Substituted 6,7-dihydro-5h-benzo[7]annulene compounds and derivatives thereof, methods of making and therapeutic uses thereof

Abstract

This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: wherein R1 and R2 represent hydrogen or deuterium; R3 represents hydrogen, -COOH, or -OH; R3' and R3'" represent hydrogen, methyl, methoxy, chlorine, fluorine, or cyano; R4 and R4' represent hydrogen or fluorine; R5 represents hydrogen, fluorine, or (C1-C3)alkyl; R6 represents phenyl, fused phenyl, bicyclic group comprising 5 to 12 carbon atoms, heteroaryl group comprising 2 to 9 carbon atoms and comprising 1 to 3 heteroatoms, cycloalkyl group comprising 3 to 7 carbon atoms, (C3-C6)cycloalkyl(C1-C3)alkyl, 3 to 8-membered heterocycloalkyl group comprising 1 or 2 heteroatoms, (C1-C6)alkyl, and phenyl(C1-C2)alkyl; X represents - CH2-, -O-, or -S-; Y represents -CH=, -N=, or -CR”=, where R” represents (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R7 represents (C1-C3)alkyl, halogen atom, cyano, or (C1-C3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C3)alkyl, or cyclopropyl; n is 0, 1, or 2; m is 0 or 1. Further disclosed are methods for preparing compounds of formula (I), pharmaceutical compositions comprising them, and compounds of formula (I) used as estrogen receptor inhibitors and degrading agents, particularly for treating ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation.

Description

[0001] This article discloses novel substituted 6,7-dihydro-5H-benzo[7]arbutin derivatives, their preparation methods and their therapeutic uses, particularly their therapeutic use as anticancer agents via selective antagonism and degradation of estrogen receptors.

[0002] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily and are involved in the regulation of eukaryotic gene expression, cell proliferation, and differentiation in target tissues. There are two forms of ERs: 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 that are activated by estrogen (the most potent estrogen produced in vivo is 17β-estradiol). In the absence of hormones, ERs are primarily located in the cytosol of cells. When estrogen binds to an ER, the ER migrates from the cytosol to the nucleus, forms a dimer, and then binds to a specific genomic sequence called an estrogen response element (ERE). The DNA / ER complex interacts with co-regulatory factors to regulate the transcription of target genes.

[0003] ERα is primarily expressed in reproductive tissues such as the uterus, ovaries, breasts, bone, and white adipose tissue. Abnormal ERα signaling can lead to the development of a variety of diseases, including cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and osteoporosis.

[0004] ERα is expressed in no more than 10% of normal breast epithelium, but in approximately 50%–80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is well-established, and regulation of ERα signaling remains a primary focus of breast cancer treatment for most ERα-positive breast tumors. Currently, several strategies exist for inhibiting the estrogen axis in breast cancer, including: 1- blocking estrogen synthesis through aromatase inhibitors, which are used to treat patients with early and advanced ERα-positive breast cancer; 2- antagonizing the binding of estrogen ligands to ERα through tamoxifen, which is used to treat ERα-positive breast cancer patients in premenopausal and postmenopausal backgrounds; and 3- antagonizing and downregulating ERα levels through fulvestrant, which is used to treat breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] While these endocrine therapies have greatly contributed to the reduction of breast cancer development, approximately one-third of ERα-positive patients exhibit de-novo resistance or develop resistance to these existing therapies over time. Several mechanisms have been described to explain resistance to these hormone therapies. These include, for example, ERα hypersensitivity to low estrogen levels during treatment with aromatase inhibitors, the shift in tamoxifen's action from antagonist to agonist during tamoxifen treatment, or multiple growth factor receptor signaling pathways. Acquired mutations in ERα that occur after the initiation of hormone therapy can also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), result in ligand-binding DNA binding in the absence of a ligand and confer hormone-independent capabilities in cells carrying such mutated receptors.

[0006] Most identified endocrine therapy resistance mechanisms rely on ERα-dependent activity. One novel strategy to combat this resistance is to shut down ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data show that SERDs can circumvent a large number of resistance pathways.

[0007] SERD with good degradation efficacy is still needed.

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose a number of substituted 6,7-dihydro-5H-benzo[7]arbutin compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives used as SERDs.

[0009] The inventors have now discovered novel compounds (SERD compounds) capable of selectively antagonizing and degrading estrogen receptors for cancer treatment.

[0010] This article discloses compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0011]

[0012] in:

[0013] -R1 and R2 independently represent hydrogen or deuterium atoms;

[0014] -R3 represents a hydrogen atom, a -COOH group, or an -OH group;

[0015] -R3' and R3" independently represent a hydrogen atom, methyl group, methoxy group, chlorine atom, fluorine atom, or cyano group;

[0016] -R4 and R4' independently represent a hydrogen atom or a fluorine atom;

[0017] -R5 indicates a hydrogen atom, a fluorine atom, or a (C1-C3) alkyl group;

[0018] -R6 indicates that the following groups are selected:

[0019] ■ Phenyl, wherein the phenyl group is optionally substituted with one to three substituents independently selected from the following: halogen atom; (C1-C6) alkyl, optionally substituted with a cyano or -OH group; (C1-C6) fluoroalkyl; (C3-C6) cycloalkyl; (C1-C6) alkoxy; (C1-C6) fluoroalkoxy; cyano; trifluoromethylsulfonyl; (C1-C4) alkylthio; (C1-C4) fluoroalkylthio; (C1-C4) alkylsulfonyl and -OH group;

[0020] ■ Fused phenyl, selected from phenyl fused with (C3-C6) cycloalkyl, said (C3-C6) cycloalkyl optionally containing unsaturation, and said fused phenyl optionally substituted by 1 to 3 substituents independently selected from (C1-C3) alkyl, hydroxyl, halogen atom, (C1-C6) fluoroalkyl and (C1-C3) alkoxy;

[0021] ■ A bicyclic group comprising 5 to 12 carbon atoms, optionally comprising 1 to 2 degrees of unsaturation; optionally substituted by 1 to 4 substituents independently selected from the following: fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy and oxo group;

[0022] ■ A heteroaryl group, such as pyridyl, comprising 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 group is optionally substituted by 1 to 3 substituents independently selected from: halogen atom, (C1-C6)alkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkoxy, cyano, carbamoyl, and -OH group;

[0023] ■ A cycloalkyl group comprising 3 to 7 carbon atoms, wherein the cycloalkyl group is saturated or partially saturated and optionally substituted by 1 to 4 substituents independently selected from the following:

[0024] ○ Fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, oxo group,

[0025] ○ (C3-C6)cycloalkyl and phenyl, wherein the (C3-C6)cycloalkyl and phenyl are optionally substituted with one or two halogen atoms or (C1-C3) alkyl;

[0026] ■ (C3-C6)cycloalkyl (C1-C3)alkyl, optionally substituted on the cycloalkyl group by 1 to 4 independently selected substituents from the following: fluorine atom, -OH group, (C1-C4)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and oxo group;

[0027] ■ A 3- to 8-membered heterocyclic alkyl group comprising one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as tetrahydropyranyl, wherein the heterocyclic alkyl group is saturated or partially saturated and optionally substituted by one to three substituents independently selected from the following: fluorine atom, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, oxo group, (C1-C3)alkoxy and -OH group;

[0028] ■ (C1-C6)alkyl, such as isobutyl, methyl, or ethyl, said alkyl group optionally substituted by one to four independently selected substituents from: fluorine atom, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, and -OH group; and

[0029] ■ Phenyl (C1-C2)alkyl, wherein the phenyl group is optionally substituted by one to three substituents independently selected from the following: halogen atom; (C1-C3)alkyl; (C1-C3)fluoroalkyl; (C1-C3)alkoxy; (C1-C3)fluoroalkoxy; cyano; and -OH group;

[0030] -X indicates -CH2-, -O-, or -S-;

[0031] -Y represents -CH=, -N= or -CR”=, where R” represents (C1-C3) alkyl, halogen atom such as fluorine or chlorine atom, cyano or (C1-C3) fluoroalkyl, such as trifluoromethyl;

[0032] -R7 independently represents (C1-C3) alkyl such as methyl, halogen atom such as fluorine atom, cyano or (C1-C3) fluoroalkyl such as trifluoromethyl;

[0033] -R8 indicates a hydrogen atom or a fluorine atom;

[0034] -R9 indicates a hydrogen atom, (C1-C3) alkyl group, or cyclopropyl group;

[0035] -n is 0, 1, or 2; and

[0036] -m is 0 or 1.

[0037] Formula (I) indicates that the compound may contain one or more asymmetric carbon atoms. Therefore, they can exist in enantiomeric form.

[0038] Compounds of formula (I) can also exist in tautomer form.

[0039] Compounds of formula (I) may exist as bases, acids, zwitterions, or addition salts of acids or bases. Therefore, this document provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0040] These salts can be prepared from pharmaceutically acceptable acids or bases, although salts of other acids or bases that can be used, for example, to purify or isolate compounds of formula (I) are also provided.

[0041] Among suitable salts of compounds of formula (I), hydrochloride salts may be mentioned.

[0042] As used herein, unless otherwise stated in this specification, the following terms have the following definitions:

[0043] - Halogen atoms: fluorine, chlorine, bromine or iodine atoms, and especially fluorine and chlorine atoms;

[0044] -Oxyto: "=O" group;

[0045] -alkyl: Unless otherwise specified, a straight-chain or branched saturated hydrocarbon aliphatic group containing 1 to 6 carbon atoms (labeled 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.

[0046] -Cycloalkyl: Unless otherwise specified, a monocycloalkyl group comprising 3 to 7 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted. Examples may include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cycloheptenyl, especially cyclopentyl, cyclohexyl or cyclohexenyl;

[0047] -Cycloalkylalkyl: An alkyl group substituted with a cyclic alkyl group as defined above. Examples include, but are not limited to, cyclobutylmethyl;

[0048] - Heterocyclic alkyl groups: saturated or partially unsaturated 3- to 8-membered cycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, particularly oxygen or nitrogen. Examples, but not limited to: morpholinyl, piperazinyl, piperidinyl, pyrrolyl, acridineyl, oxanyl, oxetaneyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxetaneylheptyl, diazaheptanyl, dioxanyl, tetrahydropyranyl, and tetrahydrothiaranyl. Advantageously, tetrahydropyranyl is a heterocyclic alkyl group.

[0049] -Fluoroalkyl: An alkyl group as defined above, wherein the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. For example, -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be called a perfluoroalkyl group. For example, trifluoromethyl or trifluoro or trifluoroethyl, especially trifluoromethyl;

[0050] -alkoxy: -O-alkyl group, wherein the alkyl group is as defined above. Examples, but not limited to, include: methoxy, ethoxy, propoxy, isopropoxy, straight-chain sec-butoxy or tert-butoxy, isobutoxy, pentoxy or hexoxy, etc.

[0051] -Fluoroalkoxy: -O-alkyl, wherein the alkyl group is as defined above and wherein the alkyl group is replaced by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. For example, -OCH2F, -OCHF2, -OCH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group may be called a perfluoroalkoxy group. For example, trifluoromethoxy, etc. may be mentioned;

[0052] -(C1-C4)alkylthio, also known as (C1-C4)alkylthioalkyl: -S-alkyl, where the alkyl group is as defined above. Examples, but not limited to: methylthio, ethylthio, propylthio, isopropylthio, straight-chain secondary or tert-butylthio, isobutylthio, etc., may be mentioned.

[0053] -(C1-C4)alkylsulfonyl: -SO2-alkyl, wherein the alkyl group is as defined above. Examples, but not limited to, may include: -SO2CH3, -SO2CH2CH3, etc.;

[0054] -(C1-C4)fluoroalkylthio, also known as (C1-C4)fluoroalkylthioalkyl: -S-fluoroalkyl, wherein the fluoroalkyl group is as previously defined. Examples, but not limited to, include: fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.

[0055] - Fused phenyl: A bicyclic group containing 8 to 10 carbon atoms and a phenyl moiety. The phenyl moiety may be fused with a (C3-C6) cycloalkyl group, i.e., the phenyl moiety may share a bond with the (C3-C6) cycloalkyl group. The fused phenyl group may be bonded to the rest of the molecule through its phenyl moiety. It may be substituted. Examples include, but are not limited to, indanyl, bicyclo[4.2.0]octyl-1(6),2,4-trienyl, tetrahydronaphthyl, etc.;

[0056] - Heteroaryl: 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 may be substituted with oxygen atoms to form a -NO bond. This -NO bond may be in the form of an N-oxide (-N+-O-). 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, benzisoxazole, pyrrolo[2,3-b]pyridine, benzimidazole, benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridinone groups, etc. Heteroaryl compounds are advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridinone and pyrimidine, and more particularly pyridine;

[0057] - A bicyclic group, typically containing 5 to 12 carbon atoms, is a hydrocarbon group selected from groups comprising two rings linked by the following:

[0058] ● A single common atom: "spirobicyclic". This type of spirobicyclic alkyl group typically contains 5 to 11 carbon atoms, referring to "spiro(C5-C6)". 11 "Bicyclic". The ring can be saturated or partially unsaturated. This spirobicyclic ring can be unsubstituted or substituted, particularly substituted with at least one (C1-C3) alkyl group such as methyl or fluorine. As defined for R6, spirobicyclic (C5-C6) 11 Examples of bicyclic compounds may be mentioned, 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. Also for the R6 group, spiro(C5-C... 11 Bicyclic compounds are advantageously spiro[2,3]hexane, spiro[3,3]heptane, or spiro[3,3]heptene;

[0059] ● Two common atoms. In this case, the bicyclic group contains 7 to 12 carbon atoms and optionally 1 to 2 degrees of unsaturation. Examples of such bicyclic groups include, but are not limited to: cis-1,3a,4,5,6,6a-hexahydrocyclopentadienyl, bicyclo[3.1.0]hex-1-yl, bicyclo[4.1.0]heptyl, and octahydrocyclopentadienyl.

[0060] ● Three or more common atoms. In this case, the bicyclic group contains 6 to 10 carbon atoms; such bicyclic groups can be called "bridging (C6-C)". 10“Cycloalkyl”, where the rings share three or more atoms and the bridge contains at least one atom, such as 1, 2 or 3 atoms, preferably 1 atom. Examples of such bridged cycloalkyls may be mentioned, but are not limited to, bicyclo[3.2.1]oct-3-yl and bicyclo[2.2.1]hept-2-yl.

[0061] - Amphoteric ions are: generally neutral molecules that have both positive and negative charges and possess both acidic and basic groups.

[0062] In another embodiment, in the compound of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0063] In another embodiment, in the compound of formula (I) as defined above, R3 is -COOH.

[0064] In another embodiment, in the compound of formula (I) as defined above, R3' and R3” represent hydrogen atoms.

[0065] In another embodiment, in the compound of formula (I) as defined above, X represents -CH2-.

[0066] In another embodiment, in the compound of formula (I) as defined above, R4 and R4' represent hydrogen atoms.

[0067] In another embodiment, in a compound of formula (I) as defined above, R5 represents a hydrogen atom.

[0068] In another embodiment, in a compound of formula (I) as defined above, R5 represents a hydrogen atom, a -NH2 group, a methyl group, a methoxy group, or an ethoxy group.

[0069] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, which is optionally substituted by one to three groups independently selected from the following: chlorine atom, fluorine atom, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy and cyano.

[0070] In another embodiment, in the compound of formula (I) as defined above, R6 represents a fused phenyl group selected from bicyclo[4.2.0]octtrienyl, indanyl, or tetrahydronaphthyl, optionally substituted with one or two fluorine atoms.

[0071] In another embodiment, in the compound of formula (I) as defined above, R6 represents a bicyclic group selected from bicyclo[4.1.0]heptyl, bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, and bicyclo[3.2.1]oct-3-yl, optionally substituted by one to four substituents independently selected from: fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, and oxo group; advantageously, the bicyclic group is unsubstituted.

[0072] In another embodiment, in the compound of formula (I) as defined above, R6 represents a pyridyl group, which is optionally substituted with one to three substituents, which are independently selected from halogen atoms, (C1-C6)alkyl, (C1-C6)fluoroalkyl and (C1-C6)alkoxy, and more particularly selected from fluorine atoms, chlorine atoms, methyl, trifluoromethyl and methoxy.

[0073] In another embodiment, in the compound of formula (I) as defined above, R6 represents a cycloalkyl group selected from cyclohexyl or cyclopropyl, said cycloalkyl group optionally being substituted by 1 to 4 substituents independently selected from:

[0074] ○ Fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, oxo group

[0075] ○ (C1-C6) cycloalkyl and phenyl, wherein the (C3-C6) cycloalkyl or phenyl is optionally substituted with one or two halogen atoms or (C1-C3) alkyl.

[0076] The cycloalkyl group is advantageously substituted by one or two independent substituents selected from the following:

[0077] ○Methyl, phenyl, and

[0078] ○ Cyclohexyl group substituted with two halogen atoms, particularly fluorine atoms.

[0079] In another embodiment, in the compound of formula (I) as defined above, R6 represents cyclobutylmethyl, optionally substituted on the cycloalkyl group by one to four substituents independently selected from the following: fluorine atom, -OH group, (C1-C4)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and oxo group; advantageously, the cyclobutylmethyl group is unsubstituted.

[0080] In another embodiment, in the compound of formula (I) as defined above, R6 represents a tetrahydropyranyl group, which is optionally substituted by one to three substituents independently selected from the following: fluorine atom, (C1-C3)alkoxy, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and -OH group; advantageously, the tetrahydropyranyl group is unsubstituted.

[0081] In another embodiment, in the compound of formula (I) as defined above, R6 represents isobutyl, which is optionally substituted by 1 to 4 substituents independently selected from the following: fluorine atom, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy and -OH group, and particularly optionally substituted by 1 or 3 fluorine atoms; advantageously, the isobutyl is unsubstituted.

[0082] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl (C1-C2)alkyl group, particularly selected from phenylmethyl or phenylethyl.

[0083] In another embodiment, in a compound of formula (I) as defined above, R7 independently represents a methyl, cyano, trifluoromethyl, or fluorine atom, and n is 0, 1, or 2.

[0084] In another embodiment, in a compound of formula (I) as defined above, Y represents -CH=, -N= or -CR”=, and R” represents a fluorine atom, a cyano group or a trifluoromethyl group.

[0085] In another embodiment, in the compound of formula (I) as defined above, m is 1.

[0086] In another embodiment, in the compound of formula (I) as defined above, R3 is a COOH group and R6 is a phenyl group comprising two substituents independently selected from chlorine, fluorine, trifluoromethyl, and methyl, at least one substituent comprising a halogen atom. In such embodiments, R3' and R3" are specifically hydrogen atoms. Still in such embodiments, R1, R2, R4, R4', R5, R8, and R9 are hydrogen atoms. In such embodiments, Y is a -CH= group, m equals 1, and n equals 0. Still in such embodiments, X is a -CH2- group.

[0087] In addition to the embodiments described herein, other implementation methods are also provided.

