Substituted tetrahydrocyclohepta[e]indole derivatives, processes for their preparation and therapeutic uses thereof

Abstract

Formula (I) [Formula 1] TIFF2025529974000113.tif46170 (wherein R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 and R3′ independently represent a hydrogen atom or a fluorine atom; R4 independently represent a hydrogen atom or a fluorine atom; R5 and R5′ independently represent a hydrogen atom or a fluorine atom; Y independently represents -CH2-, -CH=, -CR9=, -O-, or -NH-; (AA) independently represents a single bond or a double bond; p is 0 or 1; X independently represents -CH=, -N=, or -CR″=; R6 independently represents a phenyl group; a fused phenyl group; or a hetero(C4-C6)cycloalkyl a phenyl group fused with; a bicyclic group containing 5 to 12 carbon atoms; a heteroaryl group; a cycloalkyl group; a (C3-C6)cycloalkyl(C1-C3)alkyl group; a 4- to 7-membered heterocycloalkyl group; a (C1-C6)alkyl group; a (C1-C6)alkenyl group; and a phenyl(C1-C2)alkyl group; R7 independently represents a (C1-C3)alkyl group, a halogen atom, a cyano group, or a (C1-C3)fluoroalkyl group; R8 represents a hydrogen atom, a (C1-C3)alkyl group, or cyclopropyl; and n is 0, 1, or 2. or a pharmaceutically acceptable salt thereof. Further disclosed are processes for preparing same, pharmaceutical compositions containing same, and said compounds of formula (I) for use as inhibitors and degraders of estrogen receptors, particularly in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation.

Description

[Technical Field]

[0001] Disclosed herein are novel substituted tetrahydrocycloheptene indole derivatives, processes for their preparation and their therapeutic use, particularly as anti-cancer agents through selective antagonism and degradation of estrogen receptors. [Background technology]

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

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

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

[0005] Although these endocrine therapies have significantly contributed to reducing breast cancer incidence, approximately one-third or more of ERα-positive patients exhibit de novo resistance or develop resistance to existing therapies over time. Several mechanisms have been described to explain resistance to such hormone therapy, such as the hypersensitivity of ERα to low estrogen levels during aromatase inhibitor treatment, the switch in tamoxifen effect 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 may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), confer the ability to bind DNA in the absence of ligand, conferring hormone independence in cells harboring such mutant receptors.

[0006] Most of the identified endocrine therapy resistance mechanisms rely on ERα-dependent activity. One novel strategy to combat such resistance is to block ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data have shown that a significant number of resistance pathways can be circumvented by the use of SERDs.

[0007] There remains a need to provide SERDs with good decomposition efficacy.

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. Summary of the Invention [Means for solving the problem]

[0009] We have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in cancer therapy.

[0010] Formula (I): [ka] (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 and R3' represent a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; - Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, and R9 represents a fluorine atom or a (C1-C3)alkyl group; - [ka] represents a single or double bond; - p is 0 or 1; - X represents -CH=, -N= or -CR"=, and R" represents a (C1-C3) alkyl group, a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; - R6 ■ A phenyl group optionally substituted by 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group optionally substituted with a cyano group or a -OH group; a (C1-C6) alkylene group; a (C1-C6) fluoroalkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy group; a (C1-C6) fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4) alkylthio group; a (C1-C4) fluoroalkylthio group; a (C1-C4) alkylsulfonyl group; a -COOH group and a -OH group; ■ (C3-C6) cycloalkyl, wherein the (C3-C6) cycloalkyl ring optionally contains unsaturation, and wherein the fused phenyl group is selected from a phenyl group fused with a (C3-C6) cycloalkyl, and the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3) alkyl group, a hydroxy group, a halogen atom, a (C1-C6) fluoroalkyl group, and a (C1-C3) alkoxy group; ■ a phenyl group fused with a hetero(C4-C6)cycloalkyl, wherein the hetero(C4-C6)cycloalkyl ring optionally contains unsaturation, and the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group, and a (C1-C3)alkoxy group; ■ a bicyclic group containing 5 to 12 carbon atoms and optionally containing 1 to 2 unsaturations, optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, an —OH group, a (C1-C3)-alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group, and an oxo group; ■ A heteroaryl group containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as a pyridyl group, a pyridone group, or a pyrrolyl group, which is optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group, a (C1-C6) fluoroalkyl group, a (C1-C6) alkoxy group, a (C1-C6) fluoroalkoxy group, a cyano group, a carbamoyl group, and an —OH group; ■ A cycloalkyl group containing 3 to 7 carbon atoms, which is saturated or partially saturated, and fluorine atom, -OH group, (C1-C3) alkyl group optionally substituted with -OH group, (C1-C3) fluoroalkyl group, (C1-C3) alkoxy group, (C1-C3) fluoroalkoxy group, oxo group, and (C3-C6) cycloalkyl groups and phenyl groups optionally substituted with one or two halogen atoms or (C1-C3) alkyl groups a cycloalkyl group substituted by 1 to 4 substituents independently selected from: ■ a (C3-C6)cycloalkyl(C1-C3)alkyl group optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from a fluorine atom, an —OH group, a (C1-C4)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, and an oxo group; ■ a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as a tetrahydropyranyl, dihydropyran, or tetrahydrofuranyl group, which is saturated or partially saturated and optionally substituted with one to three substituents independently selected from a fluorine atom, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) fluoroalkoxy group, an oxo group, a (C1-C3) alkoxy group, and an —OH group; ■ (C1-C6) alkyl groups, for example, an isobutyl group or an ethylbutyl group, optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, and an —OH group; ■ A (C1-C6) alkenyl group optionally substituted with 1 to 4 substituents independently selected from: an -OH group; a halogen atom; a (C1-C3) alkyl group; a (C1-C3) fluoroalkyl group; a (C1-C3) alkoxy group; a (C1-C3) fluoroalkoxy group; a -COOH group; and a cyano group; and A phenyl(C1-C2)alkyl group optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group, a cyano group, and an —OH group. represents a group selected from: R7 independently represents a (C1-C3) alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3) fluoroalkyl group such as trifluoromethyl; R8 represents a hydrogen atom, a (C1-C3) alkyl group, or cyclopropyl; and - n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0015] Among suitable salts of the compounds of formula (I), mention may be made of trifluoroacetates. DETAILED DESCRIPTION OF THE INVENTION

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

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

[0018] In another embodiment, in the compounds of formula (I) as defined above, R3 and R3' are hydrogen atoms.

