroaryl groups containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as pyridyl groups, which heteroaryl groups are optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) haloalkyl groups, (C1-C6) alkoxy groups, (C1-C6) haloalkoxy groups, and -OH groups; cycloalkyl groups containing 3 to 9 carbon atoms, said cycloalkyl groups being saturated or partially saturated and optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, —OH groups, (C1-C6)-alkyl groups and oxo groups; a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as a tetrahydropyran group, wherein the heterocycloalkyl group is optionally substituted with one to three substituents independently selected from a fluorine atom, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group, and an —OH group; Spiro (C5-C), such as spiro[3.3]heptane or spiro[3.3]heptane 11 ) Bicyclic ring (the spiro (C5-C 11 ) the bicyclic ring is optionally substituted with 1 to 4 substituents independently selected from a (C1-C6) alkyl group, a fluorine atom, a (C1-C6) alkoxy group, a (C1-C6) haloalkoxy group, and an —OH group; (C1-C6) alkyl groups, such as isobutyl, which alkyl groups are optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, (C1-C6) alkoxy groups, (C1-C6) haloalkoxy groups, and -OH groups. represents a group selected from: - R7 b represents a hydrogen atom or a halogen atom; - X b represents -CH2-, -O- or -S-; - Y b is -CH-, -N- or -CR'' b - and R'' b represents a (C1-C4) alkyl group or a halogen atom such as a fluorine atom or a chlorine atom; - R8 b independently represent a (C1-C4) alkyl group such as methyl or a halogen atom such as fluorine; n b is 0, 1 or 2], or a pharmaceutically acceptable salt thereof.

[0039] The compounds of formula (I') may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers.

[0040] Compounds of formula (I') may likewise exist in tautomeric forms.

[0041] The compound of formula (I') can exist in the form of a base, an acid, a zwitterion, or an addition salt with an acid or a base. Accordingly, there is provided herein a compound of formula (I') or a pharmaceutically acceptable salt thereof.

[0042] Other acid or base salts useful, for example, for purifying or isolating compounds of formula (I'), are also provided, but these salts can be prepared with pharmaceutically acceptable acids or bases.

[0043] Among the suitable salts of the compound of formula (I'), mention may be made especially of the hydrochloride salt.

[0044] In one embodiment, in the compound of formula (I') as defined above, [ka] represents a single bond.

[0045] In another embodiment, in the compounds of formula (I') as defined above, R b and R2 b is a hydrogen atom.

[0046] In another embodiment, in the compounds of formula (I) as defined above, R b is -COOH.

[0047] In another embodiment, in the compounds of formula (I') as defined above, X b represents -CH2-.

[0048] In another embodiment, in the compounds of formula (I') as defined above, R4 b and R5 b independently represent a hydrogen atom, a fluorine atom, an -NH2 group, a methyl group or an -OH group, in particular independently represent a hydrogen atom, a fluorine atom or an -OH group; or R4 b and R5 b together form an oxo group, and in particular R b and R5 b Both of R and R represent a hydrogen atom or a fluorine atom, or R b and R5 b One of R represents a hydrogen atom, and the other represents a fluorine atom or an -OH group. More specifically, R b and R5 b represents a hydrogen atom.

[0049] In another embodiment, in the compounds of formula (I') as defined above, R7 b represents a hydrogen atom or a fluorine atom, and more particularly represents a hydrogen atom.

[0050] In another embodiment, in the compounds of formula (I') as defined above, R6 brepresents a phenyl group, and the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a chlorine atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, and a difluoromethoxy group.

[0051] In another embodiment, in the compounds of formula (I') as defined above, R6 b represents a pyridyl group, said pyridyl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group, a (C1-C6) haloalkyl group, a (C1-C6) alkoxy group, a (C1-C6) haloalkoxy group and an —OH group, and more particularly selected from a methoxy group.

[0052] In another embodiment, in the compounds of formula (I') as defined above, R6 b represents a cycloalkyl group selected from a cyclohexyl group, a cyclopentyl group, and a cyclohexenyl group, said cycloalkyl group being optionally substituted with 1 to 4 substituents independently selected from a fluorine atom and a methyl group.

[0053] In another embodiment, in the compounds of formula (I') as defined above, R6 b represents a tetrahydropyran group, which is optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group, and an —OH group.

[0054] In another embodiment, in the compounds of formula (I') as defined above, R6 b represents a spiro[3.3]hept-1-ene or spiro[3.3]hept-2-ane group, said spiro[3.3]hept-1-ene or spiro[3.3]hept-2-ane group optionally substituted with one to four substituents independently selected from a (C1-C6) alkyl group, a fluorine atom, a (C1-C6) alkoxy group, a (C1-C6) haloalkoxy group and an —OH group, in particular optionally substituted with one or two fluorine atoms.

[0055] In another embodiment, in the compounds of formula (I') as defined above, R6 b represents an isobutyl group, which is optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, a (C1-C6)alkoxy group, a (C1-C6)haloalkoxy group and an —OH group, and in particular is optionally substituted with 1 to 3 fluorine atoms.

[0056] In another embodiment, in the compounds of formula (I') as defined above, R8 b independently represent a methyl group or a fluorine atom, and n is 0, 1, or 2.

[0057] In another embodiment, in the compounds of formula (I') as defined above, Y b represents -CH-, -C(CH3)-, -CF- or -N-, in particular -CH- or -N-.

[0058] Among the compounds of formula (I) described herein, particularly the following compounds or pharmaceutically acceptable salts thereof, in particular the hydrochloride salts thereof: - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 8-(3-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - 8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - 8-(4-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - 8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - 8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - 8-(2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) - 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - 8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - 8-(2,4-difluorophenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (15) - 8-(2,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) - 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (17) - 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) - 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) - 8-(2,6-difluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) - 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) - 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) - 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) - 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) - 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) - 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) - 8-(5-fluoro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(4-cyclopropyl-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) - 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) 9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) - 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) - 8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) - 8-(4-cyclopropyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) - 8-(2-cyclopropyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) - 8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) - 8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (42) 9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (44) - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) 9-(3-cyano-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) - 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) - 8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) - 8-(2-fluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (49) - 8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) - 8-(2,6-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51) 9-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) - 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) - 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (54) - 8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) - 8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) - 8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) - 8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) - 9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (60) - 8-(4-fluoro-2-methylphenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (61) - 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (62) - 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (64) - 9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (65) - 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (66) - 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (69) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (70) - 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (71) - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) - 8-(2,4-dichlorophenyl)-9-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73) - 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (74) - 8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (75) - 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (76) - 8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (77) - 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (78) - 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (79) - 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (80) - 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (81) - 8-(4-chloro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (82) - 8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (83) - 8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (84) - 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (85) - 8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (86) - 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (87) - 8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (88) - 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (89) - 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (90) - 8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (91) - 8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (92) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (93) - 8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (94) - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (95) - 8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (96) - 8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (97) - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (98) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (99) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (100) - 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (101) - 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (102) - 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (103) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (104) - 8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (105) - 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, (106) - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (107) - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (108) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (109) - 8-(3-methyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (110) - 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (111) - 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (112) - 8-(2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (113) - 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride, (114) - 4-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]phenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic acid; hydrochloride, (115) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (116) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (117) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (118) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (119) 3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)-1-(3-fluoropropyl)azetidine, (120) - 8-(2-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (121) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (122) - 8-(2-chloro-5-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (123) - 8-(2,4-difluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (124) - 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (125) - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (126) - 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (127) - 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (128) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (129) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (130) - 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (131) - 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (132) - 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (133) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (134) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (135) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (136) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (137) - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (138) - 9-(2-cyano-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (139) - 8-(2-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (140) - 8-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (141) - sodium 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, (142) - 8-(3-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (143) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (144) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (145) - 8-(3,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (146) - 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (147) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (148) - 8-(4-ethoxy-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (149) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (150) - 8-(2,5-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (151) - 9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (152) - 8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (153) - 8-(4-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (154) - 8-(3-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (155) - 8-(5-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (156) - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (157) - 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (158) - 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid, (159) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (160) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (161) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (162) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (163) - 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (164) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (165) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (166) - 8-benzyl-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (167) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-phenethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (168) - 8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (169) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (170) - 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (171) - 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (172) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-((trans)-2-phenylcyclopropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (173) - 8-((1R,6S,7r)-bicyclo[4.1.0]heptan-7-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (174) - 8-(bicyclo[3.1.0]hexan-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (175) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (176) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5,6,7,8-tetrahydronaphthalen-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (177) - 8-(bicyclo[3.2.1]octan-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (178) - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (179) - 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (180) - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (181) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (182) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (183) - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (184) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (185) - 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (186) - 8-(trans-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (187) - 9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (188) Examples include:

[0059] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular as an inhibitor and degrader of estrogen receptors.

[0060] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, particularly breast cancer.

[0061] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.

[0062] Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.

[0063] Another embodiment is a method of treating cancer comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.

[0064] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, an effective dosage of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION

[0065] The compound of formula (I) can be prepared by the following method.

[0066] Compounds of formula (I), and other related compounds with 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.

[0067] The following general method for the preparation of compounds of formula (I) is optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in formula (I) as described below.

[0068] The following abbreviations and empirical formulas are used: MeCN acetonitrile NH4Cl Ammonium chloride BuLi Butyllithium CO Carbon monoxide Cs2CO3 Cesium Carbonate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane Et2O diethyl ether DIEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphino)ferrocene EtOH ethanol EtOAc ethyl acetate h time H2 Hydrogen HCl Hydrochloric acid HPLC High-Performance Liquid Chromatography LiOH Lithium hydroxide LiHMDS Lithium hexamethyldisilazane MeOH Methanol MgSO4 Magnesium Sulfate MTBE Methyl tert-butyl ether MeTHF 2-methyltetrahydrofuran min n-BuLi n-butyllithium Pd / C Palladium Carbon KOAc Potassium Acetate K2CO3 Potassium Carbonate KHMDS Potassium hexamethyldisilazane KOH Potassium hydroxide NaBH4 Sodium borohydride NaHCO3 Sodium Bicarbonate NaH sodium hydride NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NaHSO3 Sodium bisulfate SCX Strong Cation Exchange Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PhOK Potassium Phenolate SFC Supercritical Fluid Chromatography TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran PPh3 Triphenylphosphine RT room temperature Ar Argon DABCO 1,4-diazabicyclo[2.2.2]octane

[0069] Scheme 1a-part-1: Preparation of compounds of formula (I) - general method [ka]

[0070] Scheme 1a-Part-2 [ka]

[0071] According to Scheme 1a-part-1 and part-2, where R3a is H or a carboxylic acid ester such as COOMe, COOEt, or a protected OH bearing, for example, O-pivaloyl, R9 is a hydrogen atom, and R1, R2, R3, R3', R3" R4, R4', R5, R6, R7, R8, X, m, n, and Y are as defined above, compound 1A can be converted in step 1 to compound 1B by treatment with an aryl bromide or iodide in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3 and a phosphine such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) dissolved in toluene in the presence of a base such as K2CO3 or Cs2CO3 by heating the solvent to reflux.

[0072] Compound 1B can be converted to compound 1C in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or NaH, or KHMDS at −50° C. in a solvent such as MeTHF.

[0073] Compound 1C can be converted to compound 1E in step 4 by treatment with, for example, bis(pinacolato)diboron in the presence of a base such as KOPh by heating the solvent to reflux, and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, dissolved in toluene, and a phosphine, for example, triphenylphosphine.

[0074] Compound 1K can be prepared in a Suzuki coupling reaction between compounds 1C and 1D in step 3, or between compounds 1E and 1F in step 5, using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complex with DCM, in the presence of a base, such as cesium carbonate (CsCO), in a mixture of dioxane and water by heating the solvent to reflux.

[0075] Alternatively, compound 1E can be converted to compound 1H in a Suzuki coupling reaction with compound 1G in a mixture of dioxane and water by heating the solvent to reflux in the presence of a base, such as cesium carbonate (CsCO), using as a catalyst a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), with DCM. Compound 1H can be converted to compound 1I in step 7 by treatment with TFA in DCM or HCl in dioxane. Compound 1I can be converted to compound 1K in step 8 by treatment with compound 1J, where W is Br, I, or OSOR and R = CH, PhMe, CF, or CFCFCFCF 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.

[0076] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1K can be deprotected to compound I in step 9 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, extraction of the compound can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0077] Scheme 1b - Part 1: Preparation of Compounds of Formula (I) - General Method [ka]

[0078] Scheme 1b - Part 2 [ka]

[0079] 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 with, for example, O-pivaloyl, and R1, R2, R3, R3', R3" R4, R4', R6, R7, R8, R9, X, n, m, and Y are defined as above, compound 1L can be converted in step 1 to compound 1N in a Suzuki coupling reaction with compound 1M using as catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, 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] Compound 1N can be converted to compound 1O in step 2 by treatment with sodium nitrite followed by treatment with sodium iodide in a solvent such as a mixture of water and acetonitrile.

[0081] Compound 1O can be converted to compound 1P in step 3, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature. Compound 1P can be converted to compound 1R in step 4 in a Heck coupling reaction with compound 1Q in a solvent such as DMF using, for example, palladium(II) acetate as a catalyst.