[0088] Another embodiment provides a compound of formula (I') or a pharmaceutically acceptable salt thereof:

[0089]

[0090] in:

[0091] - R4 indicates a double bond or a single bond, and when it is a double bond, then R4 b and R7 b It does not exist;

[0092] -R1 b and R2 b Independently representing a hydrogen atom or a deuterium atom;

[0093] -R3 b Represents a hydrogen atom, a -COOH group, or a -OH group;

[0094] -R3' b and R3” b Independently represent a hydrogen atom, methyl group, chlorine atom, or fluorine atom;

[0095] -R4 b and R5 b Independently representing a hydrogen atom, halogen atom, -NH2 group, methyl or -OH group; or R4 and R5 together forming an oxo group;

[0096] -R6 b It indicates that the group is selected from the following:

[0097] ■ Phenyl, wherein the phenyl is optionally substituted with one to three groups independently selected from the following: halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH group;

[0098] ■ A heteroaryl group, such as pyridyl, comprising 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 group is optionally substituted by 1 to 3 substituents independently selected from: halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and -OH group;

[0099] ■ A cycloalkyl group comprising 3 to 9 carbon atoms, wherein the cycloalkyl group is saturated or partially saturated and optionally substituted by 1 to 4 substituents independently selected from the following: fluorine atom, -OH group, (C1-C6) alkyl and oxo group;

[0100] ■ A 4- to 7-membered heterocyclic alkyl group comprising one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as a tetrahydropyranyl group, wherein the heterocyclic alkyl group is optionally substituted by one to three substituents independently selected from the following: fluorine atom, (C1-C6)alkoxy group, (C1-C6)haloalkoxy group, and -OH group;

[0101] ■Screw (C5-C) 11Bicyclic, such as spiro[3.3]heptane or spiro[3.3]heptane), the spiro(C5-C 11 The bicyclic ring is optionally substituted by one to four independent substituents selected from the following: (C1-C6) alkyl, fluorine atom, (C1-C6) alkoxy, (C1-C6) haloalkoxy and -OH group;

[0102] ■ (C1-C6)alkyl, such as isobutyl, wherein the alkyl group is optionally substituted by one to four substituents independently selected from the following: fluorine atom, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH group;

[0103] -R7 b Represents a hydrogen atom or a halogen atom;

[0104] -X b It can represent -CH2-, -O-, or -S-;

[0105] -Y b Indicates -CH-, -N-, or -CR” b -, where R” b Indicates (C1-C4) alkyl or halogen atoms such as fluorine or chlorine atoms;

[0106] -R8 b Independently representing (C1-C4) alkyl groups, such as methyl, or halogen atoms, such as fluorine; and

[0107] n b It can be 0, 1, or 2.

[0108] Compounds of formula (I') may contain one or more asymmetric carbon atoms. Therefore, they can exist in enantiomeric form.

[0109] Compounds of formula (I') can also exist in tautomer form.

[0110] Compounds of formula (I') may exist as bases, acids, zwitterions, or addition salts of acids or bases. Therefore, this document provides compounds of formula (I') or pharmaceutically acceptable salts thereof.

[0111] These salts can be prepared using pharmaceutically acceptable acids or bases, although salts of other acids or bases that can be used, for example, to purify or isolate compounds of formula (I') are also provided.

[0112] Among the suitable salts of the compounds of formula (I'), hydrochloride salts may be mentioned.

[0113] In one embodiment, in a compound of formula (I') as defined above, Indicates a single key.

[0114] In another embodiment, in a compound of formula (I') as defined above, R1 b and R2 b It is a hydrogen atom.

[0115] In another embodiment, in the compound of formula (I) as defined above, R3 b It is -COOH.

[0116] In another embodiment, in a compound of formula (I') as defined above, X b It represents -CH2-.

[0117] In another embodiment, in the compound of formula (I') as defined above, R4 b and R5 b Independently representing a hydrogen atom, a fluorine atom, a -NH2 group, a methyl group, or an -OH group, especially independently representing a hydrogen atom, a fluorine atom, or an -OH group; or R4 b and R5 b Together they form oxygen groups, especially R4. b and R5 b All represent hydrogen or fluorine atoms, or R4 b and R5 b One of them represents a hydrogen atom and the other is a fluorine atom or a -OH group, more specifically R4 b and R5 b Both represent hydrogen atoms.

[0118] In another embodiment, in the compound of formula (I') as defined above, R7 b It represents a hydrogen atom or a fluorine atom, and more specifically, a hydrogen atom.

[0119] In another embodiment, in the compound of formula (I') as defined above, R6 b The phenyl group is indicated by a phenyl group, which is optionally substituted by one to three substituents independently selected from the following: chlorine atom, fluorine atom, methyl, trifluoromethyl, methoxy and difluoromethoxy.

[0120] In another embodiment, in the compound of formula (I') as defined above, R6 b The pyridyl group is optionally substituted by one to three substituents independently selected from the following: halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH group, and more particularly selected from methoxy.

[0121] In another embodiment, in the compound of formula (I') as defined above, R6 bThe term represents a cycloalkyl group selected from cyclohexyl, cyclopentyl, and cyclohexenyl, wherein the cycloalkyl group is optionally substituted by one to four substituents independently selected from fluorine atoms and methyl.

[0122] In another embodiment, in the compound of formula (I') as defined above, R6 b The symbol represents a tetrahydropyranyl group, which is optionally substituted by one to three substituents independently selected from the following: fluorine atom, (C1-C6)alkoxy group, (C1-C6)haloalkoxy group and -OH group.

[0123] In another embodiment, in the compound of formula (I') as defined above, R6 b The designation represents spiro[3.3]hept-1-ene or spiro[3.3]hept-2-alkyl, wherein the spiro[3.3]hept-1-ene or spiro[3.3]hept-2-alkyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of (C1-C6)alkyl, fluorine, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH groups, and is particularly optionally substituted with 1 or 2 fluorine atoms.

[0124] In another embodiment, in the compound of formula (I') as defined above, R6 b The term represents isobutyl, which is optionally substituted by 1 to 4 substituents independently selected from the following: fluorine atom, (C1-C6)alkoxy, (C1-C6)haloalkoxy and -OH group, and particularly optionally substituted by 1 or 3 fluorine atoms.

[0125] In another embodiment, in the compound of formula (I') as defined above, R8 b It independently represents a methyl or fluorine atom, and n is 0, 1 or 2.

[0126] In another embodiment, in a compound of formula (I') as defined above, Y b It represents -CH-, -C(CH3)-, -CF- or -N-, and especially -CH- or -N-.

[0127] Among the compounds of formula (I) described herein, the following compounds or their pharmaceutically acceptable salts, particularly their hydrochloride salts, may be specifically mentioned:

[0128] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (1)

[0129] -8-(3-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (2)

[0130] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (3)

[0131] -8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (4)

[0132] -8-(4-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (5)

[0133] -8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (6)

[0134] -8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (7)

[0135] -8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (8)

[0136] -8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (9)

[0137] -8-(2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (10)

[0138] -8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (11)

[0139] -8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (12)-8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (13)

[0140] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (14)

[0141] -8-(2,4-difluorophenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (15)

[0142] -8-(2,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (16)

[0143] -8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (17)

[0144] -8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (18)

[0145] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (19)

[0146] -8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (20)

[0147] -8-(2,6-difluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (21)

[0148] -8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (22)

[0149] -8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (23)

[0150] -8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (24)

[0151] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (25)

[0152] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (26)

[0153] -8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (27)

[0154] -8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (28)

[0155] -8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (29)

[0156] -8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (30)

[0157] -8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (31)

[0158] -8-(5-fluoro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (32)

[0159] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (33)

[0160] -8-(4-cyclopropyl-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (34)

[0161] -8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (35)

[0162] -9-(3,5-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (36)

[0163] -8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (37)

[0164] -8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (38)

[0165] -8-(4-cyclopropyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (39)

[0166] -8-(2-cyclopropyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (40)

[0167] -8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (41)

[0168] -8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (42)

[0169] -9-(2,3-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (43)

[0170] -8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (44)

[0171] -8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (45)

[0172] -9-(3-cyano-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (46)

[0173] -8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (47)

[0174] -8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (48)

[0175] -8-(2-fluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (49)

[0176] -8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (50)

[0177] -8-(2,6-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (51)

[0178] -9-(2,6-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (52)

[0179] -8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (53)

[0180] -8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (54)

[0181] -8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (55)

[0182] -8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (56)

[0183] -8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (57)

[0184] -8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (58)

[0185] -9-(3,5-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (59)

[0186] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (60)

[0187] -8-(4-fluoro-2-methylphenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (61)

[0188] -8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (62)

[0189] -8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (63)

[0190] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (64)

[0191] -9-(2,5-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate salt, (65)

[0192] -8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate salt, (66)

[0193] -8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (67)

[0194] -9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (68)

[0195] -9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (69)

[0196] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (70)

[0197] -8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (71)

[0198] -8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (72)

[0199] -8-(2,4-dichlorophenyl)-9-(2,6-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (73)

[0200] -8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (74)

[0201] -8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (75)

[0202] -8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (76)

[0203] -8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (77)

[0204] -8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (78)

[0205] -8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (79)

[0206] -8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (80)

[0207] -8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (81)

[0208] -8-(4-chloro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (82)

[0209] -8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (83)

[0210] -8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (84)

[0211] -8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (85)

[0212] -8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (86)

[0213] -8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (87)

[0214] -8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (88)

[0215] -8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (89)

[0216] -8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (90)

[0217] -8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (91)

[0218] -8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (92)

[0219] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (93)

[0220] -8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (94)

[0221] -8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (95)

[0222] -8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (96)

[0223] -8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (97)

[0224] -8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (98)

[0225] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (99)

[0226] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (100)

[0227] -8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (101)

[0228] -8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobutane-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (102)

[0229] -8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (103)

[0230] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate salt, (104)

[0231] -8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (105)

[0232] -6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate, (106)

[0233] -8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (107)

[0234] -8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (108)

[0235] -8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (109)

[0236] -8-(3-methyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (110)

[0237] -8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (111)

[0238] -8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (112)

[0239] -8-(2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (113)

[0240] -4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa -8-Formate, (114)

[0241] -4-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azacyclobutane-3-ylidene]methyl]phenyl]-2,3-dihydro-1-benzothiophene (benzothiepine)-8-carboxylic acid; hydrochloride, (115)

[0242] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (116)

[0243] -8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (117)

[0244] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (118)

[0245] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(5-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (119)

[0246] -3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)-1-(3-fluoropropyl)azacyclobutane, (120)

[0247] -8-(2-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (121)

[0248] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (122)

[0249] -8-(2-chloro-5-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (123)

[0250] -8-(2,4-difluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (124)

[0251] -8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (125)

[0252] -8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (126)

[0253] -8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (127)

[0254] -8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (128)

[0255] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (129)

[0256] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (130)

[0257] -8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (131)

[0258] -8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (132)

[0259] -8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (133)

[0260] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (134)

[0261] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (135)

[0262] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (136)

[0263] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (137)

[0264] -8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (138)

[0265] -9-(2-cyano-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (139)

[0266] -8-(2-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (140)

[0267] -8-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (141)

[0268] -8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate sodium, (142)

[0269] -8-(3-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (143)

[0270] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (144)

[0271] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (145)

[0272] -8-(3,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (146)

[0273] -8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (147)

[0274] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (148)

[0275] -8-(4-ethoxy-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (149)

[0276] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (150)

[0277] -8-(2,5-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (151)

[0278] -9-(2,3-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (152)

[0279] -8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (153)

[0280] -8-(4-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (154)

[0281] -8-(3-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (155)

[0282] -8-(5-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (156)

[0283] -8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (157)

[0284] -8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, (158)

[0285] -8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, trifluoroacetate, (159)

[0286] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (160)

[0287] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (161)

[0288] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (162)

[0289] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (163)

[0290] -8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (164)

[0291] -9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (165)

[0292] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, racemic mixture (166)

[0293] -8-Benzyl-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (167)

[0294] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-phenethyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (168)

[0295] -8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (169)

[0296] -8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol(170)

[0297] -8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, isomer 1(171)

[0298] -8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, isomer 2(172)

[0299] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-((trans)-2-phenylcyclopropyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, racemic mixture (173)

[0300] -8-((1R,6S,7r)-bicyclo[4.1.0]hept-7-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (174)

[0301] -8-(bicyclo[3.1.0]hex-1-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (175)

[0302] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hex-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (176)

[0303] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(5,6,7,8-tetrahydronaphth-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (177)

[0304] -8-(bicyclo[3.2.1]oct-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (178)

[0305] -8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, isomer 1(179)

[0306] -8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (180)

[0307] -8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (181)

[0308] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (182)

[0309] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (183)

[0310] -8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, isomer 2(184)

[0311] -9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (185)

[0312] -8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (186)

[0313] -8-(trans-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, racemic mixture (187)

[0314] -9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, a mixture of isomers (188).

[0315] Another embodiment of the invention is a compound selected from the above list or a pharmaceutically acceptable salt thereof, which is used for treatment, particularly as an inhibitor and degrader of estrogen receptors.

[0316] Another embodiment of the invention is a compound selected from the above list or a pharmaceutically acceptable salt thereof, used to treat cancer, particularly breast cancer.

[0317] Another implementation is a method for inhibiting and degrading estrogen receptors, which includes administering to a subject in need, particularly a human, a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0318] Another implementation method is a method for treating ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation, which includes administering to a subject in need, particularly a human, a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0319] Another implementation is a method for treating cancer, which involves administering a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof to a subject in need, particularly a human.

[0320] Another embodiment is a pharmaceutical composition comprising an effective dose of a compound selected from the above list or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0321] The compound of formula (I) can be prepared by the following method.

[0322] Compounds of formula (I) with different substituents, as well as other related compounds, can be synthesized using the techniques and materials described below or other techniques and materials known to those skilled in the art. Furthermore, the solvents, temperatures, and other reaction conditions given below may be varied as deemed appropriate by those skilled in the art.

[0323] The general method for preparing compounds of formula (I) as described below may optionally be modified by using suitable reagents and conditions to introduce the various parts found in formula (I) as described below.

[0324] Use the following abbreviations and empirical formulas:

[0325] MeCN Acetonitrile

[0326] NH4Cl ammonium chloride

[0327] Butyllithium (BuLi)

[0328] CO and carbon monoxide

[0329] Cs2CO3 (cesium carbonate)

[0330] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0331] DCM dichloromethane

[0332] Et2O diethyl ether

[0333] DIEA (Diisopropylethylamine)

[0334] DMF N,N-dimethylformamide

[0335] DMSO (dimethyl sulfoxide)

[0336] Dppf 1,1'-bis(diphenylphosphino)ferrocene

[0337] EtOH (ethanol)

[0338] EtOAc (ethyl acetate)

[0339] h hours

[0340] H2 hydrogen gas

[0341] HCl hydrochloric acid

[0342] HPLC (High Performance Liquid Chromatography)

[0343] LiOH (Lithium hydroxide)

[0344] LiHMDS (Lithium Hexamethyldisilazane)

[0345] MeOH (methanol)

[0346] MgSO4 Magnesium sulfate

[0347] MTBE (methyl tert-butyl ether)

[0348] MeTHF 2-methyltetrahydrofuran

[0349] min minutes

[0350] n-BuLi n-Butyllithium

[0351] Pd / C Palladium on Carbon

[0352] KOAc potassium acetate

[0353] K2CO3 (potassium carbonate)

[0354] KHMDS (Potassium Hexamethyldisilazane)

[0355] KOH (potassium hydroxide)

[0356] NaBH4 sodium borohydride

[0357] NaHCO3 (Sodium bicarbonate)

[0358] Sodium hydride (NaH)

[0359] NaOH (sodium hydroxide)

[0360] Na2SO4 Sodium sulfate

[0361] NaHSO3 Sodium bisulfate

[0362] SCX Strong Cation Exchange

[0363] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloro

[0364] Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride

[0365] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

[0366] Pd2(dba)3 tris(dibenzylacetone)dipalladium(0)

[0367] PhOK Potassium Phenol

[0368] SFC Supercritical Fluid Chromatography

[0369] TEA Triethylamine

[0370] TFA (trifluoroacetic acid)

[0371] THF Tetrahydrofuran

[0372] PPh3 triphenylphosphine

[0373] RT room temperature

[0374] Argon gas

[0375] DABCO 1,4-diazabicyclo[2.2.2]octane

[0376] Option 1a – Part 1 Preparation of compounds of formula (I) – General methods

[0377]

[0378] Option 1a – Part 2

[0379]

[0380] According to Scheme 1a – Parts 1 and 2, where R3a is H or a carboxylic acid ester, such as COOMe, COOEt or OH protected with an O-neopentyl group, R9 is a hydrogen atom, and R1, R2, R3, R3', R3', R4, R4', R5, R6, R7, R8, X, m, n and Y are defined as above, compound 1A can be converted to compound 1B in step 1 as follows: in the presence of a palladium catalyst, such as tris(dibenzylacetone)dipalladium(O)Pd2(dba)3 and a phosphine, such as (9,9-dimethyl-9H-oxanthracene-4,5-diyl)bis(diphenylphosphine) (XANTPHOS), in toluene by heating to solvent reflux, in the presence of a base, such as K2CO3 or Cs2CO3, by treatment with aryl bromide or aryl iodide.

[0381] Compound 1B can be converted to compound 1C in step 2 as follows: 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.

[0382] Compound 1C can be converted to compound 1E in step 4 as follows: in the presence of a base such as KOPh, by heating to solvent reflux, treatment with, for example, bis(pinacolyl)diboron and with a palladium catalyst such as bis(triphenylphosphine)palladium(II)Pd(PPh3)2Cl2 and a phosphine such as triphenylphosphine in toluene.

[0383] Compound 1K can be prepared as follows: in the Suzuki coupling reaction between compounds 1C and 1D in step 3 or between compounds 1E and 1F in step 5, a complex of, for example, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM is used as a catalyst in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux.

[0384] Alternatively, compound 1E can be converted to compound 1H in step 6 as follows: in the Suzuki coupling reaction with compound 1G, a complex of, for example, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM is used as a catalyst in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux. Compound 1H can be converted to compound 1I in step 7 by treatment with a solution of TFA in DCM or a solution of HCl in dioxane. Compound 1I can be converted to compound 1K in step 8 as follows: in DMF at 70°C in the presence of a base such as potassium carbonate, or in THF at room temperature in the presence of sodium hydroxide or potassium hydroxide, or in DCM at room temperature in the presence of an aqueous sodium hydroxide solution, by treatment with compound 1J, in which W is Br, I, or OSO2R, wherein R = CH3, PhMe, CF3, or CF2CF2CF2CF3.

[0385] When R3a is COOMe, COOEt, or a protected OH group (e.g., O-neopentyl), compound 1K can be deprotected in step 9 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH to obtain compound I. When R3 is COOH, extraction of the compound yields the sodium salt of compound I. Acidification with aqueous HCl 2N solution to pH 6-7 yields the neutral form. Acidification with aqueous HCl 2N solution to pH 1-2 yields the hydrochloride salt. Purification by HPLC yields the formate or trifluoroacetate salt.

[0386] Option 1b – Part 1 Preparation of compounds of formula (I) – General methods

[0387]

[0388] Option 1b – Part 2

[0389]

[0390] According to Scheme 1b – Parts 1 and 2, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or OH protected with, for example, O-neopentyl, and R1, R2, R3, R3', R3”, R4, R4', R6, R7, R8, R9, X, n, m, and Y as defined above, compound 1L can be converted to compound 1N in step 1 as follows: in the Suzuki coupling reaction with compound 1M, using, for example, a complex of [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM as a catalyst, in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux.

[0391] Compound 1N can be converted into compound 1O in step 2 by treatment with sodium nitrite, followed by treatment with sodium iodide in a solvent such as a mixture of water and acetonitrile.

[0392] Compound 1O can be converted to compound 1P in step 3 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature. Compound 1P can be converted to compound 1R in step 4 by Heck coupling reaction with compound 1Q using, for example, palladium(II) acetate in a solvent such as DMF as a catalyst.

[0393] Compound 1R can be converted to compound 1S in step 5 by treatment with a solution of TFA in DCM or a solution of HCl in dioxane.

[0394] Compound 1S can be converted to compound 1T in step 6 as follows: in DMF at 70°C in the presence of a base such as potassium carbonate, or in THF at room temperature in the presence of sodium hydroxide or potassium hydroxide, or in DCM at room temperature in the presence of an aqueous sodium hydroxide solution, by treatment with compound 1J, in which W is Cl, Br, I or OSO2R, wherein R = CH3, PhMe, CF3 or CF2CF2CF2CF3.