[0019] In another embodiment, in the compounds of formula (I) as defined above, R4, R5 and R5' represent a hydrogen atom.

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

[0021] In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH2-, -CH=, -O- or -NH-.

[0022] In another embodiment, in the compounds of formula (I) as defined above, R7 represents a hydrogen atom and n is 1.

[0023] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom; a chlorine atom; a (C1-C4) alkyl group, such as a methyl or ethyl group, optionally substituted with an OH group; a trifluoromethyl group; a (C1-C4) alkoxy group, such as a methoxy group; a cyano group; a -COOH group and a -OH group.

[0024] In another embodiment, in a compound of formula (I) as defined above, R6 represents a pyridyl group, said pyridyl group being optionally substituted with 1 to 3 substituents independently selected from fluorine atoms and (C1-C6)alkoxy groups, in particular methoxy groups.

[0025] In another embodiment, in a compound of formula (I) as defined above, R6 represents a saturated or partially saturated cyclohexyl, said cycloalkyl optionally substituted with 1 to 2 fluorine atoms.

[0026] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a saturated or partially saturated 6-membered heterocycloalkyl group containing an oxygen atom, such as dihydropyranyl.

[0027] In another embodiment, in the compounds of formula (I) as defined above, R8 represents a hydrogen atom.

[0028] Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or their pharmaceutically acceptable salts, in particular their hydrochlorides: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (1), 7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (2), 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (3), (S)-7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (4), (S)-7-(4,4-difluorocyclohex-1-en-1-yl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (5), 2,6-difluoro-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenol (6), 7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (7), 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (8), 7-(2,3-dimethoxyphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (9), 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (10), 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzonitrile (11), 2-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzonitrile (12), 4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzonitrile (13), 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(2-methoxypyridin-4-yl)-3,8,9,10-tetrahydrocyclohepta[e]indole (14), 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(6-methoxypyridin-3-yl)-3,8,9,10-tetrahydrocyclohepta[e]indole (15) 7-(3,6-dihydro-2H-pyran-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (16), (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)prop-2-en-1-ol (17), (E)-4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)-2-methylbut-3-en-2-ol (18), (3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenyl)methanol (19), (4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenyl)methanol (20), 2-(3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenyl)ethan-1-ol (21), 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzoic acid (22), 4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzoic acid, 2,2,2-trifluoroacetic acid (23), (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)acrylic acid (24), 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)propan-1-ol (25), 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (26), N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine (27), (S)—N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (28), and - (Z)-7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (29).

[0029] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, particularly as an inhibitor and degrader of the estrogen receptor.

[0030] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, particularly breast cancer.

[0031] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0032] Another embodiment is a method for treating ovulatory disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0033] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.

[0034] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, an effective dose of a compound selected from the above list or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0035] The compounds of formula (I) may be prepared by the following process.

[0036] Compounds of formula (I) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, solvents, temperatures, and other reaction conditions shown below may be varied as deemed appropriate by those skilled in the art.

[0037] The following general methods for preparing compounds of formula (I), optionally modified by the use of appropriate reagents, and conditions for introducing the various moieties found in formula (I), are described below.

[0038] The following abbreviations and empirical formulas are used: MeCN acetonitrile NH4Cl Ammonium chloride Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CO2 Carbon dioxide Cs2CO3 Cesium Carbonate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane Et2O diethyl ether DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) EtOH ethanol EtOAc ethyl acetate H2 Hydrogen HCl Hydrochloric acid LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate 2-MeTHF 2-methyltetrahydrofuran Pd / C Palladium Carbon Pd(OAc)2 Palladium Acetate Pd(PPh3)2Cl2 Palladium(II) bis(triphenylphosphine) dichloride PtO2 platinum oxide AcOK Potassium Acetate KHMDS Potassium bis(trimethylsilyl)amide K2CO3 Potassium Carbonate KOH Potassium hydroxide PG protecting group NaHCO3 Sodium bicarbonate NaBH4 Sodium borohydride NaH sodium hydride NaOH Sodium hydroxide Na2SO4 Sodium Sulfate SCX Strong Cation Exchange SFC Supercritical Fluid Chromatography TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) RT room temperature

[0039] Scheme 1a Parts 1 and 2: Preparation of Compounds of Formula (I) - General Process Scheme 1a - Part 1: [ka] Scheme 1a - Part 2: [ka] R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, [ka] According to Scheme 1a—Part 1 and Part 2, where Y and Y are as defined above, and PG is a protecting group (PG) such as a tosyl group, a benzenesulfonamide group, a methoxymethylamine, an ethoxymethylamine, or an 1-adamantylcarbamate group, compound 1A can be converted to compound 1B in step 1 by treatment with an aryl or heteroaryl bromide or iodide in the presence of a base such as KCO or CsCO in the presence of a palladium catalyst, for example, tris(dibenzylideneacetone)dipalladium(0)Pd(dba) and a phosphine, such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), dissolved in toluene, by heating the solvent to reflux. An alternative method for preparing compound 1B, where R can be any of the groups defined above for R in Formula (I), is illustrated in Scheme 1g below.

[0040] Compound 1B can be converted to compound 1C in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU, or NaH, or KHMDS in a solvent such as 2-MeTHF.