[0082] Compound 1R can be converted to compound 1S in step 5 by treatment with TFA in DCM or HCl in dioxane.

[0083] Compound 1S can be converted to compound 1T in step 6 by treatment with compound 1J, where W is Cl, Br, or I, or OSOR, and R = CH, PhMe, CF, or CFCFCFCFCF 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.

[0084] Compound 1T can be converted to compound 1U in step 7 by treatment with, for example, bis(pinacolato)diboron in the presence of a base such as KOPh by heating the solvent to reflux, and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, dissolved in toluene, and a phosphine, for example, triphenylphosphine.

[0085] Compound 1K can be prepared in a Suzuki coupling reaction between compound 1T and R6B(OR')2 or R6BF3K in step 8, or between compound 1U and R6Br or R6I in step 9, using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, in the presence of a base, such as cesium carbonate (Cs2CO3), in a mixture of dioxane and water by heating the solvent to reflux.

[0086] Compound 1K can be converted to a compound of formula (I) in step 12 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH).

[0087] Intermediate 1T can be converted to compound 1Ta in step 10 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH).

[0088] In step 11, compound 1Ta can be converted to compound I by Suzuki conditions using a suitable boronic reagent R6B(OR')2 or R6BF3K, where -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, for example Pd(dppf)Cl2, complex with DCM, as a catalyst, in a mixture of dioxane and water as solvent at room temperature or by heating the solvent to reflux.

[0089] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1K can be deprotected to compound I in step 12 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, extraction of the compound can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0090] Scheme 1c-part-1: Alternative method for preparing intermediate 1T [ka]

[0091] Scheme 1c-Part-2 [ka]

[0092] According to Scheme 1c-part-1 and part-2, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH with, for example, O-pivaloyl, and R1, R2, R3, R3', R3" R4, R7, R8, R9, X, n, m, and Y are defined as above, compound 1V can be converted to compound 1X in step 1 in a Suzuki coupling reaction with compound 1W using as catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM, in the presence of a base such as cesium carbonate (Cs2CO3) in a mixture of dioxane and water by heating the solvent to reflux.

[0093] Compound 1X can be converted to compound 1Y in step 2, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0094] Compound 1Y can be converted to compound 1Z in step 3 by treatment with TFA in DCM or HCl in dioxane.

[0095] Compound 1Z can be converted to compound 1AA in step 4 by treatment with compound 1J, where W is Cl, Br, or I, or OSOR, and R = CH, PhMe, CF, or CFCFCFCFCF 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.

[0096] Compound 1AA can be converted to compound 1AB in step 5 by treatment with sodium borohydride in MeOH.

[0097] Compound 1AB can also be prepared from compound 1V using Suzuki coupling reaction with compound 1AC in step 6 using as catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complex with DCM, in the presence of a base, for example, cesium carbonate (CsCO), in a mixture of dioxane and water by heating the solvent to reflux, followed by bromination of the resulting compound 1AD in step 7, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0098] Compound 1AB can be converted to compound 1T in step 8 by treatment with trifluoromethanesulfonic anhydride and pyridine in DCM.

[0099] Scheme 1d: Preparation of Compounds of Formula (I) - General Method [ka]

[0100] According to Scheme 1d, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH, such as with O-pivaloyl, R9 is a hydrogen atom, and R1, R2, R3, R3', R3'', R4, R4', R5, R6, R7, R8, X, n, m, and Y are as defined above, compound 1E can be converted in step 1 to compound 1AF in a Suzuki coupling reaction by treatment with compound 1AE in a mixture of dioxane and water by heating the solvent to reflux, in the presence of a base such as cesium carbonate (Cs2CO3), using as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complex with DCM.

[0101] Compound 1AF can be converted to compound 1AG in step 2 by treatment with an alkyl magnesium bromide in a solvent such as THF.

[0102] Compound 1AG can be converted to compound 1K in step 3 by treatment with sulfuric acid in water.

[0103] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1K can be deprotected to compound I in step 4 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, extraction of the compound can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt. Purification using HPLC can provide the formate or trifluoroacetate salt.

[0104] Scheme 1e: Alternative preparation of compounds of formula (1B) - general method [ka] According to Scheme 1e, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH bearing, for example, O-pivaloyl, and R3', R3'', R9, X, and m are defined as above, compound 1B can alternatively be prepared as follows: in step 1, compound 1A can be converted to compound 1Aa, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0105] Compound 1Aa can be converted to compound 1Ab in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0106] Compound 1Ac can be prepared in Step 3 by Suzuki coupling reaction between compound 1Ab and R6B(OR')2 or R6BF3K using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, as a 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. When R6 is a substituted cycloalkene, heterocycloalkene, or aliphatic ethylene, it may be reduced, for example, by hydrogenation over a catalyst such as Pd / C at a temperature of up to 70°C under about 5 bar of hydrogen pressure (H2) to give the corresponding saturated compound 1Ac.

[0107] Compound 1Ac can be converted to compound 1B in step 4 by hydrolysis with aqueous HCl, for example by heating in methanol and DCM.

[0108] A process for preparing a compound of formula (I) as defined above, comprising reacting a compound of formula 1K [ka] wherein R1, R2, R3', R3'', R4, R4', R5, R6, R7, R8, R9, m, n, X and Y are as defined above, and R3a is a carboxylic acid ester, such as COOMe, COOEt, or a protected OH, such as with O-pivaloyl. is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH dissolved in methanol, optionally preceded by a step to obtain compound 1K, and a compound of formula 1T [ka] wherein R1, R2, R3', R3'', R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above. is subjected to Suzuki coupling with a boron reagent R6B(OR')2 or R6BF3K, where -B(OR')2 is a boronic acid or pinacolatoate ester, and R6 is as defined above.

[0109] A process for preparing a compound of formula (I) as described above, comprising the step of: [ka] [In the formula, R1, R2, R3a, R3', R3'', R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above.] is subjected to Suzuki coupling with a boron reagent R6B(OR')2 or R6BF3K, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, to obtain a compound 1Ta, optionally preceded by a step of [ka] wherein R1, R2, R3', R3'', R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined above, and R3a is as defined above. is converted to compound 1Ta in the presence of a hydroxide ion source, such as NaOH dissolved in methanol.

[0110] Compounds of formula 1T, 1K, and 1Ta, or any of their pharmaceutically acceptable salts [ka] wherein R, R, R, R, R, R, R, R, m, n, X and Y are as defined above, and R is a protected OH bearing a carboxylic acid ester, such as COOMe, COOEt, or O-pivaloyl. Also provided herein is an intermediate compound selected from:

[0111] any of the intermediate compounds of formula 1F, or pharmaceutically acceptable salts thereof [ka] [In the formula, R1, R2, R4, R4', R5, R7, R8, Y and n are as defined above.] is further provided herein.

[0112] The present application also relates to an intermediate compound of formula 1E, or any of its pharmaceutically acceptable salts. [ka] wherein R, R, R, X, m, R, and R are atoms as defined above. Also described is:

[0113] In another aspect, also provided herein is a process for the preparation of a compound of formula (I) wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula IG as defined above, optionally followed by a purification step.

[0114] Said purification step may for example consist of an acidification step with, for example, an aqueous solution of hydrochloric acid, as exemplified in step 6 of Example 1 below.

[0115] At 400 and 500 MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, and chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) were referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0116] Liquid chromatography / mass spectra (LC / MS) were acquired on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210–400 nm and a flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1 × 30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H.

[0117] Tables 1a and 1b below respectively list specific compounds of formula (I) (names and structures) according to the present disclosure, as well as their characterization ( 1 H NMR and liquid chromatography / mass).

[0118] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65

[0119] Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29]

[0120] The following examples describe the preparation of some compounds of formula (I) described herein. The compound numbers exemplified below correspond to those shown in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0121] In the following examples, where the source of a starting product is not specified, it is to be understood that said product is a known compound.

[0122] Intermediates: Intermediate 1: 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0123] Step 1: Tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate [ka]

[0124] Method 1: To a solution of (4-bromobenzyl)triphenylphosphonium bromide (79.2 g, 155 mmol) in DMF (400 mL) was added NaH (6.18 g, 155 mmol, 60 wt% purity) at 0° C. The mixture was stirred at 0° C. for 15 minutes. To this reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (24.1 g, 141 mmol) in DMF (160 mL). The mixture was stirred at 20° C. for 9 hours. The reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl (100 mL) at 0° C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 60.0 g (crude) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a yellow solid. LC / MS(m / z, MH+): 324 Method 2: A mixture of tert-butyl 3-methyleneazetidine-1-carboxylate (12.5 g, 73.9 mmol), 1-bromo-4-iodobenzene (23 g, 81.3 mmol), potassium carbonate (20.4 g, 148 mmol), tetrabutylammonium bromide (23.8 g, 73.9 mmol), and palladium(II) acetate (1.66 g, 7.39 mmol) in DMF (125 mL) was heated to 60° C. for 16 h. After cooling to room temperature, EtOAc (500 ml) and water (500 mL) were added. After decantation, the organic phase was washed twice with water (500 ml), dried over MgSO, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with DCM to give 20.7 g (86%) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a beige solid. LC / MS(m / z, MH+): 324

[0125] Step 2: 3-(4-bromobenzylidene)azetidine, trifluoroacetic acid [ka] A mixture of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate (60 g, 185 mmol) and TFA (192 mL, 2.59 mol) in DCM (300 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (50 mL) and filtered to give 3-(4-bromobenzylidene)azetidine, trifluoroacetic acid 28 g (45%). LC / MS(m / z, MH+):224

[0126] Step 3: 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine [ka] A mixture of 1-fluoro-3-iodopropane (11.5 g, 61.2 mmol), 3-[(4-bromophenyl)methylene]azetidine, trifluoroacetic acid (23.0 g, 68.0 mmol), and KOH (5.72 g, 102 mmol) in DMF (100 mL) was stirred at room temperature for 10 h. The reaction mixture was quenched by the addition of water (200 mL) and then extracted with EtOAc (500 mL). After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 95 / 05 to give 8.9 g (47% yield) of 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):284

[0127] Intermediate 2: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine [ka] A mixture of 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (2 g, 7.04 mmol), bis(pinacolato)diboron (2.5 g, 9.85 mmol), KOAc (1.73 g, 17.6 mmol), and Pd(dppf)Cl (257 mg, 0.35 mmol) in dioxane (40 mL) was degassed and purged with argon, and then the mixture was refluxed for 2.5 h. After cooling to room temperature, AcOEt (50 mL), EtO (20 mL), water (30 mL), and brine (30 mL) were added under stirring. After decantation, the organic phase was washed twice with 30 mL of brine and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 0 to 0 / 100 cyclohexane / AcOEt followed by a gradient of 99 / 01 to 95 / 05 DCM / MeOH to give 1.2 g (51% yield) of 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine. LC / MS(m / z, MH+): 332

[0128] Intermediate 3: Methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (15 g, 42.82 mmol) (prepared according to WO2017140669), Pd(PPh3)2Cl2 (1.53 g, 2.14 mmol), PPh3 (673.87 mg, 2.57 mmol), bis(pinacolato)diboron (144.08 g, 52.67 mmol), and PhOK (8.04 g, 60.80 mmol) in toluene (150 ml) was heated to 75 °C for 1.5 h. The yellow suspension turned orange and then brown. After cooling to room temperature, DCM (150 mL) and water (150 mL) were added, and decantation was performed using 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

[0129] Intermediate 4: Methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 4 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2020 / 049153) following a procedure similar to that for Intermediate 3 to afford 3.9 g (82%) of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid. LC / MS(m / z, MH+): 473

[0130] Intermediate 5: Methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0131] Step 1: Methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Argon was bubbled through a mixture of 1-bromo-2,4-difluorobenzene (6.63 g, 34.37 mmol), methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (5 g, 22.91 mmol), and K2CO3 (12.67 g, 91.66 mmol) in toluene (40 mL) for 10 min. After the addition of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.32 g, 2.29 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.05 g, 1.15 mmol), the reaction mixture was heated to reflux for 72 h. After cooling to room temperature, water (40 mL) and DCM (40 mL) were added. After decantation, the aqueous phase was washed three times with 40 mL of DCM. The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 heptane / EtOAc to give 2.55 g (34%) of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 331

[0132] Step 2: Methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a suspension of sodium hydride (545 mg, 13.62 mmol, 60 wt% purity) in Me-THF (22 mL) cooled to 5 °C, DBU (277 mg, 0.27 mL, 1.82 mmol) was added, followed by a solution of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate (3 g, 9.08 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (4.2 g, 11.81 mmol) in THF. The cooling bath was removed, and the temperature was allowed to rise to room temperature. A mixture of acetic acid (0.4 mL) and water (32 mL) was added dropwise, followed by water (100 mL) and EtOAc (150 mL). After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with DCM / heptane 50 / 50 to give 2.77 g (66%) of methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 463

[0133] Step 3: Methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 5, step 3, was prepared from 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 3 to afford 1.89 g (72%) of methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 441