[0395] Compound 1T can be converted to compound 1U in step 7 as follows: in the presence of a base such as KOPh, by heating to solvent reflux, treatment with, for example, bis(pinacolyl)diboron and with a palladium catalyst such as bis(triphenylphosphine)palladium(II)Pd(PPh3)2Cl2 and a phosphine such as triphenylphosphine in toluene.

[0396] Compound 1K can be prepared as follows: in the Suzuki coupling reaction between compound 1T and R6B(OR')2 or R6BF3K in step 8 or between compound 1U and R6Br or R6I in step 9, a complex of, for example, [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM is used as a catalyst, in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux.

[0397] Compound 1K can be converted into compound (I) in step 12 in the presence of a hydroxide ion source such as NaOH in methanol (MeOH).

[0398] Intermediate 1T can be converted into compound 1Ta in step 10 in the presence of a hydroxide ion source such as NaOH in methanol (MeOH).

[0399] The compound 1Ta can be converted to compound I in step 11 as follows: under Suzuki conditions, using a suitable boron reagent R6B(OR')2 or R6BF3K, where -B(OR')2 is boric acid or pinacid ester and R6 is as defined above, using, for example, a complex of Pd(dppf)Cl2 with DCM as a catalyst, in a mixture of dioxane and water as a solvent and in the presence of a base such as Cs2CO3, at room temperature or by heating to solvent reflux.

[0400] When R3a is COOMe, COOEt, or a protected OH group (e.g., O-neopentyl), compound 1K can be deprotected in step 12 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH to obtain compound I. When R3 is COOH, extraction of the compound yields the sodium salt of compound I. Acidification with aqueous HCl 2N solution to pH 6-7 yields the neutral form. Acidification with aqueous HCl 2N solution to pH 1-2 yields the hydrochloride salt. Purification by HPLC yields the formate or trifluoroacetate salt.

[0401] Option 1c – Part 1 Alternative methods for preparing intermediate 1T

[0402]

[0403] Option 1c – Part 2

[0404]

[0405] According to Scheme 1c - Parts 1 and 2, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or OH protected with, for example, O-neopentyl, and R1, R2, R3, R3', R3”, R4, R7, R8, R9, X, n, m, and Y as defined above, compound 1V can be converted to compound 1X in step 1 as follows: in the Suzuki coupling reaction with compound 1W, using, for example, a complex of [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM as a catalyst, in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux.

[0406] Compound 1X can be converted to compound 1Y in step 2 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0407] Compound 1Y can be converted to compound 1Z in step 3 by treatment with a solution of TFA in DCM or a solution of HCl in dioxane.

[0408] Compound 1Z can be converted to compound 1AA in step 4 as follows: in DMF at 70°C in the presence of a base such as potassium carbonate, or in THF at room temperature in the presence of sodium hydroxide or potassium hydroxide, by treatment with compound 1J, in which W is Cl, Br, I or OSO2R, wherein R = CH3, PhMe, CF3 or CF2CF2CF2CF3.

[0409] Compound 1AA can be converted to compound 1AB in step 5 by treatment with a solution of sodium borohydride in MeOH.

[0410] Compound 1AB can also be prepared from compound 1V as follows: in step 6, a Suzuki coupling reaction with compound 1AC is used, using, for example, a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM as a catalyst, in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux, followed by treatment with pyridinium tribromide in DCM or THF at room temperature in step 7.

[0411] Compound 1AB can be converted to compound 1T in step 8 by treatment with trifluoromethanesulfonic anhydride and pyridine in the DCM.

[0412] Option 1dPreparation of compounds of formula (I) – General methods

[0413]

[0414] According to scheme 1d, where R3a is H, a carboxylic acid ester such as COOMe, COOEt, or OH protected with, for example, an O-neopentyl group, and R9 is a hydrogen atom, and R1, R2, R3, R3', R3”, R4, R4', R5, R6, R7, R8, X, n, m, and Y are as defined above, compound 1E can be converted to compound 1AF in step 1 as follows: by a Suzuki coupling reaction treated with compound 1AE, for example using a complex of, for example, [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM as a catalyst, in a mixture of dioxane and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux.

[0415] Compound 1AF can be converted to compound 1AG in step 2 by treatment with alkyl magnesium bromide in a solvent such as THF.

[0416] Compound 1AG can be converted to compound 1K in step 3 by treating water with sulfuric acid.

[0417] When R3a is COOMe, COOEt, or a protected OH group (e.g., O-neopentyl), compound 1K can be deprotected in step 4 by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH to obtain compound I. When R3 is COOH, extraction of the compound yields the sodium salt of compound I. Acidification with an aqueous solution of HCl 2N to pH 6-7 yields the neutral form. Acidification with an aqueous solution of HCl 2N to pH 1-2 yields the hydrochloride salt. Purification by HPLC yields the formate or trifluoroacetate salt. Scheme 1e: Alternative preparation method for compounds of formula (1B) – General method

[0418]

[0419] According to scheme 1e, where R3a is H, a carboxylic ester such as COOMe, COOEt, or OH protected with, for example, an O-neopentyl group, and R3', R3'', R9, X, and m are defined as described above, compound 1B can be prepared alternatively as follows: compound 1A can be converted to compound 1Aa in step 1 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0420] Compound 1Aa can be converted to compound 1AB in step 2 by deprotonation with a base such as LiHMDS in THF, followed by treatment with acetic anhydride.

[0421] Compound 1Ac can be prepared in step 3 as follows: in a Suzuki coupling reaction between compound 1Ab and R6B(OR')2 or R6BF3K, using, for example, a complex of [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM as a catalyst, in a mixture of toluene and water, and in the presence of a base such as cesium carbonate (Cs2CO3), by heating to solvent reflux. When R6 is a substituted cyclic olefin, heterocyclic olefin, or aliphatic ethylene, it can be reduced by hydrogenation with a catalyst such as Pd / C at a hydrogen pressure (H2) of about 5 bar, for example, at a temperature up to 70 °C, to give the corresponding saturated compound 1Ac.

[0422] Compound 1AC can be converted into compound 1B in step 4 by heating in, for example, methanol and DCM, via hydrolysis with an aqueous HCl solution.

[0423] This article also provides a method for preparing compounds of formula (I) as defined above, wherein the compounds of formula 1K

[0424]

[0425] Wherein R1, R2, R3', R3”, R4, R4', R5, R6, R7, R8, R9, m, n, X, and Y are as defined above, and R3a is a carboxylic acid ester, such as COOMe, COOEt, or an OH protected with, for example, an O-neopentyl group, which is converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH in methanol, optionally preceded by a step to obtain compound 1K, wherein the compound of formula 1T

[0426]

[0427] Wherein, R1, R2, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X, and Y are as described above, and R3a is as defined above.

[0428] Suzuki coupling is performed with boron reagents R6B(OR')2 or R6BF3K, where -B(OR')2 is boric acid or pinacolate, and R6 is as defined above.

[0429] This article also provides a method for preparing compounds of formula (I) above, wherein the compound of formula (I) Ta

[0430]

[0431] Wherein, R1, R2, R3a, R3', R3"', R4, R4', R5, R7, R8, R9, m, n, X, and Y are, as described above, Suzuki-coupled with boron reagent R6B(OR')2 or R6BF3K, wherein -B(OR')2 is boric acid or pinacolate and R6 is, as described above, the step of obtaining compound 1Ta is optionally preceded by the step of obtaining compound 1T, wherein the compound of formula 1T

[0432]

[0433] Wherein, R1, R2, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X, and Y are as described above, and R3a is as defined above.

[0434] In the presence of a hydroxide ion source such as NaOH in methanol, it is converted into compound 1Ta.

[0435] This article also provides intermediate compounds selected from compounds of formula 1T, 1K, and 1Ta, or any pharmaceutically acceptable salt thereof.

[0436]

[0437] R1, R2, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X, and Y are as defined above, and R3a is a carboxylic acid ester, such as COOMe, COOEt, or an OH protected with an O-neopentyl group.

[0438] This article further provides intermediate compounds of formula 1F, or any pharmaceutically acceptable salt thereof.

[0439]

[0440] R1, R2, R4, R4', R5, R7, R8, Y, and n are as described above.

[0441] This application also describes intermediate compounds of Formula 1E, or any pharmaceutically acceptable salt thereof.

[0442]

[0443] R3a, R3', R3”, X, m, R6, and R9 are hydrogen atoms, as described above.

[0444] On the other hand, this article also provides a method for preparing a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula IG as defined above, optionally followed by a purification step.

[0445] The purification step may consist of an acidification step, as shown in step 6 of Example 1 below, for example, using an aqueous hydrochloric acid solution.

[0446] 400 and 500MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, with the chemical shift (δ, in ppm) in dimethyl sulfoxide-d6 (d6-DMSO) at 303 K as a reference of 2.5 ppm. Coupling constants (J) are in Hertz.

[0447] Liquid chromatography / mass spectrometry (LC / MS) was performed on an Acquity Waters UPLC instrument with a Sedere light scattering detector and an SQDWaters mass spectrometer using UV detection (DAD 210-400 nm) and flash detection (Acquity UPLC CSH C18 1.7 μm, 2.1 x 30 mm). The mobile phase was H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H.

[0448] Tables 1a and 1b below respectively contain the specific compounds (names and structures) according to formula (I) of this disclosure and their characterization. 1 H NMR and liquid chromatography / mass).

[0449] Table 1a:

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503] Table 1b:

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538] The following examples describe the preparation of some compounds of formula (I) described herein. The number of compounds illustrated below corresponds to the number given in Tables 1a and 1b above. Unless otherwise stated, all reactions were carried out under an inert atmosphere.

[0539] In the following embodiments, when the source of the starting product is not specified, the product should be understood to be a known compound.

[0540] Intermediate:

[0541] Intermediate 1: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0542]

[0543] Step 1: tert-butyl 3-(4-bromobenzyl)azacyclobutane-1-carboxylate

[0544]

[0545] Method 1:

[0546] NaH (6.18 g, 155 mmol, 60% by weight purity) was added to a solution of (4-bromobenzyl)triphenylphosphonium bromide (79.2 g, 155 mmol) in DMF (400 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min. A solution of tert-butyl 3-oxazacyclobutane-1-carboxylate (24.1 g, 141 mmol) in DMF (160 mL) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 9 h. The reaction mixture was quenched by adding 100 mL of saturated aqueous NH4Cl solution at 0 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 60.0 g of (crude) tert-butyl 3-(4-bromobenzyl)azacyclobutane-1-carboxylate as a yellow solid.

[0547] LC / MS (m / z, MH+): 324

[0548] Method 2:

[0549] A mixture of tert-butyl 3-methyleneazacyclobutane-1-carboxylate (12.5 g, 73.9 mmol), 1-bromo-4-iodobenzene (23 g, 81.3 mmol), potassium carbonate (20.4 g, 148 mmol), tetrabutylammonium bromide (23.8 mmol, 73.9 mmol), and palladium(II) acetate (1.66 g, 7.39 mmol) in DMF (125 mL) was heated to 60 °C for 16 hours. After cooling to room temperature, EtOAc (500 mL) and water (500 mL) were added. After decantation, the organic phase was washed twice with water (500 mL), dried over MgSO4, filtered, concentrated under reduced pressure, and purified by rapid chromatography, eluting with DCM to give 20.7 g (86%) of tert-butyl 3-(4-bromobenzyl)azacyclobutane-1-carboxylate as a pale yellow solid.

[0550] LC / MS (m / z, MH+): 324

[0551] Step 2: 3-(4-bromobenzyl)azacyclobutane, trifluoroacetate

[0552]

[0553] A mixture of 60 g (185 mmol) of 3-(4-bromobenzyl)azacyclobutane-1-carboxylic acid tert-butyl ester and TFA (192 mL (2.59 mol)) in DCM (300 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was ground with EtOAc (50 mL) and filtered to give 28 g (45%) of 3-(4-bromobenzyl)azacyclobutane, trifluoroacetate.

[0554] LC / MS (m / z, MH+): 224

[0555] Step 3: 3-(4-bromobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0556]

[0557] A mixture of 1-fluoro-3-iodopropane (11.5 g, 61.2 mmol), 3-[(4-bromophenyl)methylene]-azacyclobutane, trifluoroacetate (23.0 g, 68.0 mmol), and KOH (5.72 g, 102 mmol) in DMF (100 mL) was stirred at room temperature for 10 hours. The reaction mixture was quenched by adding water (200 mL) and then extracted with EtOAc (500 mL). After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of DCM / MeOH from 100 / 00 to 95 / 05 to give 8.9 g (47% yield) of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azacyclobutane.

[0558] LC / MS (m / z, MH+): 284

[0559] Intermediate 2: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzylidene)azacyclobutane

[0560]

[0561] A mixture of 3-(4-bromobenzyl)-1-(3-fluoropropyl)azacyclobutane (2 g, 7.04 mmol), bis(pinacol)diborone (2.5 g, 9.85 mmol), KOAc (1.73 g, 17.6 mmol), and Pd(dppf)Cl2 (257 mg, 0.35 mmol) in dioxane (40 mL) was degassed and purged with argon, then refluxed for 2.5 h. After cooling to room temperature, AcOEt (50 mL), Et2O (20 mL), water (30 mL), and brine (30 mL) were added with stirring. After decantation, the organic phase was washed twice with 30 mL of brine and then concentrated under reduced pressure. The resulting residue was purified by rapid chromatography, eluting with a cyclohexane / AcOEt gradient from 100 / 0 to 0 / 100, followed by a DCM / MeOH gradient from 99 / 01 to 95 / 05, to give 1.2 g (51% yield) of 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzylidene)azacyclobutane.

[0562] LC / MS (m / z, MH+): 332

[0563] Intermediate 3: methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[0564]

[0565] A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]cycloene-3-carboxylate (15 g, 42.82 mmol) (prepared according to WO 2017140669), Pd(PPh3)2Cl2 (1.53 g, 2.14 mmol), PPh3 (673.87 mg, 2.57 mmol), bis(pinacol)diboron (144.08 g, 52.67 mmol), and PhOK (8.04 g, 60.80 mmol) was heated to 75 °C for 1.5 h. The yellow suspension first turned orange and then brown. After cooling to room temperature, DCM (150 mL) and water (150 mL) were added, and the mixture was decanted through a hydrophobic column. The organic phase was concentrated under reduced pressure. The resulting residue was purified by rapid chromatography with a gradient elution of heptane / DCM from 85 / 15 to 20 / 80 to give 10.1 g (72%) of methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a white solid.

[0566] LC / MS (m / z, MH+): 329

[0567] Intermediate 4: methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[0568]

[0569] Intermediate 4 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (prepared according to WO2020 / 049153) in a white solid, similar to intermediate 3, to obtain 3.9 g (82%) of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0570] LC / MS (m / z, MH+): 473

[0571] Intermediate 5: methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[0572]

[0573] Step 1: Methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

[0574]

[0575] Argon was bubbled for 10 minutes in 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), K2CO3 (12.67 g, 91.66 mmol) in toluene (40 mL). The reaction mixture was heated to reflux for 72 hours after the addition of 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (1.32 g, 2.29 mmol) and tris(dibenzylideneacetone)dipalladium(O) (1.05 g, 1.15 mmol). 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 MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography and eluted with a heptane / EtOAc gradient from 100 / 00 to 90 / 10 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.

[0576] LC / MS (m / z, MH+): 331

[0577] Step 2: Methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[0578]

[0579] DBU (277 mg, 0.27 mL, 1.82 mmol) was added to a suspension of sodium hydride (545 mg, 13.62 mmol, 60% by weight) in Me-THF (22 mL) cooled at 5 °C, 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 to allow the temperature 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 with MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography and eluted 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.

[0580] LC / MS (m / z, MH+): 463

[0581] Step 3: methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate

[0582]

[0583] Step 3 of intermediate 5 was prepared from 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate in a similar manner to intermediate 3, yielding 1.89 g (72%) of methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate.

[0584] LC / MS (m / z, MH+): 441

[0585] Intermediate 6: methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate

[0586]

[0587] Step 1: Methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate

[0588]

[0589] Step 1 of intermediate 6 was prepared from 1-bromo-2-methyl-4-fluoro-benzene in a similar manner to step 1 of intermediate 5, yielding 700 mg (47%) of methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate.

[0590] LC / MS (m / z, MH+): 327

[0591] Step 2: Methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[0592]

[0593] Step 2 of intermediate 6 was prepared from methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulen-2-carboxylate in a similar manner to step 2 of intermediate 5, yielding 7.86 g (82%) of methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0594] LC / MS (m / z, MH+): 459

[0595] Step 3: methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0596]

[0597] Step 3 of intermediate 6 was prepared from methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to intermediate 3, yielding 3.93 g (43%) of methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0598] LC / MS (m / z, MH+): 437

[0599] Intermediate 7: methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0600]

[0601] Method 1

[0602] Step 1: Methyl 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0603]

[0604] Methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (20 g, 57.09 mmol) (prepared according to WO 2017140669), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)aniline (13.13 g, 59.95 mmol), Cs2CO3 (37.21 g, 114.2 mmol) and the complex of Pd(dppf)Cl2 with DCM (1.25 g, 1.71 mmol) in dioxane (160 mL) and water (40 mL) were heated to 95 °C for 1 hour. Water (200 mL) and EtOAc (500 mL) were added. After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography and eluted with cyclohexane / EtOAc:85 / 15 to give 14.5 g (87%) of methyl 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0605] LC / MS (m / z, MH+): 294

[0606] Step 2: Methyl 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0607]

[0608] A solution of sodium nitrite (3.58 g, 51.9 mmol) in water (20 mL) was slowly added to a mixture of methyl 9-(4-aminophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (14.5 g, 49.4 mmol) in MeCN (270 mL) and 4N HCl (300 mL, 1200 mmol) cooled at 0 °C. After stirring the reaction mixture at 0 °C for 1 hour, a solution of sodium iodide (14.8 g, 98.9 mmol) in water (40 mL) was added. The cooling bath was removed, and the temperature was allowed to rise to room temperature. After stirring at room temperature for 4 hours, Et2O (500 mL) and 2N NaHSO3 solution (200 mL) were added. After decantation, the organic phase was washed twice with water (100 mL) and then with brine (100 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography and eluted with cyclohexane / EtOAc:95 / 05 to give 14.8 g (74%) of methyl 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0609] LC / MS (m / z, MH+): 405

[0610] Step 3: Methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0611]

[0612] Add pyridinium tribromide (12.9 g, 40.3 mmol) to a mixture of methyl 9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (14.8 g, 36.6 mmol) in DCM (500 mL). The reaction mixture was stirred at room temperature for 18 hours, then diluted with Et2O (500 mL) and pentane (500 mL), washed with 0.2 N NaHSO3 solution (100 mL), and washed twice with water (200 mL). After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 17.7 g (100%) of methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0613] LC / MS (m / z, MH+): 484

[0614] Step 4: 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azacyclobutane-1-carboxylic acid tert-butyl ester

[0615]

[0616] A solution of tert-butyl 3-methyleneazacyclobutane-1-carboxylate (7.44 g, 44 mmol) and methyl 8-bromo-9-(4-iodophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (17.7 g, 36.6 mmol) in DMF (200 mL) was degassed and purged with Ar for 5 min. K2CO3 (10.1 g, 73.3 mmol), tetrabutylammonium bromide (11.8 g, 36.6 mmol) and palladium(II) acetate (0.83 g, 3.66 mmol) were added to the solution with stirring. The mixture was heated to 50 °C for 30 h and then cooled to room temperature. Et2O (300 mL) and water (300 mL) were added. After decantation, the aqueous phase was extracted with another 300 mL of Et2O, and the combined organic phase was washed twice with water (200 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and purified by rapid chromatography with a gradient elution of cyclohexane / EtOAc (95 / 05 to 80 / 20) to give 14.7 g (76.5%) tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azacyclobutane-1-carboxylate.