[0041] Compound 1C can be converted to compound 1G in step 4, for example, by treatment with compound 1F and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh)Cl, and a phosphine, such as triphenylphosphine, dissolved in toluene, in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0042] Compound 1D can be prepared by Suzuki coupling reaction between compounds 1C and 1E in step 3 or between compounds 1G and 1H in step 5 using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) complex with DCM in a solvent such as a mixture of dioxane and water in the presence of a base such as cesium carbonate (CsCO) by heating the solvent to reflux.

[0043] Alternatively, compound 1G can be converted to compound 1K in step 6 by Suzuki coupling with compound 1J using, for example, a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) complex with DCM in a mixture of dioxane and water in the presence of a base such as cesium carbonate (CsCO) by heating the solvent to reflux. Compound 1K can be converted to compound 1L in step 7 by treatment with TFA in DCM or HCl in dioxane. Compound 1L can be converted to compound 1D in step 8 by treatment with compound 1M (W is Br, I, or OSOR, and R = CH, PhMe, CF, or CFCFCFCF) in the presence of a base such as potassium carbonate in DMF at 70 °C, or in the presence of sodium hydroxide or potassium hydroxide in THF at room temperature, or in the presence of aqueous sodium hydroxide in DCM at room temperature.

[0044] The PG of compound 1D can be deprotected to compound I in step 9 using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter G.M.W. Buts, John Wiley & Sons Inc.). In particular, when PG is a tosyl group or a benzenesulfonamide group, deprotection can be carried out, for example, by treatment with aqueous potassium hydroxide in methanol. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be carried out, for example, in the presence of aqueous HCl. When PG is an adamantyl carbamate group, deprotection can be achieved, for example, by treatment with aqueous NaOH.

[0045] When Y=CH, compound I can be reduced in step 10 by hydrogenation under hydrogen (H) pressure over a catalyst such as Pd / C or platinum oxide (PtO) to give the corresponding saturated compound I'.

[0046] Alternatively, when Y=CH, compound I' can be prepared in step 11 by hydrogenation of compound 1D with a catalyst such as Pd / C or platinum oxide (PtO) under hydrogen (H) pressure, followed by deprotection of the protecting group of compound 1D' using the appropriate conditions cited above depending on PG.

[0047] Scheme 1b Parts 1 and 2: Preparation of Compounds of Formula (I') - General Process Scheme 1b - Part 1: [ka] Scheme 1b - Part 2: [ka] According to Scheme 1b - Part 1 and Part 2, where R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and PG is a protecting group (PG) such as a tosyl group, a benzenesulfonamide group, a t-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group or a 1-adamantylcarbamate group, compound 1A can be converted to compound 1N in step 1 by treatment with trifluoromethanesulfonic anhydride dissolved in DCM in the presence of pyridine as a base.

[0048] Compound 1N can be converted to compound 1P in step 3 by treatment with, for example, compound 1F and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, dissolved in toluene, in the presence of a base, such as KOPh, and a phosphine, such as triphenylphosphine, by heating the solvent to reflux.

[0049] Compound 1O can be prepared by Suzuki coupling reaction between compounds 1P and 1H in step 4 or between compounds 1N and 1E' in step 2 using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) complex with DCM in a mixture of dioxane and water in the presence of a base, for example, cesium carbonate (CsCO), by heating the solvent to reflux.

[0050] Compound 1O can be converted to compound 1Q in step 5 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0051] Compound 1Q can be converted to compound 1R in step 7 by treatment with, for example, compound 1F and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2 dissolved in toluene and a phosphine, such as triphenylphosphine, in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0052] Compound 1D' can be prepared by a Suzuki coupling reaction between compound 1Q and a suitable boronic acid reagent R6B(OR')2 (where -B(OR')2 is a boronic acid or pinacolato ester, and R6 is as defined above) in step 6, or between compound 1R and either R6Br, R6I, or R6OTf (where R6 is as defined above) in step 8, using, for example, the DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as a catalyst in a mixture of dioxane and water in the presence of a base, such as cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0053] The PG of compound 1D' can be deprotected to compound I' in step 9 using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter G.M.W. Buts, John Wiley & Sons Inc.). In particular, when PG is a tosyl group or a benzenesulfonamide group, deprotection can be carried out, for example, by treatment with aqueous potassium hydroxide in methanol. When PG is a t-butyl carbamate group, deprotection can be carried out, for example, in the presence of aqueous TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be carried out, for example, in the presence of aqueous HCl. When PG is an adamantyl carbamate group, deprotection can be achieved, for example, by treatment with aqueous NaOH.

[0054] Alternatively, PG of compound 1Q can be deprotected to compound 1S in step 10 using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter G.M.Wuts, John Wiley & Sons Inc.). In particular, when PG is a tosyl group or a benzenesulfonamide group, deprotection can be carried out, for example, by treatment with aqueous potassium hydroxide in methanol. When PG is a t-butyl carbamate group, deprotection can be carried out, for example, in the presence of aqueous TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be carried out, for example, in the presence of aqueous HCl. When PG is an adamantyl carbamate group, deprotection can be achieved, for example, by treatment with aqueous NaOH.

[0055] The deprotection step can be followed in step 11 by treatment of the resulting compound 1S with a suitable boronic acid reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above), for example, using 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 in the presence of a base, such as cesium carbonate (Cs2CO3), and heating the solvent to reflux. When R6 is a substituted partially unsaturated cycloalkoxy group, partially unsaturated heterocycloalkyl group, or acyclic alkenyl group, compound 1' can be reduced, for example, by hydrogenation over a catalyst such as Pd / C under a hydrogen pressure of approximately 5 bar at a temperature from room temperature to 70°C, to give the corresponding saturated compound 1'.

[0056] Scheme 1c: Preparation of compounds of formula (I) - General process [ka] R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, [ka] According to Scheme 1c, where Y and Y are as defined above, and PG is a tosyl group, a benzenesulfonamide group, a t-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group, or a 1-adamantylcarbamate group, compound 1N can be converted to compound 1U in step 1 by a Suzuki coupling reaction with compound 1T using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) complex with DCM in a mixture of dioxane and water in the presence of a base, for example, cesium carbonate (CsCO), by heating the solvent to reflux.

