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

Abstract

Formula (I): [Formula 1] TIFF2023546899000547.tif72112 [wherein R1 and R2 represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a -COOH group or a -OH group; R3' and R3" represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom or a cyano group; R4 and R5 represent a hydrogen atom, a halogen atom, a -NH2 group, a (C1-C3) alkyl group, a (C1-C3) alkoxy group or a -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form a =NOCH3 group or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group, a -OH group or a fluorine atom; R6 represents a phenyl group, a fused phenyl group, a bicyclic group containing 5 to 12 carbon atoms, a bicyclic group containing 2 to 9 carbon atoms and having 1 to 3 carbon atoms. represents a heteroaryl group containing a heteroatom, a cycloalkyl group containing 3 to 7 carbon atoms, a (C3-C6)cycloalkyl(C1-C3)alkyl group, a 3 to 8-membered heterocycloalkyl group, a (C1-C6)alkyl group, or a phenyl(C1-C2)alkyl group; X represents -CH2-, -O-, or -S-; Y represents -CH=, -N=, or -CR"=; R8 represents a (C1-C3)alkyl group, a halogen atom, a cyano group, or a (C1-C3)fluoroalkyl group; R9 represents a hydrogen atom or a fluorine atom; R10 and R10' represent a hydrogen atom or a fluorine atom; R11 represents a hydrogen atom, a (C1-C3)alkyl group, or a cyclopropyl group; n is 0, 1, or 2, and m is 0 or 1. Further disclosed are compounds of formula (I) as 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 proliferation, and 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 the incidence of breast cancer, approximately one-third of ERα-positive patients develop new resistance or resistance to these existing therapies over time. Several mechanisms have been described to explain this resistance to 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 effectiveness.

[0008] Documents WO2017 / 140669 and WO2018 / 091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs.

[0009] 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. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO2017 / 140669 [Patent Document 2] WO2018 / 091153 Summary of the Invention [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 R5 independently represent a hydrogen atom, a fluorine atom, an -NH2 group, a (C1-C3) alkyl group such as a methyl group, a (C1-C3) alkoxy group such as a methoxy group or an ethoxy group, or an -OH group; or R4 and R5 together form an oxo group, or R4 and R5 together form, together with the carbon atom to which they are attached, a =NOCH3 group, or a (C3-C5) cycloalkyl group; R7 represents a hydrogen atom, a methyl group, an —OH group or a fluorine atom; Alternatively, R4 and R7 together with the bond attached thereto form a cyclopropyl group, which together with the adjacent azetidine group gives an azaspiro[2.3]hexane; - 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 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 (the (C3-C6)cycloalkyl ring optionally contains unsaturation and the fused phenyl is optionally substituted with 1 to 3 substituents independently selected from (C1-C3)alkyl groups, hydroxy groups, halogen atoms, (C1-C6)fluoroalkyl groups and (C1-C3)alkoxy groups); bicyclic groups containing 5 to 12 carbon atoms and optionally containing one or two unsaturations; optionally substituted with one to four substituents independently selected from fluorine atoms, —OH groups, (C1-C3)-alkyl groups, (C1-C3)fluoroalkyl groups, (C1-C3)alkoxy groups, (C1-C3)fluoroalkoxy groups and oxo groups; heteroaryl groups, such as pyridyl, pyridone or pyrrolyl groups, containing 2 to 9 carbon atoms, 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, said heteroaryl groups being 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 groups, and phenyl groups, wherein the (C3-C6)cycloalkyl or phenyl groups are optionally substituted with one or two halogen atoms or (C1-C3)alkyl groups(s). 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; a 3-8 membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group or a tetrahydrofuranyl group, which heterocycloalkyl group is saturated or partially saturated and optionally substituted with one to three substituents independently selected from a fluorine atom, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) fluoroalkoxy group, an oxo group, a (C1-C3) alkoxy group and an —OH group; a (C1-C6) alkyl group, such as an isobutyl group or an ethylbutyl group, wherein the alkyl group is 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; R8 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R9 represents a hydrogen atom or a fluorine atom; - R10 and R10' independently represent a hydrogen atom or a fluorine atom; R11 represents a hydrogen atom, a (C1-C3) alkyl group or a cyclopropyl group; - n is 0, 1 or 2; - m is 0 or 1, 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, cycloheptyl, cycloheptenyl, or cyclohexenyl; - cycloalkylalkyl group: an alkyl group substituted with a cyclic alkyl group as defined above, including but not limited to cyclobutylmethyl; - Heterocycloalkyl group: a saturated or partially unsaturated 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 tetrahydrofuranyl or tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above (wherein the alkyl group is substituted with at least one fluorine atom). In other words, at least one hydrogen atom of the alkyl group is replaced 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 called a perfluoroalkyl group. Examples include a trifluoromethyl group or a trifluoroethyl 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 groups: -S-alkyl groups, where 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 7 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. The heteroaryl group is advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, more particularly pyridine, pyridone and pyrrole; 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 11These 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 a 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, X represents -CH2-.

[0021] In another embodiment, in the compounds of formula (I) as defined above, R4 and R5, independently of one another, represent a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a -NH2 group or a -OH group; or R4 and R5 together form, with the carbon atom to which they are attached, an oxo group, a =NOCH3 group or a cyclopropyl group, or R4 and R7 together form, with the bond to which they are attached, a cyclopropyl group, in particular, R4 and R5 both represent a hydrogen atom or a fluorine atom, or one of R4 and R5 represents a hydrogen atom and the other represents a fluorine atom or a -OH group, or one of R4 and R5 represents a methyl group and the other represents a hydroxy group or a fluorine atom, more particularly, R4 and R5 both represent a hydrogen atom.

[0022] In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 represent a hydrogen atom, a -NH2 group, a methyl group, a methoxy group, an ethoxy group.

[0023] In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 represent a hydrogen atom.

[0024] In another embodiment, in the compounds of formula (I) as defined above, R7 represents a hydrogen atom, an -OH group, a methyl group or a fluorine atom, and more particularly a hydrogen atom.

[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, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, fluoromethyl, difluoromethyl, 2,2-difluoroethyl, methoxy, ethoxy, cyano, cyanomethyl, trifluoromethylsulfonyl, methylsulfanyl, difluoromethylsulfanyl, methylsulfonyl and difluoromethoxy.

[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 and an indanyl group, said group optionally substituted with one or two fluorine atoms.

[0027] In another embodiment, in the compounds of formula (I) as defined above, R6 is - pyridyl groups (the pyridyl 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, carbamoyl and -OH groups, more particularly selected from methyl groups, methoxy groups, fluorine atoms, chlorine atoms, trifluoromethyl groups, difluoromethyl groups, methoxy groups and carbamoyl groups), - pyridone optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C3) alkyl groups, (C1-C3) fluoroalkyl groups, (C1-C3) alkoxy groups and (C1-C3) fluoroalkoxy groups, more particularly selected from methyl groups, methoxy groups, fluorine atoms, chlorine atoms, trifluoromethyl groups and difluoromethyl groups; or - a pyrrole group optionally substituted with one or two substituents selected from (C1-C6) alkyl groups, such as methyl groups; Represents.

[0028] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cycloalkyl group selected from cyclohexyl, cyclopentyl, cycloheptyl, cycloheptenyl and cyclohexenyl, said cycloalkyl group being ○ 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. and optionally substituted with 1 to 4 substituents independently selected from The cycloalkyl is Fluorine atoms, methyl groups, and Two halogen atoms, especially fluorine atoms a cyclohexyl group substituted by Advantageously, it is substituted with 1 to 2 substituents independently selected from:

[0029] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a heterocycloalkyl group, more particularly a tetrahydropyranyl group, said heterocycloalkyl group being optionally substituted with 1 to 3 substituents independently selected from a (C1-C6) alkyl group, a fluorine atom and an —OH group.

[0030] In another embodiment, in the compounds of formula (I) as defined above, R6 is - spiro[3.3]hept-1-ene or spiro[3.3]hept-2-ane groups, which are optionally substituted with one to four substituents independently selected from (C1-C3) alkyl groups, fluorine atoms, (C1-C3) alkoxy groups, (C1-C3) fluoroalkoxy groups and -OH groups, in particular optionally substituted with one or two fluorine atoms, a bicyclic group selected from a bicyclo[2.2.1]heptan-2-yl or bicyclo[3.2.1]octan-3-yl group, which is optionally substituted with 1 to 4 substituents independently selected from a (C1-C3) alkyl group, a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and an —OH group; Represents.

[0031] In another embodiment, in the compound of formula (I) as defined above, R6 represents a (C1-C6) alkyl group selected from ethyl, isobutyl and ethylbutyl, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from fluorine atoms, (C1-C3) alkoxy groups, (C1-C3) fluoroalkoxy groups and -OH groups, in particular optionally substituted with 1 or 3 fluorine atoms.

[0032] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cis-1,3a,4,5,6,6a-hexahydropentalenyl group.

[0033] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a cyclobutylmethyl group.

[0034] 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.

[0035] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3" represent a hydrogen atom.

[0036] In another embodiment, in the compounds of formula (I) as defined above, R 8 independently represents a methyl group or a fluorine atom; and n is 0, 1 or 2.

[0037] In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH=, -C(CH3)=, -CF= or -N=, in particular -CH= or -N=.

[0038] In another embodiment, in the compounds of formula (I) as defined above, R9 represents a hydrogen atom.

[0039] In another embodiment, in the compounds of formula (I) as defined above, R10 and R10' represent a hydrogen atom.

[0040] In another embodiment, in the compounds of formula (I) as defined above, R11 represents a hydrogen atom.

[0041] In another embodiment, in the compounds of formula (I) as defined above, m is 1.

[0042] In another embodiment, in the compound of formula (I), R3 is a COOH group and R6 is a phenyl group containing two or three substitutions independently selected from chlorine atoms, fluorine atoms, trifluoromethyl groups, and methyl groups, wherein at least one of the substitutions contains a halogen atom. In such embodiments, R3' and R3" are, in particular, hydrogen atoms. In further such embodiments, R1, R2, R4; R5, R7, R9, R10, R10', and R11 are hydrogen atoms. In such embodiments, Y is a -CH= group and n is equal to 0. In further such embodiments, X is a -CH2- group. In further such embodiments, m is 1.

[0043] In addition to the above embodiments, further embodiments are provided herein.

[0044] 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 - represents 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.

[0045] The compounds of formula (I') may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers.

[0046] Compounds of formula (I') may likewise exist in tautomeric forms.

[0047] 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.

[0048] 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.

[0049] Among the suitable salts of the compound of formula (I'), mention may be made especially of the hydrochloride salt.

[0050] In one embodiment, in the compound of formula (I') as defined above, [ka] represents a single bond.

[0051] In another embodiment, in the compounds of formula (I') as defined above, R b and R2 b is a hydrogen atom.

[0052] In another embodiment, in the compounds of formula (I) as defined above, R b is -COOH.

[0053] In another embodiment, in the compounds of formula (I') as defined above, X b represents -CH2-.

[0054] In another embodiment, in the compounds of formula (I') as defined above, R4 b and R5 bindependently 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.

[0055] 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.

[0056] In another embodiment, in the compounds of formula (I') as defined above, R6 b represents 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.

[0057] 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.

[0058] In another embodiment, in the compounds of formula (I') as defined above, R6 brepresents 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] In another embodiment, in the compounds of formula (I') as defined above, Y brepresents -CH-, -C(CH3)-, -CF- or -N-, in particular -CH- or -N-.

[0064] Among the compounds of formula (I) described herein, particularly the following compounds or pharmaceutically acceptable salts thereof, in particular the hydrochloride salts thereof: - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - 8-cyclopentyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - 8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - 8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl) Azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) - 8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - 8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) - 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-((1s,4s)-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-((1r,4r)-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) - 8-(2-fluoro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) - 8-(2,3-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) - 8-(4-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxypyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) - 8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) - 8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) - 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) - 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) - 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) - 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) - 8-(2-fluoro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(2-chloro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) 8-(2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) - 8-(4-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) - 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) - 8-(2,4-dichlorophenyl)-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) and (42) 8-(2,4-dichlorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) and (44) - 8-(3,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7] Annulene-3-carboxylic acid, (45) 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) - 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) 4-(2-chlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid, (49) - 8-(6,6-difluorospiro[3.3]hept-1-en-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(6,6-difluorospiro[3.3]heptan-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51), and 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylic acid, (52), - 8-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (53), - 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (54), - 8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (55), - 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (56), - 8-(2-(difluoromethyl)-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (57), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (58), - 8-(2-chloro-4-fluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (59), - 8-(3-chloro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (60), - 8-(3,4-bis(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (61), - 8-(4-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3 -fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (62), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (63), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(trans-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (64), - 8-(3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (65), - 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (66), - 8-(3-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (67), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (68), - 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (69), - 8-(5-fluoro-2-methoxypyridin-4-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (70), - 8-(3-fluoro-2-methoxypyridin-4-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (71), - 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (72), - 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (73), - 8-(4-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (74), - 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (75), - 8-(4-chloro-2-(difluoromethyl)phenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (76), - 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (77), - 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (78), - 8-(4-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (79), - 8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (80), - 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (81), - 8-(5-chloro-3-(difluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (82), - 8-(3-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (83), - 8-(3-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (84), - 8-(3,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (85), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (86), - 8-(2-chloro-3-fluorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (87), - 8-(3-chloro-4-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (88), - 8-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (89), - 8-(3-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (90), - 8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (91), - 8-(2,4-dichlorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (92), - 8-(6-(difluoromethyl)-2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (93), - 8-(3-chlorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (94), - 8-(6-(difluoromethyl)-4-methylpyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7- Dihydro-5H-benzo[7]annulene-3-carboxylic acid (95), - 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 (96), - 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 2 (97), - 8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (98), - 8-(4-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (99), - 8-(2-cyano-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (100), - 8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (101), - 8-(3-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (102), - 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (103), - 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (104), - 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (105), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (106), - 8-(2-chloro-4-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (107), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(trans-3-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (108), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-3-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (109), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (110), - 8-(4-chloro-2-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (111), - 8-(4-chloro-2-methylphenyl)-9-(4-(fluoro(1-(3-fluoro)phenyl)-2-methylphenyl)-4-(fluorophenyl)-1-(3-fluorophenyl)-2-methylphenyl (Oropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (112), - 8-(4-ethyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (113), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-((trifluoromethyl)sulfonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (114), - 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (115), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-mesityl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (116), - 8-(4-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (117), - 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (118), - 8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (119), - 8-(2-fluoro-4-(methylthio)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (120), - 8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (121), - 8-(2,4-dimethylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (122), - 8-(2-chloro-3-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (123), - 8-(2-chloro-4-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (124), - 8-(2-chloro-4-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (125), - 8-(2-chloro-3-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (126), - 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (127), - 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (128), - 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (129), - 8-(2-fluoro-4-(methylsulfonyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (130), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1-methyl-1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (131), - 8-(2,6-dimethylpyridin-3-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (132), - 8-(4-chloro-2-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (133), - 8-(2,5-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (134), 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (135), - 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (136), - 8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (137), - 8-(4-((difluoromethyl)thio)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (138), - 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (139), - 8-(4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (140), - 8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (141), - 8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (142), - 8-(2,6-dimethylpyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (143), - 8-(4-chloro-2-(cyanomethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (144), - 8-(2-chloro-4-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylic acid hydrochloride (145), - 8-(2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (146), - 8-(3-cyanophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (147), - 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (148), - 8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (149), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (150), - 8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (151), - 8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (152), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (153), - 8-(4-chloro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (154), - 8-(2-cyano-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (155), - 8-(5-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (156), - 8-(2-cyano-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (157), - 8-(2-cyano-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (158), - 8-(4,6-bis(trifluoromethyl)pyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (159), - 8-(2-chloro-4-fluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (160), - 8-(2,3-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (161), - 8-(cyclohept-1-en-1-yl)-9-(4-((1-(3-fluoropropanediol) (hydroxyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (162), - 8-cycloheptyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (163), - 8-(2-(difluoromethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (164), - 8-(3-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (165), - 8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (166), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (167), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (168), - 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (169), - 8-(4-chloro-2-cyanophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (170), - 8-(4-chloro-2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (171), - 8-(3-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (172), - 8-(2-chloro-3-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (173), - 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (174), - 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 (175), - 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 2 (176), - 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (177), - 8-(4-chloro-2-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (178), - 8-(2-chloro-4-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (179), - 8-(2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (180), - 8-(2,4-dimethylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (181), - 8-(2-chloro-3-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (182), - 8-(4-chloro-2-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (183), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-3-methylazetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (184), - 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (185), - 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (186), - 8-(2-chloro-4-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (187), - 8-(2-chloro-3-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (188), - 8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (189), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (190), - 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (191), - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (192), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methylpyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (193), - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (194), - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[ 7] annulene-3-carboxylic acid isomer 2 (195), -(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid (196), -(Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid (197), - 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (198), - 8-(4-chloro-2-methylphenyl)-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (199), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (200), - 8-(4-ethoxy-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (201), - 8-(5-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (202), - 8-(5-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (203), - 8-(2-fluoro-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (204), - 8-(2-chlorophenyl)-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (205), - 8-(2,4-dichlorophenyl)-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (206), - 8-(3,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (207), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (208), - 8-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (209), - 8-(2,3-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (210), - 8-(2,4-dichloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (211), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropanediol) (phenyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (212), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (213), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (214), - 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)cyclopropyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (215), - 8-(2-chloro-4-fluorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (216), - 8-(2-chloro-4-methylphenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (217), - 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (218), - 8-(5-chloro-3-fluoropyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (219), - 8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (220), - 8-(4-chloro-2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (221), - 8-(2,6-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (222), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (223), - 8-(2-chlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl) Methyl )phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (224), - 8-(2,4-dichlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (225), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (226), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (227), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (228), - 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (229), - 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (230), - 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (231), - 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (232), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-3-hydroxyazetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (233), - 8-(3,5-dichloropyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (234), - 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (235), - 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (236), - 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (237), 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (238), - 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (239), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (240), 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (241), - 8-(2-chloro-4-fluorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (242), - 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (243), - 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (244), - 2-cyano-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzyl benzo[7]annulene-3-carboxylic acid (245), - 4-cyano-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (246), - 4-chloro-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (247), 2-chloro-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (248), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (249), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (250), - sodium 8-(3-(difluoromethyl)-5-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (251), - 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (252), - 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (253), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (254), - 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (255), - 8-(2-methyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (256), - 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (257), - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (258), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (259), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (260), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (261), - 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl) Azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride (262), 4-(4-chloro-2-methylphenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid (263), - sodium 4-(2-chloro-4-fluorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate (264), - 8-(2-chloro-4-methylphenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (265), - 8-(3,5-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (266), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (267), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (268), - 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (269), - 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (270), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (271), - 8-(4-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (272), - sodium 8-(5-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (273), - sodium 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (274), - 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (275), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (276), - 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (277), - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7- Dihydro-5H-benzo[7]annulene-3-carboxylic acid (278), - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (279), - 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (280), - 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (281), - 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (282), - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (283), - 8-(2-(difluoromethyl)-4,6-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (284), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (285), - 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (286), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (287), - 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (288), - 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (289), - 8-(4-fluoro-3-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (290), - 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (291), - 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (292), - 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (293), - 8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (294), - 8-(2-fluoro-5-(2,2,2-trifluoroethyl)phenyl)-9-( 4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (295), - 8-(2-(difluoromethyl)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (296), - 8-(3-(2,2-difluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (297), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (298), - sodium 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (299), - 8-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (300), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (301), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (302), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (303), 3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine (304), - 8-(2,4-dichlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (305), - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (306) - 8-(bicyclo[2.2.1]heptan-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (307) - 3-(2,4-dichlorophenyl)-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid (308) - 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (309) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (310)- 8-benzyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carvone Acid(311) - 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (312) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (313) - 3-(2,4-difluorophenyl)-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid (314) - 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (315) - 8-(bicyclo[3.2.1]octan-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (316) - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (317) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (318) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(2-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (319) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (320) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (321) - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (322) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (323) - 8-(4-chlorophenyl)-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (324) - 8-(4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (325) - 8-(3,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (326) - 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (327) - 18-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (328) - 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (329) - 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (330) - 8-((1R,2S)-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (331) - 8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (332) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (333) - 8-(3-chloro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (334) - 8-(3-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (335) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(octahydropentalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (336) Examples include:

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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

[0071] The compound of formula (I) can be prepared by the following method.

[0072] 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.

[0073] 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.

[0074] The following abbreviations and empirical formulas are used: MeCN acetonitrile NH4Cl Ammonium chloride NH4OH Ammonium hydroxide 9-BBN 9-Borabicyclo[3.3.1]nonane CO Carbon monoxide Cs2CO3 Cesium Carbonate DCM dichloromethane DIEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphino)ferrocene EtOH ethanol EtOAc ethyl acetate H2 Hydrogen HCl Hydrochloric acid HPLC High-Performance Liquid Chromatography LiAlH4 Lithium Aluminum Hydride LiHMDS Lithium hexamethyldisilazane MeOH Methanol MgSO4 Magnesium Sulfate m-CPBA metachloroperbenzoic acid MTBE Methyl tert-butyl ether n-BuLi n-butyllithium Pd / C Palladium Carbon K2CO3 Potassium Carbonate KHMDS Potassium hexamethyldisilazane KOH Potassium hydroxide NaBH4 Sodium borohydride NaCl Sodium chloride NaHCO3 Sodium Bicarbonate NaH sodium hydride NaHMDS Sodium hexamethyldisilazane NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NaHSO3 Sodium bisulfate SCX Strong Cation Exchange Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride PhOK Potassium 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

[0075] Scheme 1a-part-1: Preparation of compounds of formula (I) - general method [ka]

[0076] Scheme 1a-Part-2: [ka]

[0077] According to Scheme 1a-part-1 and part-2, where R3a is H, a carboxylic acid ester, for example COOMe, COOEt, or a protected OH, such as O-pivaloyl, and R1, R2, R3, R3', R3'', R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X, and Y are defined as above, compound 1A (prepared according to WO2017140669 when X=C) can be converted in step 1 to compound 1C by treatment with compound 1B in the presence of a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, dissolved in toluene, and a phosphine, for example triphenylphosphine, in the presence of a base such as KOPh by heating the solvent to reflux.

[0078] Compound 1C can be converted to compound 1E in step 2 by treatment with compound 1D in a Suzuki coupling reaction 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.

[0079] Alternatively, compound 1E can be obtained in step 1′ by Suzuki coupling between compound 1A and compound 1D′ 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, for example, cesium carbonate (CsCO), in a mixture of dioxane and water by heating the solvent to reflux.

[0080] Compound 1E can be converted to compound 1F in step 3, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0081] This bromo derivative intermediate 1F can then be subjected in step 4 to a second Suzuki coupling with a suitable boronic reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester, and R6 is defined as above, in a mixture of dioxane and water as the solvent at room temperature or by heating to reflux, in the presence of a base such as Cs2CO3, using, for example, Pd(dppf)Cl2 complex with DCM as a catalyst, to give compound 1G. When R6 is a substituted cycloalkene, heterocycloalkene, or aliphatic ethylene, it may be reduced, for example, by hydrogenation with a catalyst such as Pd / C at temperatures up to 70°C under about 5 bar of hydrogen pressure (H2) to give the corresponding saturated compound 1G.

[0082] Alternatively, compound 1F can be subjected to a photocatalytic coupling reaction with RBr (wherein R is an alkyl group, cycloalkyl, or spiro-bicyclic alkyl as defined above) using a catalyst such as (Ir[dF(CF)ppy](dtbpy))PF and nickel(II) chloride ethylene glycol dimethyl ether complex in the presence of tris(trimethylsilyl)silane and a base such as 4,4'-di-tert-butyl-2,2'-bipyridine and sodium carbonate to give the corresponding compound 1G.

[0083] Compound 1G can be converted to a compound of formula (I) in step 5 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH).

[0084] Intermediate 1F can be converted to compound 1Fa in step 6 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH).

[0085] This compound 1Fa can be converted in step 7 to compound I by Suzuki conditions using a suitable boron reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, in the presence of a base such as Cs2CO3, for example Pd(dppf)Cl2, complexed with DCM, as a catalyst, in a mixture of dioxane and water as solvent at room temperature or by heating the solvent to reflux. When R6 is a substituted cycloalkene, heterocycloalkene, or aliphatic ethylene, it may be reduced, for example, by hydrogenation over a catalyst such as Pd / C at temperatures up to 70°C under about 5 bar of hydrogen (H2) pressure to give the corresponding saturated compound I.

[0086] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, deprotection can be achieved in step 5 by treatment with 2N aqueous sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, extraction of the product can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form of compound I. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of compound I.

[0087] A process for preparing a compound of formula (I) as defined above, comprising reacting a compound of formula 1G [ka] wherein R1, R2, R3', R3'', R4, R5, R6, R7, Y, R8, R9, R10, R10', R11, n, m, X are as defined above, and R3a is a carboxylic acid ester, such as COOMe, COOEt, or a protected OH, 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 1G, and a compound of formula 1F [ka] [In the formula, R1, R2, R3', R3'', R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, and R3a is as defined above.] is subjected to Suzuki coupling with a boron reagent R6-B(OR')2, where -B(OR')2 is a boronic acid or pinacolatoate ester, and R6 is as defined above.

[0088] A process for preparing a compound of formula (I) as described above, comprising the step of: [ka] [In the formula, R1, R2, R3, R3', R3'', R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above.] is subjected to Suzuki coupling with a boron reagent R6-B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above, to obtain compound 1Fa, optionally preceded by a step [ka] [In the formula, R1, R2, R3', R3'', R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, and R3a is as defined above.] is converted to compound 1Fa in the presence of a hydroxide ion source, such as NaOH dissolved in methanol.

[0089] A compound of formula 1E, 1F, 1G, and 1Fa, or any of its pharmaceutically acceptable salts [ka] wherein R1, R2, R3, R3', R3'', R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined above, and R3a is a protected OH bearing a carboxylic acid ester, such as COOMe, COOEt, or O-pivaloyl. Also provided herein is an intermediate compound selected from:

[0090] any of the intermediate compounds of formula 1D and 1D', or pharmaceutically acceptable salts thereof [ka] [In the formula, R1, R2, R4, R5, R7, R8, R9, R10, R10', n, and Y are as defined above.] is further provided herein.

[0091] 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.

[0092] Said purification step may for example consist of an acidification step with, for example, an aqueous solution of hydrochloric acid, as exemplified in step 2 of Example 1 below.

[0093] Scheme 1b-part-1: Preparation of compounds of formula (I) - general method [ka]

[0094] Scheme 1b-Part-2 [ka]

[0095] According to Scheme 1b, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH bearing, for example, O-pivaloyl, R11 is a hydrogen atom, and R1, R2, R3, R3', R3'', R4, R5, R6, R7, R8, R9, R10, R10', n, m, X, and Y are as defined above, compound 1I can be converted in step 1 to compound 1J by treatment with an aryl bromide or iodide in the presence of a palladium catalyst, for example, tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), dissolved in toluene in the presence of a base such as K2CO3 or Cs2CO3, by heating the solvent to reflux.

[0096] Compound 1J can be converted to compound 1K in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or NaH or KHMDS at −50° C. in a solvent such as MeTHF.

[0097] Compound 1K can be converted to compound 1L in step 3 by treatment with, for example, bis(pinacolato)diboron (compound 1B) 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.

[0098] Compound 1G can be prepared in a Suzuki coupling reaction between compounds 1L and 1D in step 4 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, for example, cesium carbonate (CsCO), in a mixture of dioxane and water by heating the solvent to reflux.

[0099] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 5 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH). When R3 is a -COOH group, extraction of the product can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form of compound I. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of compound I.

[0100] Alternatively, in step 4′, compound 1L can be converted to compound 1N in a Suzuki coupling reaction with compound 1M using, for example, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complex with DCM as a catalyst, in the presence of a base, for example, cesium carbonate (CsCO), in a mixture of dioxane and water by heating the solvent to reflux.

[0101] Compound 1N can be reduced to compound 1O in step 5' by hydrogenation over a catalyst such as PtO2 at room temperature under hydrogen (H2) pressure, for example, about 2 bar.

[0102] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 10 can be converted to a compound of formula (I) in step 6' in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH). When R3 is a -COOH group, extraction of the product can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form of compound I. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of compound I.

[0103] an intermediate compound of formula 1L, or any of its pharmaceutically acceptable salts [ka] [In the formula, R3a, R3', R3'', X, m, and R6 are as defined above, and R11 is a hydrogen atom.] is further provided herein.

[0104] Scheme 1c: Preparation of Compounds of Formula (I) - General Method [ka]

[0105] According to Scheme 1c, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH bearing, for example, O-pivaloyl, R11 is a hydrogen atom, and R1, R2, R3, R3', R3'', R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X, and Y are as defined above, compound 1F can be converted to compound 1H in step 1 by treatment with, for example, bis(pinacolato)diboron (compound 1B) in the presence of a base such as KOPh by heating the solvent to reflux, and treatment with a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2 in toluene, and a phosphine, for example, triphenylphosphine.

[0106] Compound 1G, where R6 is phenyl or heteroaryl, can be prepared in step 2 in a Suzuki coupling reaction between compound 1H and either R6Br or R6I or R6OTf 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.

[0107] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 3 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH). When R3 is a -COOH group, extraction of the product can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form of compound I. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of compound I.

[0108] Scheme 1d: Preparation of compounds of formula (1A) where R3a = CO2Me - General method [ka]

[0109] According to Scheme 1d, where X, m, R3', R3'' and R11 are defined as above, compound 1A is commercially available or can be prepared as follows: Compound 1Aa (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted to compound 1Ab in step 1 by treatment with trifluoromethanesulfonic anhydride dissolved in DCM in the presence of pyridine as a base.

[0110] In step 2, compound 1Ab can be converted to compound 1Ac by carbonylation with carbon monoxide in DMF and MeOH in the presence of a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complexed with DCM.

[0111] Compound 1Ac can be converted in step 3 to compound 1A, where R3a = CO2Me, by treatment with trifluoromethanesulfonic anhydride in DCM in the presence of pyridine as a base.

[0112] Scheme 1e: Preparation of Compounds of Formula (I) - General Method [ka]

[0113] According to Scheme 1e, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH with, for example, O-pivaloyl, R11 is a hydrogen atom, and R1, R2, R3, R3', R3'', R4, R5, R6, R7, R8, R9, R10, R10', R11, n, m, X, and Y are as defined above, compound 1K can be converted to compound 1G in step 1 by treatment with compound 1D' in the presence of a palladium catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, in a mixture of dioxane and water in the presence of a base, for example, cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0114] When R3a is COOMe, COOEt, or a protected OH, such as O-pivaloyl, compound 1G can be converted to a compound of formula (I) in step 2 in the presence of a hydroxide ion source such as NaOH dissolved in methanol (MeOH). When R3 is a -COOH group, extraction of the product can provide the sodium salt of compound I. Acidification to pH 6-7 with 2N aqueous HCl can provide the neutral form of compound I. Acidification to pH 1-2 with 2N aqueous HCl can provide the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of compound I.

[0115] Scheme 1f: Alternative preparation of compounds of formula (1J) - general method [ka]

[0116] According to Scheme 1f, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or a protected OH bearing, for example, O-pivaloyl, and R3', R3'', R11, X, and m are defined as above, compound 1J can alternatively be prepared as follows: in step 1, compound 1I can be converted to compound 1Ia, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0117] Compound 1Ia can be converted to compound 1Ib in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0118] Compound 1Ic can be prepared in step 3 by Suzuki coupling reaction between compound 1Ib and R6B(OR')2 or R6BF3K 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 toluene and water by heating the solvent to reflux.

[0119] Compound 1Ic can be converted to compound 1J in step 4 by hydrolysis with aqueous HCl, for example by heating in methanol and DCM.

[0120] 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.

[0121] 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.

[0122] 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).

[0123] [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 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

Table 1-100

Table 1-110

[0124] 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 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40 Table 2-41 Table 2-42 Table 2-43 Table 2-44 Table 2-45 Table 2-46 Table 2-47 [Table 2-48] [Table 2-49] [Table 2-50] [Table 2-51] [Table 2-52] [Table 2-53] [Table 2-54]

[0125] The following examples describe the preparation of some compounds of formula (I) described herein. The compound numbers exemplified below correspond to those shown in Table 1a above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0126] 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.

[0127] Intermediates: Intermediate 1: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine. [ka]

[0128] Method 1: A suspension of 3-(4-bromobenzyl)azetidine, trifluoroacetic acid (4.5 g, 13.23 mmol), K2CO3 (5.67 g, 41.01 mmol), and 1-fluoro-3-iodopropane (2.49 g, 13.32 mmol) in DMF (45 ml) was heated to 70 °C for 2 h. After cooling to room temperature, water (500 ml) was added, and the reaction mixture was extracted three times with 200 ml of EtOAc. The organic phase was collected, washed with water (150 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 95 / 05 to give 2.3 g (61%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine as a viscous oil. LC / MS(m / z, MH+):286

[0129] Method 2: A mixture of 3-(4-bromobenzyl)azetidine, trifluoroacetic acid (4 g, 11.76 mmol), 1-fluoro-3-iodopropane (2.21 g, 11.76 mmol), and NaOH 5N (7.06 mL, 35.28 mmol) in THF (20 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. Water (150 mL) was added to the resulting residue, and the reaction mixture was extracted three times with 150 mL of EtOAc. The organic phase was collected, washed with water (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 95 / 05 to give 1.58 g (47%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine as a viscous oil.