[0134] Intermediate 6: Methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0135] Step 1: Methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 6, step 1, was prepared from 1-bromo-2-methyl-4-fluoro-benzene following a procedure similar to that of Intermediate 5, step 1, to afford 700 mg (47%) of methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 327

[0136] Step 2: Methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 6, step 2, was prepared from methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 5, step 2, to afford 7.86 g (82%) of methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 459

[0137] Step 3: Methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 6, step 3, was prepared from methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 3 to afford 3.93 g (43%) of methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 437

[0138] Intermediate 7: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0139] 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), CsCO (37.21 g, 114.2 mmol), and Pd(dppf)Cl, complex with DCM (1.25 g, 1.71 mmol) in dioxane (160 mL) and water (40 mL) was heated to 95 °C for 1 h. Water (200 mL) and EtOAc (500 mL) were added. After decantation, the organic phase was dried over MgSO, 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

[0140] 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 4 N HCl (300 mL, 1200 mmol) cooled to 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 cooling bath was removed, and the temperature was allowed to warm to room temperature. After stirring at room temperature for 4 h, EtO (500 mL) and a 2 N solution of NaHSO (200 mL) were added. After decantation, the organic phase was washed with water (100 mL) and then twice with brine (100 mL), dried over MgSO, 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

[0141] 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 EtO (500 mL) and pentane (500 mL), washed with a 0.2 N solution of NaHSO (100 mL), and washed twice with water (200 mL). After decantation, the organic phase was dried over MgSO, 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

[0142] Step 4: Tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate [ka] A solution of tert-butyl 3-methyleneazetidine-1-carboxylate (7.44 g, 44 mmol) and methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (17.7 g, 36.6 mmol) in DMF (200 mL) was degassed and purged with Ar for 5 minutes. To this stirred solution was added KCO (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 hours and then cooled to room temperature. EtO (300 mL) and water (300 mL) were added. After decantation, the aqueous phase was extracted with an additional 300 mL of EtO, and the combined organic phases were washed twice with water (200 mL), dried over MgSO, filtered, concentrated under reduced pressure, and purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (95 / 05 to 80 / 20) to give 14.7 g (76.5%) 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

[0143] Step 5: Methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid [ka] Intermediate 7, step 5, was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid 9.66 g (94%). LC / MS(m / z, MH+): 425

[0144] 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, trifluoroacetic acid (8.24 g, 15.3 mmol) in a mixture of NaOH 1N (46 mL, 46 mmol) and DCM (70 mL) was stirred at room temperature for 48 hours. 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

[0145] 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. After the mixture was stirred for 30 minutes, 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 hours. The solution was warmed to −25° C. and slowly quenched with an aqueous solution of saturated NH4Cl (2000 mL). The mixture was extracted twice with MTBE (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 10 / 1 to 0 / 1 petroleum ether / EtOAc to afford 180 g (65%) of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate as a white solid. LC / MS(m / z, MH+): 340

[0146] Step 2: Tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate [ka] Step 2 of Intermediate 7 (Method 2) was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate following a procedure similar to that of Step 1 of Intermediate 7 (Method 1) to afford 8.5 g (99%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzoyl)azetidine-1-carboxylate. LC / MS(m / z, MH+):462

[0147] Step 3: Tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate [ka] Step 3 of Intermediate 7 (Method 2) was prepared from tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate following a procedure similar to that of Step 3 of Intermediate 7 (Method 1) to afford 6.1 g (88%) of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azetidine-1-carboxylate. LC / MS (m / z, MH+): 540

[0148] Step 4: Methyl 9-(4-(azetidine-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid [ka] Intermediate 7 (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 procedure similar to that of Intermediate 1, step 2, to afford methyl 9-(4-(azetidine-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid 5g (100%). LC / MS(m / z, MH+): 440

[0149] 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, trifluoroacetic acid (5 g, 9.24 mmol), KCO (4.71 g, 34 mmol) in MeCN (200 mL) was heated to 70° C. for 1 h. The reaction mixture was quenched by the addition of water (200 mL) and then extracted with EtOAc (500 mL). After decantation, the organic phase was dried over MgSO, 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 methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate 3 g (53%). LC / MS (m / z, MH+): 500

[0150] 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 to 0 °C was added NaBH (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 MgSO, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 05 / 95 to give 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 (99%). LC / MS(m / z, MH+):502

[0151] 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 DCM / MeOH gradient: 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

[0152] Alternative Method for Preparation of Step 6 of Intermediate 7 (Method 2) Step 1: 3-Azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid [ka] Step 1 was prepared from tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate following a procedure similar to that of Step 2 of Intermediate 1 to afford 41.6 g (100%) of 3-azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid. LC / MS (m / z, MH+): 240

[0153] Step 2: (4-Bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone [ka] Step 2 was prepared from 3-azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid following a procedure similar to that of Step 3 of Intermediate 1 to afford 20 g (54%) of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone. LC / MS (m / z, MH+): 300

[0154] Step 3: (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol [ka] To a solution of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone (20.0 g, 66.6 mmol) in MeOH (100 mL) was added NaBH (5.04 g, 133 mmol) at 0 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was slowly quenched with water (100 mL) and concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted three times with EtOAc (80 mL). After decantation, the organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 98 / 02 to 90 / 10 DCM:MeOH to afford 16 g (77%) of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol as a mixture of two isomers. LC / MS(m / z, MH+):302

[0155] Step 4: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 4 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 (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol following a procedure similar to that of Step 1 of Intermediate 7 (Method 1) to afford 1.39 g (79%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 424

[0156] Step 5: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 5 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 3 of Intermediate 7 (Method 1) to afford 1.59 g (100%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):502

[0157] Intermediate 8: 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 7) (605 mg, 1.25 mmol), Pd(PPh)Cl (35 mg, 50 μmol), PPh (26 mg, 100 μmol), bis(pinacolato)diboron (793 mg, 3.12 mmol), KCO (38 mg, 0.27 mmol), and PhOK (413 mg, 3.12 mmol) in toluene (30 mL) was degassed and purged with Ar for 5 min, then heated to 75 °C for 6 h. After cooling to room temperature, EtO (100 mL) and a 5% solution of NaCO (50 mL) were added. After decantation, the organic phase was washed with water (50 mL), dried over MgSO, 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 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

[0158] Intermediate 9: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0159] Step 1: 3,3-Difluoropropyl trifluoromethanesulfonate [ka] To a solution of 3,3-difluoropropan-1-ol (1 g, 10.41 mmol) and 2,6-lutidine (2.66 mL, 22.9 mmol) in DCM (20 mL) cooled to 0 °C, trifluoromethanesulfonic anhydride (1.93 mL, 11.45 mmol) was added dropwise. The mixture was stirred at 0 °C for 30 minutes. EtO and water were added. The aqueous phase was separated and extracted three times with ether. The combined organic phase was washed with a 10% aqueous solution of citric acid, then twice with water, dried over Na SO , 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.

[0160] Step 2: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a suspension of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (Intermediate 7, Method 1, Step 5) (3 g, 5.57 mmol), 3,3-difluoropropyl trifluoromethanesulfonate (1.27 g, 5.57 mmol) in DCM (70 mL) was added NaOH 1N (22.29 mL, 22.29 mmol). The mixture was stirred at room temperature for 18 h. Water (100 mL) was added. The aqueous phase was separated and extracted with a mixture of 150 mL EtO and 150 mL EtOAc. The combined organic phases were washed with 100 mL water, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 0 to 80 / 20 to give 1.02 g (36%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):502

[0161] Intermediate 10: Methyl 9-(4-((1-(3,3-difluoropropyl)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] Intermediate 10 was prepared from methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for intermediate 8 to yield 118 mg (50%) of methyl 9-(4-((1-(3,3-difluoropropyl)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+): 550

[0162] Intermediate 11: 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] A mixture of 1-fluoro-3-iodopropane (501 mg, 2.66 mmol), 3-(4-bromo-2,3-difluorobenzylidene)azetidine, trifluoroacetic acid (950 mg, 2.54 mmol), and commercially available powdered NaOH (304.7 mg, 7.6 mmol) in acetonitrile (30 mL) was stirred at room temperature for 18 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL). After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / EtOAc gradient: 100 / 00 to 00 / 100 to give 0.65 g (34%) of 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0163] Intermediate 12: 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0164] Step 1: (4-bromo-2,6-difluorophenyl)methanol [ka] To a solution of 4-bromo-2,6-difluorobenzaldehyde (2 g, 9.05 mmol) in DCM (40 mL) and MeOH (10 mL) at 0° C. was added NaBH (377 mg, 9.95 mmol) in small portions. The reaction mixture was stirred at 0° C. for 1 h and then slowly quenched with a 1N aqueous solution of HCl at 0° C. After stirring at 0° C. for 30 min, water was added, and the mixture was transferred into a separatory funnel and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over NaSO, filtered, concentrated to dryness, triturated with pentane, and filtered to give 1.83 g (91%) of (4-bromo-2,6-difluorophenyl)methanol. LC / MS(m / z, MH+): 223

[0165] Step 2: 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene [ka] To a solution of (4-bromo-2,6-difluorophenyl)methanol (2.67 g, 11.99 mmol) in EtO (60 mL) at 0 °C, tribromophosphane (0.57 mL, 6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 h and then slowly poured onto a saturated aqueous solution of NaHCO under stirring. After stirring for 30 min, the mixture was transferred into a separatory funnel and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated to dryness to give 3.04 g (88%) of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene as a colorless oil, which was used in the next step without further purification. LC / MS(m / z, MH+): 285

[0166] Step 3: Diethyl (4-bromo-2,6-difluorobenzyl)phosphonate [ka] A mixture of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (2.5 g, 8.74 mmol) and triethyl phosphite (2.25 mL, 13.12 mmol) was heated to 130° C. in a sealed tube for 4 h. The resulting mixture was purified by flash chromatography eluting with a gradient of 100 / 0 to 80 / 20 cyclohexane / EtOAc to afford 2.95 g (98%) of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate as a colorless oil. LC / MS(m / z, MH+): 343

[0167] Step 4: Tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate [ka] Under an argon atmosphere, a 2.5 M solution of n-butyllithium in hexane (3.5 mL, 8.74 mmol) was added dropwise to a solution of diisopropylamine (1.35 mL, 9.62 mmol) in THF (15 mL) at −78° C. The reaction mixture was stirred for 5 minutes, and then a solution of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate (3 g, 8.74 mmol) in THF (15 mL) was added. After stirring for 45 minutes, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.65 g, 9.62 mmol) in THF (30 mL) was added. The reaction mixture was stirred until completion, while warming to room temperature. It was then transferred to a separatory funnel containing a saturated aqueous solution of NH4Cl and extracted three times with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then purified by flash chromatography eluting with a gradient of 100 / 0 to 50 / 50 cyclohexane / EtOAc to afford 1.67 g (53%) of tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate as a colorless viscous oil. LC / MS (m / z, MH+): 360

[0168] Step 5: 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 12, step 5, was prepared from tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 1.65 g (98%) of 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid as a white solid. LC / MS (m / z, MH+): 260

[0169] Step 6: 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 12, step 6, was prepared from 3-(4-bromo-2,6-difluorobenzylidene)azetidine trifluoroacetic acid following a procedure similar to that of Intermediate 11 to afford 79 mg (18%) of 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0170] Intermediate 13: 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0171] Step 1: (4-bromo-2,6-dimethylphenyl)methanol [ka] Intermediate 13, step 1, was prepared from 4-bromo-2,6-dimethylbenzaldehyde following a procedure similar to that of Intermediate 12, step 1, to afford 1.86 g (92%) of (4-bromo-2,6-dimethylphenyl)methanol. LC / MS (m / z, MH+): 215

[0172] Step 2: 5-Bromo-2-(bromomethyl)-1,3-dimethylbenzene [ka] Intermediate 13, step 2, was prepared from (4-bromo-2,6-dimethylphenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to afford 1.27 g (98%) of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene. LC / MS(m / z, MH+): 277

[0173] Step 3: Diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate [ka] Intermediate 13, step 3, was prepared from 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene following a procedure similar to that of Intermediate 12, step 3, to afford 1.16 g (86%) of diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate. LC / MS(m / z, MH+): 335

[0174] Step 4: Tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate [ka] Intermediate 13, step 4, was prepared from diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate following a procedure similar to that of Intermediate 12, step 4, to afford 0.86 g (27%) of tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate. LC / MS(m / z, MH+): 352

[0175] Step 5: 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 13, step 5, was prepared from tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 0.77 g (86%) of 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid. LC / MS(m / z, MH+):252

[0176] Step 6: 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 13, step 6, was prepared from 3-(4-bromo-2,6-dimethylbenzylidene)azetidine trifluoroacetic acid following a procedure similar to that of Intermediate 11 to afford 0.7 g (50%) of 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 312

[0177] Intermediate 14: 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0178] Step 1: Diethyl (4-bromo-2,5-difluorobenzyl)phosphonate [ka] Intermediate 14, Step 1, was prepared from commercially available 1-bromo-4-(bromomethyl)-2,5-difluorobenzene following a procedure similar to that of Intermediate 12, Step 3, to afford 6.48 g (87%) of diethyl (4-bromo-2,5-difluorobenzyl)phosphonate. LC / MS(m / z, MH+): 343