[0617] LC / MS (m / z, MH+): 525

[0618] Step 5: Methyl 9-(4-(azacyclobut-3-ylemethylene)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate

[0619]

[0620] Step 5 of intermediate 7 was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 9.66 g (94%) of methyl 9-(4-(azacyclobutane-3-ylidenemethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate.

[0621] LC / MS (m / z, MH+): 425

[0622] Step 6: methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0623]

[0624] A mixture of 1-fluoro-3-iodopropane (2.88 g, 15.3 mmol) and 9-(4-(azacyclobut-3-ylemethylene)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate (8.24 g, 15.3 mmol) in a mixture of NaOH 1N (46 mL, 46 mmol) and DCM (70 mL) was stirred at room temperature for 48 hours. DCM (200 mL) and water (100 mL) were added. After decantation, the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The resulting residue was purified by rapid chromatography and eluted with a gradient of cyclohexane / EtOAc from 100 / 00 to 00 / 100 to give 4.41 g (59% yield) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0625] LC / MS (m / z, MH+): 485

[0626] Method 2

[0627] Step 1: tert-butyl 3-(4-bromobenzoyl)azacyclobutane-1-carboxylate

[0628]

[0629] n-BuLi (2.5 M, 491 mL) was added to a solution of 1,4-dibromobenzene (290 g, 1.23 mol, 157 mL) in THF (1050 mL) at -70 °C. The mixture was stirred for 30 min, and then tert-butyl 3-(methoxy(methyl)carbamoyl)azacyclobutane-1-carboxylate (200 g, 819 mmol) in THF (420 mL) was added at -70 °C. The reaction mixture was stirred for 1.5 h. The solution was heated to -25 °C and slowly quenched with a saturated aqueous solution of 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 rapid chromatography, eluting with a petroleum ether / EtOAc gradient from 10 / 1 to 0 / 1, to give 180 g (65%) of tert-butyl 3-(4-bromobenzoyl)azacyclobutane-1-carboxylate as a white solid.

[0630] LC / MS (m / z, MH+): 340

[0631] Step 2: 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0632]

[0633] Step 2 of intermediate 7 (method 2) was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate (intermediate 3) and tert-butyl 3-(4-bromobenzoyl)azacyclobutane-1-carboxylate in a similar manner to step 1 of intermediate 7 (method 1), yielding 8.5 g (99%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]arunnel-9-yl)benzoyl)azacyclobutane-1-carboxylate.

[0634] LC / MS (m / z, MH+): 462

[0635] Step 3: 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0636]

[0637] Step 3 of intermediate 7 (method 2) was prepared from tert-butyl 3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azacyclobutane-1-carboxylate in a similar manner to step 3 of intermediate 7 (method 1) to obtain 6.1 g (88%) of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azacyclobutane-1-carboxylate.

[0638] LC / MS (m / z, MH+): 540

[0639] Step 4: Methyl 9-(4-(azacyclobutane-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate

[0640]

[0641] Step 4 of intermediate 7 (method 2) was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzoyl)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 5 g (100%) of methyl 9-(4-(azacyclobutane-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate.

[0642] LC / MS (m / z, MH+): 440

[0643] Step 5: methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0644]

[0645] A mixture of 1-fluoro-3-iodopropane (4.27 g, 22.7 mmol), 9-(4-(azacyclobutane-3-carbonyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetate (5 g, 9.24 mmol), and K2CO3 (4.71 g, 34 mmol) in MeCN (200 mL) was heated to 70 °C for 1 hour. The reaction mixture was quenched by adding water (200 mL) and then extracted with EtOAc (500 mL). After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of cyclohexane / EtOAc from 100 / 00 to 00 / 100 to give 3 g (53%) of methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0646] LC / MS (m / z, MH+): 500

[0647] Step 6: methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0648]

[0649] NaBH4 (340 mg, 9 mmol) was added to a mixture of methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (3 g, 6 mmol) in methanol (5 mL) cooled at 0 °C. The reaction mixture was stirred at 0 °C for 30 hours. 10% aqueous citric acid (20 mL) and DCM (250 mL) were added. After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of DCM / MeOH from 100 / 00 to 05 / 95 to give 3 g (99%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0650] LC / MS (m / z, MH+): 502

[0651] Step 7: methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0652]

[0653] Add pyridine (945 mg, 11.94 mmol, 0.96 mL) and trifluoromethanesulfonyl trifluoromethanesulfonate (3.37 g, 11.94 mmol, 2 mL) to a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate (3 g, 5.97 mmol, 2 mL) in DCM (200 mL). Stir the reaction mixture at room temperature for 18 hours. Add DCM (400 mL) and saturated aqueous bicarbonate solution (300 mL). After decantation, dry the organic phase with MgSO4, filter and concentrate under reduced pressure to give the residue. The resulting residue was purified by rapid chromatography with a gradient elution of DCM / MeOH from 100 / 00 to 05 / 95 to give 1.9 g (66%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0654] LC / MS (m / z, MH+): 484

[0655] An alternative method (Method 2) for step 6 in preparing intermediate 7.

[0656] Step 1: 3-azacyclobutane(4-bromophenyl)-methyl ketone, trifluoroacetate

[0657]

[0658] Step 1 was prepared from tert-butyl 3-(4-bromobenzoyl)azacyclobutane-1-carboxylate following a similar procedure to Step 2 of Intermediate 1, yielding 41.6 g (100%) of 3-azacyclobutyl(4-bromophenyl)-methyl ketone, trifluoroacetate.

[0659] LC / MS (m / z, MH+): 240

[0660] Step 2: (4-Bromophenyl)(3-Fluoropropyl)azacyclobut-3-yl ketone

[0661]

[0662] Step 2 was performed similarly to step 3 of intermediate 1 to prepare 20 g (54%) of (4-bromophenyl)(3-fluoropropyl)azacyclobutyl-3-methyl ketone from 3-azacyclobutyl(4-bromophenyl)-methyl ketone, trifluoroacetate.

[0663] LC / MS (m / z, MH+): 300

[0664] Step 3: (4-Bromophenyl)(1-(3-fluoropropyl)azacyclobut-3-yl)methanol

[0665]

[0666] NaBH4 (5.04 g, 133 mmol) was added to a solution of (4-bromophenyl)(3-fluoropropyl)azacyclobut-3-yl ketone (20.0 g, 66.6 mmol) in MeOH (100 mL) at 0 °C. The mixture was stirred at 15 °C for 1 hour. The reaction mixture was slowly quenched with water (100 mL) and concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted three times with EtOAc (80 mL). After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography, eluting with a DCM:MeOH gradient from 98 / 02 to 90 / 10, to give 16 g (77%) of (4-bromophenyl)(1-(3-fluoropropyl)azacyclobut-3-yl)methanol as a mixture of two isomers.

[0667] LC / MS (m / z, MH+): 302

[0668] Step 4: methyl 9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0669]

[0670] Step 4 was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (intermediate 3) and (4-bromophenyl)(1-(3-fluoropropyl)azacyclobut-3-yl)methanol in a similar manner to step 1 (method 1) of intermediate 7, yielding 1.39 g (79%) of methyl 9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0671] LC / MS (m / z, MH+): 424

[0672] Step 5: Methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0673]

[0674] Step 5 was performed similarly to step 3 (method 1) of intermediate 7 to prepare methyl 9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, yielding 1.59 g (100%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0675] LC / MS (m / z, MH+): 502

[0676] Intermediate 8: 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid methyl ester

[0677]

[0678] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 7) (605 mg, 1.25 mmol), Pd(PPh3)2Cl2 (35 mg, 50 μmol), PPh3 (26 mg, 100 μmol), bis(pinacol)diboron (793 mg, 3.12 mmol), K2CO3 (38 mg, 0.27 mmol), and PhOK (413 mg, 3.12 mmol) in toluene (30 mL) was degassed and purged with Ar for 5 minutes, then heated to 75 °C for 6 hours. After cooling to room temperature, a 5% solution of Et2O (100 mL) and Na2CO3 (50 mL) was added. After decantation, the organic phase was washed with water (50 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of cyclohexane / EtOAc from 100 / 00 to 00 / 100 to give 500 mg (75%) of methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0679] LC / MS (m / z, MH+): 532

[0680] Intermediate 9: methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0681]

[0682] Step 1: 3,3-Difluoropropyltrifluoromethanesulfonate

[0683]

[0684] Trifluoromethanesulfonic anhydride (1.93 mL, 11.45 mmol) was added dropwise to a solution of 3,3-difluoroprop-1-ol (1 g, 10.41 mmol) and 2,6-dimethylpyridine (2.66 mL, 22.9 mmol) in DCM (20 mL) cooled at 0 °C. The mixture was stirred at 0 °C for 30 min. Et₂O and water were added. The aqueous phase was separated and extracted three times with diethyl ether. The combined organic phases were washed twice, successively with 10% citric acid aqueous solution and water, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 2.06 g (86%) of 3,3-difluoropropyltrifluoromethanesulfonate, which was used in the next step without further purification.

[0685] Step 2: methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0686]

[0687] Add NaOH 1N (22.29 mL, 22.29 mmol) to a suspension of methyl 9-(4-(azacyclobut-3-ylemmethyl)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate (intermediate 7, method 1, step 5) (3 g, 5.57 mmol), and 3,3-difluoropropyltrifluoromethanesulfonate (1.27 g, 5.57 mmol) in DCM (70 mL). Stir the mixture at room temperature for 18 hours. Add water (100 mL). Separate the aqueous phase and extract with a mixture of 150 mL Et2O and 150 mL EtOAc. Wash the combined organic phases with 100 mL of water, dry with Na2SO4, filter, and concentrate under reduced pressure. The resulting residue was purified by rapid chromatography with a gradient elution of DCM / MeOH from 100 / 0 to 80 / 20 to give 1.02 g (36%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0688] LC / MS (m / z, MH+): 502

[0689] Intermediate 10: 9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid methyl ester

[0690]

[0691] Intermediate 10 was prepared from methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to intermediate 8, yielding 118 mg (50%) of methyl 9-(4-((1-(3,3-difluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[0692] LC / MS (m / z, MH+): 550

[0693] Intermediate 11: 3-(4-bromo-2,3-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0694]

[0695] A solution of 1-fluoro-3-iodopropane (501 mg, 2.66 mmol), 3-(4-bromo-2,3-difluorobenzyl)azacyclobutane, trifluoroacetate (950 mg, 2.54 mmol) (commercially available), and powdered NaOH (304.7 mg, 7.6 mmol) in acetonitrile (30 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding 50 mL of saturated aqueous NH4Cl solution and extracted with EtOAc (50 mL). After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography using a gradient elution of DCM / EtOAc from 100 / 00 to 00 / 100 to give 0.65 g (34%) of 3-(4-bromo-2,3-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane.

[0696] LC / MS (m / z, MH+): 320

[0697] Intermediate 12: 3-(4-bromo-2,6-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0698]

[0699] Step 1: (4-Bromo-2,6-difluorophenyl)methanol

[0700]

[0701] NaBH4 (377 mg, 9.95 mmol) was added dropwise 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. The reaction mixture was stirred at 0 °C for 1 hour, and then slowly quenched at 0 °C with 1 N aqueous HCl solution. After stirring at 0 °C for 30 minutes, water was added, and the mixture was transferred to a separatory funnel and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated to dryness, prepared with pentane, and filtered to give 1.83 g (91%) of (4-bromo-2,6-difluorophenyl)methanol.

[0702] LC / MS (m / z, MH+): 223

[0703] Step 2: 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene

[0704]

[0705] Phosphorus tribromide (0.57 mL, 6 mmol) was added dropwise to a solution of (4-bromo-2,6-difluorophenyl)methanol (2.67 g, 11.99 mmol) in Et₂O (60 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours, and then slowly poured into a saturated aqueous solution of NaHCO₃ with stirring. After stirring for 30 minutes, the mixture was transferred to a separatory funnel and extracted three times with EtOAc. The combined organic phases 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.

[0706] LC / MS (m / z, MH+): 285

[0707] Step 3: Diethyl (4-bromo-2,6-difluorobenzyl)phosphonate

[0708]

[0709] 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 for 4 hours in a sealed tube. The resulting mixture was purified by rapid chromatography, eluting with a cyclohexane / EtOAc gradient from 100 / 0 to 80 / 20, to give 2.95 g (98%) of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate as a colorless oil.

[0710] LC / MS (m / z, MH+): 343

[0711] Step 4: tert-butyl 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane-1-carboxylate

[0712]

[0713] Under an argon atmosphere, at -78°C, 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). 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-oxoazacyclobutane-1-carboxylate (1.65 g, 9.62 mmol) in THF (30 mL) was added. The reaction mixture was stirred and the temperature was raised to room temperature until complete. The mixture was then transferred to a separatory funnel containing a saturated aqueous solution of NH4Cl and extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then purified by rapid chromatography, eluting with a cyclohexane / EtOAc gradient from 100 / 0 to 50 / 50, to give 1.67 g (53%) of tert-butyl 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane-1-carboxylate as a colorless, viscous oil.

[0714] LC / MS (m / z, MH+): 360

[0715] Step 5: 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane, trifluoroacetate

[0716]

[0717] Step 5 of intermediate 12 was prepared from tert-butyl 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 1.65 g (98%) of 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane, trifluoroacetate, as a white solid.

[0718] LC / MS (m / z, MH+): 260

[0719] Step 6: 3-(4-bromo-2,6-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0720]

[0721] Step 6 of intermediate 12 was prepared from 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane trifluoroacetic acid in a similar manner to intermediate 11, yielding 79 mg (18%) of 3-(4-bromo-2,6-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane.

[0722] LC / MS (m / z, MH+): 320

[0723] Intermediate 13: 3-(4-bromo-2,6-dimethylbenzyl)-1-(3-fluoropropyl)azacyclobutane

[0724]

[0725] Step 1: (4-bromo-2,6-dimethylphenyl)methanol

[0726]

[0727] Step 1 of intermediate 13 was prepared from 4-bromo-2,6-dimethylbenzaldehyde in a similar manner to step 1 of intermediate 12, yielding 1.86 g (92%) of (4-bromo-2,6-dimethylphenyl)methanol.

[0728] LC / MS (m / z, MH+): 215

[0729] Step 2: 5-Bromo-2-(bromomethyl)-1,3-dimethylbenzene

[0730]

[0731] Step 2 of intermediate 13 was prepared from (4-bromo-2,6-dimethylphenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 1.27 g (98%) of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene.

[0732] LC / MS (m / z, MH+): 277

[0733] Step 3: Diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate

[0734]

[0735] Step 3 of intermediate 13 was prepared from 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene in a similar manner to step 3 of intermediate 12, yielding 1.16 g (86%) of diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate.

[0736] LC / MS (m / z, MH+): 335

[0737] Step 4: tert-butyl 3-(4-bromo-2,6-dimethylbenzyl)azacyclobutane-1-carboxylate

[0738]

[0739] Step 4 of intermediate 13 was prepared from diethyl (4-bromo-2,6-dimethylbenzyl)phosphonate in a similar manner to step 4 of intermediate 12, yielding 0.86 g (27%) of tert-butyl 3-(4-bromo-2,6-dimethylbenzyl)azacyclobutane-1-carboxylate.

[0740] LC / MS (m / z, MH+): 352

[0741] Step 5: 3-(4-bromo-2,6-dimethylbenzyl)azacyclobutane, trifluoroacetate

[0742]

[0743] Step 5 of intermediate 13 is prepared from tert-butyl 3-(4-bromo-2,6-dimethylbenzyl)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 0.77 g (86%) of 3-(4-bromo-2,6-dimethylbenzyl)azacyclobutane, trifluoroacetate.

[0744] LC / MS (m / z, MH+): 252

[0745] Step 6: 3-(4-bromo-2,6-dimethylbenzyl)-1-(3-fluoropropyl)azacyclobutane

[0746]

[0747] Step 6 of intermediate 13 is prepared from 3-(4-bromo-2,6-dimethylbenzyl)azacyclobutane trifluoroacetic acid in a similar manner to intermediate 11, yielding 0.7 g (50%) of 3-(4-bromo-2,6-dimethylbenzyl)-1-(3-fluoropropyl)azacyclobutane.

[0748] LC / MS (m / z, MH+): 312

[0749] Intermediate 14: 3-(4-bromo-2,5-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0750]

[0751] Step 1: Diethyl (4-bromo-2,5-difluorobenzyl)phosphonate

[0752]

[0753] Step 1 of intermediate 14 is prepared from commercially available 1-bromo-4-(bromomethyl)-2,5-difluorobenzene in a similar manner to step 3 of intermediate 12, yielding 6.48 g (87%) of diethyl (4-bromo-2,5-difluorobenzyl)phosphonate.

[0754] LC / MS (m / z, MH+): 343

[0755] Step 2: tert-butyl 3-(4-bromo-2,5-difluorobenzyl)azacyclobutane-1-carboxylate

[0756]

[0757] Step 2 of intermediate 14 was prepared from diethyl (4-bromo-2,5-difluorobenzyl)phosphonate in a similar manner to step 4 of intermediate 12, yielding 1.16 g (73%) of tert-butyl 3-(4-bromo-2,5-difluorobenzyl)azacyclobutane-1-carboxylate.

[0758] LC / MS (m / z, MH+): 360

[0759] Step 3: 3-(4-bromo-2,5-difluorobenzyl)azacyclobutane, trifluoroacetate

[0760]

[0761] Step 3 of intermediate 14 was prepared from tert-butyl 3-(4-bromo-2,5-difluorobenzyl)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 1.07 g (89%) of 3-(4-bromo-2,5-difluorobenzyl)azacyclobutane, trifluoroacetate.

[0762] LC / MS (m / z, MH+): 260

[0763] Step 4: 3-(4-bromo-2,5-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0764]

[0765] Step 4 of intermediate 14 is prepared from 3-(4-bromo-2,5-difluorobenzyl)azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, to obtain 0.7 g (76%) of 3-(4-bromo-2,5-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane.

[0766] LC / MS (m / z, MH+): 320

[0767] Intermediate 15: 3-[(4-bromo-3-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0768]

[0769] Step 1: (4-Bromo-3-fluoro-phenyl)methanol

[0770]

[0771] Step 1 of intermediate 15 was prepared from 4-bromo-3-fluoro-benzaldehyde in a similar manner to step 1 of intermediate 12, yielding 5 g (99%) of (4-bromo-3-fluoro-phenyl)methanol.

[0772] LC / MS (m / z, MH+): 205

[0773] Step 2: 1-Bromo-4-(bromomethyl)-2-fluorobenzene

[0774]

[0775] Step 2 of intermediate 15 was prepared from (4-bromo-3-fluoro-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 5.1 g (77%) of 1-bromo-4-(bromomethyl)-2-fluoro-benzene.

[0776] LC / MS (m / z, MH+): 267

[0777] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-benzene

[0778]

[0779] Step 3 of intermediate 15 was prepared from 1-bromo-4-(bromomethyl)-2-fluorobenzene in a similar manner to step 3 of intermediate 12, yielding 3 g (99%) of 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluorobenzene.

[0780] LC / MS (m / z, MH+): 325

[0781] Step 4: 3-[(4-bromo-3-fluoro-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0782]

[0783] Step 4 of intermediate 15 was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-benzene in a similar manner to step 4 of intermediate 12, yielding 3.75 g (85%) of tert-butyl 3-[(4-bromo-3-fluoro-phenyl)methylene]azacyclobutane-1-carboxylate.