[0130] Intermediate 2: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine [ka] A mixture of intermediate 1 (5 g, 17.47 mmol), bis(pinacolato)diboron (6.65 g, 26.21 mmol), KOAc (5.14 g, 52.41 mmol), and Pd(dppf)Cl (1.28 g, 1.75 mmol) in dioxane (50 mL) was degassed and purged with Ar three times, and then the mixture was stirred under Ar at 80 °C for 12 h. The reaction mixture was filtered through Celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 90 / 10 to give 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine 4 g (69% yield) as a brown oil. LC / MS(m / z, MH+): 334

[0131] Intermediate 3: 3-(4-Bromobenzyl)-1-(1,1-dideuterio-3-fluoro-propyl)azetidine [ka]

[0132] Step 1: 1-(3-(4-bromobenzyl)azetidin-1-yl)-3-fluoropropan-1-one [ka] A mixture of 3-(4-bromobenzyl)azetidine 4-methylbenzenesulfonate (19.39 g, 48.68 mmol), DMAP (17.98 g, 145.70 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (11.29 g, 58.30 mmol), and 3-fluoropropanoic acid (4.7 g, 48.50 mmol) in DMF (120 ml) was stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure. To the resulting residue, water (150 ml) and EtOAc (300 ml) were added. After decantation, the organic phase was washed successively with NaOH 1N (50 ml), water (100 ml), HCl 1N (50 ml), and water (200 ml). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 8.5 g (58%) of 1-(3-(4-bromobenzyl)azetidin-1-yl)-3-fluoropropan-1-one. LC / MS(m / z, MH+): 299

[0133] Step 2: 3-(4-Bromobenzyl)-1-(1,1-dideuterio-3-fluoro-propyl)azetidine [ka] To a mixture of 1-(3-(4-bromobenzyl)azetidin-1-yl)-3-fluoropropan-1-one (510 mg, 1.70 mmol) in diethyl ether (10 mL) at room temperature was added lithium aluminum deuteride (147 mg, 3.43 mmol). After 30 min, the reaction mixture was cooled to 4 °C. After successive addition of EtOAc (1 mL), water (150 μL), NaOH 15% (150 μL), and water (450 μL), the white precipitate was filtered off. The filtrate was 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 214 mg (44%) of 3-(4-bromobenzyl)-1-(1,1-dideuterio-3-fluoropropyl)azetidine. LC / MS(m / z, MH+):287

[0134] Intermediate 4: 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

[0135] Intermediate 5: 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 5 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 4 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

[0136] Intermediate 6: 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]

[0137] 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 minutes. After the addition of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.32 g, 2.91 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.05 g, 1.15 mmol), the reaction mixture was heated to reflux for 72 hours. 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

[0138] 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) 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 MgSO, 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

[0139] 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 6 was prepared from methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for intermediate 4 to yield 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+): 473

[0140] Intermediate 7: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0141] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) (17 g, 52.41 mmol), 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine (Intermediate 1) (15 g, 52.41 mmol), Pd(dppf)Cl complex with DCM (2.42 g, 3.14 mmol), and CsCO (43.56 g, 134 mmol) in dioxane (120 mL) and water (50 mL) was heated to reflux for 1 h. After cooling to room temperature, DCM (500 mL) and water (300 mL) were added, and the mixture was decanted using a hydrophobic column. The organic phase was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 98 / 02 to afford 16.19 g (90%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange viscous oil. LC / MS(m / z, MH+):408

[0142] Step 2: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (19 g, 46.62 mmol) in DCM (150 ml) was added pyridinium tribromide (21.54 g, 60.61 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (100 ml) and DCM (150 ml) were added and the pH was adjusted to 8 with a concentrated solution of NaHCO3. The aqueous phase was washed three times with DCM and the collected organic phases were dried over MgSO4, 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 afford 7.48 g (33%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown viscous oil. LC / MS(m / z, MH+): 486

[0143] Intermediate 8: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (9.7 g, 20 mmol), Pd(PPh3)2Cl2 (1.5 g, 2 mmol), PPh3 (1 g, 4 mmol), bis(pinacolato)diboron (13 g, 50 mmol), and PhOK (7.9 g, 60 mmol) in toluene (150 ml) was heated to 100 °C for 3 h. After cooling to room temperature, a saturated solution of Na2CO3 (50 ml) was added. After decantation, the organic phase was washed with water (25 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 00 to 95 / 05 to give 8.2 g (75%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):534

[0144] Intermediate 9: Methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka]

[0145] 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 minutes. Water (50 ml) was added. The organic phase was separated and washed with a saturated solution of NaHCO3 (50 ml). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 311

[0146] 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 with EtOAc (3 times 300 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 85 / 15 to 80 / 20 to give 4.6 g (87.6%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+):221

[0147] Step 3: Methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] To a mixture of methyl-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate (1.5 g, 6.811 mmol) and pyridine (812 mg, 0.826 mL, 10.22 mmol) in DCM (60 mL) cooled to 1.5°C, trifluoromethanesulfonic anhydride (3.92 g, 2.31 mL, 13.62 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours. Ice (25 g) and water (25 mL) were added. The organic phase was separated and washed with water (35 mL) and a saturated solution of NaHCO3 (35 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / heptane: 50 / 50 to 100 / 00 to give 2.06 g (86%) of methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 353

[0148] Step 4: Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 9, step 4, was prepared from methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of Intermediate 4 to afford 1.34 g (73%) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 331

[0149] Step 5: Methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 9, step 5, was prepared from methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate and 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine following a procedure similar to that for Intermediate 7, step 1, to afford 230 mg (55%) of methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 410

[0150] Step 6: Methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Intermediate 9, step 6, was prepared from methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 111 mg (40.5%) of methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z, MH+): 488

[0151] Intermediate 10: Methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate [ka]

[0152] Step 1: 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl trifluoromethanesulfonate: [ka] Intermediate 10, 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 9, 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

[0153] Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carboxylate: [ka] Intermediate 10, 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 9, 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

[0154] Step 3: Methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate: [ka] Intermediate 10, 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 9, step 3, to afford 1.84 g (79%) of methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate. LC / MS(m / z, MH+): 369

[0155] Step 4: Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate: [ka] Intermediate 10, step 4, was prepared from methyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepine-8-carboxylate following a procedure similar to that of Intermediate 4 to afford 867 mg (50%) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate. LC / MS(m / z, MH+): 347

[0156] Step 5: Methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate: [ka] Intermediate 10, step 5, was prepared from methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate and 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine following a procedure similar to that of Intermediate 7, step 1, to afford 650 mg (86%) of methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate. LC / MS(m / z, MH+): 410

[0157] Step 6: Methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate: [ka] Intermediate 10, step 6, was prepared from methyl 5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 445 mg (84%) of methyl 4-bromo-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylate. LC / MS(m / z, MH+):504

[0158] Intermediate 11: (4-Bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone [ka]

[0159] 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, 1.50 equiv.) in THF (1050 mL) was added n-BuLi (2.5 M, 491 mL, 1.50 equiv.) at −70° C. After stirring the mixture for 30 minutes, 1-azetidinecarboxylic acid, 3-[(methoxymethylamino)carbonyl]-1,1-dimethylethyl ester (200 g, 819 mmol, 1.00 equiv.) in THF (420 mL) was added at −70° C. The mixture was stirred for 1.5 hours. The solution was warmed to −25° C. and slowly quenched with saturated aqueous NH4Cl (2000 mL). The mixture was extracted twice with MTBE (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 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

[0160] Step 2: 3-Azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid [ka] To a solution of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate (40 g, 117 mmol) in DCM (200 ml) was added TFA (88.6 g, 777 mmol, 57.5 ml). The mixture was stirred at 15° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 41.6 g (100%) of 3-azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid. LC / MS (m / z, MH+): 240

[0161] Step 3: (4-Bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone [ka] Intermediate 11, step 3, was prepared from 3-azetidinyl(4-bromophenyl)-methanone, trifluoroacetic acid following a procedure similar to that of Intermediate 1, method 2, to afford (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone 20 g (54%). LC / MS (m / z, MH+): 300

[0162] Intermediate 12: 3-((4-bromophenyl)difluoromethyl)-1-(3-fluoropropyl)azetidine [ka]

[0163] Step 1: Tert-butyl 3-((4-bromophenyl)difluoromethyl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(4-bromobenzoyl)azetidine-1-carboxylate (40 g, 117 mmol) in DCM (200 mL) was added Deoxo-Fluor (260 g, 1.18 mol, 257 mL). The mixture was stirred at 40 °C for 48 h. The mixture was poured into ice and saturated aqueous NaHCO (1000 mL) and extracted with DCM (300 mL). The organic layer 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 00 / 100 petroleum ether / EtOAc to give 36 g (85%) of tert-butyl 3-((4-bromophenyl)difluoromethyl)azetidine-1-carboxylate as a yellow oil. LC / MS(m / z, MH+): 362

[0164] Step 2: 3-[(4-bromophenyl)difluoromethyl]-azetidine, trifluoroacetic acid [ka] Intermediate 12, step 2, was prepared from tert-butyl 3-((4-bromophenyl)difluoromethyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 11, step 2, to afford 3-[(4-bromophenyl)difluoromethyl]-azetidine, trifluoroacetic acid 37.4 g (100%) as a yellow solid. LC / MS(m / z, MH+):262

[0165] Step 3: 3-((4-bromophenyl)difluoromethyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 12, step 3, was prepared from 3-[(4-bromophenyl)difluoromethyl]-azetidine, trifluoroacetic acid following a procedure similar to that of Intermediate 1, Method 2 to afford 13.3 g (41%) of 3-((4-bromophenyl)difluoromethyl)-1-(3-fluoropropyl)azetidine as a yellow oil. LC / MS(m / z, MH+): 322

[0166] Intermediate 13: Methyl 8-bromo-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0167] Step 1: Methyl 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 13, step 1, was prepared from 3-((4-bromophenyl)difluoromethyl)-1-(3-fluoropropyl)azetidine (Intermediate 12) following a procedure similar to that of Intermediate 7, step 1, to afford 3.5 g (99%) of methyl 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a yellow oil. LC / MS(m / z, MH+): 444

[0168] Step 2: Methyl 8-bromo-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 13, step 2, was prepared from methyl 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 3.48 g (84%) of methyl 8-bromo-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown oil. LC / MS(m / z, MH+):522

[0169] Intermediates 14 and 15: (4-Bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 1 and Isomer 2 [ka] To a solution of (4-bromophenyl)(3-fluoropropyl)azetidin-3-ylmethanone intermediate 11 (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 to remove MeOH. The aqueous layer was extracted three times with EtOAc (80 mL). After decantation, the organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of 98 / 02 to 90 / 10 DCM:MeOH to give 16.0 g (77%) of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol as a mixture of two isomers. LC / MS(m / z, MH+):302 A mixture of two isomers of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol was separated by SFC (conditions: flash DAICEL CHIRALPAK AD (250 × 50 mm, 10 μm); supercritical CO 80% / MeOH 20% / [0.1% NH OH MeOH]) to give 5.3 g of isomer 1 and 5.2 g of isomer 2.

[0170] Intermediates 16 and 17: 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine isomer 1 and isomer 2 [ka] To a solution of racemic (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol (Intermediate 14 and 15) (30.0 g, 99.3 mmol) in DCM (150 ml) was added Deoxo-Fluor (26.4 g, 119 mmol, 26.1 ml) at -70 °C. The mixture was stirred at 15 °C for 0.5 h. The mixture was quenched with a saturated aqueous solution of NaHCO (500 ml) and extracted with DCM (200 ml). After decantation, the organic layer 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 00 / 100 petroleum ether / EtOAc to give 10.5 g (32%) of 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine as a mixture of two isomers. LC / MS(m / z, MH+):304 A mixture of two isomers of 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine was separated by SFC (conditions: flash DAICEL CHIRALPAK AD (250 × 50 mm, 10 μm); supercritical CO 60% / MeOH 40% / [0.1% NH OH MeOH]) to give 5.9 g of isomer 1 and 6.3 g of isomer 2.

[0171] Intermediate 18: Methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 [ka]

[0172] Step 1: Methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 [ka] Intermediate 18, 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 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine isomer 1 following a procedure similar to that for Intermediate 7, step 1, to afford methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 1.18 g (84%). LC / MS(m / z, MH+): 426

[0173] Step 2: Methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 [ka] Intermediate 18, step 2, was prepared from methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 following a procedure similar to that for Intermediate 7, step 2, to afford methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 833 mg (60%). LC / MS(m / z, MH+):504

[0174] Intermediate 19: Methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 [ka]

[0175] Step 1: Methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 [ka] Intermediate 19, step 1, was prepared from 3-((4-bromophenyl)fluoromethyl)-1-(3-fluoropropyl)azetidine isomer 2 following a procedure similar to that of Intermediate 7, step 1, to afford methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 2.59 g (92%). LC / MS(m / z, MH+): 426

[0176] Step 2: Methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 [ka] Intermediate 19, step 2, was prepared from methyl 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 following a procedure similar to that for Intermediate 7, step 2, to afford methyl 8-bromo-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 1.03 g (36%). LC / MS(m / z, MH+):504

[0177] Intermediate 20: 3-(4-bromobenzyl)-3-fluoro-1-(3-fluoropropyl)azetidine [ka]

[0178] Step 1: Tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate [ka] 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) 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 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

[0179] Step 2: Tert-butyl 2-(4-bromophenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylate [ka] To a solution of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate (72.0 g, 222 mmol) in DCM (500 mL) was added m-CPBA (57.5 g, 266 mmol, 80% purity). The mixture was stirred at 50 °C for 12 h. The reaction mixture was quenched by the addition of aqueous NaHSO (650 mL) at 0 °C, then diluted with EtOAc (500 mL) and extracted with EtOAc (300 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc from 00 / 100 to 90 / 10 to give tert-butyl 2-(4-bromophenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylate 35.0 g (46.3%) as a yellow solid. LC / MS(m / z, MH+): 340

[0180] Step 3: Tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate [ka] To a solution of tert-butyl 2-(4-bromophenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (35.0 g, 103 mmol) in THF (200 mL) was added LiAlH (4.30 g, 113 mmol) at −70°C. The mixture was stirred at −70°C for 2 h. The reaction mixture was quenched with water (100 mL) and then extracted with EtOAc (100 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 gradient of 99 / 01 to 90 / 10 petroleum ether / EtOAc to give 28 g (79.5%) of tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate as a white solid. LC / MS(m / z, MH+): 342

[0181] Step 4: tert-Butyl 3-(4-bromobenzyl)-3-fluoroazetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate (10.0 g, 29.2 mmol) in DCM (60.0 ml) was added deoxofluor (5.65 g, 35.1 mmol, 4.63 ml) at −70° C. The mixture was stirred at −60° C. for 2 h. The reaction mixture was quenched with water (60 ml). After decantation, the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / EtOAc from 99 / 01 to 95 / 05 to afford 10 g (50%) of tert-butyl 3-(4-bromobenzyl)-3-fluoroazetidine-1-carboxylate as a white solid. LC / MS(m / z, MH+): 344

[0182] Step 5: 3-(4-bromobenzyl)-3-fluoroazetidine, trifluoroacetic acid [ka] Intermediate 20, step 5, was prepared from 1-azetidinecarboxylic acid, 3-[(4-bromophenyl)methyl]-3-fluoro-1,1-dimethylethyl ester following a procedure similar to that of Intermediate 11, step 2, to afford 9.80 g (94%) of 3-(4-bromobenzyl)-3-fluoroazetidine, trifluoroacetic acid as a crude product, which was used in the next step without further purification. LC / MS(m / z, MH+): 244

[0183] Step 6: 3-(4-bromobenzyl)-3-fluoro-1-(3-fluoropropyl)azetidine [ka] Intermediate 20, step 6, was prepared from 3-(4-bromobenzyl)-3-fluoroazetidine, trifluoroacetic acid following a procedure similar to that of Method 2, Intermediate 1, to afford 5.10 g (61.3%) of 3-(4-bromobenzyl)-3-fluoro-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):304

[0184] Intermediate 21: Methyl 8-bromo-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0185] Step 1: Methyl 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 21, 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 3-(4-bromobenzyl)-3-fluoro-1-(3-fluoropropyl)azetidine following a procedure similar to that for Intermediate 7, step 1, to afford 0.93 g (71%) of methyl 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 426

[0186] Step 2: Methyl 8-bromo-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 21, step 2, was prepared from methyl 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 404 mg (59%) of methyl 8-bromo-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):504

[0187] Intermediate 22: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol [ka]

[0188] Step 1: 3-(4-bromobenzyl)azetidin-3-ol, trifluoroacetic acid [ka] Intermediate 22, step 1, was prepared from tert-butyl 3-(4-bromobenzyl)-3-hydroxyazetidine-1-carboxylate following a procedure similar to that of Intermediate 11, step 2, to afford 3-(4-bromobenzyl)azetidin-3-ol, trifluoroacetic acid 36.8 g (76%) as a yellow solid. LC / MS(m / z, MH+):242

[0189] Step 2: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol [ka] Intermediate 22, step 2, was prepared from 3-(4-bromobenzyl)azetidin-3-ol, trifluoroacetic acid following a procedure similar to that of Intermediate 1, method 1 to afford 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol 10 g (31%). LC / MS(m / z, MH+):302

[0190] Intermediate 23: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol [ka] A mixture of commercially available 3-(1-(4-bromophenyl)cyclopropyl)azetidine hydrochloride (0.3 g, 1.04 mmol), K2CO3 (0.36 g, 2.6 mmol), and 1-fluoro-3-iodopropane (108.5 μL, 1.06 mmol) in acetonitrile (20 mL) was stirred at room temperature overnight. It was then concentrated under reduced pressure. The residue was taken up in EtOAc and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 95 / 5 to 90 / 10 to give 0.1 g (31%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidin-3-ol as a brown oil. LC / MS(m / z, MH+): 312