[0179] Step 2: Tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate [ka] Intermediate 14, step 2, was prepared from diethyl (4-bromo-2,5-difluorobenzyl)phosphonate following a procedure similar to that of Intermediate 12, step 4, to afford 1.16 g (73%) of tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate. LC / MS (m / z, MH+): 360

[0180] Step 3: 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 14, step 3, was prepared from tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 1.07 g (89%) of 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid. LC / MS (m / z, MH+): 260

[0181] Step 4: 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 14, step 4, was prepared from 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid following a procedure similar to that for Intermediate 11 to afford 0.7 g (76%) of 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0182] Intermediate 15: 3-[(4-bromo-3-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0183] Step 1: (4-Bromo-3-fluoro-phenyl)methanol [ka] Intermediate 15 step 1 was prepared from 4-bromo-3-fluoro-benzaldehyde following a procedure similar to that of Intermediate 12 step 1 to afford (4-bromo-3-fluoro-phenyl)methanol 5g (99%). LC / MS(m / z, MH+):205

[0184] Step 2: 1-Bromo-4-(bromomethyl)-2-fluoro-benzene [ka] Intermediate 15 step 2 was prepared from (4-bromo-3-fluoro-phenyl)methanol following a procedure similar to that of Intermediate 12 step 2 to afford 5.1 g (77%) of 1-bromo-4-(bromomethyl)-2-fluoro-benzene. LC / MS(m / z, MH+):267

[0185] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-benzene [ka] Intermediate 15, step 3, was prepared from 1-bromo-4-(bromomethyl)-2-fluoro-benzene following a procedure similar to that of Intermediate 12, step 3, to afford 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-benzene 3 g (99%). LC / MS(m / z, MH+): 325

[0186] Step 4: Tert-butyl 3-[(4-bromo-3-fluoro-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 15, step 4, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 3.75 g (85%) of tert-butyl 3-[(4-bromo-3-fluoro-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 342

[0187] Step 5: 3-[(4-bromo-3-fluoro-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 15, step 5, was prepared from tert-butyl 3-[(4-bromo-3-fluoro-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.66 g of 3-[(4-bromo-3-fluoro-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+):242

[0188] Step 6: 3-[(4-bromo-3-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 15 step 6 was prepared from 3-[(4-bromo-3-fluoro-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of Intermediate 11 to afford 2.1 g (95%) of 3-[(4-bromo-3-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):302

[0189] Intermediate 16: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0190] Step 1: (4-Bromo-2-fluoro-5-methyl-phenyl)methanol [ka] Intermediate 16 step 1 was prepared from 4-bromo-2-fluoro-5-methyl-benzaldehyde following a procedure similar to that of Intermediate 12 step 1 to afford (4-bromo-2-fluoro-5-methyl-phenyl)methanol 2 g (99%). LC / MS(m / z, MH+): 219

[0191] Step 2: 1-Bromo-4-(bromomethyl)-5-fluoro-2-methyl-benzene [ka] Intermediate 16, step 2, was prepared from (4-bromo-2-fluoro-5-methyl-phenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to afford 2.7 g (91%) of 1-bromo-4-(bromomethyl)-5-fluoro-2-methyl-benzene. LC / MS(m / z, MH+):281

[0192] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-5-fluoro-2-methyl-benzene [ka] Intermediate 16, step 3, was prepared from 1-bromo-4-(bromomethyl)-5-fluoro-2-methyl-benzene following a procedure similar to that of Intermediate 12, step 3, to yield 3.2 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-5-fluoro-2-methyl-benzene. LC / MS(m / z, MH+): 339

[0193] Step 4: Tert-butyl 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 16, step 4, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-5-fluoro-2-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 2.75 g (80%) of tert-butyl 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 356

[0194] Step 5: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 16, step 5, was prepared from tert-butyl 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 3.6 g of 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 256

[0195] Step 6: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 16, step 6, was prepared from 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 145 mg (48%) of 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 316

[0196] Intermediate 17: 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0197] Step 1: (4-Bromo-2-fluoro-3-methyl-phenyl)methanol [ka] Intermediate 17 step 1 was prepared from 4-bromo-2-fluoro-3-methyl-benzaldehyde following a procedure similar to that of Intermediate 12 step 1 to yield 5.1 g (100%) of (4-bromo-2-fluoro-5-methyl-phenyl)methanol. LC / MS(m / z, MH+): 219

[0198] Step 2: 1-Bromo-4-(bromomethyl)-3-fluoro-2-methyl-benzene [ka] Intermediate 17, step 2, was prepared from (4-bromo-2-fluoro-3-methyl-phenyl)methanol according to a procedure similar to that of Intermediate 12, step 2, to afford 2.33 g (91%) of 1-bromo-4-(bromomethyl)-3-fluoro-2-methyl-benzene. LC / MS(m / z, MH+):281

[0199] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-2-methyl-benzene [ka] Intermediate 17, step 3, was prepared from 1-bromo-4-(bromomethyl)-3-fluoro-2-methyl-benzene following a procedure similar to that of Intermediate 12, step 3, to yield 2.8 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-2-methyl-benzene. LC / MS(m / z, MH+): 339

[0200] Step 4: Tert-butyl 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 17, step 4, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-2-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 2.3 g (77%) of tert-butyl 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 356

[0201] Step 5: 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 17, step 5, was prepared from tert-butyl 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.86 g of 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 256

[0202] Step 6: 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 17, step 6, was prepared from 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 203 mg (68%) of 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 316

[0203] Intermediate 18: 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0204] Step 1: 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene [ka] Intermediate 18, step 1, was prepared from commercially available (4-bromo-2,6-difluoro-phenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to afford 5-bromo-2-(bromomethyl)-1,3-difluorobenzene 6 g (94%). LC / MS(m / z, MH+): 285

[0205] Step 2: Diethyl (4-bromo-2,6-difluorobenzyl)phosphonate [ka] Intermediate 18, step 2, was prepared from 5-bromo-2-(bromomethyl)-1,3-difluorobenzene following a procedure similar to that of Intermediate 12, step 3, to afford 6.5 g (88%) of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate as a colorless oil. LC / MS(m / z, MH+): 343

[0206] Step 3: Tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate [ka] Intermediate 18, step 3, was prepared from diethyl (4-bromo-2,6-difluorobenzyl)phosphonate following a procedure similar to that of Intermediate 12, step 4, to afford 7 g (86%) of tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate as a colorless viscous oil. LC / MS (m / z, MH+): 360

[0207] Step 4: 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 18, step 4, was prepared from tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid 12 g as a white solid. LC / MS (m / z, MH+): 260

[0208] Step 5: 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 18, step 5, was prepared from 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid following a procedure similar to that for Intermediate 11 to afford 600 mg (52%) of 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0209] Intermediate 19: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0210] Step 1: (4-Bromo-2-fluoro-6-methyl-phenyl)methanol [ka] Intermediate 19, step 1, was prepared from 4-bromo-2-fluoro-6-methyl-benzaldehyde following a procedure similar to that of Intermediate 12, step 1, to afford 2.3 g (73%) of (4-bromo-2-fluoro-6-methyl-phenyl)methanol. LC / MS(m / z, MH+): 219

[0211] Step 2: 1-Bromo-4-(bromomethyl)-3-fluoro-5-methyl-benzene [ka] Intermediate 19, step 2, was prepared from (4-bromo-2-fluoro-6-methyl-phenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to yield 1-bromo-4-(bromomethyl)-3-fluoro-5-methyl-benzene 5.8 g (100%). LC / MS(m / z, MH+):281

[0212] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-5-methyl-benzene [ka] Intermediate 19, step 3, was prepared from 1-bromo-4-(bromomethyl)-3-fluoro-5-methyl-benzene following a procedure similar to that of Intermediate 12, step 3, to afford 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-5-methyl-benzene 3 g (100%). LC / MS(m / z, MH+): 339

[0213] Step 4: Tert-butyl 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 19, step 4, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-5-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 3.5 g (78%) of tert-butyl 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 356

[0214] Step 5: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 19, step 5, was prepared from tert-butyl 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 5.4 g of 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 256

[0215] Step 6: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 19, step 6, was prepared from 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 203 mg (68%) of 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 316

[0216] Intermediate 20: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0217] Step 1: (4-Bromo-3-fluoro-5-methyl-phenyl)methanol [ka] Intermediate 20, step 1, was prepared from 4-bromo-3-fluoro-5-methyl-benzaldehyde following a procedure similar to that of Intermediate 12, step 1, to yield 4.97 g (99%) of (4-bromo-3-fluoro-5-methyl-phenyl)methanol. LC / MS(m / z, MH+): 219

[0218] Step 2: 2-Bromo-5-(bromomethyl)-1-fluoro-3-methyl-benzene [ka] Intermediate 20, step 2, was prepared from (4-bromo-3-fluoro-5-methyl-phenyl)methanol according to a procedure similar to that of Intermediate 12, step 2, to afford 2-bromo-5-(bromomethyl)-1-fluoro-3-methyl-benzene 5.3 g (83%). LC / MS(m / z, MH+):281

[0219] Step 3: 2-Bromo-5-(diethoxyphosphorylmethyl)-1-fluoro-3-methyl-benzene [ka] Intermediate 20, step 3, was prepared from 2-bromo-5-(bromomethyl)-1-fluoro-3-methyl-benzene following a procedure similar to that of Intermediate 12, step 3, to yield 5.7 g (88%) of 2-bromo-5-(diethoxyphosphorylmethyl)-1-fluoro-3-methyl-benzene. LC / MS(m / z, MH+): 339

[0220] Step 4: Tert-butyl 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 20, step 4, was prepared from 2-bromo-5-(diethoxyphosphorylmethyl)-1-fluoro-3-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 4.16 g (70%) of tert-butyl 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 356

[0221] Step 5: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 20, step 5, was prepared from tert-butyl 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.33 g of 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 256

[0222] Step 6: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 20, step 6, was prepared from 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of Intermediate 11 to yield 850 mg (51%) of 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 316

[0223] Intermediate 21: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0224] Step 1: 4-Bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene [ka] Intermediate 21, Step 1, was prepared from commercially available 4-bromo-1-(bromomethyl)-2-methylbenzene following a procedure similar to that of Intermediate 12, Step 3, to afford 1.46 g (60%) of 4-bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene. LC / MS(m / z, MH+): 321

[0225] Step 2: Tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 21, step 2, was prepared from 4-bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 0.82 g (43%) of tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 338

[0226] Step 3: 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 21, step 3, was prepared from tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 0.65 g (78%) of 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 238

[0227] Step 4: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 21, step 4, was prepared from 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of Intermediate 11 to afford 160 mg (49%) of 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):298

[0228] Intermediate 22: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0229] Step 1: 1-Bromo-4-(bromomethyl)-2,5-dimethyl-benzene [ka] Intermediate 22, step 1, was prepared from commercially available (4-bromo-2,5-dimethyl-phenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to afford 3.75 g (97%) of 1-bromo-4-(bromomethyl)-2,5-dimethyl-benzene. LC / MS(m / z, MH+): 277

[0230] Step 2: 1-Bromo-4-(diethoxyphosphorylmethyl)-2,5-dimethyl-benzene [ka] Intermediate 22, step 2, was prepared from 1-bromo-4-(bromomethyl)-2,5-dimethyl-benzene following a procedure similar to that of Intermediate 12, step 3, to afford 1-bromo-4-(diethoxyphosphorylmethyl)-2,5-dimethyl-benzene 3 g (67%). LC / MS(m / z, MH+): 335

[0231] Step 3: Tert-butyl 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 22, step 3, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2,5-dimethyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 0.90 g (28%) of tert-butyl 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 352

[0232] Step 4: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 22, step 4, was prepared from tert-butyl 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 0.81 g (86%) of 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+):252

[0233] Step 5: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 22 step 5 was prepared from 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 0.48 g (69%) of 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 312

[0234] Intermediate 23: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0235] Step 1: (4-Bromo-3,5-difluoro-phenyl)methanol [ka] Intermediate 23 step 1 was prepared from 4-bromo-3,5-difluoro-benzaldehyde following a procedure similar to that of Intermediate 12 step 1 to afford (4-bromo-3,5-difluoro-phenyl)methanol 3g (99%). LC / MS(m / z, MH+): 223

[0236] Step 2: 2-Bromo-5-(bromomethyl)-1,3-difluoro-benzene [ka] Intermediate 23, step 2, was prepared from (4-bromo-3,5-difluoro-phenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to afford 2-bromo-5-(bromomethyl)-1,3-difluoro-benzene 3.7 g (96%). LC / MS(m / z, MH+): 285

[0237] Step 3: 2-Bromo-5-(diethoxyphosphorylmethyl)-1,3-difluoro-benzene [ka] Intermediate 23, step 3, was prepared from 2-bromo-5-(bromomethyl)-1,3-difluoro-benzene following a procedure similar to that of Intermediate 12, step 3, to yield 4.27 g (96%) of 2-bromo-5-(diethoxyphosphorylmethyl)-1,3-difluoro-benzene. LC / MS(m / z, MH+): 343