[0784] LC / MS (m / z, MH+): 342

[0785] Step 5: 3-[(4-bromo-3-fluoro-phenyl)methylene]azacyclobutane, trifluoroacetate

[0786]

[0787] Step 5 of intermediate 15 is prepared from tert-butyl 3-[(4-bromo-3-fluoro-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.66 g of 3-[(4-bromo-3-fluoro-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0788] LC / MS (m / z, MH+): 242

[0789] Step 6: 3-[(4-bromo-3-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0790]

[0791] Step 6 of intermediate 15 is prepared from 3-[(4-bromo-3-fluoro-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, to obtain 2.1 g (95%) of 3-[(4-bromo-3-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0792] LC / MS (m / z, MH+): 302

[0793] Intermediate 16: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0794]

[0795] Step 1: (4-bromo-2-fluoro-5-methyl-phenyl)methanol

[0796]

[0797] Step 1 of intermediate 16 is prepared from 4-bromo-2-fluoro-5-methylbenzaldehyde in a similar manner to step 1 of intermediate 12, yielding 2 g (99%) of (4-bromo-2-fluoro-5-methylphenyl)methanol.

[0798] LC / MS (m / z, MH+): 219

[0799] Step 2: 1-Bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene

[0800]

[0801] Step 2 of intermediate 16 was prepared from (4-bromo-2-fluoro-5-methyl-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 2.7 g (91%) of 1-bromo-4-(bromomethyl)-5-fluoro-2-methyl-benzene.

[0802] LC / MS (m / z, MH+): 281

[0803] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-5-fluoro-2-methylbenzene

[0804]

[0805] Step 3 of intermediate 16 was prepared from 1-bromo-4-(bromomethyl)-5-fluoro-2-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 3.2 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-5-fluoro-2-methylbenzene.

[0806] LC / MS (m / z, MH+): 339

[0807] Step 4: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0808]

[0809] Step 4 of intermediate 16 was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-5-fluoro-2-methylbenzene in a similar manner to step 4 of intermediate 12, yielding 2.75 g (80%) of tert-butyl 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[0810] LC / MS (m / z, MH+): 356

[0811] Step 5: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[0812]

[0813] Step 5 of intermediate 16 is prepared from tert-butyl 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 3.6 g of 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0814] LC / MS (m / z, MH+): 256

[0815] Step 6: 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0816]

[0817] Step 6 of intermediate 16 is prepared from 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 145 mg (48%) of 3-[(4-bromo-2-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0818] LC / MS (m / z, MH+): 316

[0819] Intermediate 17: 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0820]

[0821] Step 1: (4-Bromo-2-fluoro-3-methyl-phenyl)methanol

[0822]

[0823] Step 1 of intermediate 17 was prepared from 4-bromo-2-fluoro-3-methylbenzaldehyde in a similar manner to step 1 of intermediate 12, yielding 5.1 g (100%) of (4-bromo-2-fluoro-5-methyl-phenyl)methanol.

[0824] LC / MS (m / z, MH+): 219

[0825] Step 2: 1-Bromo-4-(bromomethyl)-3-fluoro-2-methylbenzene

[0826]

[0827] Step 2 of intermediate 17 was prepared from (4-bromo-2-fluoro-3-methyl-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 2.33 g (91%) of 1-bromo-4-(bromomethyl)-3-fluoro-2-methyl-benzene.

[0828] LC / MS (m / z, MH+): 281

[0829] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-2-methylbenzene

[0830]

[0831] Step 3 of intermediate 17 was prepared from 1-bromo-4-(bromomethyl)-3-fluoro-2-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 2.8 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-2-methylbenzene.

[0832] LC / MS (m / z, MH+): 339

[0833] Step 4: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0834]

[0835] Step 4 of intermediate 17 was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-2-methyl-benzene in a similar manner to step 4 of intermediate 12, yielding 2.3 g (77%) of tert-butyl 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[0836] LC / MS (m / z, MH+): 356

[0837] Step 5: 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[0838]

[0839] Step 5 of intermediate 17 is prepared from tert-butyl 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.86 g of 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0840] LC / MS (m / z, MH+): 256

[0841] Step 6: 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0842]

[0843] Step 6 of intermediate 17 was prepared from 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 203 mg (68%) of 3-[(4-bromo-2-fluoro-3-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0844] LC / MS (m / z, MH+): 316

[0845] Intermediate 18: 3-(4-bromo-2,6-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0846]

[0847] Step 1: 5-Bromo-2-(Bromomethyl)-1,3-Difluorobenzene

[0848]

[0849] Step 1 of intermediate 18 is prepared from commercially available (4-bromo-2,6-difluoro-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 6 g (94%) of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene.

[0850] LC / MS (m / z, MH+): 285

[0851] Step 2: Diethyl (4-bromo-2,6-difluorobenzyl)phosphonate

[0852]

[0853] Step 2 of intermediate 18 was prepared from 5-bromo-2-(bromomethyl)-1,3-difluorobenzene in a similar manner to step 3 of intermediate 12, yielding 6.5 g (88%) of diethyl (4-bromo-2,6-difluorobenzyl)phosphonate as a colorless oil.

[0854] LC / MS (m / z, MH+): 343

[0855] Step 3: tert-butyl 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane-1-carboxylate

[0856]

[0857] Step 3 of intermediate 18 was prepared from diethyl (4-bromo-2,6-difluorobenzyl)phosphonate in a similar manner to step 4 of intermediate 12, yielding 7 g (86%) of tert-butyl 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane-1-carboxylate as a colorless, viscous oil.

[0858] LC / MS (m / z, MH+): 360

[0859] Step 4: 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane, trifluoroacetate

[0860]

[0861] Step 4 of intermediate 18 is prepared from tert-butyl 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 12 g of 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane, trifluoroacetate, as a white solid.

[0862] LC / MS (m / z, MH+): 260

[0863] Step 5: 3-(4-bromo-2,6-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane

[0864]

[0865] Step 5 of intermediate 18 is prepared from 3-(4-bromo-2,6-difluorobenzyl)azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, to obtain 600 mg (52%) of 3-(4-bromo-2,6-difluorobenzyl)-1-(3-fluoropropyl)azacyclobutane.

[0866] LC / MS (m / z, MH+): 320

[0867] Intermediate 19: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0868]

[0869] Step 1: (4-bromo-2-fluoro-6-methyl-phenyl)methanol

[0870]

[0871] Step 1 of intermediate 19 was prepared from 4-bromo-2-fluoro-6-methylbenzaldehyde in a similar manner to step 1 of intermediate 12, yielding 2.3 g (73%) of (4-bromo-2-fluoro-6-methylphenyl)methanol.

[0872] LC / MS (m / z, MH+): 219

[0873] Step 2: 1-Bromo-4-(bromomethyl)-3-fluoro-5-methylbenzene

[0874]

[0875] Step 2 of intermediate 19 was prepared from (4-bromo-2-fluoro-6-methyl-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 5.8 g (100%) of 1-bromo-4-(bromomethyl)-3-fluoro-5-methyl-benzene.

[0876] LC / MS (m / z, MH+): 281

[0877] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-5-methylbenzene

[0878]

[0879] Step 3 of intermediate 19 is prepared from 1-bromo-4-(bromomethyl)-3-fluoro-5-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 3 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-5-methylbenzene.

[0880] LC / MS (m / z, MH+): 339

[0881] Step 4: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0882]

[0883] Step 4 of intermediate 19 was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-3-fluoro-5-methylbenzene in a similar manner to step 4 of intermediate 12, yielding 3.5 g (78%) of tert-butyl 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[0884] LC / MS (m / z, MH+): 356

[0885] Step 5: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[0886]

[0887] Step 5 of intermediate 19 is prepared from tert-butyl 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 5.4 g of 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0888] LC / MS (m / z, MH+): 256

[0889] Step 6: 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0890]

[0891] Step 6 of intermediate 19 was prepared from 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 203 mg (68%) of 3-[(4-bromo-2-fluoro-6-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0892] LC / MS (m / z, MH+): 316

[0893] Intermediate 20: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0894]

[0895] Step 1: (4-Bromo-3-fluoro-5-methyl-phenyl)methanol

[0896]

[0897] Step 1 of intermediate 20 was prepared from 4-bromo-3-fluoro-5-methylbenzaldehyde in a similar manner to step 1 of intermediate 12, yielding 4.97 g (99%) of (4-bromo-3-fluoro-5-methylphenyl)methanol.

[0898] LC / MS (m / z, MH+): 219

[0899] Step 2: 2-Bromo-5-(bromomethyl)-1-fluoro-3-methylbenzene

[0900]

[0901] Step 2 of intermediate 20 is prepared from (4-bromo-3-fluoro-5-methyl-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 5.3 g (83%) of 2-bromo-5-(bromomethyl)-1-fluoro-3-methyl-benzene.

[0902] LC / MS (m / z, MH+): 281

[0903] Step 3: 2-Bromo-5-(diethoxyphosphorylmethyl)-1-fluoro-3-methylbenzene

[0904]

[0905] Step 3 of intermediate 20 was prepared from 2-bromo-5-(bromomethyl)-1-fluoro-3-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 5.7 g (88%) of 2-bromo-5-(diethoxyphosphorylmethyl)-1-fluoro-3-methylbenzene.

[0906] LC / MS (m / z, MH+): 339

[0907] Step 4: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0908]

[0909] Step 4 of intermediate 20 is prepared from 2-bromo-5-(diethoxyphosphorylmethyl)-1-fluoro-3-methyl-benzene in a similar manner to step 4 of intermediate 12, yielding 4.16 g (70%) of tert-butyl 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[0910] LC / MS (m / z, MH+): 356

[0911] Step 5: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[0912]

[0913] Step 5 of intermediate 20 is prepared from tert-butyl 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.33 g of 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0914] LC / MS (m / z, MH+): 256

[0915] Step 6: 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0916]

[0917] Step 6 of intermediate 20 is prepared from 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, to obtain 850 mg (51%) of 3-[(4-bromo-3-fluoro-5-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0918] LC / MS (m / z, MH+): 316

[0919] Intermediate 21: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0920]

[0921] Step 1: 4-Bromo-1-(diethoxyphosphorylmethyl)-2-methylbenzene

[0922]

[0923] Step 1 of intermediate 21 is prepared from commercially available 4-bromo-1-(bromomethyl)-2-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 1.46 g (60%) of 4-bromo-1-(diethoxyphosphorylmethyl)-2-methylbenzene.

[0924] LC / MS (m / z, MH+): 321

[0925] Step 2: 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0926]

[0927] Step 2 of intermediate 21 is prepared from 4-bromo-1-(diethoxyphosphorylmethyl)-2-methyl-benzene in a similar manner to step 4 of intermediate 12, yielding 0.82 g (43%) of tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[0928] LC / MS (m / z, MH+): 338

[0929] Step 3: 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[0930]

[0931] Step 3 of intermediate 21 is prepared from tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 0.65 g (78%) of 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0932] LC / MS (m / z, MH+): 238

[0933] Step 4: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0934]

[0935] Step 4 of intermediate 21 is prepared from 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 160 mg (49%) of 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0936] LC / MS (m / z, MH+): 298

[0937] Intermediate 22: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0938]

[0939] Step 1: 1-Bromo-4-(bromomethyl)-2,5-dimethylbenzene

[0940]

[0941] Step 1 of intermediate 22 was prepared from commercially available (4-bromo-2,5-dimethyl-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 3.75 g (97%) of 1-bromo-4-(bromomethyl)-2,5-dimethyl-phenyl.

[0942] LC / MS (m / z, MH+): 277

[0943] Step 2: 1-Bromo-4-(diethoxyphosphorylmethyl)-2,5-dimethylbenzene

[0944]

[0945] Step 2 of intermediate 22 was prepared from 1-bromo-4-(bromomethyl)-2,5-dimethylbenzene in a similar manner to step 3 of intermediate 12, yielding 3 g (67%) of 1-bromo-4-(diethoxyphosphorylmethyl)-2,5-dimethylbenzene.

[0946] LC / MS (m / z, MH+): 335

[0947] Step 3: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0948]

[0949] Step 3 of intermediate 22 was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2,5-dimethylbenzene in a similar manner to step 4 of intermediate 12, yielding 0.90 g (28%) of tert-butyl 3-[(4-bromo-2,5-dimethylphenyl)methylene]azacyclobutane-1-carboxylate.

[0950] LC / MS (m / z, MH+): 352

[0951] Step 4: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[0952]

[0953] Step 4 of intermediate 22 is prepared from tert-butyl 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 0.81 g (86%) of 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0954] LC / MS (m / z, MH+): 252

[0955] Step 5: 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0956]

[0957] Step 5 of intermediate 22 is prepared from 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 0.48 g (69%) of 3-[(4-bromo-2,5-dimethyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0958] LC / MS (m / z, MH+): 312

[0959] Intermediate 23: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0960]

[0961] Step 1: (4-Bromo-3,5-difluoro-phenyl)methanol

[0962]

[0963] Step 1 of intermediate 23 was prepared from 4-bromo-3,5-difluoro-benzaldehyde in a similar manner to step 1 of intermediate 12, yielding 3 g (99%) of (4-bromo-3,5-difluoro-phenyl)methanol.

[0964] LC / MS (m / z, MH+): 223

[0965] Step 2: 2-Bromo-5-(bromomethyl)-1,3-difluorobenzene

[0966]

[0967] Step 2 of intermediate 23 was prepared from 4-bromo-3,5-difluoro-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 3.7 g (96%) of 2-bromo-5-(bromomethyl)-1,3-difluoro-benzene.

[0968] LC / MS (m / z, MH+): 285

[0969] Step 3: 2-Bromo-5-(diethoxyphosphorylmethyl)-1,3-difluoro-benzene

[0970]

[0971] Step 3 of intermediate 23 was prepared from 2-bromo-5-(bromomethyl)-1,3-difluorobenzene in a similar manner to step 3 of intermediate 12, yielding 4.27 g (96%) of 2-bromo-5-(diethoxyphosphorylmethyl)-1,3-difluorobenzene.

[0972] LC / MS (m / z, MH+): 343

[0973] Step 4: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[0974]

[0975] Step 4 of intermediate 23 was prepared from 2-bromo-5-(diethoxyphosphorylmethyl)-1,3-difluoro-benzene in a similar manner to step 4 of intermediate 12, yielding 2.54 g (57%) of tert-butyl 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azacyclobutane-1-carboxylate.

[0976] LC / MS (m / z, MH+): 360

[0977] Step 5: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azacyclobutane, trifluoroacetate

[0978]

[0979] Step 5 of intermediate 23 is prepared from tert-butyl 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.45 g (93%) of 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azacyclobutane, trifluoroacetate.

[0980] LC / MS (m / z, MH+): 260

[0981] Step 6: 3-[(4-bromo-3,5-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0982]

[0983] Step 6 of intermediate 23 was prepared from 3-[(4-bromo-3,5-difluoro-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 191 mg (45%) of 3-[(4-bromo-3,5-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[0984] LC / MS (m / z, MH+): 320

[0985] Intermediate 24: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[0986]

[0987] Step 1: (4-Bromo-3-fluoro-2-methyl-phenyl)methanol

[0988]

[0989] Step 1 of intermediate 24 was prepared from 4-bromo-3-fluoro-2-methylbenzaldehyde in a similar manner to step 1 of intermediate 12, yielding 2.87 g (97%) of (4-bromo-3-fluoro-2-methylphenyl)methanol.

[0990] LC / MS (m / z, MH+): 219

[0991] Step 2: 1-Bromo-4-(bromomethyl)-2-fluoro-3-methylbenzene

[0992]

[0993] Step 2 of intermediate 24 was prepared from (4-bromo-3-fluoro-2-methyl-phenyl)methanol in a similar manner to step 2 of intermediate 12, yielding 3.63 g (98%) of 1-bromo-4-(bromomethyl)-2-fluoro-3-methyl-benzene.

[0994] LC / MS (m / z, MH+): 281

[0995] Step 3: 1-Bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-3-methylbenzene

[0996]

[0997] Step 3 of intermediate 24 was prepared from 1-bromo-4-(bromomethyl)-2-fluoro-3-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 4.3 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-3-methylbenzene.

[0998] LC / MS (m / z, MH+): 339

[0999] Step 4: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1000]

[1001] Step 4 of intermediate 24 was prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2-fluoro-3-methyl-benzene in a similar manner to step 4 of intermediate 12, yielding 1.8 g (40%) of tert-butyl 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[1002] LC / MS (m / z, MH+): 356

[1003] Step 5: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[1004]

[1005] Step 5 of intermediate 24 is prepared from tert-butyl 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 979 mg (66%) of 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[1006] LC / MS (m / z, MH+): 256

[1007] Step 6: 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[1008]

[1009] Step 6 of intermediate 24 was prepared from 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 219 mg (51%) of 3-[(4-bromo-3-fluoro-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[1010] LC / MS (m / z, MH+): 316

[1011] Intermediate 25: 3-[(4-bromo-2-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[1012]

[1013] Intermediate 25 was prepared from commercially available 3-[(4-bromo-2-fluoro-phenyl)methylene]azacyclobutane hydrochloride in a similar manner to intermediate 11, yielding 730 mg (58%) of 3-[(4-bromo-2-fluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[1014] LC / MS (m / z, MH+): 302

[1015] Intermediate 26: 3-[(4-bromo-2,3-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[1016]

[1017] Intermediate 26 was prepared from commercially available 3-[(4-bromo-2,3-difluoro-phenyl)methylene]azacyclobutane hydrochloride in a similar manner to intermediate 11, yielding 952 mg (77%) of 3-[(4-bromo-2,3-difluoro-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[1018] LC / MS (m / z, MH+): 320

[1019] Intermediate 27: 5-bromo-2-[[1-(3-fluoropropyl)azacyclobut-3-ylidene]methyl]benzylnitrile

[1020]

[1021] Step 1: 5-Bromo-2-(diethoxyphosphorylmethyl)benzylnitrile

[1022]

[1023] Step 1 of intermediate 27 was prepared from commercially available 5-bromo-2-(bromomethyl)benzyl nitrile in a similar manner to step 3 of intermediate 12, yielding 2.93 g (97%) of 5-bromo-2-(diethoxyphosphorylmethyl)benzyl nitrile.

[1024] LC / MS (m / z, MH+): 332

[1025] Step 2: 3-[(4-bromo-2-cyano-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1026]

[1027] Step 2 of intermediate 27 was prepared from 5-bromo-2-(diethoxyphosphorylmethyl)benzyl nitrile in a similar manner to step 4 of intermediate 12, yielding 2.19 g (71%) of tert-butyl 3-[(4-bromo-2-cyano-phenyl)methylene]azacyclobutane-1-carboxylate.

[1028] LC / MS (m / z, MH+): 349

[1029] Step 3: 2-(azacyclobut-3-methylenemethyl)-5-bromobenzylnitrile, trifluoroacetate

[1030]

[1031] Step 3 of intermediate 27 was prepared from tert-butyl 3-[(4-bromo-2-cyano-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.18 g (96%) of 2-(azacyclobutane-3-methylenemethyl)-5-bromobenzyl nitrile, trifluoroacetate.

[1032] LC / MS (m / z, MH+): 249

[1033] Step 4: 5-Bromo-2-[[1-(3-fluoropropyl)azacyclobut-3-ylidene]methyl]benzylnitrile

[1034]

[1035] Step 4 of intermediate 27 was prepared from 2-(azacyclobut-3-ylidenemethyl)-5-bromobenzanilonitrile, trifluoroacetate, in a similar manner to intermediate 11, yielding 1.35 g (73%) of 5-bromo-2-[[1-(3-fluoropropyl)azacyclobut-3-ylidene]methyl]benzanilonitrile.