[0191] Intermediate 24: 3-(4-bromobenzyl)-1-(3-fluoropropyl)-3-methylazetidine [ka] Intermediate 24 was prepared from commercially available 3-(4-bromobenzyl)-3-methylazetidine hydrochloride following a procedure similar to that for Intermediate 23 to afford 295 mg (90%) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)-3-methylazetidine as a yellow oil. LC / MS (m / z, MH+): 300

[0192] Intermediate 25: 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 1 [ka]

[0193] Step 1: 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine isomer 1 [ka] To a solution of (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol isomer 1 (1 g, 3.31 mmol) in DCM (40 mL) at 0 °C, thionyl chloride (0.48 mL, 6.62 mmol) was slowly added. The mixture was stirred at room temperature for 3 h. DCM (75 mL) and saturated aqueous NaHCO (200 mL) were added. The organic layer was separated, dried over NaSO, filtered, and concentrated under reduced pressure to give 1 g (94%) of 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine isomer 1 as a yellow oil. LC / MS (m / z, MH+): 320

[0194] Step 2: 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 1 [ka] To a solution of 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine isomer 1 (0.65 g, 2.03 mmol) in DMF (20 mL) was added sodium azide (269 mg, 4.05 mmol). The mixture was stirred at 78 °C for 4 h. Ether (100 mL) and water (100 mL) were added. The aqueous layer was separated and extracted three times with ether (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 0 to 95 / 5 to give 0.55 g (83%) of 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 1 as a colorless oil. LC / MS(m / z, MH+): 327

[0195] Intermediate 26: 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 2 [ka]

[0196] Step 1: 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine isomer 2 [ka] Intermediate 26, step 1, was prepared from (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol isomer 2 according to a procedure similar to that of Intermediate 25, step 1, to afford 1.1 g (95%) of 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine isomer 2 as a yellow oil. LC / MS (m / z, MH+): 320

[0197] Step 2: 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 2 [ka] Intermediate 26, step 2, was prepared from 3-((4-bromophenyl)chloromethyl)-1-(3-fluoropropyl)azetidine isomer 2 according to a procedure similar to that of Intermediate 25, step 2, to afford 0.64 g (96%) of 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 2 as a yellow oil. LC / MS(m / z, MH+): 327

[0198] Intermediate 27: 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine [ka]

[0199] 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) at 0° C., trifluoromethanesulfonic anhydride (1.93 mL, 11.45 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 minutes. Ether and water were added. The aqueous layer was separated and extracted three times with ether. The combined organic layers were washed with a 10% aqueous solution of citric acid, then twice with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2.06 g (86%) of 3,3-difluoropropyl trifluoromethanesulfonate, which was used in the next step without further purification.

[0200] Step 2: 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine [ka] To a suspension of 3-(4-bromobenzyl)azetidine para-toluenesulfonate (5 g, 12.55 mmol) and 3,3-difluoropropyl trifluoromethanesulfonate (3.44 g, 15.06 mmol) in DCM (100 mL) was added a 1N aqueous solution of sodium hydroxide (31.38 mL, 31.38 mmol). The mixture was stirred at room temperature for 4 hours. Water (100 mL) was added. The aqueous layer was separated and extracted twice with ether (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a DCM / MeOH gradient: 100 / 0 to 80 / 20 to afford 1.71 g (45%) of 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine as a yellow oil. LC / MS(m / z, MH+):304

[0201] Intermediate 28: (3-(4-bromo-3-fluorobenzyl)-1-(3-fluoropropyl)azetidine [ka]

[0202] Step 1: (tert-butyl (E)-3-((2-tosylhydrazono)methyl)azetidine-1-carboxylate [ka] A solution of 4-methylbenzenesulfonohydrazide (2.01 g, 10.80 mmol) and tert-butyl-3-formylazetidine-1-carboxylate (2 g, 10.80 mmol) in 1,4-dioxane (40 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was then transferred to a separatory funnel containing a saturated aqueous solution of NaCl. The mixture was extracted three times with EtOAc. The combined organic layers were then dried over MgSO, filtered, and concentrated to dryness to give 3.775 g (99%) of (tert-butyl (E)-3-((2-tosylhydrazono)methyl)azetidine-1-carboxylate. LC / MS(m / z, MH+): 354

[0203] Step 2: (tert-butyl 3-(4-bromo-3-fluorobenzyl)azetidine-1-carboxylate [ka] To a solution of tert-butyl (E)-3-((2-tosylhydrazono)methyl)azetidine-1-carboxylate (623 mg, 1.76 mmol) in 1,4-dioxane (10 ml), K2CO3 (365.42 mg, 2.64 mmol) and (4-bromo-3-fluorophenyl)boronic acid (578.56 mg, 2.64 mmol) were added successively. The reaction mixture was then refluxed for 16 hours. After cooling to room temperature, the reaction mixture was transferred into a separatory funnel containing a saturated aqueous solution of NH4Cl and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane / EtOAc 80 / 20 to give 335 mg (55%) of (tert-butyl 3-(4-bromo-3-fluorobenzyl)azetidine-1-carboxylate. LC / MS(m / z, MH+): 344

[0204] Step 3: 3-(4-bromo-3-fluorobenzyl)azetidine, hydrochloride [ka] To a solution of tert-butyl 3-(4-bromo-3-fluorobenzyl)azetidine-1-carboxylate (326 mg, 947.06 μmol) in 1,4-dioxane (9 ml), 9.47 ml (37.88 mmol) of a 4 M solution of HCl in 1,4-dioxane was added dropwise. The resulting reaction mixture was then stirred overnight at room temperature. The reaction mixture was concentrated to dryness to give 266 mg of 3-(4-bromo-3-fluorobenzyl)azetidine hydrochloride, which was used in the next step without further purification. LC / MS(m / z, MH+): 244

[0205] Step 4: (3-(4-bromo-3-fluorobenzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 28, step 4, was prepared from 3-(4-bromo-3-fluorobenzyl)azetidine hydrochloride following a procedure similar to that of Intermediate 23 to afford 89 mg (18%) of (3-(4-bromo-3-fluorobenzyl)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):304

[0206] Intermediate 29: Methyl 8-bromo-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0207] Step 1: Methyl 9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 29, 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 (3-(4-bromo-3-fluorobenzyl)-1-(3-fluoropropyl)azetidine following a procedure similar to that for Intermediate 7, step 1, to afford 1.28 g (100%) of methyl 9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 426

[0208] Step 2: Methyl 8-bromo-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 29, step 2, was prepared from methyl 9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 840 mg (55%) of methyl 8-bromo-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):504

[0209] Intermediate 30: (3-(4-bromo-2-methylbenzyl)-1-(3-fluoropropyl)azetidine [ka]

[0210] Step 1: Tert-butyl 3-(4-bromo-2-methylbenzyl)azetidine-1-carboxylate [ka] Intermediate 30, Step 1, was prepared from (4-bromo-2-methylphenyl)boronic acid following a procedure similar to that of Intermediate 28, Step 2, to afford 593 mg (56%) of tert-butyl 3-(4-bromo-2-methylbenzyl)azetidine-1-carboxylate. LC / MS(m / z, MH+): 341

[0211] Step 2: 3-(4-bromo-2-methylbenzyl)azetidine hydrochloride [ka] Intermediate 30, step 2, was prepared from tert-butyl 3-(4-bromo-2-methylbenzyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 28, step 3, to afford 480 mg (100%) of 3-(4-bromo-2-methylbenzyl)azetidine hydrochloride. LC / MS(m / z, MH+):241

[0212] Step 3: 3-(4-bromo-2-methylbenzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 30, step 3, was prepared from 3-(4-bromo-2-methylbenzyl)azetidine hydrochloride following a procedure similar to that of Intermediate 23 to afford 86 mg (17%) of 3-(4-bromo-2-methylbenzyl)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):301

[0213] Intermediate 31: 3-(4-bromo-2-fluorobenzyl)-1-(3-fluoropropyl)azetidine [ka]

[0214] Step 1: Tert-butyl 3-(4-bromo-2-fluorobenzyl)azetidine-1-carboxylate [ka] Intermediate 31, step 1, was prepared from (4-bromo-2-fluorophenyl)boronic acid following a procedure similar to that of Intermediate 28, step 2, to afford 126 mg (26%) of tert-butyl 3-(4-bromo-2-fluorobenzyl)azetidine-1-carboxylate. LC / MS(m / z, MH+): 344

[0215] Step 2: 3-(4-bromo-2-fluorobenzyl)azetidine, hydrochloride [ka] Intermediate 31, step 2, was prepared from tert-butyl 3-(4-bromo-2-fluorobenzyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 28, step 3, to afford 320 mg (100%) of 3-(4-bromo-2-fluorobenzyl)azetidine hydrochloride. LC / MS(m / z, MH+): 244

[0216] Step 3: 3-(4-bromo-2-fluorobenzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 31, step 3, was prepared from 3-(4-bromo-2-fluorobenzyl)azetidine hydrochloride following a procedure similar to that of Method 2, Intermediate 1, to afford 2.19 g (82%) of 3-(4-bromo-2-fluorobenzyl)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):304

[0217] Intermediate 32: Methyl 8-bromo-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0218] Step 1: Methyl 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 32, Step 1, was prepared from 3-(4-bromo-2-fluorobenzyl)-1-(3-fluoropropyl)azetidine (Intermediate 31) following a procedure similar to that of Intermediate 7, Step 1, to afford 2.58 g (84%) of methyl 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 426

[0219] Step 2: Methyl 8-bromo-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 32, step 2, was prepared from methyl 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 967 mg (82%) of methyl 8-bromo-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):504

[0220] Intermediate 33: 3-(4-bromo-3-methylbenzyl)-1-(3-fluoropropyl)azetidine [ka]

[0221] Step 1: Tert-butyl 3-(4-bromo-3-methylbenzyl)azetidine-1-carboxylate [ka] Intermediate 33, step 1, was prepared from (4-bromo-3-methylphenyl)boronic acid following a procedure similar to that of Intermediate 28, step 2, to afford 850 mg (61%) of tert-butyl 3-(4-bromo-3-methylbenzyl)azetidine-1-carboxylate as a white solid. LC / MS(m / z, MH+): 340

[0222] Step 2: 3-(4-bromo-3-methylbenzyl)azetidine, hydrochloride [ka] Intermediate 33, step 2, was prepared from tert-butyl 3-(4-bromo-3-methylbenzyl)azetidine-1-carboxylate following a procedure similar to that of Intermediate 28, step 3, to afford 0.84 g (100%) of 3-(4-bromo-3-methylbenzyl)azetidine hydrochloride, which was used in the next step without further purification. LC / MS (m / z, MH+): 240

[0223] Step 3: 3-(4-bromo-3-methylbenzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 33, step 3, was prepared from 3-(4-bromo-3-methylbenzyl)azetidine hydrochloride following a procedure similar to that of Method 2, Intermediate 1, to afford 63 mg (19%) of 3-(4-bromo-3-methylbenzyl)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 300

[0224] Intermediate 34: 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 34 was prepared from commercially available 3-(4-bromo-2,3-difluorobenzylidene)azetidine following a procedure similar to that of Method 2 for Intermediate 1 to afford 0.65 g (34%) of 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine as an orange oil. LC / MS (m / z, MH+): 320

[0225] Intermediate 35: 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0226] 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 sodium borohydride (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 to a separatory funnel and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated to dryness, triturated with pentane, and filtered to give 1.83 g (91%) of (4-bromo-2,6-difluorophenyl)methanol as a pinkish solid. LC / MS(m / z, MH+): 223

[0227] 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 diethyl ether (60 ml) at 0° C., tribromophosphane (0.57 mL, 6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours and then slowly poured onto a saturated aqueous solution of NaHCO3 under stirring. After stirring for 30 minutes, the mixture was transferred into a separatory funnel and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, 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

[0228] 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

[0229] Step 4: Tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate [ka] Under an Ar 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 layers were 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

[0230] Step 5: 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 35, step 5, was prepared from tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 11, 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

[0231] Step 6: 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 35, step 6, was prepared from 3-(4-bromo-2,6-difluorobenzylidene)azetidine, trifluoroacetic acid following a procedure similar to that of Method 1, Intermediate 1, to afford 79 mg (18%) of 3-(4-bromo-2,6-difluorobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0232] Intermediate 36: 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0233] Step 1: (4-bromo-2,6-dimethylphenyl)methanol [ka] Intermediate 36, step 1, was prepared from 4-bromo-2,6-dimethylbenzaldehyde following a procedure similar to that of Intermediate 35, step 1, to afford 1.86 g (92%) of (4-bromo-2,6-dimethylphenyl)methanol as a white solid. LC / MS (m / z, MH+): 215

[0234] Step 2: 5-Bromo-2-(bromomethyl)-1,3-dimethylbenzene [ka] Intermediate 36, step 2, was prepared from tert-butyl 3-(4-bromo-2,6-difluorobenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 35, step 2, to afford 1.27 g (98%) of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene as a white solid. LC / MS(m / z, MH+): 277

[0235] Step 3: Diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate [ka] Intermediate 36, step 3, was prepared from 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene following a procedure similar to that of Intermediate 35, step 3, to afford 1.16 g (86%) of diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate as a colorless oil. LC / MS(m / z, MH+): 335

[0236] Step 4: Tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate [ka] Intermediate 36, step 4, was prepared from diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate following a procedure similar to that of Intermediate 35, step 4, to afford 0.86 g (27%) of tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate as a colorless viscous oil. LC / MS(m / z, MH+): 352

[0237] Step 5: 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 36, step 5, was prepared from tert-butyl 3-(4-bromo-2,6-dimethylbenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 11, step 2, to afford 0.77 g (86%) of 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid as a white solid. LC / MS(m / z, MH+):252

[0238] Step 6: 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 36, step 6, was prepared from 3-(4-bromo-2,6-dimethylbenzylidene)azetidine, trifluoroacetic acid following a procedure similar to that of Method 1, Intermediate 1, to afford 0.7 mg (50%) of 3-(4-bromo-2,6-dimethylbenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 312

[0239] Intermediate 37: 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka]

[0240] Step 1: Diethyl (4-bromo-2,5-difluorobenzyl)phosphonate [ka] Intermediate 37, Step 1, was prepared from commercially available 1-bromo-4-(bromomethyl)-2,5-difluorobenzene following a procedure similar to that of Intermediate 35, Step 3, to afford 6.48 g (87%) of diethyl (4-bromo-2,5-difluorobenzyl)phosphonate as a colorless oil. LC / MS(m / z, MH+): 343

[0241] Step 2: Tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate [ka] Intermediate 37, step 2, was prepared from diethyl (4-bromo-2,5-difluorobenzyl)phosphonate following a procedure similar to that of Intermediate 35, step 4, to afford 1.16 g (73%) of tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate as a white solid. LC / MS (m / z, MH+): 360

[0242] Step 3: 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid [ka] Intermediate 37, step 3, was prepared from tert-butyl 3-(4-bromo-2,5-difluorobenzylidene)azetidine-1-carboxylate following a procedure similar to that of Intermediate 11, step 2, to afford 1.07 g (89%) of 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid as a white solid. LC / MS (m / z, MH+): 260

[0243] Step 4: 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 37, step 4, was prepared from 3-(4-bromo-2,5-difluorobenzylidene)azetidine, trifluoroacetic acid following a procedure similar to that of Method 2, Intermediate 1, to afford 0.7 g (76%) of 3-(4-bromo-2,5-difluorobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 320

[0244] Intermediate 38: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0245] Step 1: 1-Bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] To a solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (500 mg, 2.63 mmol) and NBS (468 mg, 2.63 mmol) in HO (5 mL) was added a solution of concentrated HSO (286 μL, 5.26 mmol) in HO (0.5 mL), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was extracted with EtOAc (30 mL), and after decantation, the organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of 0 to 15% ethyl acetate in petroleum ether to give 260 mg (37%) of 1-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 130 mg (18%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):268

[0246] Step 2: 2-Methoxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 1-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1 g, 3.72 mmol) in a mixture of dioxane (20 mL) and HO (5 mL) was purged with Ar for 15 minutes. KCO (1.54 g, 11.15 mmol), MeB(OH) (266.90 mg, 4.46 mmol), and Pd(PPh) (214.68 mg, 185.78 μmol) were added sequentially under a N atmosphere. The reaction mixture was sealed and heated to 100 °C for 2 hours. The mixture was poured into water (20 mL) and extracted three times with EtOAc (20 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-15% gradient of ethyl acetate in petroleum ether to give 880 mg (100%) of 2-methoxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):205

[0247] Step 3: 2-hydroxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 2-methoxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (760 mg, 3.72 mmol) in DCM (10 mL) was cooled to -60 °C, and BBr (1.08 mL, 11.16 mmol) was slowly added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by the addition of HO (10 mL) and extracted twice with EtOAc (10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a 0-35% gradient of ethyl acetate in petroleum ether to give 500 mg (71%) of the compound 2-hydroxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):191

[0248] Step 4: 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate [ka] Intermediate 38, step 4, was prepared from 2-hydroxy-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that of Intermediate 9, step 1, to afford 610 mg (100%) of 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 323

[0249] Step 5: Methyl 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 38, step 5, was prepared from 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 9, step 2, to afford 70 mg (97%) of methyl 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS (m / z, MH+): 233.