[0238] Step 4: Tert-butyl 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 23, step 4, was prepared from 2-bromo-5-(diethoxyphosphorylmethyl)-1,3-difluoro-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 2.54 g (57%) of tert-butyl 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azetidine-1-carboxylate. LC / MS (m / z, MH+): 360

[0239] Step 5: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 23, step 5, was prepared from tert-butyl 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.45 g (93%) of 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS (m / z, MH+): 260

[0240] Step 6: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 23 step 6 was prepared from 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 191 mg (45%) of 3-[(4-bromo-3,5-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0241] Intermediate 24: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0242] Step 1: (4-Bromo-3-fluoro-2-methyl-phenyl)methanol [ka] Intermediate 24, step 1, was prepared from 4-bromo-3-fluoro-2-methyl-benzaldehyde following a procedure similar to that of Intermediate 12, step 1, to yield 2.87 g (97%) of (4-bromo-3-fluoro-2-methyl-phenyl)methanol. LC / MS(m / z, MH+): 219

[0243] Step 2: 1-Bromo-4-(bromomethyl)-2-fluoro-3-methyl-benzene [ka] Intermediate 24, step 2, was prepared from (4-bromo-3-fluoro-2-methyl-phenyl)methanol following a procedure similar to that of Intermediate 12, step 2, to yield 3.63 g (98%) of 1-bromo-4-(bromomethyl)-2-fluoro-3-methyl-benzene. LC / MS(m / z, MH+):281

[0244] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-3-methyl-benzene [ka] Intermediate 24, step 3, was prepared from 1-bromo-4-(bromomethyl)-2-fluoro-3-methyl-benzene following a procedure similar to that of Intermediate 12, step 3, to yield 4.3 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-3-methyl-benzene. LC / MS(m / z, MH+): 339

[0245] Step 4: Tert-butyl 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 24, step 4, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-3-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 1.8 g (40%) of tert-butyl 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 356

[0246] Step 5: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 24, step 5, was prepared from tert-butyl 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 979 mg (66%) of 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 256

[0247] Step 6: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 24, step 6, was prepared from 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 219 mg (51%) of 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 316

[0248] Intermediate 25: 3-[(4-bromo-2-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 25 was prepared from commercially available 3-[(4-bromo-2-fluoro-phenyl)methylene]azetidine hydrochloride according to a procedure similar to that for Intermediate 11 to yield 730 mg (58%) of 3-[(4-bromo-2-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):302

[0249] Intermediate 26: 3-[(4-bromo-2,3-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 26 was prepared from commercially available 3-[(4-bromo-2,3-difluoro-phenyl)methylene]azetidine hydrochloride according to a procedure similar to that for Intermediate 11 to yield 952 mg (77%) of 3-[(4-bromo-2,3-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0250] Intermediate 27: 5-Bromo-2-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]benzonitrile [ka]

[0251] Step 1: 5-Bromo-2-(diethoxyphosphorylmethyl)benzonitrile [ka] Intermediate 27, Step 1, was prepared from commercially available 5-bromo-2-(bromomethyl)benzonitrile following a procedure similar to that of Intermediate 12, Step 3, to afford 2.93 g (97%) of 5-bromo-2-(diethoxyphosphorylmethyl)benzonitrile. LC / MS(m / z, MH+): 332

[0252] Step 2: Tert-butyl 3-[(4-bromo-2-cyano-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 27, step 2, was prepared from 5-bromo-2-(diethoxyphosphorylmethyl)benzonitrile following a procedure similar to that of Intermediate 12, step 4, to afford 2.19 g (71%) of tert-butyl 3-[(4-bromo-2-cyano-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 349

[0253] Step 3: 2-(azetidin-3-ylidenemethyl)-5-bromo-benzonitrile, trifluoroacetic acid [ka] Intermediate 27, step 3, was prepared from tert-butyl 3-[(4-bromo-2-cyano-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.18 g (96%) of 2-(azetidin-3-ylidenemethyl)-5-bromo-benzonitrile, trifluoroacetic acid. LC / MS(m / z, MH+): 249

[0254] Step 4: 5-Bromo-2-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]benzonitrile [ka] Intermediate 27, step 4, was prepared from 2-(azetidin-3-ylidenemethyl)-5-bromo-benzonitrile, trifluoroacetic acid following a procedure similar to that for intermediate 11 to afford 1.35 g (73%) of 5-bromo-2-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]benzonitrile. LC / MS(m / z, MH+): 309

[0255] Intermediate 28: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azetidine [ka]

[0256] Step 1: 4-Bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene [ka] Intermediate 28, Step 1, was prepared from commercially available [4-bromo-2-(trifluoromethyl)phenyl]methanol following a procedure similar to that of Intermediate 12, Step 2, to afford 2.87 g (92%) of 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene. LC / MS(m / z, MH+): 317

[0257] Step 2: 4-Bromo-1-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene [ka] Intermediate 28, step 2, was prepared from 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene following a procedure similar to that of Intermediate 12, step 3, to afford 3.13 g (93%) of 4-bromo-1-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene. LC / MS(m / z, MH+): 375

[0258] Step 3: Tert-butyl 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azetidine-1-carboxylate [ka] Intermediate 28, step 3, was prepared from 4-bromo-1-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene following a procedure similar to that of Intermediate 12, step 4, to afford 2.42 g (74%) of tert-butyl 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 392

[0259] Step 4: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azetidine, trifluoroacetic acid [ka] Intermediate 28, step 4, was prepared from tert-butyl 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 3.07 g of 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+):291

[0260] Step 5: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 28, step 5, was prepared from 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azetidine, trifluoroacetic acid following a procedure similar to that for intermediate 11 to afford 1.29 g (60%) of 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 352

[0261] Intermediate 29: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka]

[0262] Step 1: 4-Bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene [ka] Intermediate 29, Step 1, was prepared from commercially available 4-bromo-1-(bromomethyl)-2-methylbenzene following a procedure similar to that of Intermediate 12, Step 3, to afford 1.46 g (60%) of 4-bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene. LC / MS(m / z, MH+): 321

[0263] Step 2: Tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 29, step 2, was prepared from 4-bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene following a procedure similar to that of Intermediate 12, step 4, to afford 0.82 g (53%) of tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 338

[0264] Step 3: 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid [ka] Intermediate 29, step 3, was prepared from tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 0.65 g (78%) of 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+): 238

[0265] Step 4: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 29, step 4, was prepared from 3-[(4-bromo-2-methyl-phenyl)methylene]azetidine, trifluoroacetic acid following a procedure similar to that of intermediate 11 to afford 170 mg (57%) of 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):298

[0266] Intermediate 30: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azetidine [ka]

[0267] Step 1: 1-Bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene [ka] Intermediate 30, Step 1, was prepared from commercially available [4-bromo-2-(trifluoromethyl)phenyl]methanol following a procedure similar to that of Intermediate 12, Step 2, to afford 2.35 g (94%) of 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene. LC / MS(m / z, MH+): 317

[0268] Step 2: 1-Bromo-4-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene [ka] Intermediate 30, step 2, was prepared from 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene following a procedure similar to that of Intermediate 12, step 3, to afford 2.86 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene. LC / MS(m / z, MH+): 375

[0269] Step 3: Tert-butyl 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azetidine-1-carboxylate [ka] Intermediate 30, step 3, was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene following a procedure similar to that of Intermediate 12, step 4, to afford 2.24 g (75%) of tert-butyl 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 392

[0270] Step 4: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azetidine, trifluoroacetic acid [ka] Intermediate 30, step 4, was prepared from tert-butyl 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.13 g (92%) of 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azetidine, trifluoroacetic acid. LC / MS(m / z, MH+):291

[0271] Step 5: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azetidine [ka] Intermediate 30, step 5, was prepared from 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azetidine, trifluoroacetic acid following a procedure similar to that for Intermediate 11 to afford 1.83 g (99%) of 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 352

[0272] Intermediate 31: 2-Bromo-5-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]benzonitrile [ka]

[0273] Step 1: 2-Bromo-5-(hydroxymethyl)benzonitrile [ka] Intermediate 31, step 1, was prepared from 2-bromo-5-formylbenzonitrile following a procedure similar to that of Intermediate 12, step 1, to afford 2.06 g (100%) of 2-bromo-5-(hydroxymethyl)benzonitrile. LC / MS(m / z, MH+):212

[0274] Step 2: 2-Bromo-5-(bromomethyl)benzonitrile [ka] Intermediate 31, step 2, was prepared from 2-bromo-5-(hydroxymethyl)benzonitrile following a procedure similar to that of Intermediate 12, step 2, to afford 2.3 g (97%) of 2-bromo-5-(bromomethyl)benzonitrile. LC / MS(m / z, MH+):274

[0275] Step 3: 2-Bromo-5-(diethoxyphosphorylmethyl)benzonitrile [ka] Intermediate 31, Step 3, was prepared from 2-bromo-5-(bromomethyl)benzonitrile following a procedure similar to that of Intermediate 12, Step 3, to afford 3.18 g (93%) of 2-bromo-5-(diethoxyphosphorylmethyl)benzonitrile. LC / MS(m / z, MH+): 332

[0276] Step 4: Tert-butyl 3-[(4-bromo-3-cyano-phenyl)methylene]azetidine-1-carboxylate [ka] Intermediate 31, step 4, was prepared from 2-bromo-5-(diethoxyphosphorylmethyl)benzonitrile following a procedure similar to that of Intermediate 12, step 4, to afford 2.56 g (80%) of tert-butyl 3-[(4-bromo-3-cyano-phenyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 349

[0277] Step 5: 5-(azetidin-3-ylidenemethyl)-2-bromo-benzonitrile, trifluoroacetic acid [ka] Intermediate 31, step 5, was prepared from tert-butyl 3-[(4-bromo-3-cyano-phenyl)methylene]azetidine-1-carboxylate following a procedure similar to that of Intermediate 1, step 2, to afford 2.1 g (81%) of 5-(azetidin-3-ylidenemethyl)-2-bromo-benzonitrile, trifluoroacetic acid. LC / MS(m / z, MH+): 249

[0278] Step 6: 2-Bromo-5-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]benzonitrile [ka] Intermediate 31, step 6, was prepared from 5-(azetidin-3-ylidenemethyl)-2-bromo-benzonitrile, trifluoroacetic acid following a procedure similar to that for Intermediate 11 to afford 2-bromo-5-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]benzonitrile 900 mg (96%). LC / MS(m / z, MH+): 309

[0279] Intermediate 32: 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate [ka]

[0280] Step 1: 6-(2-chlorophenyl)-6,7,8,9-tetrahydrobenzo[7]annulen-5-one [ka] Intermediate 32, step 1, was prepared from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that for Intermediate 5, step 1, to afford 580 mg (16%) of 6-(2-chlorophenyl)-6,7,8,9-tetrahydrobenzo[7]annulen-5-one. LC / MS(m / z, MH+):271

[0281] Step 2: 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate [ka] To a solution of 6-(2-chlorophenyl)-6,7,8,9-tetrahydrobenzo[7]annulen-5-one (580 mg, 2.14 mmol) in THF (15 mL) was added KHMDS (1 M, 2.57 mL, 2.57 mmol) under an Ar atmosphere at −50° C. The mixture was stirred for 30 minutes, and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (765 mg, 2.14 mmol) was added to the resulting mixture. The reaction mixture was slowly warmed to 20° C. and stirred for 90 minutes. The reaction mixture was quenched with saturated aqueous citric acid, then diluted with HO and extracted twice with EtO. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-50% gradient of ethyl acetate in cyclohexane to give 608 mg (71%) of 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate. LC / MS(m / z, MH+):403

[0282] Intermediate 33: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka]

[0283] Step 1: 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate [ka] To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO2018091153) and pyridine (2.82 g, 2.89 mL, 35.36 mmol) in DCM (120 mL) cooled to -20 °C, trifluoromethanesulfonic anhydride (8.14 g, 6 mL, 28.28 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min. Water (50 mL) was added. The organic phase was separated and washed with a saturated aqueous solution of NaHCO (50 mL). The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 311

[0284] Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate [ka] To a solution of the compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate (7.4 g, 23.85 mmol) in DMF (30 mL) and MeOH (15 mL), DIEA (3.15 g, 4.16 mL, 23.85 mmol) and Pd(dppf)Cl complex with DCM (1.10 g, 1.43 mmol) were added, and the suspension was degassed and purged with CO three times. The mixture was stirred under CO (5 bar) at 75 °C for 2 h. The reaction was filtered through Celite. The filtrate was diluted with water (400 mL) and extracted three times with EtOAc (300 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 85 / 15 to 80 / 20 to give 4.6 g (88%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+):221

[0285] Step 3: Methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 33, Step 3, was prepared from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of Intermediate 5, Step 1, to afford 1.13 g (67%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 365

[0286] Step 4: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 33, step 4, was prepared from methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that for Intermediate 5, step 2, to afford 0.48 g (31%) of methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+):496

[0287] Intermediate 34: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate [ka]