[0057] Compound 1U can be converted to compound 1V 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.

[0058] Compound 1V can be converted to compound 1W in step 3, for example, by treatment with pyridinium tribromide in DCM or THF at room temperature. Compound 1W can be converted to compound 1Y in step 4 by a coupling reaction with one of compounds 1X under coupling reaction conditions.

[0059] Compound 1Y can be converted to compound 1D in step 5 under Suzuki coupling conditions with a suitable boronic acid reagent R6B(OR')2 (where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above) using, for example, the DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as catalyst in a mixture of dioxane and water in the presence of a base, for example cesium carbonate Cs2CO3, by heating the solvent to reflux.

[0060] The PG of compound 1D can be deprotected to compound I in step 6 using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter G.M.W. Buts, John Wiley & Sons Inc.). In particular, when PG is a tosyl group or a benzenesulfonamide group, deprotection can be carried out, for example, by treatment with aqueous potassium hydroxide in methanol. When PG is a t-butyl carbamate group, deprotection can be carried out, for example, in the presence of aqueous TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be carried out, for example, in the presence of aqueous HCl. When PG is an adamantyl carbamate group, deprotection can be achieved, for example, by treatment with aqueous NaOH.

[0061] Alternatively, PG of compound 1Y can be deprotected to compound 1Z in step 7 using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter G.M.W. Buts, John Wiley & Sons Inc.). In particular, when PG is a tosyl group or a benzenesulfonamide group, deprotection can be carried out, for example, by treatment with aqueous potassium hydroxide in methanol. When PG is a t-butyl carbamate group, deprotection can be carried out, for example, in the presence of aqueous TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be carried out, for example, in the presence of aqueous HCl. When PG is an adamantyl carbamate group, deprotection can be achieved, for example, by treatment with aqueous NaOH.

[0062] Deprotection may be followed in step 8 by treatment of the resulting compound 1Z with a suitable boronic acid reagent R6B(OR')2 (where -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above), for example using a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM as catalyst, in a mixture of dioxane and water in the presence of a base, for example cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0063] Scheme 1d: Alternative preparation of compounds of formula (1D) - general process [ka] R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, [ka] According to Scheme 1d, where Y and Y are as defined above, and PG is a protecting group (PG) such as a tosyl group, a benzenesulfonamide group, a para-methoxybenzylamine group, a 3,4-dimethoxybenzylamine group, a methoxymethylamine group, an ethoxymethylamine group, or a 1-adamantylcarbamate group, compound 1W can be converted to compound 2A in step 1 by a coupling reaction with one of compounds 1X′ under coupling reaction conditions.

[0064] Compound 2A can be converted to compound 2B in step 2 by treatment with TFA or HCl.

[0065] Compound 2B can be converted to compound 1Y in step 3 by treatment with compound 1M (wherein W is Cl, Br, or I, or OSO2R, and R = CH3, PhMe, CF3, or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate (K2CO3) in DMF as a solvent.

[0066] Compound 1Y can be converted to compound 2C in step 5, for example, by treatment with compound 1F and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh)Cl, and a phosphine, such as triphenylphosphine, dissolved in toluene in the presence of a base, such as KOPh, by heating the solvent to reflux.

[0067] Compound 1D can be prepared in a Suzuki coupling reaction between compound 1Y and a suitable boronic acid reagent R6B(OR')2 (where -B(OR')2 is a boronic acid or pinacolato ester, and R6 is as defined above) in step 4, or between compound 2C and either R6Br, or RI, or R6OTf (where R6 is as defined above) in step 6, using, for example, the DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as a catalyst, in a mixture of dioxane and water, in the presence of a base, such as cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0068] Scheme 1e: Preparation of compounds of formula (IA') - General process [ka] According to Scheme 1e, where R3 and R3' are as defined above and PG is a tosyl group, compound 2D can be converted to compound 2E in step 1 by treatment with tosyl chloride in the presence of a base such as NaOH.

[0069] Compound 2E can be converted to compound 2G in step 2 by treatment with compound 2F in a Wittig reaction in the presence of a base such as KHMDS.

[0070] Compound 2H can be prepared in step 3 by hydrogenation of compound 2G under hydrogen (H2) pressure with a catalyst such as Pd / C.

[0071] Compound 2H can be converted to compound 2J in step 4 by treatment with a base such as LiOH.

[0072] Compound 1A' can be prepared by treating compound 2J with Eaton's reagent.

[0073] Scheme 1f: Preparation of compounds of formula (1A) - General process [ka] According to Scheme 1f, where R3, R3' and R8 are as defined above and PG is a protecting group (PG), such as a tosyl group, compound 1A' can be converted to compound 2K in step 1 by treatment with pyridinium tribromide.

[0074] Compound 2K can be converted to compound 2L in step 2 by treatment with a base such as DBU.

[0075] Compound 2L can be converted to compound 1A in step 3 by treatment with R8-Li in the presence of CuI in a solvent such as THF.

[0076] Scheme 1g: Alternative preparation of compounds of formula (1B) - General process [ka] According to Scheme 1g, where R3, R3', R6 and R8 are as defined above and PG is a protecting group (PG) such as a tosyl group, compound 1B can alternatively be prepared as follows: Compound 1A can be converted to compound 2M in step 1 by treatment with pyridinium tribromide, for example, in DCM or THF at room temperature.

[0077] Compound 2M can be converted to compound 2N in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0078] Compound 2O can be prepared in step 3 by Suzuki coupling reaction between compound 2N and R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacolato ester) or R6BF3K (wherein R6 is as defined above) using, for example, a DCM complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) as a catalyst in a mixture of toluene and water in the presence of a base, for example, cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0079] Compound 2O can be converted to compound 1B in step 4 by hydrolysis with aqueous HCl by heating, for example, in methanol and DCM.