[0250] Step 6: Methyl 4-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 38, step 6, was prepared from methyl 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of Intermediate 9, step 3, to afford 480 mg (93%) of methyl 4-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 365

[0251] Step 7: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a solution of methyl 4-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (480 mg, 1.32 mmol), CsCO (1.5 M, 1.76 ml), and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine (Intermediate 2) (571 mg, 1.71 mmol) in dioxane (10 ml) was added Pd(dppf)Cl (96.40 mg, 131.75 μmol). The mixture was stirred at 60 °C under an Ar atmosphere for 1 h. The residue was poured into water (20 ml) and extracted three times with EtOAc (20 ml). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-10% gradient of DCM in MeOH to afford 610 mg (91%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 422

[0252] Step 8: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 38, step 8, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 400 mg (77% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 500

[0253] Intermediate 39: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0254] Step 1: 2-Methoxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] Intermediate 39, step 1, was prepared from 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that for Intermediate 38, step 2, to afford 183 mg (73%) of 2-methoxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):205

[0255] Step 2: 2-hydroxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] To a solution of 2-methoxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (310 mg, 1.52 mmol) in toluene (3 mL) was added AlCl (1.01 g, 7.59 mmol), and the mixture was stirred at 80 °C for 3 h. The residue was poured into water (10 mL) and extracted three times with EtOAc (10 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-50% gradient of ethyl acetate in petroleum ether to give 319 mg (99%) of 2-hydroxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):191

[0256] Step 3: 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate [ka] Intermediate 39, step 3, was prepared from 2-hydroxy-3-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that for Intermediate 9, step 1, to afford 437 mg (80%) of 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 323

[0257] Step 4: Methyl 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 39, step 4, was prepared from 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl trifluoromethanesulfonate following a procedure similar to that for Intermediate 9, step 2, to afford 300 mg (95%) of methyl 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 233

[0258] Step 5: Methyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 39, step 5, was prepared from methyl 3-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate according to a procedure similar to that of Intermediate 9, step 3, to obtain 315 mg (67%) of the compound methyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 365

[0259] Step 6: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 39, step 6, was prepared from methyl 2-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 38, step 7, to afford 439 mg (96%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 422

[0260] Step 7: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 39, step 7, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 349 mg (72%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 500

[0261] Intermediate 40: Methyl 8-bromo-4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0262] Step 1: 1-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 3-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] To a solution of 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (10 g, 52.57 mmol) and N-chlorosuccinimide (7.72 g, 57.82 mmol) in HO (100 ml) was added HSO (5.72 ml, 105.13 mmol, 98% purity) in HO (20 ml), and the mixture was stirred at 60° C. for 5 h. The reaction mixture was extracted twice with EtOAc (200 ml), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a 0–15% gradient of ethyl acetate in petroleum ether to give 5.3 g (45%) of 1-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one and 4.8 g (20%) of 3-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS (m / z, MH+): 225

[0263] Step 2: 1-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] Intermediate 40, step 2, was prepared from 1-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that of Intermediate 39, step 2, to afford 1.8 g of 1-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (crude). LC / MS(m / z, MH+):211

[0264] Step 3: 1-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene [ka] To a solution of 1-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.8 g, 8.54 mmol) in DCM (20 mL) was added TEA (2.16 g, 21.36 mmol, 2.97 mL). SO2F2 (gas) was then introduced via needle from a gas-filled balloon, and the mixture was stirred at 25 °C for 1 h. The residue was poured into HO (10 mL) and extracted with DCM (40 mL). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using a 0-30% ethyl acetate in petroleum ether gradient to give 2 g (80%) of 1-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene. LC / MS(m / z, MH+):292

[0265] Step 4: Methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 40, step 4, was prepared from 1-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene following a procedure similar to that for Intermediate 9, step 2, to afford 900 mg (52%) of methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 253

[0266] Step 5: Methyl 4-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a solution of methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (200 mg, 791 μmol) in THF (3 mL) was added NaHMDS (1 M, 950 μL) under an Ar atmosphere at −78°C. The mixture was stirred for 30 minutes, and a mixture of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (368 mg, 1.03 mmol) in THF (1 mL) was added to the resulting mixture. The reaction mixture was slowly warmed to 20°C and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL), then diluted with HO (15 mL), and extracted twice with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-25% gradient of ethyl acetate in petroleum ether to give 250 mg (82%) of methyl 4-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 385

[0267] Step 6: Methyl 4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 40, step 6, was prepared from methyl 4-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 38, step 7, to afford 280 mg (93%) of methyl 4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 422

[0268] Step 7: Methyl 8-bromo-4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 40, step 7, was prepared from methyl 4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 290 mg (83%) of methyl 8-bromo-4-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):522

[0269] Intermediate 41: Methyl 8-bromo-2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0270] Step 1: 3-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] Intermediate 41, step 1, was prepared from 3-chloro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that for Intermediate 39, step 2, to yield 650 mg (69.33%) of 3-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):211

[0271] Step 2: 3-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene [ka] Intermediate 41, step 2, was prepared from 3-chloro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that of Intermediate 40, step 3, to afford 1.4 g (92%) of 3-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene. LC / MS(m / z, MH+):292

[0272] Step 3: Methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 41, step 3, was prepared from 3-chloro-2-fluorosulfonyloxy-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene following a procedure similar to that for Intermediate 9, step 2, to afford 700 mg (58%) of methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 253

[0273] Step 4: Methyl 2-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 41, step 4, was prepared from methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 40, step 5, to afford 40 mg (53%) of methyl 2-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 385

[0274] Step 5: Methyl 2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 41, step 5, was prepared from methyl 2-chloro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 38, step 7, to afford 300 mg (crude) of methyl 2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 442

[0275] Step 6: Methyl 8-bromo-2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 41, step 6, was prepared from methyl 2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 260 mg (crude) of methyl 8-bromo-2-chloro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):522

[0276] Intermediate 42: Methyl 8-bromo-4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0277] Step 1: Methyl 1-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] To a solution of methyl 1-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (2.1 g, 8.31 mmol), Zn (163 mg, 2.49 mmol), Zn(CN) (976 mg, 8.31 mmol), and dppf (461 mg, 831 μmol) in DMA (25 mL) was added Pd(dba) (761 mg, 0.83 mmol). The mixture was stirred at 150 °C for 2 h. The residue was poured into HO (20 mL) and extracted three times with EtOAc (30 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with a 0-40% gradient of ethyl acetate in petroleum ether to give 750 mg (37%) of methyl 1-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 244

[0278] Step 2: Methyl 4-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 42, step 2, was prepared from methyl 1-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 40, step 5, to afford 500 mg (88%) of methyl 4-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 376

[0279] Step 3: Methyl 4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 42, step 3, was prepared from methyl 4-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 38, step 7, to afford 350 mg (80%) of methyl 4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 433

[0280] Step 4: Methyl 8-bromo-4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 42, step 4, was prepared from methyl 4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 440 mg (91%) of methyl 8-bromo-4-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):513

[0281] Intermediate 43: Methyl 8-bromo-2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0282] Step 1: Methyl 3-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 43, step 1, was prepared from methyl 3-chloro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 42, step 1, to afford 360 mg (36%) of methyl 3-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 244

[0283] Step 2: Methyl 2-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 43, step 2, was prepared from methyl 3-cyano-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 40, step 5, to afford 200 mg (47%) of methyl 2-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 376

[0284] Step 3: Methyl 2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 43, step 3, was prepared from methyl 2-cyano-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 38, step 7, to afford 200 mg of methyl 2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (crude). LC / MS(m / z, MH+): 433

[0285] Step 4: Methyl 8-bromo-2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 43, step 4, was prepared from methyl 2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 100 mg (64%) of methyl 8-bromo-2-cyano-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):513

[0286] Intermediate 44: Methyl 8-bromo-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0287] Step 1: 3-Fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate [ka] Intermediate 44, step 1, was prepared from 3-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that for Intermediate 9, step 1, to afford 4.2 g (81%) of 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 327

[0288] Step 2: Methyl 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 44, step 2, was prepared from 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 9, step 2, to afford 2.9 g (95%) of methyl 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 237

[0289] Step 3: Methyl 2-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 44, step 3, was prepared from methyl 3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that for Intermediate 9, step 3, to afford 3.6 g (80%) of methyl 2-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 369

[0290] Step 4: Methyl 2-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 44, step 4, was prepared from methyl 2-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 4 to afford 4.3 g (100% yield) of methyl 2-fluoro-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+): 347

[0291] Step 5: Methyl 2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 44, step 5, was prepared from methyl 2-fluoro-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 for Intermediate 7, step 1, to afford 827 mg (38% yield) of methyl 2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 426

[0292] Step 6: Methyl 8-bromo-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 44, step 6, was prepared from methyl 2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 405 mg (41% yield) of methyl 8-bromo-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):504

[0293] Intermediate 45: Methyl 8-bromo-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0294] Step 1: Methyl 4-fluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 45, step 1, was prepared from methyl 4-fluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2017140669) following a procedure similar to that for Intermediate 4 to afford 3.1 g (67% yield) of methyl 4-fluoro-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+): 347

[0295] Step 2: Methyl 4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 45, step 2, was prepared from methyl 4-fluoro-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 for Intermediate 7, step 1, to afford 1.9 g (40% yield) of methyl 4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 426

[0296] Step 3: Methyl 8-bromo-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 45, step 3, was prepared from methyl 4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 1.24 g (55% yield) of methyl 8-bromo-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):504

[0297] Intermediate 46: Methyl 8-bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0298] Step 1: Ethyl (Z)-5-(2,4-difluoro-3-methoxyphenyl)pent-4-enoate [ka] To a solution of [3-(ethoxycarbonyl)propyl]triphenylphosphonium bromide (5.42 g, 11.5 mmol) in THF (40 mL) at −78° C., a 1 M solution of potassium bis(trimethylsilyl)amide THF (11.5 mL, 11.5 mmol) was slowly added. The reaction mixture was stirred at −78° C. for 1 hour, and a solution of 2,4-difluoro-3-methoxybenzaldehyde (1 g, 5.75 mmol) in THF (5 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour and then allowed to reach room temperature under stirring overnight. The mixture was poured into water and extracted with DCM. The aqueous layer was separated and extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 100 / 0 to 90 / 10 to give 1.1 g (71%) of ethyl (Z)-5-(2,4-difluoro-3-methoxyphenyl)pent-4-enoate. LC / MS(m / z, MH+):271

[0299] Step 2: Ethyl 5-(2,4-difluoro-3-methoxyphenyl)pentanoate [ka] To a solution of ethyl (Z)-5-(2,4-difluoro-3-methoxyphenyl)pent-4-enoate (8.4 g, 31 mmol) in ethanol (40 mL) was added Pd / C 10% (0.33 g). The black suspension was hydrogenated in an autoclave under 3.5 bar of hydrogen at room temperature for 1 hour. The mixture was filtered with an ethanol wash, and the filtrate was concentrated under reduced pressure to give 8.4 g (99%) of ethyl 5-(2,4-difluoro-3-methoxyphenyl)pentanoate as a colorless oil. LC / MS(m / z, MH+): 273

[0300] Step 3: 5-(2,4-difluoro-3-methoxyphenyl)pentanoic acid [ka] To a solution of ethyl 5-(2,4-difluoro-3-methoxyphenyl)pentanoate (5.7 g, 20.9 mmol) in ethanol (15 mL) was added aqueous NaOH (8.8 mL, 44 mmol). The reaction mixture was stirred at 50° C. for 40 minutes. After cooling to room temperature, ice was added, and the reaction mixture was then acidified to pH 3 with 1 M aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give 5.1 g (99%) of 5-(2,4-difluoro-3-methoxyphenyl)pentanoic acid. LC / MS(m / z, MH+): 245

[0301] Step 4: 1,3-Difluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A mixture of 5-(2,4-difluoro-3-methoxyphenyl)pentanoic acid (5.5 g, 22.5 mmol) and Eaton's reagent (143 mL, 0.9 mol) was stirred at room temperature for 12 hours, and then ice was added. A saturated aqueous solution of NaHCO3 and DCM were added. The organic layer was separated, and the aqueous layer was extracted three times with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 5 g (98%) of 1,3-difluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+): 227

[0302] Step 5: 1,3-Difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] To 1,3-difluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (6.79 g, 30 mmol) was slowly added a 33% solution of hydrobromic acid in acetic acid (34 mL, 0.6 mol). The brown reaction mixture was heated at 75° C. overnight. An additional 33% solution of hydrobromic acid in acetic acid (17 mL, 0.3 mol) was added, and the mixture was heated at 75° C. for 2 days. After cooling to room temperature, the mixture was poured onto ice. A saturated aqueous solution of NaHCO3 and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 95 / 5 to 50 / 50 to give 4.2 g (66%) of 1,3-difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one as a yellow solid. LC / MS(m / z, M-H):211

[0303] Step 6: 1,3-Difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate [ka] Intermediate 46, step 6, was prepared from 1,3-difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that of Intermediate 9, step 1, to afford 6.1 g (89%) of 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate as a yellow oil. LC / MS(m / z, MH+): 345

[0304] Step 7: Methyl 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 46, step 7, was prepared from 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 9, step 2, to afford methyl 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate 3 g (66%) as a colorless oil. LC / MS(m / z, MH+): 255

[0305] Step 8: Methyl 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 46, step 8, was prepared from methyl 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of Intermediate 9, step 3, to afford methyl 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate 1 g (37%). LC / MS(m / z, MH+): 387

[0306] Step 9: Methyl 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 46, step 9, was prepared from methyl 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for intermediate 4 to afford 0.75 g (80% yield) of methyl 2,4-difluoro-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+): 365

[0307] Step 10: Methyl 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 46, step 10, was prepared from methyl 2,4-difluoro-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 for Intermediate 7, step 1, to afford 1.28 g (93% yield) of methyl 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 444

[0308] Step 11: Methyl 8-bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 46, step 11, was prepared from methyl 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 0.67 g (46% yield) of methyl 8-bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brownish foam. LC / MS(m / z, MH+):522

[0309] Intermediate 47: 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine [ka] Intermediate 47 was prepared from 3-(4-bromobenzylidene)azetidine hydrochloride following a procedure similar to that of Method 2 for Intermediate 1 to yield 0.34 g (40%) of 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):284

[0310] Intermediate 48: Tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate [ka]

[0311] Step 1: Tert-butyl 3-((6-bromopyridin-3-yl)methyl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-methyleneazetidine-1-carboxylate (2.54 g, 15 mmol) in anhydrous THF (30 mL) under an Ar atmosphere was added 9-BBN (33 mL, 16.5 mmol). The resulting mixture was heated to 75 °C for 2 h. After cooling to room temperature, 2-bromo-5-iodopyridine (3.84 g, 13.5 mmol), K2CO3 (910 mg, 6.58 mmol), anhydrous DMF (21 mL), and Pd(dppf)Cl2 (0.33 g, 0.45 mmol) were added, and the mixture was heated to 60 °C overnight under an Ar atmosphere. After cooling to room temperature, EtOAc and water were added. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 50 / 50 cyclohexane / EtOAc to afford 2.07 g (42%) of tert-butyl 3-((6-bromopyridin-3-yl)methyl)azetidine-1-carboxylate. LC / MS(m / z, MH+): 327

[0312] Step 2: Tert-butyl 3-((6-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate [ka] Step 2 of intermediate 48 was prepared from tert-butyl 3-((6-bromopyridin-3-yl)methyl)azetidine-1-carboxylate following a procedure similar to that of Step 1 of Intermediate 7 to afford 0.4 g (58%) of tert-butyl 3-((6-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate as a brownish foam. LC / MS(m / z, MH+): 449

[0313] Step 3: Tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate [ka] Step 3 of intermediate 48 was prepared from tert-butyl 3-((6-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate following a procedure similar to that of step 2 of intermediate 7 to afford 60 mg (27%) of tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate as a yellowish foam. LC / MS(m / z, MH+):527

[0314] Intermediate 49: 8-Bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka]

[0315] Step 1: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 49, step 1, was prepared from 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate (prepared according to WO2018091153) and 3-(4-bromobenzyl)-1-(3-fluoropropyl)azetidine following a procedure similar to that for Intermediate 7, step 1, to afford 1.27 g (70%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate. LC / MS (m / z, MH+): 450

[0316] Step 2: 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 49, step 2, was prepared from 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate following a procedure similar to that for Intermediate 7, step 2, to afford 1.7 g (89%) of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate. LC / MS(m / z, MH+):528

[0317] Step 3: 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] To a solution of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (0.8 g, 1.51 mmol) in MeOH (15 mL) was added a solution of NaOH (1.51 mL, 1 M), and the reaction mixture was heated to 50° C. for 1 h. After cooling, EtOAc and water were added, and the pH was adjusted to 4 with HCl 5N. After separation, the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give 0.6 g (90%) of 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as a brown solid. LC / MS(m / z, MH+): 444