[0288] Step 1: 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl trifluoromethanesulfonate [ka] Intermediate 34, step 1, was prepared from 8-hydroxy-3,4-dihydrobenzo[b]thiepin-5(2H)-one (prepared according to WO2018091153) following a procedure similar to that of Intermediate 33, step 1, to afford 6.3 g (48%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 327

[0289] Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate [ka] Intermediate 34, Step 2, was prepared from 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 33, Step 2, to afford 6.36 g (94%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-8-carboxylate. LC / MS(m / z, MH+): 237

[0290] Step 3: Methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate [ka] Intermediate 34, step 3, was prepared from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate following a procedure similar to that of Intermediate 5, step 1, to afford 0.9 g (60%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate. LC / MS(m / z, MH+): 381

[0291] Step 4: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate [ka] Intermediate 34, step 4, was prepared from methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate following a procedure similar to that of Intermediate 5, step 2, to afford 1.31 g (44%) of methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate. LC / MS(m / z, MH+):512

[0292] Intermediate 35: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate [ka]

[0293] Step 1: Methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate [ka] Intermediate 35, step 1, was prepared from methyl 1-oxotetralin-6-carboxylate following a procedure similar to that of Intermediate 5, step 1, to afford 459 mg (19%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 349

[0294] Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate [ka] Intermediate 35, step 2, was prepared from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate following a procedure similar to that of Intermediate 32, step 2, to afford 0.48 g (31%) of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z, MH+): 481

[0295] Intermediate 36: Methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 36 was prepared from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (Intermediate 7, Method 1, Step 5) and 1,1,1-trifluoro-3-iodo-propane following a procedure similar to that in Step 2 of Intermediate 9 to yield 332 mg (27%) of methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 520

[0296] Intermediate 37: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0297] Step 1: 1,1-dideuterio-3-fluoro-propan-1-ol [ka] To a solution of lithium aluminum deuteride (911 mg, 21.7 mmol) in EtO (50 mL) cooled to 0 °C was added dropwise a solution of 3-fluoropropanoic acid (1 g, 10.41 mmol) in EtO (30 mL). The reaction mixture was slowly warmed to 20 °C and stirred for 48 h. The reaction mixture was poured into a mixture of ice, HCl 2N, and EtO. The organics were dried over NaSO, filtered, and concentrated under reduced pressure to give 400 mg (38%) of 1,1-dideuterio-3-fluoro-propan-1-ol, which was used in the next step without further purification.

[0298] Step 2: (1,1-dideuterio-3-fluoro-propyl)trifluoromethanesulfonate [ka] Intermediate 37, step 2, was prepared from 1,1-dideuterio-3-fluoro-propan-1-ol following a procedure similar to that of Intermediate 9, step 1, to afford 600 mg (37%) of (1,1-dideuterio-3-fluoro-propyl)trifluoromethanesulfonate, which was used in the next step without further purification.

[0299] Step 3: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 37, step 3, was prepared from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (Intermediate 7, Method 1, step 5) and (1,1-dideuterio-3-fluoro-propyl)trifluoromethanesulfonate following a procedure similar to that for Intermediate 9, step 2, to afford 270 mg (67%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 487

[0300] Intermediate 38: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0301] Step 1: 1,1-dideuterio-3,3-difluoro-propan-1-ol [ka] Intermediate 38, step 1, was prepared from 3,3-difluoropropanoic acid following a procedure similar to that of Intermediate 37, step 1, to afford 810 mg (47%) of 1,1-dideuterio-3,3-difluoro-propan-1-ol, which was used in the next step without further purification.

[0302] Step 2: (1,1-dideuterio-3,3-difluoro-propyl)trifluoromethanesulfonate [ka] Intermediate 38, step 2, was prepared from 1,1-dideuterio-3,3-difluoro-propan-1-ol following a procedure similar to that of Intermediate 9, step 1, to afford 1.1 g (79%) of (1,1-dideuterio-3,3-difluoro-propyl)trifluoromethanesulfonate, which was used in the next step without further purification.

[0303] Step 3: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 38, step 3, was prepared from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (Intermediate 7, Method 1, step 5) and (1,1-dideuterio-3,3-difluoro-propyl)trifluoromethanesulfonate following a procedure similar to that for Intermediate 9, step 2, to afford 243 mg (51%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):505

[0304] Intermediate 39: Methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0305] 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) in small portions. The reaction mixture was stirred at room temperature overnight. Water (500 mL) and ether (1 L) were added. The organic phase was separated, washed twice with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+):297

[0306] 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 an Ar atmosphere, LiHMDS (1 M, 27 mL) was added. The mixture was stirred for 2 h and then treated with acetic anhydride (8.8 mL, 75 mmol) while warming to 0 °C. After pouring onto diisopropyl ether and water, the aqueous layer was separated and extracted with diisopropyl ether. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-50% gradient of ethyl acetate 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

[0307] Step 3: Methyl 9-acetoxy-8-(3,3-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 39, step 3, was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 2-(3,3-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following a procedure similar to that of step 1 of example 79 to yield 2.9 g (89%) of methyl 9-acetoxy-8-(3,3-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 369

[0308] Step 4: Methyl 9-acetoxy-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 39, step 4, was prepared from methyl 9-acetoxy-8-(3,3-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of step 2 of example 100 to afford 1.19 g (54%) of methyl 9-acetoxy-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 371

[0309] Step 5: Methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] To a solution of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (285 mg, 0.81 mmol) in methanol (8 mL) and DCM (4 mL) was added a 12 N solution of HCl (0.44 mL, 5.29 mmol). The resulting reaction mixture was heated to reflux for 7 hours and then stirred at room temperature overnight. After pouring onto diisopropyl ether and water, the aqueous layer was separated and extracted with diisopropyl ether. The combined organic layers were washed with water, a 5% aqueous solution of Na2CO3, and water, then dried over Na2SO4, filtered, and concentrated under reduced pressure to give 220 mg (88%) of methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, which was used in the next step without further purification. LC / MS(m / z, MH+): 309

[0310] Step 6: Methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 39, step 6, was prepared from methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 32, step 2, to afford 760 mg (77%) of methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 461

[0311] Intermediate 40: Methyl 8-(bicyclo[3.1.0]hexan-1-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0312] Step 1: Methyl 9-acetoxy-8-(bicyclo[3.1.0]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (0.4 g, 1.18 mmol), potassium bicyclo[3.1.0]hexan-1-yltrifluoroborate (266 mg, 1.41 mmol), CsCO (1.15 g, 3.54 mmol), and Pd(dppf)Cl complex with DCM (91 mg, 120 μmol) in toluene (6 mL) and water (2 mL) was heated to 90 °C for 6 h in a sealed tube. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After separation, the organic layer was washed with water (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-20% gradient of ethyl acetate in cyclohexane to give 0.45 g (40%) of methyl 9-acetoxy-8-(bicyclo[3.1.0]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 341

[0313] Step 2: Methyl 6-(bicyclo[3.1.0]hexan-1-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 40, step 2, was prepared from methyl 9-acetoxy-8-(bicyclo[3.1.0]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 39, step 5, to afford 0.3 g (100%) of methyl 6-(bicyclo[3.1.0]hexan-1-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 299

[0314] Step 3: Methyl 8-(bicyclo[3.1.0]hexan-1-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 40, step 3, was prepared from methyl 6-(bicyclo[3.1.0]hexan-1-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 32, step 2, to afford 247 mg (56%) of methyl 8-(bicyclo[3.1.0]hexan-1-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 431

[0315] Intermediate 41: Methyl 8-(bicyclo[3.2.1]octan-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0316] Step 1: Methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 41, step 1, was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 2-(3-bicyclo[3.2.1]oct-2-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane following a procedure similar to that of step 1 of example 79 to afford 1.07 g (99%) of methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 367

[0317] Step 2: Methyl 9-acetoxy-8-(bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 41, step 2, was prepared from methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of step 2 of example 100 to afford 0.58 g (54%) of methyl 9-acetoxy-8-(bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 369

[0318] Step 3: Methyl 6-(bicyclo[3.2.1]octan-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 41, step 3, was prepared from methyl 9-acetoxy-8-(bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 39, step 5, to afford 0.51 mg (99%) of methyl 6-(bicyclo[3.2.1]octan-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 327

[0319] Step 4: Methyl 8-(bicyclo[3.2.1]octan-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 41, step 4, was prepared from methyl 6-(bicyclo[3.2.1]octan-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 32, step 2, to afford 0.48 g (67%) of methyl 8-(bicyclo[3.2.1]octan-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 459

[0320] Intermediate 42: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka]

[0321] Step 1: 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate [ka] Intermediate 42, step 1, was prepared from 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ylpivalate (prepared according to WO2018091153) following a procedure similar to that of Intermediate 5, step 1, to afford 795 mg (30%) of 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ylpivalate. LC / MS(m / z, MH+): 405

[0322] Step 2: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 42, step 2, was prepared from 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate following a procedure similar to that of Intermediate 32, step 2, to afford 0.33 g (69%) of 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z, MH+):537

[0323] Intermediate 43: Tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate, Isomer 1 and Isomer 2 [ka]

[0324] 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) in small portions. The reaction mixture was stirred at room temperature overnight. Water (500 mL) and ether (1 L) were added. The organic phase was separated, washed twice with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+):297

[0325] Step 2: Methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate [ka] To a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (10 g, 33.66 mmol) in acetonitrile (100 mL) was added DABCO (7.4 mL, 67.32 mmol). The reaction mixture was heated to 55 °C under Ar for 2.5 h. Ether and 1 N HCl were added. The organic phase was separated, washed twice with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane / EtOAc 85 / 15 to give 1.88 g (26%) of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 217

[0326] Step 3: Methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, racemic mixture [ka] To a solution of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate (1.88 g, 8.6 mmol) in THF (30 mL) at 0 °C under Ar was added a 0.328 M cuprate solution (35 mL, 11.5 mmol) prepared by adding 15 mL of a 1.6 N solution of methyllithium in ether to a suspension of 2.5 g (13 mmol) of CuI in 25 mL of ether at 0 °C under Ar. The reaction mixture was stirred at 0 °C for 30 min. Ether (200 mL) and 1 N HCl (200 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ether. The combined organic phases were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane / EtOAc 95 / 5 to give 1.95 g (86%) of methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 233

[0327] Step 4: Methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 43, step 4, was prepared from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 32, step 2, to afford 2.5 g (86%) of methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 365

[0328] Step 5: Methyl 9-(4-aminophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 43, step 5, was prepared from methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 1 (Method 1) to afford 0.87 g (100%) of methyl 9-(4-aminophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+):308

[0329] Step 6: Methyl 9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 43, step 6, was prepared from methyl 9-(4-aminophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 2 (method 1) to afford 0.96 g (80%) of methyl 9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 419

[0330] Step 7: Methyl 8-bromo-9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 43, step 7, was prepared from methyl 9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 3 (method 1) to afford 1.09 g (95%) of methyl 8-bromo-9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 497

[0331] Step 8: Tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate, Isomer 1 and Isomer 2 [ka] Intermediate 43, step 8, was prepared from methyl 8-bromo-9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 4 (method 1) to afford 0.73 g (62%) of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate as a racemic mixture of Isomer 1 and Isomer 2. LC / MS(m / z, MH+):538 The racemic mixture of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol was separated by chiral chromatography (conditions: flash CHIRALPAK AD 20 μm (350 × 76.5 mm); heptane 7% / EtOH 30%) to give 0.188 g of isomer 1 and 0.201 g of isomer 2. [Example]

[0332] Method A: Example 1 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0333] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) (100 mg, 211 μmol), 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 1) (60 mg, 211 μmol), CsCO (178 mg, 534.5 μmol), and Pd(dppf)Cl complex with DCM (11 mg, 13 μmol) in dioxane (1 mL) and water (0.4 mL) was heated to reflux for 1 h. Water (2 mL) and DCM (5 mL) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure, and the residue was loaded onto an SCX column. The resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to afford 101 mg (86%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 550

[0334] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (101 mg, 183.6 μmol) in MeOH (0.50 mL) and THF (1 mL) was added a solution of NaOH 1N (0.55 mL) and the reaction mixture was heated to reflux for 1 h. After cooling, water (5 mL) and DCM (5 mL) were added and the pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by SFC (Flash DCPAK B 5 μm; 250 × 30 mm; supercritical CO 70% / MeOH 30% / TEA 0.1% at 120 mL / min) to give 47.5 mg (45%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0335] Method B: Example 79 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0336] Step 1: Methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-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 7) (100 mg, 206 μmol), (2-chloro-4-fluoro-phenyl)boronic acid (54 mg, 310 μmol), CsCO (141 mg, 433 μmol), and Pd(dppf)Cl complex with DCM (15 mg, 21 μmol) in dioxane (4 mL) and water (1 mL) was heated to reflux for 30 min. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure to give 65 mg (59%) of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):534

[0337] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] To a solution of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (65 mg, 121.7 μmol) in MeOH (5 mL) and water (1 mL), LiOH (15 mg, 608 μmol) was added and the reaction mixture was heated to 50° C. for 2 h. After cooling, water (50 mL), EtOAc (100 mL) and EtO (100 mL) were added and the pH was adjusted to 7 with HCl 0.1 N. After decantation, the organic phase was dried over MgSO, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 43 mg (68%) of 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0338] Method C: Example 8 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0339] Step 1: Methyl 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-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 8) (200 mg, 376 μmol), 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (137 mg, 752 μmol), CsCO (245 mg, 752 μmol), and Pd(dppf)Cl, complex with DCM (14 mg, 19 μmol) in dioxane (8 mL) and water (2 mL) was heated to 95 °C for 3 h. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a cyclohexane / EtOAc gradient (100 / 0 to 100 / 0, v / v) to give 55 mg (29%) of methyl 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):508

[0340] Step 2: 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 8 was prepared from methyl 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 79 to provide 16 mg (30%) of 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0341] Method D: Example 114 4-(2,4-Dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride [ka]

[0342] Step 1: Methyl 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] A mixture of methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate (Intermediate 30) (250 mg, 504 μmol), 1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]azetidine (Intermediate 2) (158 mg, 478 μmol), CsCO (447 mg, 1.37 mmol), and Pd(dppf)Cl, complex with DCM (33 mg, 41 μmol) in dioxane (2 mL) and water (0.8 mL) was heated to 85 °C for 2 h. After cooling to room temperature, DCM (4 mL) and water (2 mL) were added. After decantation on a hydrophobic column, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc to give 69 mg (26%) of methyl 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+):552

[0343] Step 2: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid [ka] Step 2 of Example 115 was prepared from methyl 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of Step 2 of Example 79 to provide 46 mg (65%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride.