[0080] A process for preparing a compound of formula (I) as defined above, comprising the steps of: [ka] (In the formula, R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, [ka] and Y are as defined above, and PG is a protecting group such as a tosyl group, a benzenesulfonamide group, a t-butylcarbamate group, a methoxymethylamine, an ethoxymethylamine, or a 1-adamantylcarbamate group. is converted to a compound of formula (I) by a deprotection step, optionally followed by a hydrogenation step over a catalyst such as Pd / C or platinum oxide (PtO) under hydrogen (H) pressure, [ka] to give the corresponding compound of formula (I) wherein is a single bond, The deprotection step may optionally be preceded by a step to obtain compound 1D, [ka] wherein R, R, R, and R are as defined above, and PG is a protecting group as defined above. or compound 1G [ka] (wherein R3, R3', R6 and R8 are as defined above, and PG is as defined above). In the Suzuki coupling step, either of these compounds can be converted to compound 1E, respectively. [ka] (In the formula, R1, R2, R4, R5, R5', R7, n, p, X, [ka] and Y is as defined above). or compound 1H [ka] (In the formula, R1, R2, R4, R5, R5', R7, n, p, X, [ka] and Y is as defined above). is reacted with either of the following using a catalyst, such as a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) with DCM in a solvent, such as a mixture of dioxane and water, in the presence of a base, such as cesium carbonate (Cs2CO3), by heating the solvent to reflux.

[0081] In this specification, [ka] is a single bond, alternatively, by providing a compound of formula 1D' [ka] (wherein R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and PG is a protecting group (PG) such as a tosyl group, a benzenesulfonamide group, a t-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group or a 1-adamantylcarbamate group.) is deprotected, or formula 1s [ka] (wherein R1, R2, R3, R3', R4, R5, R5', R7, R8, n, p, X and Y are as defined above). is reacted with a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complex with DCM in a solvent such as a mixture of dioxane and water and in the presence of a base, for example cesium carbonate, by heating the solvent to reflux; Optionally, before said alternative step, a step of obtaining a compound of formula 1D' or a compound of formula 1S, respectively, [ka] wherein R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and PG is a protecting group such as those protected above. with a boronic acid reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolato ester, and R6 is as defined above, to obtain the compound of formula 1D'; or A process is provided in which the step is preceded by a deprotection step, in particular by treatment with aqueous potassium hydroxide in methanol, to give the compound of formula 1S.

[0082] As used herein, the compounds of formulae 1D, 1K, 1L, 1D', 1O, 1Q, 1S, 1R, 1Y, 1Z, 2A and 2C [ka] [ka] (In the formula, R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, [ka] and Y are as defined above, and PG is a protecting group such as a tosyl group, as defined above. Also provided is an intermediate compound selected from any of the compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0083] 400 and 500MHz 1 H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0084] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument using UV detection DAD210-400 nm and a flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1 x 30 mm, mobile phase H2O + 0.1% HC02H / CH3CN + 0.1% HC02H, light scattering detector Sedere and an SQD Waters mass spectrometer.

[0085] Tables 1a and 1b below respectively list specific compounds (names and structures) of formula (I) according to the present disclosure and their characterization ( 1 1 H NMR and liquid chromatography / mass).

[0086]

Table 1

[0087]

Table 2

[0088]

Table 3

[0089]

Table 4

[0090]

Table 5

[0091]

Table 6

[0092]

Table 7

[0093]

Table 8

[0094]

Table 9

[0095]

Table 10

[0096] [Table 11]

[0097] [Table 12]

[0098] [Table 13]

[0099] [Table 14]

[0100] [Table 15]

[0101] [Table 16] [Example]

[0102] The following examples describe the preparation of some compounds of formula (I) described herein. The compound numbers exemplified below correspond to those given in Table 1 above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0103] In the following examples, unless the source of a starting product is specified, it is to be understood that said product is a known compound.

[0104] Intermediates: Intermediate 1: 3-Tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one [ka] Step 1: 1-Tosyl-1H-indole-4-carbaldehyde [ka] To a mixture of indole-4-carbaldehyde (60 g, 413 mmol) in DCM (100 mL) was added a solution of tetrabutylammonium hydrogen sulfate (14 g, 41.3 mmol) and NaOH (82.7 g, 2.07 mol) in water (80 mL). Then, 4-methylbenzenesulfonyl chloride (86.7 g, 455 mmol) in DCM (200 mL) was added. The mixture was vigorously stirred at room temperature for 2 h. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with petroleum ether / EtOAc 70 / 30 to give 110 g (89%) of 1-tosyl-1H-indole-4-carbaldehyde as a pale yellow solid. LC / MS (m / z, MH+): 300

[0105] Step 2: Ethyl-5-(1-tosyl-1H-indol-4-yl)pent-4-enoate [ka] To a suspension of (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide (252 g, 551 mmol) in anhydrous THF (1350 mL) was added dropwise a 1 M solution of potassium bis(trimethylsilyl)amide in THF (551 mL, 826.5 mmol) at −78°C. The mixture was stirred at −78°C for 1.5 hours. A solution of 1-tosyl-1H-indole-4-carbaldehyde (110 g, 367.47 mmol) in anhydrous THF (450 mL) was added. The reaction mixture was stirred at −78°C for 2 hours and allowed to warm to room temperature. After stirring overnight, the reaction mixture was poured into a saturated aqueous solution of NH₄Cl and extracted twice with EtOAc. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with petroleum ether / EtOAc from 70 / 30 to give 103 g (71%) of ethyl-5-(1-tosyl-1H-indol-4-yl)pent-4-enoate as a white solid. LC / MS(m / z, MH+): 398