[0318] Intermediate 50: 3-(4-bromobenzyl)-1-(2,3-difluoropropyl)azetidine [ka] Intermediate 50 was prepared from 2,3-difluoropropyl trifluoromethanesulfonate following a procedure similar to that in Step 2 of Intermediate 27 to yield 211 mg (40%) of 3-(4-bromobenzyl)-1-(2,3-difluoropropyl)azetidine. LC / MS(m / z, MH+):304

[0319] Intermediate 51: Methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0320] Step 1: 3-(4-bromobenzyl)-1-(3,3,3-trifluoropropyl)azetidine [ka] Intermediate 51, step 1, was prepared from 3-(4-bromobenzyl)azetidine, 4-methylbenzenesulfonic acid and 1,1,1-trifluoro-3-iodopropane following a procedure similar to that for Intermediate 23 to afford 0.8 g (49%) of 3-(4-bromobenzyl)-1-(3,3,3-trifluoropropyl)azetidine. LC / MS(m / z, MH+): 322

[0321] Step 2: Methyl 9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 51, step 2, was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 4) and 3-(4-bromobenzyl)-1-(3,3,3-trifluoropropyl)azetidine following a procedure similar to that for Intermediate 7, step 1, to afford 1.4 g (86%) of methyl 9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 444

[0322] Step 3: Methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 51, step 3, was prepared from methyl 9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 1.2 g (73%) of methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a brown foam. LC / MS(m / z, MH+):522

[0323] Intermediate 52: Methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate [ka]

[0324] Step 1: Methyl 6-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate [ka] Intermediate 52, step 1, was prepared from methyl 1-oxotetralin-6-carboxylate following a procedure similar to that of Intermediate 6, step 1, to afford 459 mg (19%) of methyl 6-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate. LC / MS(m / z, MH+): 349

[0325] Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate [ka] To a solution of methyl 6-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.29 g, 0.83 mmol) in THF (5 mL) at −78° C. under an Ar atmosphere, N,N-bis(trifluoromethylsulfonyl)aniline (0.39 g, 1.08 mmol) was added, followed by KHMDS (1 M, 1.08 mL, 1.08 mmol). The reaction mixture was stirred for 5 hours while warming to −10° C., then poured into brine and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-10% gradient of ethyl acetate in cyclohexane to give 0.33 g (82%) of methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z, MH+): 481

[0326] Intermediate 53: 8-Bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka]

[0327] Step 1: 1,3-Difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate [ka] To a suspension of 1,3-difluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Step 5 of Intermediate 46) (2.3 g, 10.84 mmol) and K2CO3 (3.75 g, 27.1 mmol) in acetone (150 mL) was added dropwise 2,2-dimethylpropanoyl chloride (3.18 mL, 23.85 mmol). The reaction mixture was stirred at room temperature for 20 minutes. Water was added, and the reaction mixture was extracted three times with EtOAc. The organic phase was collected, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH: 100 / 00 to 97 / 03 to afford 3 g (93%) of 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate as a yellow oil. LC / MS(m / z, MH+):297

[0328] Step 2: 2,4-Difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 53, step 2, was prepared from 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate following a procedure similar to that of Intermediate 9, step 3, to afford 1.35 g (31%) of 2,4-difluoro-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z, MH+): 429

[0329] Step 3: 2,4-Difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 53, step 3, was prepared from 1,3-difluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate following a procedure similar to that for intermediate 4 to afford 310 mg (63%) of 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z, MH+): 407

[0330] Step 4: 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 53, step 4, was prepared from 2,4-difluoro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate following a procedure similar to that for Intermediate 7, step 1, to afford 180 mg (43%) of 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate. LC / MS(m / z, MH+): 486

[0331] Step 5: 8-Bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Intermediate 53, step 5, was prepared from 2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate following a procedure similar to that of Intermediate 7, step 2, to afford 210 mg (76%) of 8-bromo-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate. LC / MS(m / z, MH+):564

[0332] Intermediate 54: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0333] Step 1: 3-Formyl-2-methoxyphenyl pivalate [ka] Intermediate 54, step 1, was prepared from 3-hydroxy-2-methoxy-benzaldehyde following a procedure similar to that of Intermediate 53, step 1, to afford 11.5 g (74%) of 3-formyl-2-methoxyphenyl pivalate. LC / MS(m / z, MH+): 237

[0334] Step 2: Ethyl (Z)-5-(2-methoxy-3-(pivaloyloxy)phenyl)pent-4-enoate [ka] Intermediate 54, step 2, was prepared from 3-formyl-2-methoxyphenyl pivalate following a procedure similar to that of Intermediate 46, step 1, to afford ethyl (Z)-5-(2-methoxy-3-(pivaloyloxy)phenyl)pent-4-enoate 11 g (67%). LC / MS(m / z, MH+): 335

[0335] Step 3: Ethyl 5-(2-methoxy-3-(pivaloyloxy)phenyl)pentanoate [ka] Intermediate 54, step 3, was prepared from ethyl (Z)-5-(2-methoxy-3-(pivaloyloxy)phenyl)pent-4-enoate following a procedure similar to that of Intermediate 46, step 2, to afford ethyl 5-(2-methoxy-3-(pivaloyloxy)phenyl)pentanoate 11 g (99%). LC / MS(m / z, MH+): 337

[0336] Step 4: 2-Hydroxy-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] Intermediate 54, step 4, was prepared from ethyl 5-(2-methoxy-3-(pivaloyloxy)phenyl)pentanoate following a procedure similar to that of Intermediate 46, step 4, to afford 3.6 g (53%) of 2-hydroxy-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. LC / MS(m / z, MH+):207

[0337] Step 5: 1-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate [ka] Intermediate 54, step 5, was prepared from 2-hydroxy-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that for Intermediate 9, step 1, to afford 4.6 g (70%) of 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 339

[0338] Step 6: Methyl 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate [ka] Intermediate 54, step 6, was prepared from 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 9, step 2, to afford 2.4 g (70%) of methyl 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate. LC / MS(m / z, MH+): 249

[0339] Step 7: Methyl 4-methoxy-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 54, step 7, was prepared from methyl 1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate following a procedure similar to that of Intermediate 9, step 3, to afford 3.8 g (100%) of methyl 4-methoxy-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 381

[0340] Step 8: Methyl 4-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 54, step 8, was prepared from methyl 4-methoxy-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for intermediate 4 to afford methyl 4-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate 2 g (56%). LC / MS(m / z, MH+): 359

[0341] Step 9: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 54, step 9, was prepared from methyl 4-methoxy-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 for Intermediate 7, step 1, to afford 180 mg (43%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 438

[0342] Step 10: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 54, step 10, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 576 mg (62%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):516

[0343] Intermediate 55: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0344] Step 1: Methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 55, 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 (Intermediate 4) and 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine (Intermediate 27) following a procedure similar to that for Intermediate 7, step 1, to afford 4.7 g (98%) of methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 426

[0345] Step 2: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 55, step 2, was prepared from methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 7, step 2, to afford 3.4 g (61%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):504

[0346] Intermediate 56: Methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 56 was prepared from methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 55) following a procedure similar to that for Intermediate 8 to yield 164 mg (50%) of methyl 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):552

[0347] Intermediate 57: Methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0348] Step 1: 6,7-Dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate [ka] Intermediate 57, step 1, was prepared from 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one following a procedure similar to that of Intermediate 9, step 3, to afford 1.68 g (85%) of 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate. LC / MS(m / z, MH+):293

[0349] Step 2: 2-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Intermediate 57, step 2, was prepared from 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate following a procedure similar to that for Intermediate 4 to afford 91 mg (65%) of 2-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LC / MS(m / z, MH+):271

[0350] Step 3: 3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 57, step 3, was prepared from 2-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 3-(4-bromobenzyl)-1-(3,3-difluoropropyl)azetidine (Intermediate 27) following a procedure similar to that for Intermediate 7, step 1, to afford 782 mg (59%) of 3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine. LC / MS (m / z, MH+): 350

[0351] Step 4: 3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine [ka] Intermediate 57, step 4, was prepared from 3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine following a procedure similar to that of Intermediate 7, step 2, to afford 211 g (86%) of 3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+): 428

[0352] Intermediate 58: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka]

[0353] 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

[0354] 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

[0355] 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

[0356] Step 4: Methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 58, step 4, was prepared from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 9, step 3, 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

[0357] Step 5: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 58, step 5, was prepared from methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 38, step 7, to afford 1.1 g (95%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 422

[0358] Step 6: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka] Intermediate 58, step 6, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 7, step 2, to afford 1.4 g (100% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS (m / z, MH+): 500 A mixture of two isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by SFC (conditions: column DAICEL IH (250 × 50 mm, 5 μm); supercritical CO 87% / MeOH 13% / [0.1% EtN in EtOH]; 40 °C; 100 bar) to give 217 mg of isomer 1 and 174 mg of isomer 2.

[0359] Intermediate 59: Methyl 8-benzyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0360] Step 1: 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

[0361] Step 2: Methyl 9-acetoxy-8-benzyl-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 (300 mg, 0.89 mmol), potassium benzyltrifluoroborate (193 mg, 0.97 mmol), CsCO (874 mg, 2.63 mmol), and Pd(dppf)Cl complex with DCM (74 mg, 88 μmol) in toluene (9 mL) and water (3 mL) was heated to 90 °C for 30 min in a sealed tube. After cooling to room temperature, the reaction mixture was extracted with EtOAc (200 mL). The organic layer was washed twice with water (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-100% gradient of ethyl acetate in cyclohexane to give 285 mg (92%) of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 351

[0362] Step 3: 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

[0363] Step 4: Methyl 8-benzyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Intermediate 59, step 4, 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 52, step 2, to afford 249 mg (79%) of methyl 8-benzyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 441

[0364] Intermediate 60: Methyl 3-bromo-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate [ka]

[0365] Step 1: 4-Oxothiochroman-7-yl trifluoromethanesulfonate [ka] Intermediate 60, step 1, was prepared from 7-hydroxythiochroman-4-one (prepared according to WO2018091153) following a procedure similar to that of Intermediate 9, step 1, to afford 1.14 g (33%) of 4-oxothiochroman-7-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 313

[0366] Step 2: Methyl 4-oxothiochroman-7-carboxylate [ka] Intermediate 60, step 2, was prepared from 4-oxothiochroman-7-yl trifluoromethanesulfonate following a procedure similar to that of Intermediate 9, step 2, to afford 0.61 g (76%) of methyl 4-oxothiochroman-7-carboxylate. LC / MS(m / z, MH+): 223

[0367] Step 3: Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate [ka] Intermediate 60, step 3, was prepared from methyl 4-oxothiochroman-7-carboxylate following a procedure similar to that of Intermediate 52, step 2, to afford 199 mg (41%) of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate. LC / MS(m / z, MH+): 355

[0368] Step 4: Methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate [ka] Intermediate 60, step 4, was prepared from methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxylate following a procedure similar to that of Intermediate 38, step 7, to afford 72 mg (62%) of methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate. LC / MS(m / z, MH+): 412

[0369] Step 5: Methyl 3-bromo-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate [ka] Intermediate 60, step 5, was prepared from methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate following a procedure similar to that of Intermediate 7, step 2, to afford 923 mg (80%) of methyl 3-bromo-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylate. LC / MS(m / z, MH+): 490

[0370] Intermediate 61: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka]

[0371] Step 1: Methyl 7-ethyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, racemic mixture [ka] Intermediate 61, step 1, was prepared from methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate and lithium diethylcopper following a procedure similar to that for Intermediate 58, step 3, to afford 0.4 g (80%) of methyl 7-ethyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 247

[0372] Step 2: Methyl 7-ethyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 61, step 2, was prepared from methyl 7-ethyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 9, step 3, to afford 0.62 g (98%) of methyl 7-ethyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 379

[0373] Step 3: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 61, Step 3, was prepared from methyl 7-ethyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 38, Step 7, to afford 0.67 g (94%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 436

[0374] Step 4: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka] Intermediate 61, step 4, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 7, step 2, to afford 0.66 g (100% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+):514 A mixture of two isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-ethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral HPLC (conditions: column CHIRALPACK AD (350 × 76.5 mm, 20 μm); heptane 90% / EtOH 10% / [0.1% EtN in MeOH]; 400 mL / min) to give 220 mg of isomer 1 and 220 mg of isomer 2.

[0375] Intermediate 62: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka]

[0376] Step 1: Methyl 7-isopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, racemic mixture [ka] Intermediate 62, step 1, was prepared from methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate and lithium diisopropylcopper following a procedure similar to that for Intermediate 58, step 3, to afford 0.37 g (77%) of methyl 7-isopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture. LC / MS(m / z, MH+):261

[0377] Step 2: Methyl 7-isopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 62, step 2, was prepared from methyl 7-isopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 9, step 3, to afford 0.56 g (100%) of methyl 7-isopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 393

[0378] Step 3: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 62, Step 3, was prepared from methyl 7-isopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that of Intermediate 38, Step 7, to afford 0.507 g (79%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS (m / z, MH+): 450

[0379] Step 4: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and Isomer 2 [ka] Intermediate 62, step 4, was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 7, step 2, to afford 0.453 g (76% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+):528 A mixture of two isomers of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by SFC (conditions: column CHIRALCEL OD-H (250 × 30 mm, 5 μm); supercritical CO 85% / MeOH 15% / [0.1% EtN in MeOH]; 120 mL / min; 40 °C; 100 bar) to give 99 mg of isomer 1 and 100 mg of isomer 2.

[0380] Intermediate 63: Methyl 8-bromo-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka]

[0381] Step 1: Methyl 7-cyclopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, racemic mixture [ka] Intermediate 63, step 1, was prepared from methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate and lithium dicyclopropylcopper following a procedure similar to that for Intermediate 58, step 3, to afford 0.175 g (37%) of methyl 7-cyclopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 259

[0382] Step 2: Methyl 7-cyclopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 63, step 2, was prepared from methyl 7-cyclopropyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 9, step 3, to afford 0.16 g (61%) of methyl 7-cyclopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 391

[0383] Step 3: Methyl 7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 63, step 3, was prepared from methyl 7-cyclopropyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 38, step 7, to afford 0.145 g (100%) of methyl 7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+): 448

[0384] Step 4: Methyl 8-bromo-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture [ka] Intermediate 63, step 4, was prepared from methyl 7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (racemic mixture) following a procedure similar to that for Intermediate 7, step 2, to afford 0.268 g (82% yield) of methyl 8-bromo-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture. LC / MS(m / z, MH+):526

[0385] Intermediate 64: Methyl 8-(bicyclo[3.2.1]octan-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka]

[0386] 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 64, step 1, was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that for Intermediate 38, step 7, 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

[0387] Step 2: Methyl 9-acetoxy-8-(bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (1.07 g, 2.92 mmol) and Pd / C 10% (50 mg, 4.68 mmol) in EtOAc (10 mL) was hydrogenated at room temperature and 3.5 bar of H2 for 4 h. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by flash chromatography eluting with a gradient of EtOAc in cyclohexane (99 / 01 to 90 / 10, v / v) to give 580 mg (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

[0388] 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 64, 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 of Intermediate 59, step 3, to afford 509 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

[0389] 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 64, 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 52, step 2, to afford 480 mg (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 [Example]

[0390] Method A: Example 1 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka]

[0391] Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (103 mg, 212.45 μmol), phenylboronic acid (37.14 mg, 298.51 μmol), CsCO (224 mg, 673.75 μmol), and Pd(dppf)Cl, complex with DCM (13.15 mg, 15.46 μmol) in dioxane (1 ml) and water (0.4 ml) was microwaved at 80 °C for 30 min. 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 41 mg (40%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 484

[0392] Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] To a solution of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (40.8 mg, 84.45 μmol) in MeOH (1.5 ml) was added a solution of NaOH (300 μl, 1 M) and the reaction mixture was heated to reflux for 50 min. 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 flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 30 mg (70.8%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.

[0393] Example 2 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (2) [ka]

[0394] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 2 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and 2,4-dichlorophenyl-boronic acid following a procedure similar to that of Step 1 of Example 1 to afford 100 mg (62%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):552

[0395] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)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-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (100 mg, 181 μmol) in MeOH (3 ml), a solution of NaOH (250 μl, 1 M) was added and the reaction mixture was heated to reflux for 2.5 h. After cooling, water (5 ml) and DCM (5 ml) were added and the pH was adjusted to 5 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 48 mg (49%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0396] Method B: Example 148 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0397] Step 1: Methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 148 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 8) and 2-bromo-5-chloro-3-methyl-pyridine following a procedure similar to that of Step 1 of Example 1 to afford 71 mg (47%) of methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):533

[0398] Step 2: 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 148 was prepared from methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 2 to provide 21 mg (30%) of 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0399] Method C: Example 4 8-(4,4-Difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka]

[0400] Step 1: Methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 4 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and (4,4-difluorocyclohex-1-en-1-yl)boronic acid following a procedure similar to that of Step 1 of Example 1 to afford 55 mg (347%) of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 524.