[1036] LC / MS (m / z, MH+): 309

[1037] Intermediate 28: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azacyclobutane

[1038]

[1039] Step 1: 4-Bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene

[1040]

[1041] Step 1 of intermediate 28 was prepared from commercially available [4-bromo-2-(trifluoromethyl)phenyl]methanol in a similar manner to step 2 of intermediate 12, yielding 2.87 g (92%) of 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene.

[1042] LC / MS (m / z, MH+): 317

[1043] Step 2: 4-Bromo-1-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene

[1044]

[1045] Step 2 of intermediate 28 was prepared from 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene in a similar manner to step 3 of intermediate 12, yielding 3.13 g (93%) of 4-bromo-1-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene.

[1046] LC / MS (m / z, MH+): 375

[1047] Step 3: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1048]

[1049] Step 3 of intermediate 28 was prepared from 4-bromo-1-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene in a similar manner to step 4 of intermediate 12, yielding 2.42 g (74%) of tert-butyl 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azacyclobutane-1-carboxylate.

[1050] LC / MS (m / z, MH+): 392

[1051] Step 4: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azacyclobutane, trifluoroacetate

[1052]

[1053] Step 4 of intermediate 28 is prepared from tert-butyl 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 3.07 g of 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azacyclobutane, trifluoroacetate.

[1054] LC / MS (m / z, MH+): 291

[1055] Step 5: 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azacyclobutane

[1056]

[1057] Step 5 of intermediate 28 was prepared from 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 1.29 g (60%) of 3-[[4-bromo-2-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azacyclobutane.

[1058] LC / MS (m / z, MH+): 352

[1059] Intermediate 29: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[1060]

[1061] Step 1: 4-Bromo-1-(diethoxyphosphorylmethyl)-2-methylbenzene

[1062]

[1063] Step 1 of intermediate 29 is prepared from commercially available 4-bromo-1-(bromomethyl)-2-methylbenzene in a similar manner to step 3 of intermediate 12, yielding 1.46 g (60%) of 4-bromo-1-(diethoxyphosphorylmethyl)-2-methylbenzene.

[1064] LC / MS (m / z, MH+): 321

[1065] Step 2: 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1066]

[1067] Step 2 of intermediate 29 was prepared from 4-bromo-1-(diethoxyphosphorylmethyl)-2-methylbenzene in a similar manner to step 4 of intermediate 12, yielding 0.82 g (53%) of tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylate.

[1068] LC / MS (m / z, MH+): 338

[1069] Step 3: 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate

[1070]

[1071] Step 3 of intermediate 29 is prepared from tert-butyl 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 0.65 g (78%) of 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate.

[1072] LC / MS (m / z, MH+): 238

[1073] Step 4: 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane

[1074]

[1075] Step 4 of intermediate 29 was prepared from 3-[(4-bromo-2-methyl-phenyl)methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 170 mg (57%) of 3-[(4-bromo-2-methyl-phenyl)methylene]-1-(3-fluoropropyl)azacyclobutane.

[1076] LC / MS (m / z, MH+): 298

[1077] Intermediate 30: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azacyclobutane

[1078]

[1079] Step 1: 1-Bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene

[1080]

[1081] Step 1 of intermediate 30 is prepared from commercially available [4-bromo-2-(trifluoromethyl)phenyl]methanol in a similar manner to step 2 of intermediate 12, yielding 2.35 g (94%) of 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene.

[1082] LC / MS (m / z, MH+): 317

[1083] Step 2: 1-Bromo-4-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene

[1084]

[1085] Step 2 of intermediate 30 is prepared from 1-bromo-4-(bromomethyl)-2-(trifluoromethyl)benzene in a similar manner to step 3 of intermediate 12, yielding 2.86 g (100%) of 1-bromo-4-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene.

[1086] LC / MS (m / z, MH+): 375

[1087] Step 3: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1088]

[1089] Step 3 of intermediate 30 is prepared from 1-bromo-4-(diethoxyphosphorylmethyl)-2-(trifluoromethyl)benzene in a similar manner to step 4 of intermediate 12, yielding 2.24 g (75%) of tert-butyl 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azacyclobutane-1-carboxylate.

[1090] LC / MS (m / z, MH+): 392

[1091] Step 4: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azacyclobutane, trifluoroacetate

[1092]

[1093] Step 4 of intermediate 30 is prepared from tert-butyl 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.13 g (92%) of 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azacyclobutane, trifluoroacetate.

[1094] LC / MS (m / z, MH+): 291

[1095] Step 5: 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azacyclobutane

[1096]

[1097] Step 5 of intermediate 30 is prepared from 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]azacyclobutane, trifluoroacetate, in a similar manner to intermediate 11, yielding 1.83 g (99%) of 3-[[4-bromo-3-(trifluoromethyl)phenyl]methylene]-1-(3-fluoropropyl)azacyclobutane.

[1098] LC / MS (m / z, MH+): 352

[1099] Intermediate 31: 2-bromo-5-[[1-(3-fluoropropyl)azacyclobut-3-ylidene]methyl]benzylnitrile

[1100]

[1101] Step 1: 2-Bromo-5-(hydroxymethyl)benzylnitrile

[1102]

[1103] Step 1 of intermediate 31 was prepared from 2-bromo-5-formylbenzyl nitrile in a similar manner to step 1 of intermediate 12, yielding 2.06 g (100%) of 2-bromo-5-(hydroxymethyl)benzyl nitrile.

[1104] LC / MS (m / z, MH+): 212

[1105] Step 2: 2-Bromo-5-(bromomethyl)benzylnitrile

[1106]

[1107] Step 2 of intermediate 31 was prepared from 2-bromo-5-(hydroxymethyl)benzyl nitrile in a similar manner to step 2 of intermediate 12, yielding 2.3 g (97%) of 2-bromo-5-(bromomethyl)benzyl nitrile.

[1108] LC / MS (m / z, MH+): 274

[1109] Step 3: 2-Bromo-5-(diethoxyphosphorylmethyl)benzylnitrile

[1110]

[1111] Step 3 of intermediate 31 was prepared from 2-bromo-5-(bromomethyl)benzyl nitrile in a similar manner to step 3 of intermediate 12, yielding 3.18 g (93%) of 2-bromo-5-(diethoxyphosphorylmethyl)benzyl nitrile.

[1112] LC / MS (m / z, MH+): 332

[1113] Step 4: 3-[(4-bromo-3-cyano-phenyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1114]

[1115] Step 4 of intermediate 31 was prepared from 2-bromo-5-(diethoxyphosphorylmethyl)benzyl nitrile in a similar manner to step 4 of intermediate 12, yielding 2.56 g (80%) of tert-butyl 3-[(4-bromo-3-cyano-phenyl)methylene]azacyclobutane-1-carboxylate.

[1116] LC / MS (m / z, MH+): 349

[1117] Step 5: 5-(azacyclobut-3-methylenemethyl)-2-bromobenzylnitrile, trifluoroacetate

[1118]

[1119] Step 5 of intermediate 31 is prepared from tert-butyl 3-[(4-bromo-3-cyano-phenyl)methylene]azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 2.1 g (81%) of 5-(azacyclobutane-3-methylenemethyl)-2-bromobenzyl nitrile, trifluoroacetate.

[1120] LC / MS (m / z, MH+): 249

[1121] Step 6: 2-Bromo-5-[[1-(3-fluoropropyl)azacyclobut-3-ylidene]methyl]benzylnitrile

[1122]

[1123] Step 6 of intermediate 31 is prepared from 5-(azacyclobut-3-ylidenemethyl)-2-bromobenzylnitrile, trifluoroacetate, in a similar manner to intermediate 11, to obtain 900 mg (96%) of 2-bromo-5-[[1-(3-fluoropropyl)azacyclobut-3-ylidene]methyl]benzylnitrile.

[1124] LC / MS (m / z, MH+): 309

[1125] Intermediate 32: 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yltrifluoromethanesulfonate

[1126]

[1127] Step 1: 6-(2-chlorophenyl)-6,7,8,9-tetrahydrobenzo[7]annulen-5-one

[1128]

[1129] Step 1 of intermediate 32 is performed in a similar manner to step 1 of intermediate 5 from 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa 580 mg (16%) of 6-(2-chlorophenyl)-6,7,8,9-tetrahydrobenzo[7] arbutin-5-one was prepared by methyl 8-carboxylate.

[1130] LC / MS (m / z, MH+): 271

[1131] Step 2: 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yltrifluoromethanesulfonate

[1132]

[1133] KHMDS (1M, 2.57ml, 2.57mmol) was added to a solution of 6-(2-chlorophenyl)-6,7,8,9-tetrahydrobenzo[7]anthren-5-one (580mg, 2.14mmol) in THF (15ml) at -50°C under an Ar atmosphere. The mixture was stirred for 30 minutes and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (765mg, 2.14mmol) was added to the resulting mixture. The reaction mixture was slowly heated to 20°C and stirred for 90 minutes. The reaction mixture was quenched with saturated aqueous citric acid solution, diluted with H2O, and extracted twice with Et2O. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography with a gradient of 0-50% ethyl acetate in cyclohexane to give 608 mg (71%) of 8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7] arunnelene-9-yl trifluoromethanesulfonate.

[1134] LC / MS (m / z, MH+): 403

[1135] Intermediate 33: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxa Methyl 8-carboxylate

[1136]

[1137] Step 1: 5-O-2,3,4,5-Tetrahydrobenzo[b]oxa 8-Methyltrifluoromethanesulfonate

[1138]

[1139] 8-hydroxy-3,4-dihydrobenzo[b]oxa cooled at -20°C -5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO 2018091153) and pyridine (2.82 g, 2.89 mL, 35.36 mmol) in DCM (120 mL) were added dropwise to a mixture of trifluoromethanesulfonic anhydride (8.14 g, 6 mL, 28.28 mmol). The reaction mixture was stirred at 0 °C for 30 h. Water (50 mL) was added. The organic phase was separated and washed with a saturated aqueous solution of NaHCO3 (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa -8-yltrifluoromethanesulfonate.

[1140] LC / MS (m / z, MH+): 311

[1141] Step 2: 5-O-2,3,4,5-Tetrahydrobenzo[b]oxa Methyl 8-carboxylate

[1142]

[1143] To compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa 8-yltrifluoromethanesulfonate (7.4 g, 23.85 mmol) was added to a solution of DMF (30 mL) and MeOH (15 mL) with DIEA (3.15 g, 4.16 mL, 23.85 mmol) and a complex of Pd(dppf)Cl2 with DCM (1.10 g, 1.43 mmol). The suspension was degassed and purged three times with CO. The mixture was stirred at 75 °C for 2 hours under CO (5 bar). The reaction was filtered through diatomaceous earth. The filtrate was diluted with water (400 mL) and extracted three times with EtOAc (300 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of heptane / ethyl acetate from 85 / 15 to 80 / 20 to give 4.6 g (88%) 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa Methyl 8-carboxylate.

[1144] LC / MS (m / z, MH+): 221

[1145] Step 3: 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa Methyl 8-carboxylate

[1146]

[1147] Step 3 of intermediate 33 is performed in a similar manner to step 1 of intermediate 5 from 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa was prepared from methyl 8-carboxylate to give 1.13 g (67%) of 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa Methyl 8-carboxylate.

[1148] LC / MS (m / z, MH+): 365

[1149] Step 4: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxa Methyl 8-carboxylate

[1150]

[1151] Step 4 of intermediate 33 follows a similar operation to step 2 of intermediate 5, from 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxa was prepared to give 0.48 g (31%) of methyl 8-carboxylate. Methyl 8-carboxylate.

[1152] LC / MS (m / z, MH+): 496

[1153] Intermediate 34: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thia Methyl 8-carboxylate

[1154]

[1155] Step 1: 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazo 8-Methyltrifluoromethanesulfonate

[1156]

[1157] Step 1 of intermediate 34 is performed in a similar manner to step 1 of intermediate 33 from 8-hydroxy-3,4-dihydrobenzo[b]thiazo -5(2H)-one (prepared according to WO 2018091153) was prepared to give 6.3 g (48%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazoline. -8-yltrifluoromethanesulfonate.

[1158] LC / MS (m / z, MH+): 327

[1159] Step 2: 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazo Methyl 8-carboxylate

[1160]

[1161] Step 2 of intermediate 34 is performed in a similar manner to step 2 of intermediate 33 from 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazo 8-yltrifluoromethanesulfonate was prepared to give 6.36 g (94%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazoline. Methyl 8-carboxylate.

[1162] LC / MS (m / z, MH+): 237

[1163] Step 3: 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazo Methyl 8-carboxylate

[1164]

[1165] Step 3 of intermediate 34 follows a similar operation to step 1 of intermediate 5, from 5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazo 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazoline was prepared to give 0.9 g (60%) of methyl 8-carboxylate. Methyl 8-carboxylate.

[1166] LC / MS (m / z, MH+): 381

[1167] Step 4: 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thia Methyl 8-carboxylate

[1168]

[1169] Step 4 of intermediate 34 follows a similar operation to step 2 of intermediate 5, from 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]thiazoline. 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiazoline was prepared to give 1.31 g (44%) of methyl 8-carboxylate. Methyl 8-carboxylate.

[1170] LC / MS (m / z, MH+): 512

[1171] Intermediate 35: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate

[1172]

[1173] Step 1: Methyl 2-(2,4-dichlorophenyl)-1-oxo-tetrahydronaphthalene-6-carboxylate

[1174]

[1175] Step 1 of intermediate 35 was prepared from methyl 1-oxotetrahydronaphthalene-6-carboxylate in a similar manner to step 1 of intermediate 5, yielding 459 mg (19%) of 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxa Methyl 8-carboxylate.

[1176] LC / MS (m / z, MH+): 349

[1177] Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate

[1178]

[1179] Step 2 of intermediate 35 was prepared from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetrahydronaphthalene-6-carboxylate in a similar manner to step 2 of intermediate 32, yielding 0.48 g (31%) of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate.

[1180] LC / MS (m / z, MH+): 481

[1181] Intermediate 36: methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1182]

[1183] Intermediate 36 was prepared from methyl 9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetate (intermediate 7, method 1, step 5) and 1,1,1-trifluoro-3-iodopropane in a similar manner to step 2 of intermediate 9, yielding 332 mg (27%) of methyl 8-bromo-9-(4-((1-(3,3,3-trifluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1184] LC / MS (m / z, MH+): 520

[1185] Intermediate 37: methyl 8-bromo-9-(4-((1-(3-fluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1186]

[1187] Step 1: 1,1-Dideuter-3-fluoro-prop-1-ol

[1188]

[1189] A solution of 3-fluoropropionic acid (1 g, 10.41 mmol) in Et₂O (30 ml) was added dropwise to a solution of lithium aluminum deuteride (911 mg, 21.7 mmol) cooled at 0 °C in Et₂O (50 ml). The reaction mixture was slowly heated to 20 °C and stirred for 48 hours. The reaction mixture was then poured into a mixture of ice, HCl₂N, and Et₂O. The organic matter was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 400 mg (38%) of 1,1-dideuter-3-fluoro-prop-1-ol, which was used in the next step without further purification.

[1190] Step 2: (1,1-Dideuter-3-fluoropropyl)trifluoromethanesulfonate

[1191]

[1192] Step 2 of intermediate 37 was prepared from 1,1-dideuter-3-fluoro-prop-1-ol in a similar manner to step 1 of intermediate 9, yielding 600 mg (37%) of (1,1-dideuter-3-fluoro-propyl)trifluoromethanesulfonate, which was used in the next step without further purification.

[1193] Step 3: methyl 8-bromo-9-(4-((1-(3-fluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1194]

[1195] Step 3 of intermediate 37 was prepared from methyl 9-(4-((1-(3-fluoropropyl-1,1-d2)azacyclobutane-3-ylidene)phenyl)-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate (intermediate 7, method 1, step 5) and (1,1-dideuter-3-fluoropropyl)trifluoromethanesulfonate in a similar manner to step 2 of intermediate 9, yielding 270 mg (67%) of methyl 8-bromo-9-(4-((1-(3-fluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1196] LC / MS (m / z, MH+): 487

[1197] Intermediate 38: methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1198]

[1199] Step 1: 1,1-Dideuterium-3,3-difluoro-propane-1-ol

[1200]

[1201] Step 1 of intermediate 38 was prepared from 3,3-difluoropropionic acid in a similar manner to step 1 of intermediate 37, yielding 810 mg (47%) of 1,1-dideuter-3,3-difluoro-prop-1-ol, which was used in the next step without further purification.

[1202] Step 2: (1,1-Dideuter-3,3-difluoropropyl)trifluoromethanesulfonate

[1203]

[1204] Step 2 of intermediate 38 is prepared from 1,1-dideuter-3,3-difluoro-prop-1-ol in a similar manner to step 1 of intermediate 9, yielding 1.1 g (79%) of (1,1-dideuter-3,3-difluoro-propyl)trifluoromethanesulfonate, which is used in the next step without further purification.

[1205] Step 3: methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1206]

[1207] Step 3 of intermediate 38 was prepared from methyl 9-(4-((1-(3,3-difluoropropyl-1,1-d2)azacyclobutane-3-ylidene)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetate (intermediate 7, method 1, step 5) and (1,1-dideuter-3,3-difluoropropyl)trifluoromethanesulfonate, in a similar manner to step 2 of intermediate 9, to obtain 243 mg (51%) of methyl 8-bromo-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1208] LC / MS (m / z, MH+): 505

[1209] Intermediate 39: methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1210]

[1211] Step 1: Methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate

[1212]

[1213] Add pyridinium tribromide (16.12 g, 45.4 mmol) in portions to a mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate (9.42 g, 43.2 mmol) in DCM (400 mL). Stir the reaction mixture overnight at room temperature. Add water (500 mL) and diethyl ether (1 L). Separate the organic phase and wash twice with water, dry with MgSO4, filter and concentrate under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate.

[1214] LC / MS (m / z, MH+): 297

[1215] Step 2: Methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1216]

[1217] LiHMDS (1M, 27mL) was added to a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate (7.4g, 25mmol) in THF (80mL) at -78°C under an Ar atmosphere. The mixture was stirred for 2 hours and then treated with acetic anhydride (8.8mL, 75mmol) to raise the temperature to 0°C. The aqueous layer was separated and extracted with diisopropyl ether after being poured into diisopropyl ether and water. The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography using a gradient of 0-50% ethyl acetate in cyclohexane to give 6.97g (83%) of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1218] LC / MS (m / z, MH+): 339

[1219] Step 3: Methyl 9-acetoxy-8-(3,3-dimethylcyclohex-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1220]

[1221] Step 3 of intermediate 39 was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate and 2-(3,3-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane in a similar manner to step 1 of example 79, yielding 2.9 g (89%) of methyl 9-acetoxy-8-(3,3-dimethylcyclohexen-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1222] LC / MS (m / z, MH+): 369

[1223] Step 4: Methyl 9-acetoxy-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1224]

[1225] Step 4 of intermediate 39 was prepared from methyl 9-acetoxy-8-(3,3-dimethylcyclohexyl-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 2 of example 100, yielding 1.19 g (54%) of methyl 9-acetoxy-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1226] LC / MS (m / z, MH+): 371

[1227] Step 5: Methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate

[1228]

[1229] A solution of 12N HCl (0.44 mL, 5.29 mmol) was added to a solution of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (285 mg, 0.81 mmol) in methanol (8 mL) and DCM (4 mL). The resulting reaction mixture was heated to reflux for 7 hours and then stirred overnight at room temperature. The aqueous layer was separated and extracted with diisopropyl ether after being poured into diisopropyl ether and water. The combined organic layers were washed with water, 5% aqueous Na2CO3 solution, and water, 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]annulen-2-carboxylate, which was used in the next step without further purification.