[0106] Step 3: Ethyl 5-(1-tosyl-1H-indol-4-yl)pentanoate [ka] To a solution of ethyl 5-(1-tosyl-1H-indol-4-yl)pent-4-enoate (35 g, 88.05 mmol) in EtOH (350 ml) in a Paar apparatus was added 10% Pd / C (3.5 g, 1.58 mmol, 10% purity). The mixture was subjected to 6 bar of hydrogen for 2 h, then filtered, washed with DCM, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 70 / 30 to 95 / 05 to 70 / 30 heptane / EtOAc to give 24.7 g (66%) of ethyl 5-(1-tosyl-1H-indol-4-yl)pentanoate as a colorless oil. LC / MS (m / z, MH+): 400

[0107] Step 4: 5-(1-tosyl-1H-indol-4-yl)pentanoic acid [ka] To a solution of ethyl 5-(1-tosyl-1H-indol-4-yl)pentanoate (64 g, 160.20 mmol) in dioxane (640 mL) was added LiOH (24.9 g, 1.04 mol) in water (200 mL). The mixture was stirred at room temperature overnight and then poured into an ice-cold 1N aqueous solution of HCl (50 mL) and extracted twice with EtOAc. The combined organic layers were dried over MgSO and concentrated under reduced pressure to give 56 g (79%) of 5-(1-tosyl-1H-indol-4-yl)pentanoic acid. LC / MS(m / z, MH+): 372

[0108] Step 5: 3-Tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one [ka] A mixture of 5-(1-tosyl-1H-indol-4-yl)pentanoic acid (56 g, 150.76 mmol) and Eaton's reagent (538 g, 2.26 mol, 354 mL) was heated to 50 °C for 12 h. The reaction mixture was poured into ice-cold water (3000 mL) and extracted with DCM (600 mL). After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 70 / 30 heptane / EtOAc to give 10.1 g (18%) of 3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one. LC / MS(m / z, MH+): 354

[0109] Intermediate 2: 3-Tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate [ka] To a solution of 3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one (Intermediate 1) (4.37 g, 12.4 mmol) and pyridine (1.5 mL, 19 mmol) in DCM (120 mL) was added trifluoromethanesulfonic anhydride (6.79 g, 24.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of ice and water (100 mL). After decantation, the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 50 / 50 heptane / DCM to give 5.5 g (91%) of 3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 486

[0110] Intermediate 3: (S)-7-bromo-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Step 1: (S)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] A mixture of 3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate (Intermediate 2) (940 mg, 2.01 mmol), (S)-1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine (prepared according to WO 2017140669) (772 mg, 2.21 mmol), CsCO (1.38 g, 4.22 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (155 mg, 0.2 mmol) in dioxane (40 mL) and water (10 mL) was heated at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the resulting residue were added DCM (20 ml) and water (10 ml). After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 00 / 100 cyclohexane / EtOAc to give 955 mg (85%) of (S)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+):559

[0111] Step 2: (S)-7-Bromo-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] To a mixture of (S)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole (50 mg, 0.09 mmol) in DCM (2 mL) cooled to 0 °C was added pyridinium tribromide (31 mg, 0.1 mmol). The mixture was stirred at 5 °C for 1 h. DCM (10 mL) was added, followed by a mixture of ice and water (5 mL). After decantation, the organic phase was dried over MgSO and concentrated under reduced pressure to give 45 mg (79%) of (S)-7-bromo-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+): 637

[0112] Intermediate 4: 7-Bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Step 1: 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Intermediate 4, step 1, was prepared from 3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate (Intermediate 2) and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine (prepared according to WO2022084280) following a procedure similar to Intermediate 3, step 1 to afford 6.4 g (88%) of 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+):543

[0113] Step 2: 7-Bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Intermediate 4, step 2, was prepared from 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole and pyridinium tribromide following a procedure similar to Intermediate 3, step 2 to afford 6 g (82%) of 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+):621

[0114] Intermediate 5: 7-Bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] To a mixture of 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole (Intermediate 4) (5 g, 8.04 mmol) in MeOH (1 mL), THF (10 mL) and DMSO (10 mL) was added a solution of KOH (2.25 g, 40.1 mmol) in water (2.5 mL). The reaction mixture was stirred at room temperature for 18 hours. 1N HCl was added until pH 9. EtOAc (80 mL) and water (5 mL) were added. After decantation, the organic phase was dried over MgSO4, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH from 97 / 03 to 95 / 05 to give 3.44 g (92%) of 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+): 467

[0115] Intermediate 6: 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate [ka] Step 1: 7-(3-chloro-2-methylphenyl)-3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one [ka] A mixture of 3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one (Intermediate 1) (6 g, 17 mmol), 1-bromo-3-chloro-2-methyl-benzene (7 g, 34 mmol), Xantphos (1.96 g, 3.4 mmol), Pd(dba) (1.55 g, 1.7 mmol), and CsCO (17.6 g, 51 mmol) in toluene (90 mL) was heated to reflux for 6 h. After cooling to room temperature, EtOAc (40 mL) was added, and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with DCM to give 4.46 g (55%) of 7-(3-chloro-2-methylphenyl)-3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one. LC / MS(m / z, MH+):478

[0116] Step 2: 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate [ka] To a mixture of 7-(3-chloro-2-methylphenyl)-3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one (1.44 g, 3 mmol) in THF (25 mL) cooled to −72° C., N,N-bis(trifluoromethylsulfonyl)aniline (1.4 g, 3.92 mmol) was added. Then, 0.7 M KHMDS in THF (6 mL, 3.91 mmol) was added dropwise at −72° C. The reaction mixture was stirred at −70° C. for 30 minutes. The cooling bath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 18 hours. EtOAc (50 mL) and water (30 mL) were added to the reaction mixture. After decantation, the organic phase was dried over MgSO4 and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 60 / 40 heptane / DCM to give 540 mg (29%) of 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate. LC / MS(m / z, MH+):610