[0401] Step 2: Methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] A mixture of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (55 mg, 105 μmol), Pd / C 10% (18.67 mg, 175 μmol) in MeOH (3 ml) and EtOAc (2 ml) was hydrogenated at 50° C. and 25 bar of H for 15 h. The reaction mixture was filtered, the filtrate evaporated under reduced pressure, and the residue purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 55 mg (99%) 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+):526

[0402] Step 3: 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] Step 3 of Example 4 was prepared from methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 1 to provide 46 mg (80.6%) of 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride. Method D:

[0403] Example 39 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0404] 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 39 was prepared from 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 5) and (4-bromobenzyl)(1-(3-fluoropropyl)azetidin-3yl)methanone (Intermediate 11) according to a procedure similar to that of Step 1 of Example 1 to afford 111 mg (46%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange viscous oil. LC / MS(m / z, MH+):566

[0405] Step 2: 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 39 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 2 to provide 69 mg (63%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid. Method E:

[0406] Example 231 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0407] Step 1: Methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (50 mg, 103 μmol) in THF (1 mL) was added nickel(II) chloride ethylene glycol dimethyl ether complex (1 mg, 5 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.38 mg, 5.14 μmol), sodium carbonate (21.79 mg, 205.58 μmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.15 mg, 1.03 μmol), 3-(bromomethyl)pentane (63 μL, 308 μmol), and tris(trimethylsilyl)silane (30 μL, 150 μmol). The degassed reaction mixture was irradiated under LED blue light (photoreactor Penn OC ml) for 2 h. 2 ml of 1 M potassium fluoride and EtOAc were added. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / EtOAc / MeOH from 100 / 0 / 0 to 50 / 45 / 05 to give 21 mg (42%) of methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+): 492

[0408] Step 2: 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 2 of Example 231 was prepared from methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 2 to provide 17 mg (87%) of 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid. Method F

[0409] Example 115 8-(2,4-Dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka]

[0410] Step 1: Methyl 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-carboxylate [ka] Step 1 of Example 115 was prepared from 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 5) and 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 34) according to a procedure similar to that of Step 1 of Example 1 to afford 215 mg (58%) of methyl 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-carboxylate as an orange oil. LC / MS(m / z, MH+):586

[0411] Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a solution of methyl 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-carboxylate (165 mg, 0.281 mmol) in ethanol (30 mL) was added PtO (32 mg, 0.14 mmol). The suspension was hydrogenated in an autoclave under 2 bar of hydrogen at room temperature for 2 h. The mixture was filtered with an ethanol wash, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM / MeOH:90 / 10 to give 140 mg (84%) of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):588

[0412] Step 3: 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (140 g, 0.238 mmol) in methanol (2 mL), THF (1 mL), and water (0.5 mL) was added LiOH (59 mg, 2.38 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, taken up in water, and acidified to pH 3 with 1 N aqueous HCl. The resulting precipitate was filtered and dried to give 44 mg (30%) of 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride as a white solid. Method G:

[0413] Example 262 6-(2,4-Dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride [ka]

[0414] Step 1: Methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate [ka] Step 1 of Example 262 was prepared from methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate (Intermediate 52) and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine (Intermediate 2) following a procedure similar to that of Step 1 of Example 1 to provide 48 mg (43%) of methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z, MH+):538

[0415] Step 2: 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride [ka] Step 2 of Example 262 was prepared from methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate following a procedure similar to that of Step 2 of Example 2 to provide 22 mg (47%) of 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride. Method H:

[0416] Example 77 8-(2,4-Dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride isomer 1 [ka]

[0417] 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] Step 1 of Example 77 was prepared from 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 5) and 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 47) following a procedure similar to that of Step 1 of Example 1 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

[0418] Step 2: 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] Under an argon atmosphere, a solution of diiodomethane (90 μL, 1.13 mmol) in DCM (1 mL) was added to a solution of diethylzinc (1.13 mL, 1.13 mmol, 1 M in hexane) at 0° C. The mixture was stirred at 0° C. for 30 minutes, followed by the dropwise addition of 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 (310 mg, 0.563 mmol) in DCM (6 mL). The resulting mixture was stirred overnight while warming to room temperature, then quenched with 1N aqueous HCl (10 mL) and diluted with water. The aqueous layer was separated and extracted three times with DCM. The combined organic layers were washed with a saturated aqueous solution of NaHCO, brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 80 / 20, v / v) to afford 132 mg (33%) 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 as a mixture of two isomers. LC / MS (m / z, MH+): 550 A mixture of two isomers 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 was separated by chiral HPLC (conditions: flash Chiralcel OD-H 250 × 30 mm, 5 μm; heptane 95% / isopropanol 5% / TEA 0.1%; 45 mL / min) to give 54 mg of isomer 1 and 43 mg of isomer 2.

[0419] Step 3: 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride isomer 1 [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 isomer 1 (43 mg, 80 μmol) in methanol (9 mL) / THF (3 mL) / water (3 mL) was added LiOH (30.5 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with 1N aqueous HCl to pH 1 and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 31 mg (74%) of 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride salt isomer 1 as a white solid.

[0420] Example 78 8-(2,4-Dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride isomer 2 [ka] Example 78 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in step 3 of Example 77 to afford 41 mg (78%) of 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride salt isomer 2 as a white solid.

[0421] Example 105 8-(2-Carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka]

[0422] Step 1: Methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of Example 105 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and 2-cyanopyridine-4-boronic acid pinacol ester following a procedure similar to that of Step 1 of Example 1 to afford 227 mg (44%) of methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 510

[0423] Step 2: 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride [ka] To a solution of methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (227 mg, 445 μmol) in MeOH (10 ml) was added a 1 M solution of NaOH (2.8 ml, 2.8 mmol) 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 flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 94 mg (41%) of 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.

[0424] Example 110 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride [ka]

[0425] Step 1: tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate [ka] Step 1 of Example 110 was prepared from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and N-Boc-2-pyrroleboronic acid following a procedure similar to that of Step 1 of Example 1 to afford 223 mg (89%) of tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-8-yl)-1H-pyrrole-1-carboxylate. LC / MS(m / z, MH+):573

[0426] Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride [ka] To a solution of tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate (93 mg, 162 μmol) in MeOH (10 ml), a solution of NaOH (1.02 ml, 1.02 mmol) was added 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 flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride salt 30 mg (32%) and 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride salt 12 mg (16%).

[0427] Example 175 8-(2,4-Dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 [ka]

[0428] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a solution 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 (Step 1 of Example 235) (200 mg, 343 μmol) in DCM (5 mL) at −78° C. was added diethylaminosulfur trifluoride (90 μL, 0.69 mmol). The mixture was stirred at −78° C. for 1 h, then allowed to warm to room temperature for 6 h. A saturated aqueous solution of NaHCO and DCM was added. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 0 / 0 to 90 / 10 / 1 DCM / MeOH / NH4OH to afford 153 mg (77%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a mixture of two isomers. LC / MS(m / z, MH+):584 A mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral SFC (conditions: Flash Chiralcel OD-H (250 × 30 mm, 5 μm); supercritical CO 80% / [0.1% TEA / MeOH] 20%; 3 mL / min) to give 35 mg of isomer 1 and 37 mg of isomer 2.

[0429] Step 2: 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 [ka] Example 175 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 following a procedure similar to that in step 3 of Example 77 to yield 31 mg (82%) of 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1.

[0430] Example 176 8-(2,4-Dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 2 [ka] Example 176 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in step 3 of Example 77 to yield 26 mg (75%) of 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 2.

[0431] Example 235 8-(2,4-Dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride isomer 1 [ka]

[0432] Step 1: 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 solution of 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (Step 1 of Example 39) (100 mg, 176 μmol) in THF (5 mL) at −10° C. was added a 3 M solution of methylmagnesium bromide in ether (180 μL, 530 μmol). The mixture was stirred at −10° C. for 45 min. The reaction mixture was slowly quenched by the addition of a saturated aqueous solution of NH4Cl and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 102 mg (99%) 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 as a mixture of two isomers. LC / MS(m / z, MH+):582 A mixture of two isomers 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 was separated by chiral HPLC (conditions: flash Chiralpak AY-H 250 × 4.6 mm, 5 μm; heptane 89 / EtOH 10 / MeOH 1 / TEA 0.2; 45 mL / min) to give 20 mg of isomer 1 and 19 mg of isomer 2.

[0433] Step 2: 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride isomer 1 [ka] Example 235 was prepared from 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 isomer 1 following a procedure similar to that in step 3 of Example 77 to yield 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride salt isomer 1 4 mg (21%).

[0434] Example 236 8-(2,4-Dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride isomer 2 [ka] Example 236 was prepared from 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 isomer 2 following a procedure similar to that in step 3 of Example 77 to afford 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride salt isomer 2 7 mg (35%).

[0435] Example 194 8-(2,4-Dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka]

[0436] Step 12: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and Isomer 2 [ka] Step 1 Isomer 1 and Isomer 2 of Example 194 were prepared from 3-(4-bromobenzyl)-1-(2,3-difluoropropyl)azetidine (Intermediate 50) 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 (Intermediate 5) following a procedure similar to that in Step 1 of Example 1 to afford 278 mg (66%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a mixture of Isomer 1 and Isomer 2. The mixture of two isomers was separated by chiral chromatography (conditions: Flash Chiralpak IF 5 μm (250 × 30 mm), eluent: heptane 95 EtOH 5 TEA 0.1) to give 91 mg of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 and 94 mg of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2. LC / MS(m / z, MH+): 570

[0437] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka] Step 2 isomer 1 of Example 194 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 following a procedure similar to that in Step 2 of Example 2 to yield 75 mg (84%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1.

[0438] Example 195 8-(2,4-Dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 [ka] Example 195 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in step 2 of Example 2 to yield 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 90 mg (98%).

[0439] Example 196 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid [ka]

[0440] Step 1: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] 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 acid (Step 1 of Example 39) (500 mg, 882 μmol) and O-methylhydroxylamine hydrochloride (184 mg, 2.21 mmol) in pyridine (5 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The two isomers were separated by SFC (conditions: Flash Chiralpak IG 5 μm (3 × 25 cm), eluent CO₂ / 11% (MeOH + 0.1% DEA)) to give 111 mg (21%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 34 mg (6%) of methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):595

[0441] Step 2: (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid [ka] Step 2 isomer 1 of Example 196 was prepared from methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in Step 2 of Example 2 to afford 86 mg (66%) of (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid.

[0442] Example 197 (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid [ka] Example 197 was prepared from methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in step 2 of Example 2 to afford (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetate salt 12 mg (30%).

[0443] Example 227 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka]

[0444] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 [ka] Step 1 of Example 227 was prepared from 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 5) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 1 (Intermediate 14) according to a procedure similar to that in Step 1 of Example 1 to afford 191 mg (64%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1. LC / MS(m / z, MH+):568

[0445] Step 2: Methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 [ka] To a mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (191 mg, 336 μmol) in DCM (2 ml) cooled to 0° C., thionyl chloride (53.6 μl, 739 μmol) was added. The reaction mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of NaHCO3 and DCM was added. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 0 to 00 / 100 cyclohexane / EtOAc to afford 182 mg (92%) of methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1. LC / MS(m / z, MH+):586

[0446] Step 3: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka] To a solution of methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 (100 mg, 170 μmol) in methanol (5 mL) and water (1 mL), LiOH (12 mg, 511 μmol) was added. The reaction mixture was stirred at room temperature for 3 h, then quenched with 1 N aqueous HCl to pH 6-7 and extracted three times with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 95 / 05 DCM / MeOH to afford 28 mg (29%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1.

[0447] Example 228 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 [ka]

[0448] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 [ka] Step 1 of Example 228 was prepared from 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 5) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol isomer 2 (Intermediate 15) according to a procedure similar to that in Step 1 of Example 1 to afford 186 mg (62%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2. LC / MS(m / z, MH+):568

[0449] Step 2: Methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 [ka] Step 2 of Example 228 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in Step 2 of Example 227 to afford methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 175 mg (91%). LC / MS(m / z, MH+):586

[0450] Step 3: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 [ka] Step 3 of Example 228 was prepared from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in Step 3 of Example 227 to afford 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 25 mg (26%).

[0451] Example 229 8-(2,4-Dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka] Example 229 was prepared from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and EtOH following a procedure similar to that in Step 3 of Example 227 to afford 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 15 mg (30%).

[0452] Example 230 8-(2,4-Dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 [ka] Example 230 was prepared from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 and EtOH following a procedure similar to that in step 3 of Example 227 to afford 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 34 mg (34%).

[0453] Example 243 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka]

[0454] Step 1: Methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 [ka] Step 1 of Example 243 was prepared from 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine Isomer 1 (Intermediate 25) 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 (Intermediate 5) following a procedure similar to that of Step 1 of Example 1 to yield 500 mg (99%) of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1. LC / MS(m / z, MH+):593

[0455] Step 2: Methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 [ka] A mixture of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (300 mg, 505 μmol) and triphenylphosphine (132 mg, 505 μmol) in THF (4 ml) was stirred at room temperature for 24 hours. DCM (100 ml) and water (100 ml) were added. After decantation, the organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 80 / 20 DCM / MeOH to afford 44 mg (15%) of methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1. LC / MS(m / z, MH+):567

[0456] Step 3: 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka] Step 3 of Example 243 was prepared from methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 1 following a procedure similar to that in Step 2 of Example 2 to afford 33 mg (79%) of 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1.

[0457] Example 244 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 [ka]

[0458] Step 1: Methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 [ka] Step 1 of Example 244 was prepared from 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 2 (Intermediate 26) 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 (Intermediate 5) following a procedure similar to that in Step 1 of Example 1 to afford methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 550 mg (97%). LC / MS(m / z, MH+):593

[0459] Step 2: Methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 [ka] Step 2 of Example 244 was prepared from methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in Step 2 of Example 243 to afford methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 140 mg (44%). LC / MS(m / z, MH+):567

[0460] Step 3: 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 [ka] Step 3 of Example 244 was prepared from methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 following a procedure similar to that in Step 2 of Example 2 to afford 22 mg (52%) of 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2.

[0461] Example 252 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0462] Step 1: tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate [ka] Step 1 of Example 252 was prepared from tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate (Intermediate 48) and (2-chlorophenyl)boronic acid following a procedure similar to that of Step 1 of Example 1 to afford 87 mg (41%) of tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate. LC / MS(m / z, MH+):559

[0463] Step 2: methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid [ka] Step 2 of Example 252 was prepared from tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate following a procedure similar to that for Step 2 of Intermediate 11 to afford methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid, which was used in the next step without further purification.

[0464] Step 3: Methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 3 of Example 252 was prepared from methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid following a procedure similar to that of Step 4 of Intermediate 28 to afford 35 mg (43%) of methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):519

[0465] Step 4: 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 4 of Example 252 was prepared from methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that in Step 2 of Example 2 to provide 32 mg (44%) of 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[0466] Example 253 8-(2,4-Dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka]

[0467] Step 1: tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate [ka] Step 1 of Example 253 was prepared from tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate (Intermediate 48) and (2,4-dichlorophenyl)boronic acid following a procedure similar to that of Step 1 of Example 1 to afford 105 mg (47%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate. LC / MS(m / z, MH+):593

[0468] Step 2: Methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid [ka] Step 2 of Example 253 was prepared from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate following a procedure similar to that for Step 2 of Intermediate 11 to afford methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid, which was used in the next step without further purification.

[0469] Step 3: Methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 3 of Example 253 was prepared from methyl 9-(5-(azetidin-3-ylmethyl)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 4 of Intermediate 28 to provide methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS(m / z, MH+):553

[0470] Step 4: 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] Step 4 of Example 253 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate following a procedure similar to that of Step 2 of Example 2 to afford 17 mg of 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (18% over the last two steps).

[0471] Example 254 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] Example 254 was prepared from 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Intermediate 49) and 2,4-dichlorophenyl-boronic acid according to a procedure similar to that in Step 1 of Example 1 to afford 120 mg (52%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as an off-white solid.

[0472] Example 255 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [ka] Example 255 was prepared from 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Intermediate 49) and 2-chlorophenyl-boronic acid according to a procedure similar to that in Step 1 of Example 1 to afford 130 mg (61%) of 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as a brownish solid.

[0473] The compounds according to Table 1a above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0474] Test: Estrogen receptor degrading activity The test measures the in vitro degradation activity of the compounds of Table 1a.

[0475] Degradation activity was measured using the breast cancer cell ERα in cell western assay described below.

[0476] 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.

[0477] In this test, the decomposition activity of estrogen receptors was measured using the concentration (nM) required to decompose 50% of the estrogen receptor (or IC 50 ) is obtained by

[0478] The % reduction in ERα levels was determined as follows: % inhibition = 100 * (1 - (sample - fulvestrant:DMSO - fulvestrant)).

[0479] 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.

[0480] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0481] 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.

[0482] Accordingly, also provided herein are pharmaceutical preparations comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0483] Also provided herein is a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0484] 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.

[0485] 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.

[0486] 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.

[0487] In one embodiment, the cancer is a hormone-dependent cancer.

[0488] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0489] 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.

[0490] In another embodiment, the metastasis is a brain metastasis.

[0491] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0492] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0493] 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.

[0494] 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.

[0495] 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.