[1230] LC / MS (m / z, MH+): 309

[1231] Step 6: Methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1232]

[1233] Step 6 of intermediate 39 was prepared from methyl 6-benzyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate in a similar manner to step 2 of intermediate 32, yielding 760 mg (77%) of methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1234] LC / MS (m / z, MH+): 461

[1235] Intermediate 40: methyl 8-(bicyclo[3.1.0]hex-1-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1236]

[1237] Step 1: Methyl 9-acetoxy-8-(bicyclo[3.1.0]hex-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1238]

[1239] A mixture of methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (0.4 g, 1.18 mmol), potassium bicyclo[3.1.0]hex-1-yltrifluoroborate (266 mg, 1.41 mmol), Cs2CO3 (1.15 g, 3.54 mmol), and a complex of Pd(dppf)Cl2 with DCM (91 mg, 120 μmol) in toluene (6 mL) and water (2 mL) was heated to 90 °C for 6 hours in a sealed tube. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After separation, the organic layer was washed with water (50 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography using a gradient of 0-20% ethyl acetate in cyclohexane to give 0.45 g (40%) of methyl 9-acetoxy-8-(bicyclo[3.1.0]hex-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1240] LC / MS (m / z, MH+): 341

[1241] Step 2: Methyl 6-(bicyclo[3.1.0]hex-1-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate

[1242]

[1243] Step 2 of intermediate 40 was prepared from methyl 9-acetoxy-8-(bicyclo[3.1.0]hex-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 5 of intermediate 39, yielding 0.3 g (100%) of methyl 6-(bicyclo[3.1.0]hex-1-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate.

[1244] LC / MS (m / z, MH+): 299

[1245] Step 3: Methyl 8-(bicyclo[3.1.0]hex-1-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1246]

[1247] Step 3 of intermediate 40 was prepared from methyl 6-(bicyclo[3.1.0]hex-1-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate in a similar manner to step 2 of intermediate 32, yielding 247 mg (56%) of methyl 8-(bicyclo[3.1.0]hex-1-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1248] LC / MS (m / z, MH+): 431

[1249] Intermediate 41: methyl 8-(bicyclo[3.2.1]oct-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1250]

[1251] Step 1: Methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1252]

[1253] Step 1 of intermediate 41 was prepared from methyl 9-acetoxy-8-bromo-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate and 2-(3-bicyclo[3.2.1]oct-2-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane in a similar manner to step 1 of example 79, yielding 1.07 g (99%) of methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-enyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1254] LC / MS (m / z, MH+): 367

[1255] Step 2: Methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1256]

[1257] Step 2 of intermediate 41 was prepared from methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-2-en-3-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 2 of example 100, yielding 0.58 g (54%) of methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1258] LC / MS (m / z, MH+): 369

[1259] Step 3: Methyl 6-(bicyclo[3.2.1]oct-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate

[1260]

[1261] Step 3 of intermediate 41 was prepared from methyl 9-acetoxy-8-(bicyclo[3.2.1]oct-3-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 5 of intermediate 39, yielding 0.51 mg (99%) of methyl 6-(bicyclo[3.2.1]oct-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate.

[1262] LC / MS (m / z, MH+): 327

[1263] Step 4: Methyl 8-(bicyclo[3.2.1]oct-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1264]

[1265] Step 4 of intermediate 41 was prepared from methyl 6-(bicyclo[3.2.1]oct-3-yl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate in a similar manner to step 2 of intermediate 32, yielding 0.48 g (67%) of methyl 8-(bicyclo[3.2.1]oct-3-yl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1266] LC / MS (m / z, MH+): 459

[1267] Intermediate 42: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-ylneopentate

[1268]

[1269] Step 1: 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ylneopentate

[1270]

[1271] Step 1 of intermediate 42 was prepared from 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]arunnel-2-yl neopentanoate (prepared according to WO 2018091153) in a similar manner to step 1 of intermediate 5, yielding 795 mg (30%) of 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]arunnel-2-yl neopentanoate.

[1272] LC / MS (m / z, MH+): 405

[1273] Step 2: 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-ylneopentate

[1274]

[1275] Step 2 of intermediate 42 was prepared from 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl neopentanoate in a similar manner to step 2 of intermediate 32, yielding 0.33 g (69%) of 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl neopentanoate.

[1276] LC / MS (m / z, MH+): 537

[1277] Intermediate 43: tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azacyclobutane-1-carboxylate, isomer 1 and isomer 2

[1278]

[1279] Step 1: Methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate

[1280]

[1281] Add pyridinium tribromide (16.12 g, 45.4 mmol) in portions to a mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate (9.42 g, 43.2 mmol) in DCM (400 mL). Stir the reaction mixture overnight at room temperature. Add water (500 mL) and diethyl ether (1 L). Separate the organic phase and wash twice with water, dry with MgSO4, filter and concentrate under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate.

[1282] LC / MS (m / z, MH+): 297

[1283] Step 2: Methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulen-2-carboxylate

[1284]

[1285] DABCO (7.4 mL, 67.32 mmol) was added to a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate (10 g, 33.66 mmol) in acetonitrile (100 mL). The reaction mixture was heated to 55 °C for 2.5 h under Ar. Diethyl ether and 1 N HCl were added. The organic phase was separated and washed twice with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was then purified by rapid 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]annulen-2-carboxylate.

[1286] LC / MS (m / z, MH+): 217

[1287] Step 3: Methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate, racemic mixture

[1288]

[1289] At 0 °C and Ar, a 0.328 M cuprate solution (35 mL, 11.5 mmol) was added to a solution of methyl 5-oxo-8,9-dihydro-5H-benzo[7]cycloene-2-carboxylate (1.88 g, 8.6 mmol) in THF (30 mL). The cuprate solution was prepared by adding 15 mL of a solution of 1.6 N methyl lithium in ether to a suspension of 2.5 g CuI (13 mmol) in 25 mL ether at 0 °C and Ar. The reaction mixture was stirred at 0 °C for 30 minutes. Diethyl ether (200 mL) and 1 N HCl (200 mL) were added. The organic phase was separated, and the aqueous phase was extracted with diethyl 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 rapid chromatography and eluted 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.

[1290] LC / MS (m / z, MH+): 233

[1291] Step 4: Methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture

[1292]

[1293] Step 4 of intermediate 43 was prepared from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate in a similar manner to step 2 of intermediate 32, yielding 2.5 g (86%) of methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a racemic mixture.

[1294] LC / MS (m / z, MH+): 365

[1295] Step 5: Methyl 9-(4-aminophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture

[1296]

[1297] Step 5 of intermediate 43 was prepared from methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 1 (method 1) of intermediate 7, yielding 0.87 g (100%) of methyl 9-(4-aminophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a racemic mixture.

[1298] LC / MS (m / z, MH+): 308

[1299] Step 6: Methyl 9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture

[1300]

[1301] Step 6 of intermediate 43 was prepared from methyl 9-(4-aminophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 2 (method 1) of intermediate 7, yielding 0.96 g (80%) of methyl 9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a racemic mixture.

[1302] LC / MS (m / z, MH+): 419

[1303] Step 7: Methyl 8-bromo-9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture

[1304]

[1305] Step 7 of intermediate 43 was prepared from methyl 9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate in a similar manner to step 3 (method 1) of intermediate 7, yielding 1.09 g (95%) of methyl 8-bromo-9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a racemic mixture.

[1306] LC / MS (m / z, MH+): 497

[1307] Step 8: tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azacyclobutane-1-carboxylate, isomer 1 and isomer 2

[1308]

[1309] Step 8 of intermediate 43 was prepared from methyl 8-bromo-9-(4-iodophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate in a similar manner to step 4 (method 1) of intermediate 7, yielding 0.73 g (62%) of tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]arunnel-9-yl)benzylidene)azacyclobutane-1-carboxylate as a racemic mixture of isomer 1 and isomer 2.

[1310] LC / MS (m / z, MH+): 538

[1311] The racemic mixture of (4-bromophenyl)(1-(3-fluoropropyl)azacyclobut-3-yl)methanol was separated by chiral chromatography (conditions: rapid CHIRALPAK AD 20 μm (350 x 76.5 mm); heptane 7% / EtOH 30%) to give 0.188 g of isomer 1 and 0.201 g of isomer 2.

[1312] Example:

[1313] Method A:

[1314] Example 1 : 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1315]

[1316] Step 1: methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate

[1317]

[1318] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate (intermediate 4) (100 mg, 211 μmol), 3-(4-bromobenzyl)-1-(3-fluoropropyl)azacyclobutane (intermediate 1) (60 mg, 211 μmol), Cs2CO3 (178 mg, 534.5 μmol), and a complex of Pd(dppf)Cl2 with DCM (11 mg, 13 μmol) in dioxane (1 mL) and water (0.4 mL) was heated to reflux for 1 hour. Water (2 mL) and DCM (5 mL) were added. After decanting from a hydrophobic column, the organic phase was concentrated under reduced pressure, and the residue was treated on an SCX column. The resulting residue was purified by rapid chromatography and eluted with a gradient of MeOH (100 / 0 to 95 / 05, v / v) in DCM to give 101 mg (86%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1319] LC / MS (m / z, MH+): 550

[1320] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1321]

[1322] A solution of 1N NaOH (0.55 mL) was added to a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (101 mg, 183.6 μmol) in MeOH (0.50 mL) and THF (1 mL), and the reaction mixture was heated to reflux for 1 hour. After cooling, water (5 mL) and DCM (5 mL) were added and the pH was adjusted to 2 with 1N HCl. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure, and the residue was purified by SFC (Flash DCPAK B 5μm; 250x30 mm; supercritical CO2 70% / MeOH 30% / TEA 0.1% at 120 mL / min) to obtain 47.5 mg (45%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7] arunculene-3-carboxylic acid.

[1323] Method B:

[1324] Example 79 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1325]

[1326] Step 1: methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1327]

[1328] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate (intermediate 7) (100 mg, 206 μmol), (2-chloro-4-fluoro-phenyl)boronic acid (54 mg, 310 μmol), Cs2CO3 (141 mg, 433 μmol), and a complex of Pd(dppf)Cl2 with DCM (15 mg, 21 μmol) in dioxane (4 mL) and water (1 mL) was heated to reflux for 30 minutes. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried with MgSO4, filtered and concentrated under reduced pressure to obtain 65 mg (59%) of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7] arunculene-3-carboxylate.

[1329] LC / MS (m / z, MH+): 534

[1330] Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1331]

[1332] LiOH (15 mg, 608 μmol) was added to a solution of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (65 mg, 121.7 μmol) in MeOH (5 mL) and water (1 mL), and the reaction mixture was heated to 50 °C for 2 hours. After cooling, water (50 mL), EtOAc (100 mL) and Et2O (100 mL) were added and the pH was adjusted to 7 with HCl 0.1 N. After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography by elution with a gradient of MeOH (100 / 0 to 90 / 10, v / v) in DCM to give 43 mg (68%) of 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7] arunculene-3-carboxylic acid.

[1333] Method C:

[1334] Example 8: 8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1335]

[1336] Step 1: 8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid methyl ester

[1337]

[1338] A mixture of 9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate (intermediate 8) (200 mg, 376 μmol), 3-bromobicyclo[4.2.0]oct-1(6),2,4-triene (137 mg, 752 μmol), Cs2CO3 (245 mg, 752 μmol), and a complex of Pd(dppf)Cl2 with DCM (14 mg, 19 μmol) in dioxane (8 mL) and water (2 mL) was heated to 95 °C for 3 hours. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of cyclohexane / EtOAc (100 / 0 to 100 / 0, v / v) to give 55 mg (29%) of methyl 8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1339] LC / MS (m / z, MH+): 508

[1340] Step 2: 8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1341]

[1342] Step 2 of Example 8 was performed similarly to step 2 of Example 79 to prepare methyl 8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, yielding 16 mg (30%) of 8-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1343] Method D:

[1344] Example 114: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa -8-formate

[1345]

[1346] Step 1: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa Methyl 8-carboxylate

[1347]

[1348] 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxa Methyl 8-carboxylate (intermediate 30) (250 mg, 504 μmol), 1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]methylene]azacyclobutane (intermediate 2) (158 mg, 478 μmol), Cs₂CO₃ (447 mg, 1.37 mmol), and a complex of Pd(dppf)Cl₂ with DCM (33 mg, 41 μmol) were heated to 85 °C for 2 hours in dioxane (2 mL) and water (0.8 mL). After cooling to room temperature, DCM (4 mL) and water (2 mL) were added. After decantation in a hydrophobic column, the organic phase was concentrated under reduced pressure, and the residue was purified by rapid chromatography, eluting with EtOAc, to give 69 mg (26%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa Methyl 8-carboxylate.

[1349] LC / MS (m / z, MH+): 552

[1350] Step 2: 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa 8-Formic acid

[1351]

[1352] Step 2 of Example 115 follows a similar operation to Step 2 of Example 79, from 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa 4,3-dihydrobenzo[b]oxa was prepared from methyl 8-carboxylate to obtain 46 mg (65%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxa -8-Formate.

[1353] Method E:

[1354] Example 60: 9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1355]

[1356] Step 1: methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1357]

[1358] Add 0.5 M tetrahydropyran-4-yl zinc iodide solution (0.6 mL, 309.7 μmol) to a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 7) (100 mg, 206 μmol), tri-o-tolylphosphine (10 mg, 33 μmol), and Pd2(dba)3 (9.5 mg, 16.5 μmol) in DMF (4 mL). After stirring at room temperature for 2 hours, add EtOAc (100 mL), Et2O (100 mL), and water (150 mL). After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of cyclohexane / EtOEt (100 / 0 to 00 / 100, v / v) to give 60 mg (59%) of methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1359] LC / MS (m / z, MH+): 490

[1360] Step 2: 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1361]

[1362] Step 2 of Example 60 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid by a similar operation to Step 2 of Example 79, yielding 10 mg (17%) of 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1363] Method F:

[1364] Example 100 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1365]

[1366] Step 1: methyl 9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1367]

[1368] Step 1 of Example 100 was prepared from methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate (intermediate 7 of step 5 (method 2)) and 4,4,5,5,-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxacyclopentaborane to obtain 224 mg (62%) of methyl 9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate.

[1369] LC / MS (m / z, MH+): 476

[1370] Step 2: Methyl 5-[4-[1-(3-fluoropropyl)azacyclobutane-3-carbonyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

[1371]

[1372] A mixture of methyl 9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (224 mg, 471 μmol), Pd / C 10% (90 mg, 85 μmol) in EtOH (30 mL) and EtOAc (15 mL) was hydrogenated at 50 °C and 5 bar of H2 for 20 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by rapid chromatography and eluted with a gradient of DCM / MeOH (100 / 0 to 95 / 05, v / v) to give 150 mg (66%) of methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1373] LC / MS (m / z, MH+): 478

[1374] Step 3: Methyl 5-[4-[[1-(3-fluoropropyl)azacyclobut-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate

[1375]

[1376] In step 3 of Example 100, methyl 5-[4-[1-(3-fluoropropyl)azacyclobutane-3-carbonyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate was prepared from intermediate 7 by a similar operation to step 6 (method 2), yielding 75 mg (50%) of methyl 5-[4-[[1-(3-fluoropropyl)azacyclobutane-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate.

[1377] LC / MS (m / z, MH+): 480

[1378] Step 4: methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1379]

[1380] In Example 100, step 4 was performed similarly to step 7 (method 2) of intermediate 7, from methyl 5-[4-[[1-(3-fluoropropyl)azacyclobutane-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-carboxylate to obtain 71 mg (66%) of methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1381] LC / MS (m / z, MH+): 462

[1382] Step 5: 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1383]

[1384] Step 5 of Example 100 was prepared from methyl 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid by a similar operation to step 2 of Example 79, yielding 44 mg (40%) of 9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1385] Method G:

[1386] Example 102: 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobut-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1387]

[1388] Step 1: methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1389]

[1390] Step 1 of Example 102 was prepared from (4-bromophenyl)(1-(3-fluoropropyl)azacyclobut-3-yl) methyl ketone and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate by a similar operation to Step 1 of Example 1, yielding 270 mg (34%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1391] LC / MS (m / z, MH+): 566

[1392] Step 2: methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobut-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1393]

[1394] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azacyclobutane-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (430 mg, 759 μmol) in THF (20 mL) was cooled at -20 °C. Methyl magnesium bromide 3M in Et2O (759 μL, 2.28 mmol) was added. After stirring at -10 °C for 45 minutes, saturated aqueous NH4Cl solution (5 mL), EtOAc (50 mL), and water (20 mL) were added. After decantation, the organic phase was dried with MgSO4, filtered, and concentrated under reduced pressure to obtain 442 mg (100%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobut-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1395] LC / MS (m / z, MH+): 582

[1396] Step 3: methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobutane-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1397]

[1398] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobut-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate (50 mg, 85.83 μmol) in water (0.5 mL) and sulfuric acid (1 mL, 18.76 mmol) was stirred at room temperature for 2 hours. Ice and EtOAc were added, and the pH was adjusted to 9 by adding a saturated aqueous solution of NaHCO3 and Na2CO3. After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of DCM / MeOH (100 / 0 to 95 / 05, v / v) to give 24 mg (49%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobutane-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1399] LC / MS (m / z, MH+): 564

[1400] Step 4: 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobutane-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1401]

[1402] Step 4 of Example 102 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobutane-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid by a similar operation to step 2 of Example 79, yielding 6 mg (26%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azacyclobutane-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1403] Method H:

[1404] Example 159: 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1405]

[1406] Step 1: Methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate

[1407]

[1408] Step 1 of Example 159 was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate and 5-bromo-2-iodopyridine in a similar manner to step 1 (method 1) of intermediate 7, yielding 108 mg (10%) of methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1409] LC / MS (m / z, MH+): 502

[1410] Step 2: 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azacyclobutane-1-carboxylic acid tert-butyl ester

[1411]

[1412] Step 2 of Example 159 was prepared from methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylate in a similar manner to step 1 (method 2) of intermediate 1, yielding 87 mg (68%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]arunnel-9-yl)pyridin-3-yl)methylene)azacyclobutane-1-carboxylate.

[1413] LC / MS (m / z, MH+): 590

[1414] Step 3: methyl 9-(5-(azacyclobut-3-ylemethylene)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate

[1415]

[1416] Step 3 of Example 159 was prepared from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azacyclobutane-1-carboxylate, a trifluoroacetate, in a similar manner to step 2 of intermediate 1, to obtain methyl 9-(5-(azacyclobutane-3-methylenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, which was used without further purification.

[1417] LC / MS (m / z, MH+): 491

[1418] Step 4: methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate

[1419]

[1420] Step 4 of Example 159 was prepared from methyl 9-(5-(azacyclobut-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate, in a similar manner to step 5 (method 2) of intermediate 7, yielding 40 mg (49% for steps 3 and 4) of methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1421] LC / MS (m / z, MH+): 551

[1422] Step 5: 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, trifluoroacetate

[1423]

[1424] Step 4 of Example 159 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(5-(((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid by a similar operation to step 2 of Example 79, yielding 34 mg (72%) of methyl 8-(2,4-dichlorophenyl)-9-(5-(((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, trifluoroacetate.

[1425] Method I:

[1426] Example 158: 8-(2,4-Dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1427]

[1428] Step 1: 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azacyclobutane-1-carboxylic acid tert-butyl ester

[1429]

[1430] In Example 158, step 1 was prepared from 2-bromo-3-fluoro-5-iodo-pyridine in a similar manner to step 1 (method 2) of intermediate 1, yielding 587 mg (61%) of tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azacyclobutane-1-carboxylate.