[0344] Method E: Example 60 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0345] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To 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 7) (100 mg, 206 μmol), tri-o-tolylphosphine (10 mg, 33 μmol), and Pd(dba) (9.5 mg, 16.5 μmol) in DMF (4 mL) that had been degassed and purged with argon for 5 min, a 0.5 M solution of tetrahydropyran-4-ylzinc iodide (0.6 mL, 309.7 μmol) was added. After stirring at room temperature for 2 h, EtOAc (100 mL), EtO (100 mL), and water (150 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 cyclohexane / EtOEt gradient (100 / 0 to 00 / 100, v / v) to give 60 mg (59%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 490

[0346] Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 60 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 79 to provide 10 mg (17%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0347] Method F: Example 100 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0348] Step 1: Methyl 9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 100 was prepared from methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7 Step 5 (Method 2)) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane according to a procedure similar to that of Step 1 of Example 79 to afford 224 mg (62%) of methyl 9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 476

[0349] Step 2: Methyl 5-[4-[1-(3-fluoropropyl)azetidine-3-carbonyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] A mixture of methyl 9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (224 mg, 471 μmol), Pd / C 10% (90 mg, 85 μmol) in EtOH (30 mL) and EtOAc (15 mL) was hydrogenated at 50° C. and 25 bar of H 2 for 20 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a DCM / MeOH gradient (100 / 0 to 95 / 05, v / v) to give 150 mg (66%) of methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):478

[0350] Step 3: Methyl 5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Example 100, Step 3, was prepared from methyl 5-[4-[1-(3-fluoropropyl)azetidine-3-carbonyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of Intermediate 7, Step 6 (Method 2) to afford 75 mg (50%) of methyl 5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS (m / z, MH+): 480

[0351] Step 4: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 4 of Example 100 was prepared from methyl 5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of Step 7 (Method 2) of Intermediate 7 to afford 71 mg (66%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):462

[0352] Step 5: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 5 of Example 100 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in Step 2 of Example 79 to provide 44 mg (40%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0353] Method G: Example 102 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0354] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 102 was prepared from (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanone and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 1 of Example 1 to afford 270 mg (34%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):566

[0355] Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (430 mg, 759 μmol) in THF (20 mL) cooled to −20° C. was added 3 M methylmagnesium bromide in EtO (759 μL, 2.28 mmol). After stirring at −10° C. for 45 min, saturated aqueous NH4Cl (5 mL), EtOAc (50 mL), and water (20 mL) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure to give 442 mg (100%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):582

[0356] Step 3: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (50 mg, 85.83 μmol) in water (0.5 mL) and sulfuric acid (1 mL, 18.76 mmol) was stirred at room temperature for 2 hours. Ice and EtOAc were added, and the pH was adjusted to 9 by the addition of saturated aqueous solutions of NaHCO and NaCO. After decantation, the organic phase was dried over MgSO, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient (100 / 0 to 95 / 05, v / v) to give 24 mg (49%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):564

[0357] Step 4: 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 4 of Example 102 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in Step 2 of Example 79 to provide 6 mg (26%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0358] Method H: Example 159 8-(2,4-Dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0359] Step 1: Methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Example 159, Step 1, was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 5-bromo-2-iodopyridine following a procedure similar to that for Intermediate 7, Step 1 (Method 1) to afford 108 mg (10%) of methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):502

[0360] Step 2: Tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azetidine-1-carboxylate [ka] Step 2 of Example 159 was prepared from methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 1 (Method 2) of Intermediate 1 to afford 87 mg (68%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azetidine-1-carboxylate. LC / MS(m / z, MH+):590

[0361] Step 3: Methyl 9-(5-(azetidin-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid [ka] Step 3 of Example 159 was prepared from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azetidine-1-carboxylate following a procedure similar to that of Step 2 of Intermediate 1 to provide methyl 9-(5-(azetidin-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid, which was used without further purification. LC / MS(m / z, MH+): 491

[0362] Step 4: Methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 4 of Example 159 was prepared from methyl 9-(5-(azetidin-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid following a procedure similar to that of Step 5 (Method 2) of Intermediate 7 to afford 40 mg (49% over steps 3 and 4) of methyl 8-(2,4-dichlorophenyl)-9-(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+):551

[0363] Step 5: 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid [ka] Step 4 of Example 159 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 79 to afford 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid 34 mg (72%).

[0364] Method I: Example 158 8-(2,4-Dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0365] Step 1: Tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate [ka] Step 1 of Example 158 was prepared from 2-bromo-3-fluoro-5-iodo-pyridine following a procedure similar to that of Step 1 (Method 2) of Intermediate 1 to afford 587 mg (61%) of tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate. LC / MS(m / z, MH+): 343

[0366] Step 2: 9-(5-((1-(Tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 158 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 and tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate following a procedure similar to that in Step 1 of Example 1 (Method A) to afford 585 mg (81%) of 9-(5-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid. LC / MS(m / z, MH+):595

[0367] Step 3: Tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate [ka] A mixture of 9-(5-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (585 mg, 0.98 mmol), K2CO3 (271 mg, 1.96 mmol), and methyl iodide (209 mg, 1.47 mmol, 0.09 mL) in DMF (10 mL) was stirred at room temperature for 20 min. The reaction mixture was quenched by the addition of water (50 mL) and then extracted with a mixture of EtOAc (30 mL) and Et2O (70 mL). After decantation, the organic phase was washed twice with water (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc: 100 / 00 to 75 / 25 to afford 327 mg (55%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate. LC / MS(m / z, MH+):609

[0368] Step 4: methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid [ka] Example 158, Step 4, was prepared from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate following a procedure similar to that for Step 2 of Intermediate 1 to afford methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid 287 mg (98%). LC / MS(m / z, MH+):509

[0369] Step 5: Methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 5 of Example 158 was prepared from methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid following a procedure similar to that of Step 5 (Method 2) of Intermediate 7 to afford 90 mg (41%) of methyl 8-(2,4-dichlorophenyl)-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+):569

[0370] Step 6: 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 6 of Example 158 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in Step 2 of Example 79 to provide 7 mg (14%) of 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0371] Method J: Example 166 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture [ka]

[0372] Step 1: 9-(4-((1-(Tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture [ka] Step 1 of Example 166 was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzylidene)azetidine-1-carboxylate (Intermediate 43) according to a procedure similar to that of Step 1 of Example 79 to afford 217 mg (88%) of 9-(4-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a racemic mixture. LC / MS(m / z, MH+):590

[0373] Step 2: Methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (racemic mixture) [ka] Example 166, Step 2, was prepared from 9-(4-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid following a procedure similar to that of Intermediate 1, Step 2, to afford methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid 252 mg (100%) as a racemic mixture. LC / MS(m / z, MH+):504

[0374] Step 3: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Step 3 of Example 166 was prepared from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid following a procedure similar to that of Step 6 (Method 1) of Intermediate 7 to afford 70 mg (30%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+):564

[0375] Step 4: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture [ka] Step 4 of Example 166 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in Step 2 of Example 79 to afford 38 mg (55%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a racemic mixture.

[0376] Method K: Example 186 8-(3,3-Dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture [ka]

[0377] Step 1: Tert-butyl 3-((5-fluoro-6-(tributylstannyl)pyridin-3-yl)methylene)azetidine-1-carboxylate [ka] A mixture of tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate (4 g, 11.66 mmol), Pd(PPh)Cl (0.82 g, 1.17 mmol), and 1,1,1,2,2,2-hexabutyldistannane (17.64 mL, 34.97 mmol) in toluene (50 mL) was degassed and purged with Ar for 5 min, then heated to 110 °C in a sealed tube for 17 h. After cooling to room temperature, the reaction mixture was filtered and purified by flash chromatography eluting with a cyclohexane / EtOAc gradient: 100 / 00 to 50 / 50 to give tert-butyl 3-((5-fluoro-6-(tributylstannyl)pyridin-3-yl)methylene)azetidine-1-carboxylate 2 g (31%). LC / MS(m / z, MH+): 555

[0378] Step 2: Tert-butyl 3-((6-(8-(3,3-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate, racemic mixture [ka] A mixture of methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 39) (0.46 g, 1 mmol), Pd(PPh3)4 (231 mg, 200 μmol), and tert-butyl 3-((5-fluoro-6-(tributylstannyl)pyridin-3-yl)methylene)azetidine-1-carboxylate (1.11 g, 2 mmol) in toluene (20 mL) was degassed and purged with Ar for 5 min, then heated to 80 °C in a sealed tube for 2.5 h. After cooling to room temperature, the reaction mixture was filtered and transferred to a new tube. Pd(PPh3)4 (50 mg, 47 μmol) was then added, and the mixture was degassed. The tube was sealed and heated to 80 °C for 3 h. After cooling to room temperature, EtO (50 mL), EtOAc (50 mL), and 10% aqueous KF (50 mL) were added, and the mixture was filtered. After decantation, the organic phase was washed, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a cyclohexane / EtOAc gradient: 100 / 00 to 00 / 100 to give 67 mg (10%) of tert-butyl 3-((6-(8-(3,3-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 575

[0379] Step 3: Methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (racemic mixture) [ka] Example 186, Step 3, was prepared from 9-(4-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid following a procedure similar to that in Intermediate 1, Step 2, to afford methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid as a racemic mixture. LC / MS(m / z, MH+): 475

[0380] Step 4: Methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Step 4 of Example 186 was prepared from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid following a procedure similar to that of Step 6 (Method 1) of Intermediate 7 to afford 35 mg (33%) of methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 535

[0381] Step 5: 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture [ka] Step 5 of Example 186 was prepared from methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 79 to afford 25 mg (73%) of 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a racemic mixture.

[0382] The compounds according to Table 1a above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0383] Test: Estrogen receptor degrading activity The test measures the in vitro degradation activity of the compounds of Table 1a.

[0384] Degradation activity was measured using the breast cancer cell ERα in cell western assay described below.

[0385] MCF7 cells (ATCC) were seeded at 10,000 cells per well in 30 μL of red phenol-free MEMα medium (Invitrogen) containing 5% charcoal-dextran-striped FBS in a 384-well microplate (coated with collagen). The following day, nine serial 1:5 dilutions of each compound were added to the cells in 2.5 μL at final concentrations of 0.3–0.0000018 μM (Table 2) or 0.1 μM for fulvestrant (used as a positive control). Four hours after compound addition, cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton) for 10 minutes at room temperature and then washed twice with PBS. Next, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate at room temperature for 30 minutes. The LI-COR blocking buffer was removed, and the cells were incubated overnight in a cold room 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 served as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa488 (1:1000) and Syto-64 a DNA dye (2 μM final concentration). The cells were then washed three times with PBS and scanned using an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0386] The degradation activity of the estrogen receptor in this test was measured by the 50 ) (nM) is obtained by the concentration that decomposes 50%.

[0387] The % reduction in ERα levels was determined as follows: % inhibition = 100 * (1 - (sample - fulvestrant:DMSO - fulvestrant)).

[0388] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1a tested at 0.3 μM, demonstrating that the compounds have significant degrading activity against the estrogen receptor.

[0389] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0390] Therefore, it is clear that the test compound has an IC50 of less than 1 μM and a degradation level of more than 50% for the estrogen receptor. Therefore, the compound of formula (I) can be used to manufacture a pharmaceutical, particularly a pharmaceutical that is an estrogen receptor degrading agent.

[0391] Accordingly, also provided herein are pharmaceutical preparations comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0392] Also provided herein is a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0393] Also provided herein are compounds of formula (I), as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, particularly as inhibitors and degraders of estrogen receptors.