[0496] 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.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] As an example, a unit dosage form of a compound of formula (I) in the form of 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:

[0501] 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. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula: R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3' and R3" independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R5 are each a hydrogen atom, a fluorine atom, or —NH 2 Group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) independently represent an alkoxy group, or an —OH group; or R4 and R5 together form an oxo group, or R4 and R5 together with the carbon atom to which they are attached represent =NOCH 3 group or (C 3 ~C 5 ) forming a cycloalkyl group; R7 represents a hydrogen atom, a methyl group, an —OH group or a fluorine atom; Alternatively, R4 and R7 together with the bond attached thereto form a cyclopropyl group which, together with the adjacent azetidine group, gives an azaspiro[2.3]hexane; - 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 ) alkylsulfonyl groups; and —OH groups; ・ (C 3 ~C 6 ) a fused phenyl group ((C 3 ~C 6 ) cycloalkyl rings optionally contain unsaturation, and fused phenyls are (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 ) optionally substituted with 1 to 3 substituents independently selected from fluoroalkoxy, cyano, carbamoyl, and —OH groups; cycloalkyl groups containing 3 to 7 carbon atoms, said cycloalkyl groups being saturated or partially saturated; ○ Fluorine atom, —OH group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) 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; - 3-8 membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, said heterocycloalkyl groups 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; 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; - R8 is (C 1 ~C 3 ) an alkyl group, a halogen atom, a cyano group, or (C 1 ~C 3 ) independently represent a fluoroalkyl group; R9 represents a hydrogen atom or a fluorine atom; R10 and R10' independently represent a hydrogen atom or a fluorine atom; R11 is a hydrogen atom or (C 1 ~C 3 ) an alkyl group or cyclopropyl; n is 0, 1 or 2; - m is 0 or 1].

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. X is -CH 2 4. A compound of formula (I) according to any one of claims 1 to 3, characterized in that it represents -, or a pharmaceutically acceptable salt thereof.

5. R4 and R5 are each independently a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, or —NH 2 or R4 and R5 together with the carbon atom to which they are attached form an oxo group, a =NOCH3 group, or a cyclopropyl group; or R4 and R7 together with the bond to which they are attached form a cyclopropyl group.

5. A compound of formula (I) according to claim 1, wherein R4 and R5 form a chloropropyl group, and in particular R4 and R5 both represent a hydrogen atom or a fluorine atom, or one of R4 and R5 represents a hydrogen atom and the other represents a fluorine atom or an -OH group, or one of R4 and R5 represents a methyl group and the other represents a hydroxy group or a fluorine atom, more particularly R4 and R5 both represent a hydrogen atom, or a pharmaceutically acceptable salt thereof.

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

7. 7. The compound of formula (I) according to claim 1, wherein R6 represents a phenyl group, which is optionally substituted with 1 to 3 substituents independently selected from chlorine, fluorine, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, fluoromethyl, difluoromethyl, 2,2-difluoroethyl, methoxy, ethoxy, cyano, cyanomethyl, trifluoromethylsulfonyl, methylsulfanyl, difluoromethylsulfanyl, methylsulfonyl and difluoromethoxy.

8. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that R6 represents a fused phenyl group selected from a bicyclo[4.2.0]octa-trienyl group and an indanyl group, said group being optionally substituted with one or two fluorine atoms.

9. R6 is, - a pyridyl group (the pyridyl group is a halogen atom, (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) fluoroalkyl group, (C 1 ~C 6 ) an alkoxy group, (C 1 ~C 6 ) optionally substituted with 1 to 3 substituents independently selected from fluoroalkoxy groups, carbamoyl and —OH groups, more particularly selected from methyl groups, methoxy groups, fluorine atoms, chlorine atoms, trifluoromethyl groups, difluoromethyl groups, methoxy groups and carbamoyl groups; - halogen atoms, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) fluoroalkyl group, (C 1 ~C 3 ) alkoxy groups and (C 1 ~C 3 ) pyridone optionally substituted with 1 to 3 substituents independently selected from fluoroalkoxy groups, more particularly selected from methyl groups, methoxy groups, fluorine atoms, chlorine atoms, trifluoromethyl groups and difluoromethyl groups; or -(C 1 ~C 6 ) a pyrrole group optionally substituted with one or two substituents selected from alkyl groups; Compounds of formula (I) according to any one of claims 1 to 6, characterized in that they represent

10. R6 represents a cycloalkyl group selected from a cyclohexyl group, a cyclopentyl group, a cycloheptyl group, a cycloheptenyl group, and a cyclohexenyl group, and the cycloalkyl group is ○ 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 ) the cycloalkyl group or the phenyl group is substituted with one or two halogen atoms or (C 1 ~C 3 ) optionally substituted with alkyl groups optionally substituted with 1 to 4 substituents independently selected from The cycloalkyl is Fluorine atoms, methyl groups, and Compounds of formula (I) according to any one of claims 1 to 6, characterized in that they are advantageously substituted with one to two substituents independently selected from cyclohexyl groups substituted by two halogen atoms, in particular fluoro atoms.

11. R6 represents a heterocycloalkyl group, more particularly a tetrahydropyranyl group, and said heterocycloalkyl group is 1 ~C 6 10. The compound of formula (I) according to claim 1, wherein the compound is optionally substituted with 1 to 3 substituents independently selected from alkyl groups, fluorine atoms and -OH groups.

12. R6 is, spiro[3.3]hept-1-ene or spiro[3.3]hept-2-ane groups (said groups are defined as (C 1 ~C 3 ) an alkyl group, 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 in particular optionally substituted with 1 or 2 fluorine atoms); bicyclo[2.2.1]heptan-2-yl or bicyclo[3.2.1]octan-3-yl group (said group is (C 1 ~C 3 ) an alkyl group, a fluorine atom, (C 1 ~C 3 ) an alkoxy group, (C 1 ~C 3 ) a bicyclic group selected from the group consisting of: Compounds of formula (I) according to any one of claims 1 to 6, characterized in that they represent

13. R6 is selected from ethyl, isobutyl and ethylbutyl (C 1 ~C 6 ) alkyl group, and the alkyl group is 1 ~C 3 ) an alkoxy group, (C 1 ~C 3 10. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that they are optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and -OH groups, in particular with 1 or 3 fluorine atoms.

14. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that R6 represents a cis-1,3a,4,5,6,6a-hexahydropentalenyl or octahydropentalenyl group.

15. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that R6 represents a cyclobutylmethyl group.

16. R6 is in particular a phenyl (C 1 ~C 2 7. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that they represent an alkyl group.

17. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that R3' and R3" represent a hydrogen atom.

18. Compounds of formula (I) according to any one of claims 1 to 6, characterized in that R8 independently represents a methyl group or a fluorine atom and n is 0, 1 or 2.

19. Y is -CH=, -C(CH 3 19. Compounds of formula (I) according to any one of claims 1 to 18, wherein -CH=, -CF= or -N=, in particular -CH= or -N=.

20. Compounds of formula (I) according to any one of claims 1 to 19, wherein R9 represents a hydrogen atom.

21. Compounds of formula (I) according to any one of claims 1 to 20, wherein R10 and R10' represent a hydrogen atom.

22. Compounds of formula (I) according to any one of claims 1 to 21, wherein R11 represents a hydrogen atom.

23. 23. A compound of formula (I) according to any one of claims 1 to 22, wherein m is 1.

24. The compound is The following compound: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 8-cyclopentyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) 8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) 8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) 8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) 8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-((1s,4s)-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-((1r,4r)-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) 8-(2-fluoro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) 8-(2,3-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) 8-(4-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxypyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) 8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) 8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[ 7] annulene-3-carboxylic acid, (30) 8-(2-fluoro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(2-chloro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) 8-(2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) 8-(4-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) 8-(2,4-dichlorophenyl)-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) and (42) 8-(2,4-dichlorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) and (44) 8-(3,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) - 4-(2-chlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin (3-(2 ... 8-(6,6-difluorospiro[3.3]hept-1-en-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(6,6-difluorospiro[3.3]heptan-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51), and 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylic acid, (52), 8-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (53), 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (54), 8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (55), 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (56), 8-(2-(difluoromethyl)-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (57), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (58), 8-(2-chloro-4-fluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (59), 8-(3-chloro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (60), 8-(3,4-bis(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (61), 8-(4-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (62), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (63), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(trans-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (64), 8-(3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (65), 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (66), 8-(3-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (67), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (68), 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (69), 8-(5-fluoro-2-methoxypyridin-4-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (70), 8-(3-fluoro-2-methoxypyridin-4-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (71), 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (72), 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (73), 8-(4-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (74), 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (75), 8-(4-chloro-2-(difluoromethyl)phenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (76), - 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (77), - 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (78), - 8-(4-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (79), 8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (80), - 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (81), - 8-(5-chloro-3-(difluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7- Dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (82), 8-(3-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (83), 8-(3-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (84), 8-(3,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (85), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (86), 8-(2-chloro-3-fluorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (87), 8-(3-chloro-4-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (88), 8-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (89), 8-(3-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (90), 8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (91), 8-(2,4-dichlorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (92), 8-(6-(difluoromethyl)-2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (93), 8-(3-chlorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (94), 8-(6-(difluoromethyl)-4-methylpyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (95), - 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 (96), - 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 2 (97), 8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (98), - 8-(4-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-( 3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (99), 8-(2-cyano-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (100), - 8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (101), 8-(3-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (102), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (103), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (104), - 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (105), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (106), 8-(2-chloro-4-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (107), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(trans-3-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (108), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-3-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (109), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (110), 8-(4-chloro-2-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (111), 8-(4-chloro-2-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (112), 8-(4-ethyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (113), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-((trifluoromethyl)sulfonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (114), 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (115), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-mesityl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (116), 8-(4-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (117), 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (118), 8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (119), 8-(2-fluoro-4-(methylthio)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (120), 8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (121), 8-(2,4-dimethylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (122), 8-(2-chloro-3-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (123), 8-(2-chloro-4-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (124), 8-(2-chloro-4-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (125), 8-(2-chloro-3-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (126), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (127), 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (128), 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (129), 8-(2-fluoro-4-(methylsulfonyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (130), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1-methyl-1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (131), - 8-(2,6-dimethylpyridin-3-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro rho-5H-benzo[7]annulene-3-carboxylic acid (132), 8-(4-chloro-2-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (133), 8-(2,5-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (134), 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (135), 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (136), 8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (137), 8-(4-((difluoromethyl)thio)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (138), - 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (139), 8-(4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (140), 8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (141), 8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (142), 8-(2,6-dimethylpyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (144), 8-(4-chloro-2-(cyanomethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (144), 8-(2-chloro-4-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (145), 8-(2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (146), 8-(3-cyanophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (147), 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (148), - 8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl) (propyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (149), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (150), 8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (151), 8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (152), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (153), 8-(4-chloro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (154), 8-(2-cyano-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (155), 8-(5-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (156), 8-(2-cyano-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (157), 8-(2-cyano-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (158), 8-(4,6-bis(trifluoromethyl)pyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (159), 8-(2-chloro-4-fluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (160), 8-(2,3-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (161), 8-(cyclohept-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (162), 8-cycloheptyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (163), 8-(2-(difluoromethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (164), 8-(3-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (165), 8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (166), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (167), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (168), 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (169), 8-(4-chloro-2-cyanophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (170), - 8-(4-chloro-2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (171), 8-(3-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (172), 8-(2-chloro-3-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (173), 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (174), - 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 1 (175), - 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride isomer 2 (176), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (177), 8-(4-chloro-2-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (178), 8-(2-chloro-4-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (179), 8-(2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (180), 8-(2,4-dimethylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (181), 8-(2-chloro-3-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H -benzo[7]annulene-3-carboxylic acid isomer 1 (182), 8-(4-chloro-2-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (183), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-3-methylazetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (184), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (185), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (186), 8-(2-chloro-4-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (187), 8-(2-chloro-3-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (188), 8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (189), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (190), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (191), 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (192), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methylpyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (193), - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (194), - 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (195), -(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid (196), -(Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid (197), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (198), - 8-(4-chloro-2-methylphenyl)-9-(4-(difluoro(1-(3-fluorophenyl)- (fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (199), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (200), 8-(4-ethoxy-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (201), 8-(5-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (202), 8-(5-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (203), 8-(2-fluoro-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (204), 8-(2-chlorophenyl)-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (205), 8-(2,4-dichlorophenyl)-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (206), 8-(3,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (207), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (208), 8-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (209), 8-(2,3-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (210), 8-(2,4-dichloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (211), 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (212), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (213), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (214), 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)cyclopropyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (215), 8-(2-chloro-4-fluorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (216), 8-(2-chloro-4-methylphenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (217), 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (218), 8-(5-chloro-3-fluoropyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (219), 8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (220), 8-(4-chloro-2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (221), 8-(2,6-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (222), 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (223), 8-(2-chlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (224), 8-(2,4-dichlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (225), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (226), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (227), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (228), 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (229), 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (230), 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (231), - 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydriodide rho-5H-benzo[7]annulene-3-carboxylic acid (232), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-3-hydroxyazetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (233), 8-(3,5-dichloropyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (234), 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (235), - 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (236), 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (237), 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (238), 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (239), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (240), 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (241), 8-(2-chloro-4-fluorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (242), 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (243), 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (244), 2-cyano-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (245), 4-cyano-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (246), 4-chloro-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (247), 2-chloro-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (248), - 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl) (azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (249), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (250), sodium 8-(3-(difluoromethyl)-5-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (251), 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (252), 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (253), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (254), 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (255), 8-(2-methyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (256), 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (257), 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (258), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (259), 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (260), 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (261), 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride (262), 4-(4-chloro-2-methylphenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylic acid (263), sodium 4-(2-chloro-4-fluorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate (264), 8-(2-chloro-4-methylphenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (265), 8-(3,5-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (266), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (267), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (268), 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (269), 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (270), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (271), 8-(4-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (272), sodium 8-(5-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (273), sodium 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (274), 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (275), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (276), 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (277), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (278), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (279), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (280), 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (281), - 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoro (isopropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (282), 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (283), 8-(2-(difluoromethyl)-4,6-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (284), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (285), 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (286), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (287), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (288), 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (289), 8-(4-fluoro-3-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (290), 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (291), 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (292), 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (293), 8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (294), 8-(2-fluoro-5-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (295), 8-(2-(difluoromethyl)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (296), 8-(3-(2,2-difluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (297), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (298), sodium 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (299), 8-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (300), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (301), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (302), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (303), 3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine (304), 8-(2,4-dichlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (305), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (306) 8-(bicyclo[2.2.1]heptan-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (307) 3-(2,4-dichlorophenyl)-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid (308) 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (309) - 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (310) - 8-benzyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (311) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (312) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (313) 3-(2,4-difluorophenyl)-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid (314) 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (315) 8-(bicyclo[3.2.1]octan-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (316) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (317) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (318) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(2-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (319) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (320) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (321) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (322) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (323) 8-(4-chlorophenyl)-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (324) 8-(4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (325) 8-(3,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (326) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (327) 18-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (328) 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (329) 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 2 (330) - 8-((1R,2S)-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl (Nyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (331) 8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (332) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (333) 8-(3-chloro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (334) 8-(3-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (335) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(octahydropentalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, isomer 1 (336) 24. A compound of formula (I) according to any one of claims 1 to 23, characterized in that it is selected from: or a pharmaceutically acceptable salt thereof, in particular the hydrochloride thereof.

25. A process for preparing a compound of formula (I) according to any one of claims 1 to 24, comprising the step of: 【Chemistry 2】 wherein R1, R2, R3′, R3″, R4, R5, R6, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as defined in any one of claims 1 to 24, 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 1G, and a compound of formula 1F 【Transformation 3】 wherein R1, R2, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, and X are as defined in any one of claims 1 to 24, and R3a is as defined above. is the boron reagent R6B(OR') 2 [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 7 to 13,

26. A process for preparing a compound of formula (I) according to any one of claims 1 to 24, comprising the step of: 【Chemistry 4】 wherein R1, R2, R3, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', n, m, and X are as defined in any one of claims 1 to 24, is reacted with a boron reagent R6B(OR') 2 [In the formula, -B(OR') 2 is a boronic acid or pinacolato ester, and R6 is as defined in claim 1 or any one of claims 7 to 13, optionally preceded by a step to obtain compound 1Fa, 【Transformation 5】 wherein R1, R2, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, and X are as defined in any one of claims 1 to 24, and R3a is a carboxylic acid ester or a protected OH bearing O-pivaloyl, in the presence of a hydroxide ion source dissolved in methanol, is converted to compound 1Fa.

27. A compound selected from formula 1E, 1F, 1G, and 1Fa, or any of its pharmaceutically acceptable salts. 【Transformation 6】 wherein R1, R2, R3, R3', R3", R4, R5, R7, Y, R8, R9, R10, R10', R11, n, m, and X are as defined in any one of claims 1 to 24, and R3a is a carboxylic acid ester or a protected OH having an O-pivaloyl group.

28. A compound of formula 1D or 1D', or any of their pharmaceutically acceptable salts: 【Transformation 7】 wherein R1, R2, R4, R5, R7, R8, R9, R10, R10', Y and n are as defined in any one of claims 1 to 24.

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

30. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

31. A compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

32. 25. A compound of formula (I) as defined in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

33. 33. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use according to claim 32, for use in the treatment of cancer.

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