[0117] Intermediate 7(3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine [ka] Step 1: (4-Bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid [ka] To a solution of commercially available tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate (20.3 g, 57.31 mmol) in DCM (100 mL) was added TFA (100 mL) dropwise, and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with EtO. The formed solid was filtered to give 17 g (81%) of (4-bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid. LC / MS(m / z, MH+):254

[0118] Step 2: (4-Bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone [ka] A mixture of (4-bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid (9.45 g, 25.67 mmol), KCO (10.64 g, 77 mmol), and 1-fluoro-3-iodopropane (5.07 g, 26.95 mmol) in MeCN (200 mL) was heated at 80° C. for 3 h. The reaction mixture was quenched by adding saturated NHCl solution (200 mL) and extracted with EtOAc (3×200 mL). The organic phase was washed with brine (200 ml), dried over Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 50 / 50 to 90 / 10 DCM / MeOH to afford 6.34 g (78%) of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone. LC / MS(m / z, MH+): 314

[0119] Step 3: (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol [ka] To a mixture of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone (6.31 g, 20.07 mmol) in MeOH (180 mL) was added NaBH (2.28 g, 60.21 mmol), and the mixture was stirred at room temperature for 2 hours. A concentrated solution of NH Cl (100 mL) and EtOAc (300 mL) were added. After decantation, the organic phase was washed with brine (200 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give 6.69 g (crude) of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol, which was used directly in the subsequent step. LC / MS(m / z, MH+): 316

[0120] Intermediate 4: 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine, cis and trans isomers [ka] To a mixture of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol (5.16 g, 16.33 mmol) and water (10 mL) at 0 °C, sulfuric acid (35 mL) was added dropwise. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into a mixture of ice and water (500 mL). Powdered NaHCO was added to bring the pH to 9. EtOAc (300 mL) was added, and the organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 00 / 100 DCM / EtOAc to give 4.13 g (85%) of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine as a mixture of cis and trans isomers.

[0121] Step 5: (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine [ka] A mixture of cis and trans isomers of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine was separated by preparative SFC using an IF 5 × 25 cm, 5 μm column (Daicel) and a 30% CO mobile phase containing 0.1% TEA as a cosolvent in MeOH. The temperature was set to 40 °C and the backpressure regulator was set to 100 bar, yielding 1.15 g of (3Z)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine and 2.58 g of (3E)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine. LC / MS(m / z, MH+):298

[0122] Step 6: (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine [ka] A mixture of (3Z)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine (200 mg, 0.67 mmol), Pd(PPh)Cl (38 mg, 0.07 mmol), bis(pinacolato)diboron (221 mg, 0.87 mmol), and AcOK (164 mg, 1.68 mmol) in dioxane (4 mL) was heated at reflux for 2 h. After cooling, the reaction mixture was filtered through dicalite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of DCM / EtOAc / EtOH from 100 / 00 / 00 to 75 / 20 / 05 to afford 160 mg (69%) of (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine. LC / MS(m / z, MH+): 346

[0123] Intermediate 8 (S)-1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine [ka] Step 1: (S)—N-(4-bromophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine [ka] A mixture of 1-bromo-4-iodobenzene (2.5 g, 8.8 mmol), Pd(OAc) (200 mg, 0.88 mmol), Xantphos (720 mg, 1.2 mmol), CsCO (8.6 g, 27 mmol), and (3S)-1-(3-fluoropropyl)pyrrolidin-3-amine bis-2,2,2-trifluoroacetic acid (prepared according to WO 2021139756) (6.66 g, 17.8 mmol) in dioxane (60 ml) was heated at reflux for 24 h. After cooling to room temperature, DCM (120 ml) and water (60 ml) were added. After decantation, the organic phase was dried over MgSO, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100 / 00 to 95 / 05 to give 0.56 g (21%) of (S)—N-(4-bromophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine. LC / MS(m / z, MH+):301

[0124] Step 2: (S)-1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine [ka] Intermediate 8, step 2, was prepared from (S)—N-(4-bromophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine and bis(pinacolato)diboron following a procedure similar to Intermediate 7, step 6, to afford 0.3 g (46%) of (S)-1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine. LC / MS(m / z, MH+): 349

[0125] Intermediate 9: 1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-amine [ka] Step 1: tert-butyl 3-((4-bromophenyl)amino)azetidine-1-carboxylate [ka] Intermediate 10, step 1, was prepared from 1-bromo-4-iodobenzene and tert-butyl 3-aminoazetidine-1-carboxylate following a procedure similar to Intermediate 8, step 1, to afford 2.11 g (37%) of tert-butyl 3-((4-bromophenyl)amino)azetidine-1-carboxylate. LC / MS(m / z, MH+): 327

[0126] Step 2: N-(4-bromophenyl)azetidin-3-amine [ka] Intermediate 9, step 2, was prepared from tert-butyl 3-((4-bromophenyl)amino)azetidine-1-carboxylate following a procedure similar to Intermediate 7, step 1, to give 0.88 g (93%) of N-(4-bromophenyl)azetidin-3-amine after treatment with SCX. LC / MS(m / z, MH+): 227

[0127] Step 3: N-(4-bromophenyl)-1-(3-fluoropropyl)azetidin-3-amine [ka] A mixture of N-(4-bromophenyl)azetidin-3-amine (880 mg, 3.9 mmol), 1-fluoro-3-iodopropane (874 mg, 4.6 mmol), and NaOH (620 mg, 15.5 mmol) in THF (9 mL) was stirred at room temperature for 24 hours. To the resulting reaction mixture was added water (5 mL) and EtOAc (10 mL). After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100 / 00 to 95 / 05 to give 338 mg (30%) of N-(4-bromophenyl)-1-(3-fluoropropyl)azetidin-3-amine. LC / MS(m / z, MH+):287

[0128] Step 4: 1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-amine [ka] Intermediate 9, step 4, was prepared from N-(4-bromophenyl)-1-(3-fluoropropyl)azetidin-3-amine and bis(pinacolato)diboron following a procedure similar to intermediate 7, step 6, to afford 140 mg (36%) of 1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-amine. LC / MS(m / z, MH+): 335