[0394] Also provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above for use in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0395] A particular embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of cancer.

[0396] In one embodiment, the cancer is a hormone-dependent cancer.

[0397] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0398] 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.

[0399] In another embodiment, the metastasis is a brain metastasis.

[0400] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0401] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0402] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR or PI3K inhibitors.

[0403] According to another aspect, there is provided herein a method of treating the above-noted pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.

[0404] Also provided herein is the use of a compound of formula (I), or a pharmaceutically 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.

[0405] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient, which contain an effective dosage of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0406] Said additives are selected according to the pharmaceutical form and the desired method of administration from the customary additives known to those skilled in the art.

[0407] 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 its base, acid, zwitterion or salt, can be administered in unit dosage form and in admixture with conventional pharmaceutical excipients to animals and humans for the treatment of the above disorders or diseases.

[0408] Suitable unit dosage forms include tablets, soft or hard gel capsules, powders, granules, and oral forms such as oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the compounds of formula (I) can be used in the form of creams, gels, ointments or lotions.

[0409] As an example, a unit dosage form of a compound of formula (I) in a tablet may comprise the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Corn starch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg may include:

[0410] There may be special cases in which higher or lower doses are appropriate. According to usual practice, the dose that is appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3' and R3'' independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R4' independently represent a hydrogen atom or a fluorine atom; R5 is a hydrogen atom, a fluorine atom or (C 1 ~C 3 ) represents an alkyl group; - R6 is a phenyl group (the phenyl group is optionally substituted with a halogen atom; a cyano group or an —OH group (C 1 ~C 6 ) alkyl group; (C 1 ~C 6 ) fluoroalkyl group; (C 3 ~C 6 ) cycloalkyl group; (C 1 ~C 6 ) an alkoxy group; (C 1 ~C 6 ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C 1 ~C 4 ) alkylthio group; (C 1 ~C 4 ) a fluoroalkylthio group; (C 1 ~C 4 ) optionally substituted with 1 to 3 substituents independently selected from alkylsulfonyl groups and —OH groups; ・ (C 3 ~C 6 ) a fused phenyl group selected from phenyl groups fused with cycloalkyl (see (C) 3 ~C 6 ) cycloalkyl optionally contains unsaturation, and the fused phenyl group is (C 1 ~C 3 ) an alkyl group, a hydroxy group, a halogen atom, (C 1 ~C 6 ) fluoroalkyl group and (C 1 ~C 3 ) optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; containing 5 to 12 carbon atoms and optionally containing 1 or 2 unsaturations; 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 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, wherein the heteroaryl groups are not limited to halogen atoms, (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) fluoroalkyl group, (C 1 ~C 6 ) an alkoxy group, (C 1 ~C 6 ) a fluoroalkoxy group, a cyano group, a carbamoyl group, and an —OH group; optionally substituted with 1 to 3 independently selected substituents; cycloalkyl groups containing 3 to 7 carbon atoms, said cycloalkyl groups being saturated or partially saturated; ○ Fluorine atom, —OH group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 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 (as defined above in (C 3 ~C 6 ) cycloalkyl or phenyl groups may contain one or two halogen atoms or (C 1 ~C 3 ) optionally substituted with alkyl groups optionally substituted with 1 to 4 substituents independently selected from: Fluorine atom, —OH group, (C 1 ~C 4 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups (C 3 ~C 6 ) cycloalkyl (C 1 ~C 3 ) alkyl group; a 3- to 8-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, said heterocycloalkyl group being saturated or partially saturated and including fluorine atoms, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) a fluoroalkoxy group, an oxo group, (C 1 ~C 3 ) optionally substituted with 1 to 3 substituents independently selected from alkoxy groups and —OH groups; ・(C 1 ~C 6 ) alkyl group (the alkyl group is a fluorine atom, (C 1 ~C 3 ) an alkoxy group, (C 1 ~C 3 ) optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and —OH groups; and Phenyl (C 1 ~C 2 ) alkyl group (the phenyl group is a halogen atom; (C 1 ~C 3 ) alkyl group; (C 1 ~C 3 ) fluoroalkyl group; (C 1 ~C 3 ) an alkoxy group; (C 1 ~C 3 ) 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″═, where R″ is (C 1 ~C 3 ) an alkyl group, a halogen atom, a cyano group, or (C 1 ~C 3 ) represents a fluoroalkyl group; - R7 is (C 1 ~C 3 ) an alkyl group, a halogen atom, a cyano group, or (C 1 ~C 3 ) independently represent a fluoroalkyl group; R8 represents a hydrogen atom or a fluorine atom; R9 is a hydrogen atom, (C 1 ~C 3 ) represents an alkyl group or cyclopropyl; n is 0, 1 or 2; - m is 0 or 1, or a pharmaceutically acceptable salt thereof.

2. 2. The compound of formula (I) according to claim 1, wherein R1 and R2 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.

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

4. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3' and R3'' represent a hydrogen atom.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that R4 and R4' represent a hydrogen atom.

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

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

8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a phenyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from chlorine atoms, fluorine atoms, methyl groups, ethyl groups, trifluoromethyl groups, cyclopropyl groups, methoxy groups and cyano groups.

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

10. R6 is a fluorine atom, an —OH group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) an alkoxy group, (C 1 ~C 3 8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they represent a bicyclic group selected from bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, spiro[2.3]hexanyl and bicyclo[3.2.1]octan-3-yl, optionally substituted with one to four substituents independently selected from fluoroalkoxy and oxo groups; advantageously, said bicyclic group is unsubstituted.

11. R6 represents a pyridyl group, and the pyridyl group is 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) fluoroalkyl group and (C 1 ~C 6 8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they are optionally substituted by 1 to 3 substituents independently selected from alkoxy groups, more particularly fluorine atoms, chlorine atoms, methyl groups, trifluoromethyl groups and methoxy groups.

12. R6 represents a cycloalkyl selected from a cyclohexyl or cyclopropyl group, said cycloalkyl being ○ Fluorine atom, —OH group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) Fluoroalkyl Group, (C 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 (as defined above in (C 3 ~C 6 ) cycloalkyl or phenyl groups contain one or two halogen atoms or (C 1 ~C 3 ) optionally substituted with alkyl groups optionally substituted with 1 to 4 substituents independently selected from The cycloalkyl is Methyl, phenyl and a cyclohexyl group substituted by two halogen atoms, in particular by fluorine atoms Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they are advantageously substituted with 1 to 2 substituents independently selected from:

13. R6 is a fluorine atom, an OH group, (C 1 ~C 4 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) one independently selected from a fluoroalkoxy group and an oxo group; Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they represent cyclobutylmethyl, optionally substituted in the cycloalkyl group with up to four substituents, said cyclobutylmethyl being advantageously unsubstituted.

14. R6 represents a tetrahydropyranyl group, and the tetrahydropyranyl group is 1 ~C 3 ) an alkoxy group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they are optionally substituted by 1 to 3 substituents independently selected from fluoroalkoxy groups and -OH groups, and the tetrahydropyranyl group is advantageously unsubstituted.

15. R6 represents an isobutyl group, and the isobutyl group is 1 ~C 3 ) an alkoxy group, (C 1 ~C 3 8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that:

16. R6 is in particular a phenyl (C 1 ~C 2 8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they represent an alkyl group.

17. Compounds of formula (I) according to any one of claims 1 to 16, characterized in that R7 independently represents a methyl group, a cyano group, a trifluoromethyl group or a fluorine atom, and n is 0, 1 or 2.

18. Compounds of formula (I) according to any one of claims 1 to 17, characterized in that Y represents -CH=, -N= or -CR"=, and R" represents a fluorine atom, a cyano group or a trifluoromethyl group.

19. A compound of formula (I) according to any one of claims 1 to 18, wherein m is 1.

20. The compound is The following compound: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 8-(3-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro rho-5H-benzo[7]annulene-3-carboxylic acid, (2) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) 8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) 8-(4-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) 8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) 8-(2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) 8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 8-(2,4-difluorophenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (15) 8-(2,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (17) 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl (4-methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) 8-(2,6-difluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(5-fluoro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(4-cyclopropyl-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) 9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) 8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) 8-(4-cyclopropyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) 8-(2-cyclopropyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) 8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (42) 9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (44) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) 9-(3-cyano-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) 8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) 8-(2-fluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (49) 8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(2,6-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51) - 9-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro- Doro-5H-benzo[7]annulene-3-carboxylic acid, (52) 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (54) 8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) 8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) 8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) 8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) 9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (60) 8-(4-fluoro-2-methylphenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (61) 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (62) 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (64) 9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (65) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (66) 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) - 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) (2-phenyl-4-methylphenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (69) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (70) 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (71) 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) 8-(2,4-dichlorophenyl)-9-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (74) 8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (75) 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (76) 8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (77) 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (78) 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (79) 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (80) 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (81) 8-(4-chloro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (82) 8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (83) 8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (84) 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (85) 8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (86) 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (87) 8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (88) 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (89) 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (90) 8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (91) 8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (92) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (93) 8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (94) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (95) 8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (96) 8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (97) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (98) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (99) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (100) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (101) - 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo [7] Annulene-3-carboxylic acid, (102) 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (103) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (104) 8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (105) 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, (106) 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (107) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (108) 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (109) 8-(3-methyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (110) 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (111) 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (112) 8-(2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (113) 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid hydrochloride (114) 4-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]phenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic acid; hydrochloride salt (115) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (116) 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (117) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (118) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl) (phenyl)-8-(5-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (119) 3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)-1-(3-fluoropropyl)azetidine (120) 8-(2-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (121) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (122) 8-(2-chloro-5-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (123) 8-(2,4-difluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (124) 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (125) 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (126) 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (127) 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (128) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (129) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (130) 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (131) 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (132) 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (133) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (134) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (135) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (136) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (137) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (138) 9-(2-cyano-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (139) 8-(2-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (140) 8-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (141) Sodium 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (142) 8-(3-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (143) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (144) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (145) 8-(3,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (146) 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (147) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (148) 8-(4-ethoxy-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (149) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (150) 8-(2,5-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (151) - 9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7 -Dihydro-5H-benzo[7]annulene-3-carboxylic acid (152) 8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (153) 8-(4-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (154) 8-(3-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (155) 8-(5-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (156) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (157) 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (158) 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid, (159) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (160) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (161) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (162) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (163) - 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (164) - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (165) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (166) 8-benzyl-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (167) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-phenethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (168) - 8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azetidin (di-(3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (169) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (170) 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (171) 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (172) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-((trans)-2-phenylcyclopropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (173) 8-((1R,6S,7r)-bicyclo[4.1.0]heptan-7-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (174) - 8-(bicyclo[3.1.0]hexan-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (175) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (176) - 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5,6,7,8-tetrahydronaphthalen-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (177), 8-(bicyclo[3.2.1]octan-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (178) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (179) 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (180) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (181) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (182) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (183) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (184) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (185) 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (186) 8-(trans-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (187) 9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (188) 20. A compound of formula (I) according to any one of claims 1 to 19, characterized in that it is selected from: or a pharmaceutically acceptable salt thereof, in particular the hydrochloride thereof.

21. A process for preparing a compound of formula (I) according to any one of claims 1 to 20, comprising the step of: 【Chemistry 2】 wherein R1, R2, R3′, R3″, R4, R4′, R5, R6, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 19 and R3a is a carboxylic acid ester or a protected OH with O-pivaloyl, is converted to a compound of formula (I) in the presence of a hydroxide ion source dissolved in methanol, said step being optionally preceded by a step to obtain compound 1K, and a compound of formula 1T 【Transformation 3】 wherein R1, R2, R3′, R3″, R4, R4′, R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 19, and R3a is as defined above. is the boron reagent R6B(OR') 2 or R6BF 3 K [in the formula, -B(OR') 2 is a boronic acid or pinacolatoate ester, and R6 is as defined in claim 1 or any one of claims 8 to 16,

22. A process for preparing a compound of formula (I) according to any one of claims 1 to 20, comprising the step of: 【Chemistry 4】 wherein R1, R2, R3′, R3″, R4, R4′, R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 19, and R3a is as defined in any one of claims 1 to 21, is a boron reagent R6B(OR′) 2 or R6BF 3 K [in the formula, -B(OR') 2 is a boronic acid or pinacolato ester, and R6 is as defined in claim 1 or any one of claims 8 to 16, optionally preceded by a step to obtain compound 1Ta, 【Transformation 5】 wherein R1, R2, R3′, R3″, R4, R4′, R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 19, and R3a is as defined above, in the presence of a hydroxide ion source dissolved in methanol, is converted to compound 1Ta.

23. A compound selected from formula 1T, 1K, and 1Ta, or any of its pharmaceutically acceptable salts. 【Transformation 6】 wherein R1, R2, R3, R3′, R3″, R4, R4′ R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 19, and R3a is a carboxylic acid ester or a protected OH bearing O-pivaloyl.

24. or any of the pharmaceutically acceptable salts thereof: 【Transformation 7】 wherein R1, R2, R4, R4', R5, R7, R8, Y and n are as defined in any one of claims 1 to 19.

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

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

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

28. 21. A compound of formula (I) as defined in any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

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

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