[1431] LC / MS (m / z, MH+): 343

[1432] Step 2: 9-(5-((1-(tert-butoxycarbonyl)azacyclobut-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1433]

[1434] Step 2 of Example 158 was prepared from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylic acid and tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azacyclobutane-1-carboxylic acid, similar to step 1 of Example 1 (Method A), to obtain 585 mg (81%) of 9-(5-((1-(tert-butoxycarbonyl)azacyclobutane-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]arunnel-3-carboxylic acid.

[1435] LC / MS (m / z, MH+): 595

[1436] Step 3: 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azacyclobutane-1-carboxylic acid tert-butyl ester

[1437]

[1438] A mixture of 9-(5-((1-(tert-butoxycarbonyl)azacyclobutane-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid (585 mg, 0.98 mmol), K2CO3 (271 mg, 1.96 mmol), and methyl iodine (209 mg, 1.47 mmol, 0.09 mL) in DMF (10 mL) was stirred at room temperature for 20 minutes. The reaction mixture was quenched by adding water (50 mL) and then extracted with a mixture of EtOAc (30 mL) and Et2O (70 mL). After decantation, the organic phase was washed twice with water (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography with a gradient elution of cyclohexane / EtOAc: from 100 / 00 to 75 / 25 to give 327 mg (55%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azacyclobutane-1-carboxylate.

[1439] LC / MS (m / z, MH+): 609

[1440] Step 4: methyl 9-(5-(azacyclobut-3-ylemmethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate

[1441]

[1442] Step 4 of Example 158 was prepared from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azacyclobutane-1-carboxylate in a similar manner to step 2 of intermediate 1, yielding 287 mg (98%) of methyl 9-(5-(azacyclobutane-3-methylenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate.

[1443] LC / MS (m / z, MH+): 509

[1444] Step 5: methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate

[1445]

[1446] Step 5 of Example 158 was prepared from methyl 9-(5-(azacyclobut-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate, in a similar manner to step 5 of intermediate 7 (method 2), yielding 90 mg (41%) of methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate.

[1447] LC / MS (m / z, MH+): 569

[1448] Step 6: 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid

[1449]

[1450] Step 6 of Example 158 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid by a similar operation to step 2 of Example 79, yielding 7 mg (14%) of 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1451] Method J:

[1452] Example 166: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7] arunculene-3-carboxylic acid, racemic mixture

[1453]

[1454] Step 1: 9-(4-((1-(tert-butoxycarbonyl)azacyclobut-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7] arunculene-3-carboxylic acid, racemic mixture

[1455]

[1456] Step 1 of Example 166 was prepared from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azacyclobutane-1-carboxylic acid (intermediate 43) in a racemic mixture, similar to step 1 of Example 79, to obtain 217 mg (88%) of 9-(4-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1457] LC / MS (m / z, MH+): 590

[1458] Step 2: methyl 9-(4-(azacyclobut-3-ylemethylene)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate (racemic mixture)

[1459]

[1460] Step 2 of Example 166 was prepared from 9-(4-((1-(tert-butoxycarbonyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid in a racemic mixture, yielding 252 mg (100%) of methyl 9-(4-(azacyclobutane-3-ylidene)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, trifluoroacetate.

[1461] LC / MS (m / z, MH+): 504

[1462] Step 3: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture

[1463]

[1464] In Example 166, step 3 was prepared from methyl 9-(4-(azacyclobut-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate, in a similar manner to step 6 (method 1) of intermediate 7, to obtain 70 mg (30%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a racemic mixture.

[1465] LC / MS (m / z, MH+): 564

[1466] Step 4: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture

[1467]

[1468] Step 4 of Example 166 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid by a similar operation to step 2 of Example 79, yielding 38 mg (55%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid as a racemic mixture.

[1469] Method K:

[1470] Example 186: 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7] arunnel-3-carboxylic acid, racemic mixture

[1471]

[1472] Step 1: 3-((5-fluoro-6-(tributylmtinyl)pyridin-3-yl)methylene)azacyclobutane-1-carboxylic acid tert-butyl ester

[1473]

[1474] A mixture of tert-butyl 3-[(6-bromo-5-fluoro-3-pyridinyl)methylene]azacyclobutane-1-carboxylate (4 g, 11.66 mmol), Pd(PPh3)2Cl2 (0.82 g, 1.17 mmol), and 1,1,1,2,2,2-hexabutyldistannane (17.64 mL, 34.97 mmol) in toluene (50 mL) was degassed and purged with Ar for 5 min, then heated to 110 °C for 17 h in a sealed tube. After cooling to room temperature, the reaction mixture was filtered and purified by rapid chromatography, eluting with a gradient of cyclohexane / EtOAc from 100 / 00 to 50 / 50, to give 2 g (31%) of tert-butyl 3-((5-fluoro-6-(tributylmstannyl)pyridin-3-yl)methylene)azacyclobutane-1-carboxylate.

[1475] LC / MS (m / z, MH+): 555

[1476] Step 2: 3-((6-(8-(3,3-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azacyclobutane-1-carboxylic acid tert-butyl ester, racemic mixture

[1477]

[1478] A mixture of methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate (intermediate 39) (0.46 g, 1 mmol), Pd(PPh3)4 (231 mg, 200 μmol), and tert-butyl 3-((5-fluoro-6-(tributylmtinyl)pyridin-3-yl)methylene)azacyclobutane-1-carboxylate (1.11 g, 2 mmol) in toluene (20 mL) was degassed and purged with Ar for 5 min, then heated to 80 °C for 2.5 h in a sealed tube. After cooling to room temperature, the reaction mixture was filtered and transferred to a new tube, then Pd(PPh3)4 (50 mg, 47 μmol) was added and the mixture was degassed. The tube was sealed and heated to 80 °C for 3 h. After cooling to room temperature, Et2O (50 mL), EtOAc (50 mL) and 10% KF aqueous solution (50 mL) were added, and the mixture was filtered. After decantation, the organic phase was dried with MgSO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by rapid chromatography with a gradient elution of cyclohexane / EtOAc: from 100 / 00 to 00 / 100 to give 67 mg (10%) of tert-butyl 3-((6-(8-(3,3-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azacyclobutane-1-carboxylate as a racemic mixture.

[1479] LC / MS (m / z, MH+): 575

[1480] Step 3: 9-(5-(azacyclobut-3-ylemmethyl)-3-fluoropyridin-2-yl)-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, trifluoroacetate (racemic mixture)

[1481]

[1482] Step 3 of Example 186 was prepared from 9-(4-((1-(tert-butoxycarbonyl)azacyclobutane-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid as a racemic mixture, yielding methyl 9-(5-(azacyclobutane-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid, trifluoroacetate.

[1483] LC / MS (m / z, MH+): 475

[1484] Step 4: methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]anthene-3-carboxylate, racemic mixture

[1485]

[1486] In Example 186, step 4 was prepared from methyl 9-(4-(azacyclobut-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate, trifluoroacetate, in a similar manner to step 6 (method 1) of intermediate 7, yielding 35 mg (33%) of methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylate as a racemic mixture.

[1487] LC / MS (m / z, MH+): 535

[1488] Step 5: 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobut-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7] arunnel-3-carboxylic acid, racemic mixture

[1489]

[1490] Step 5 of Example 186 was prepared from methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid in a racemic mixture, similar to step 2 of Example 79, to obtain 25 mg (73%) of 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azacyclobutane-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulen-3-carboxylic acid.

[1491] Pharmacological tests were performed on the compounds listed in Table 1a above to determine their effects on the degradation of estrogen receptors.

[1492] Test: Estrogen receptor degradation activity

[1493] The tests involved measuring the in vitro degradation activity of the compounds in Table 1a.

[1494] The degradation activity of breast cancer cells ERα was measured in the Western blot assay described below.

[1495] MCF7 cells (ATCC) were seeded in 384-well (collagen-coated) microplates at a concentration of 10,000 cells / 30 μL / well in phenol red-free MEMα medium (Invitrogen) containing 5% activated charcoal dextran-treated FBS. The following day, nine consecutive 1:5 dilutions of each compound (in Table 2) at 2.5 μL (final concentrations ranging from 0.3 to 0.0000018 μM) or 0.1 μM fulvestrant (used as a positive control) were added to the cells. Four hours after compound addition, the cells were fixed for 10 minutes by adding 25 μL of formalin (final concentration of 5% formalin containing 0.1% triton) at room temperature and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% triton was added to the plates at room temperature for 30 minutes. Remove the LI-COR blocking buffer and incubate the cells 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 not with antibody were used as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated at 37°C for 60 min in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 DNA dye (final concentration 2 μM). The cells were then washed three times with PBS and scanned in ACUMEN explorer (TTP-Labtech). The integrated intensities of green and red fluorescence were measured to determine the levels of ERα and DNA, respectively.

[1496] In this test, the degradation activity against the estrogen receptor was measured by the concentration at which 50% of the estrogen receptor was degraded (or IC50). 50 (in nM) is given.

[1497] The percentage reduction in ERα level was determined as follows: Inhibition % = 100 * (1 – (sample – fulvestrant: DMSO – fulvestrant)).

[1498] Table 2 below shows the results of estrogen receptor degradation activity of the compounds in Table 1a at 0.3 μM, indicating that the compounds have significant estrogen receptor degradation activity.

[1499] Table 2 :

[1500]

[1501]

[1502]

[1503]

[1504]

[1505] Therefore, it is evident that the tested compounds exhibit estrogen receptor degradation activity, with IC50 less than 1 μM and degradation levels greater than 50%. Compounds of formula (I) can be used to prepare pharmaceuticals, particularly as estrogen receptor degraders.

[1506] Therefore, this article also provides pharmaceuticals comprising compounds of formula (I) or pharmaceutically acceptable salts thereof.

[1507] This article also provides compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, which are used as medicines.

[1508] This article also provides compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for therapeutic purposes, particularly as inhibitors and degraders of estrogen receptors.

[1509] This article also provides compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation.

[1510] One specific aspect is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which is used to treat cancer.

[1511] In one implementation, the cancer is a hormone-dependent cancer.

[1512] In another embodiment, the cancer is an estrogen receptor-dependent cancer, specifically, an estrogen receptor alpha-dependent cancer.

[1513] 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.

[1514] In another implementation, the transfer is a brain transfer.

[1515] In another embodiment, the cancer is breast cancer. Specifically, the breast cancer is estrogen receptor-positive breast cancer (ERα-positive breast cancer).

[1516] In another embodiment, the cancer is resistant to anti-hormone therapy.

[1517] In a further embodiment, the compound of formula (I) is used as a single agent or in combination with other agents such as CDK4 / 6, mTOR, or PI3K inhibitors.

[1518] According to another aspect, this article also provides a method for treating the aforementioned pathological condition, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment of this treatment method, the subject is a human being.

[1519] This article also provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of any of the pathological conditions described above, and more specifically for the treatment of cancer.

[1520] This document also provides pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[1521] The excipient is selected from conventional excipients known to those skilled in the art, depending on the desired form of the drug and the method of administration.

[1522] In the pharmaceutical composition, the active ingredient of formula (I) above, or its base, acid, zwitterion or salt thereof, may be administered in unit form, in mixture with conventional pharmaceutical excipients, orally, sublingually, subcutaneously, intramuscularly, intravenously, topically, locally, intratracheally, intranasally, transdermally or rectically, to animals and humans for the treatment of the aforementioned disorders or diseases.

[1523] Suitable forms of administration include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions; sublingual, oral, tracheal, intraocular, and intranasal forms; forms for inhalation, topical, transdermal, subcutaneous, intramuscular, or intravenous administration; rectal forms; and implants. For topical application, compounds of formula (I) may be used in creams, gels, ointments, or lotions.

[1524] As an example, a unit administration form of a compound of formula (I) in tablet form may contain the following components:

[1525]

[1526] There may be special cases where a higher or lower dose is appropriate. According to general practice, the appropriate dose for each patient is determined by the physician based on the administration method and the patient's weight and response.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: -R1 and R2 independently represent hydrogen or deuterium atoms; -R3 represents the -COOH group; -R3' and R3" independently represent a hydrogen atom, methyl group, methoxy group, chlorine atom, fluorine atom, or cyano group; -R4 and R4' independently represent a hydrogen atom or a fluorine atom; -R5 indicates a hydrogen atom, a fluorine atom, or a (C1-C3) alkyl group; -R6 indicates that the following groups are selected: The phenyl group is optionally substituted with one to three substituents independently selected from the following: halogen atom; (C1-C6) alkyl group, optionally substituted with a cyano or -OH group; (C1-C6) fluoroalkyl group; (C3-C6) cycloalkyl group; (C1-C6) alkoxy group; (C1-C6) fluoroalkoxy group; cyano group; trifluoromethylsulfonyl group; (C1-C4) alkylthio group; (C1-C4) fluoroalkylthio group; (C1-C4) alkylsulfonyl group and -OH group; Fused phenyl, selected from phenyl fused with (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl optionally contains an unsaturation degree, and wherein the fused phenyl is optionally substituted by one to three substituents independently selected from (C1-C3)alkyl, hydroxyl, halogen atom, (C1-C6)fluoroalkyl and (C1-C3)alkoxy; A bicyclic group comprising 5 to 12 carbon atoms, optionally comprising 1 to 2 degrees of unsaturation; optionally substituted by 1 to 4 substituents independently selected from the following: fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy and oxo group; A heteroaryl group comprising 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and at least 5 atoms comprising carbon atoms and heteroatoms, wherein the heteroaryl group is a 5 to 10-membered cyclic aromatic group, wherein the heteroaryl group is optionally substituted by 1 to 3 substituents independently selected from the following: halogen atom, (C1-C6)alkyl, (C1-C6)fluoroalkyl, (C1-C6)alkoxy, (C1-C6)fluoroalkoxy, cyano, carbamoyl, and -OH group; A cycloalkyl group comprising 3 to 7 carbon atoms, said cycloalkyl group being saturated or partially saturated and optionally substituted by 1 to 4 substituents independently selected from: o-fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, oxo group, o(C3-C6)cycloalkyl and phenyl, wherein the (C3-C6)cycloalkyl and phenyl are optionally substituted with one or two halogen atoms or (C1-C3)alkyl; (C3-C6)cycloalkyl (C1-C3)alkyl, optionally substituted on the cycloalkyl group by 1 to 4 independently selected substituents from the following: fluorine atom, -OH group, (C1-C4)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and oxo group; The heterocyclic alkyl group comprising one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclic alkyl group is saturated or partially saturated and optionally substituted by one to three substituents independently selected from the following: fluorine atom, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy, oxo, (C1-C3)alkoxy, and -OH group; (C1-C6)alkyl, wherein the alkyl group is optionally substituted by one to four substituents independently selected from: fluorine atom, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, and -OH group; and The phenyl group is a (C1-C2)alkyl group, wherein the phenyl group is optionally substituted by one to three substituents independently selected from the following: halogen atom; (C1-C3)alkyl; (C1-C3)fluoroalkyl; (C1-C3)alkoxy; (C1-C3)fluoroalkoxy; cyano; and -OH group; -X indicates -CH2-, -O-, or -S-; -Y represents -CH=, -N= or -CR”=, where R” represents (C1-C3) alkyl, halogen atom, cyano, or (C1-C3) fluoroalkyl; -R7 independently represents (C1-C3) alkyl, halogen atom, cyano or (C1-C3) fluoroalkyl; -R8 indicates a hydrogen atom or a fluorine atom; -R9 indicates a hydrogen atom, (C1-C3) alkyl group, or cyclopropyl group; -n is 0, 1, or 2; and -m is 0 or 1.

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

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3' and R3” represent hydrogen atoms.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R4 and R4' represent hydrogen atoms.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, X represents -CH2-.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R5 represents a hydrogen atom.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents a phenyl group, which is optionally substituted by one to three substituents independently selected from the following: chlorine atom, fluorine atom, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy and cyano.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents a fused phenyl group selected from bicyclo[4.2.0]octtrienyl, indanyl, or tetrahydronaphthyl, optionally substituted with one or two fluorine atoms.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents a bicyclic group selected from bicyclo[4.1.0]heptyl, bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, and bicyclo[3.2.1]oct-3-yl, optionally substituted by 1 to 4 substituents independently selected from: fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, and oxo group.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents pyridyl, which is optionally substituted with 1 to 3 substituents, which are independently selected from halogen atoms, (C1-C6)alkyl, (C1-C6)fluoroalkyl and (C1-C6)alkoxy.

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents a cycloalkyl group selected from cyclohexyl or cyclopropyl, wherein the cycloalkyl group is optionally substituted by one to four independent substituents selected from the following: o-fluorine atom, -OH group, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy, oxo group, o(C3-C6)cycloalkyl and phenyl, wherein the (C3-C6)cycloalkyl or phenyl is optionally substituted with one or two halogen atoms or (C1-C3)alkyl.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents cyclobutylmethyl, optionally substituted on the cycloalkyl group by 1 to 4 independently selected substituents from the following: fluorine atom, -OH group, (C1-C4)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and oxo group.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents a tetrahydropyranyl group, which is optionally substituted by one to three substituents independently selected from the following: fluorine atom, (C1-C3)alkoxy group, (C1-C3)fluoroalkyl group, (C1-C3)fluoroalkoxy group, and -OH group.

14. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents isobutyl, which is optionally substituted by one to four substituents independently selected from the following: fluorine atom, (C1-C3)alkoxy, (C1-C3)fluoroalkoxy and -OH group.

15. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R6 represents phenyl (C1-C2) alkyl.

16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R7 independently represents a methyl, cyano, trifluoromethyl, or fluorine atom, and n is 0, 1, or 2.

17. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents -CH=, -N= or -CR”=, and R” represents a fluorine atom, a cyano group or a trifluoromethyl group.

18. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

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

20. A method for preparing a compound of formula (I) as defined according to any one of claims 1 to 19, wherein the compound of formula (I) is... 1K Wherein R1, R2, R3', R3”, R4, R4', R5, R6, R7, R8, R9, m, n, X, and Y are as defined in any one of claims 1 to 18, and R3a is a carboxylic acid ester or an OH group protected with an O-neopentyl group, converted to a compound of formula (I) in the presence of a hydroxide ion source in a methanol solution, wherein the step is optionally preceded by a step to obtain compound 1K, wherein the compound of formula 1T 1T Wherein R1, R2, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X, and Y are as defined in any one of claims 1 to 18, and R3a is as defined above. Suzuki coupling with boron reagent R6B(OR')2 or R6BF3K, wherein -B(OR')2 is boric acid or pinacid ester, and R6 is as defined in claim 1 or any one of claims 7 to 15.

21. A method for preparing a compound of formula (I) as defined according to any one of claims 1 to 19, wherein the compound of formula (I) Ta 1Ta Wherein R1, R2, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X, and Y are as defined in any one of claims 1 to 18, and R3a is as defined in the preceding claim, Suzuki coupling with the boron reagent R6B(OR')2 or R6BF3K, wherein -B(OR')2 is boric acid or pinacid ester, and R6 is as defined in any one of claims 1 or 7 to 15, wherein the step is optionally preceded by a step of obtaining compound 1Ta, wherein the compound of formula 1T 1T Wherein R1, R2, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X, and Y are as defined in any one of claims 1 to 18, and R3a is as defined above. In the presence of a hydroxide ion source in a methanol solution, it is converted into compound 1Ta.

22. A compound selected from those of formula 1T, 1K, and 1Ta, or any pharmaceutically acceptable salt thereof. 1T 1K and 1Ta R1, R2, R3, R3', R3”, R4, R4', R5, R7, R8, R9, m, n, X and Y are as defined in any one of claims 1 to 18, and R3a is a carboxylic acid ester or an OH group protected with an O-neopentyl group.

23. A drug, characterized in that: It comprises a compound of formula (I) according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition, characterized in that: It comprises a compound of formula (I) according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

25. Use of a compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating diseases related to estrogen receptors.

26. Use of a compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation.

27. Use of a compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer.

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