[0129] Intermediate 10: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine [ka] Step 1: tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate [ka] A mixture of 4-bromophenol (40 g, 231 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (65.5 g, 231 mmol), and CsCO (151 g, 462 mmol) in DMF (400 mL) was stirred at room temperature for 12 hours. To the reaction mixture, water (500 mL) and EtOAc (300 mL) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure to give 30 g (crude) tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate, which was used directly in the next step. LC / MS(m / z, MH+): 328

[0130] Step 2:3 3-(4-bromobenzylidene)azetidine, 2,2,2-trifluoroacetic acid [ka] Intermediate 10, step 2, was prepared from tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate following a procedure similar to Intermediate 7, step 1, to afford 20 g (crude) of 3-(4-bromophenoxy)azetidine, 2,2,2-trifluoroacetic acid, which was used directly in the next step. LC / MS(m / z, MH+):228

[0131] Step 3: 3-(4-bromophenoxy)-1-(3-fluoropropyl)azetidine [ka] A mixture of 3-(4-bromophenoxy)azetidine, 2,2,2-trifluoroacetic acid (20 g, 58.48 mmol), 1-fluoro-3-iodopropane (11 g, 58.48 mmol), and KOH (6.54 g, 117 mmol) in DMF (100 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 97 / 03 to 00 / 100 petroleum ether / EtOAc to give 9 g (53%) of N-(4-3-(4-bromophenoxy)-1-(3-fluoropropyl)azetidine. LC / MS(m / z, MH+):288

[0132] Step 4: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine [ka] Intermediate 10, step 4, was prepared from 3-(4-bromophenoxy)-1-(3-fluoropropyl)azetidine and bis(pinacolato)diboron following a procedure similar to Intermediate 7, step 6 to afford 140 mg (36%) of 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine. LC / MS(m / z, MH+): 336

[0133] Example Method A: Example 1: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Step 1: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] A mixture of 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole (Intermediate 4) (150 mg, 0.24 mmol), (4-fluoro-2-methyl-phenyl)boronic acid (74 mg, 0.48 mmol), CsCO (165 mg, 0.51 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18 mg, 0.024 mmol) in dioxane (8 mL) and water (2 mL) was heated at 90 °C for 30 min. After cooling to room temperature, EtOAc (200 mL) and water (50 mL) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 00 / 100 cyclohexane / EtOAc to afford 106 mg (65%) of 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+):651

[0134] Step 2: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] A mixture of 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole (106 mg, 0.16 mmol) and KOH (46 mg, 0.81 mmol) in EtOH (10 ml) and water (2 ml) was heated at 70° C. for 24 h. After cooling to room temperature, 1N HCl was added until pH 7. Then, EtOAc (50 ml), diethyl ether (50 ml), and water (20 ml) were added. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 80 / 20 DCM / MeOH to afford 58 mg (72%) of 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole.

[0135] Method B: Example 2: 7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Example 2 was prepared from 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (Intermediate 5) and (3-fluoro-2-methoxy-4-pyridyl)boronic acid following a procedure similar to Step 1 of Example 1 to afford 81 mg (67%) of 7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole.

[0136] Example 17: (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)prop-2-en-1-ol [ka] Example 17 was prepared from 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (Intermediate 5) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol following a procedure similar to Step 1 of Example 1 to afford 119 mg (50%) of (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)prop-2-en-1-ol.

[0137] Method C: Example 3: 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Step 1: 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Step 1 of Example 3 was prepared following a procedure similar to Step 1 of Example 1 from 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl trifluoromethanesulfonate (Intermediate 6) and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine (according to WO 2022084298) to afford 180 mg (61%) of 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole. LC / MS(m / z, MH+):665

[0138] Step 2: 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole [ka] Example 3, Step 2, was prepared from 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrocyclohepta[e]indole following a procedure similar to Example 1, Step 2, to afford 125 mg (90%) of 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole.

[0139] Method D: Example 25: 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)propan-1-ol [ka] A mixture of (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)prop-2-en-1-ol (Example 17) (100 mg, 0.22 mmol) and Pd / C 10% (24 mg, 0.024 mmol) in EtOAc (5 ml) and EtOH (8 ml) was hydrogenated under H (1 bar) at room temperature for 15 h. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 90 / 10 DCM / MeOH to afford 70 mg (70%) of 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)propan-1-ol.

[0140] The compounds set out in Table 1 above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0141] Test: Estrogen receptor degrading activity Said test is directed to determining the in vitro degradation activity of the compounds of Table 1.

[0142] Measurement of degradation activity was performed using breast cancer cell ERα in a cell Western assay as described below.

[0143] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells per well in phenol red-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran-striped FBS. The following day, nine serial 1:5 dilutions of each compound, ranging from 0.3 to 0.0000018 μM (Table 2), or fulvestrant (used as a positive control) at a final concentration of 0.1 μM, were added to the cells in 2.5 μL. Four hours after compound addition, cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% Triton) for 10 min at room temperature, then washed twice with PBS. Next, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 min at room temperature. The LI-COR blocking buffer was removed, and the cells were incubated overnight in the cold with 50 μL of anti-ER rabbit monoclonal antibody (Thermo Scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% Tween-20. Wells treated with blocking buffer but without antibody served as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa488 (1:1000) and Syto-64, a DNA dye (2 μM final concentration). The cells were then washed three times in PBS and scanned in an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0144] The degradative activity of estrogen receptors in this test was measured as the concentration (or IC ) required to degrade 50% of the estrogen receptors, expressed in nM. 50 ) is given by

[0145] The % reduction in ERα levels was determined as follows: % inhibition = 100 * (1 - (sample - fulvestrant: DMSO - fulvestrant)).

[0146] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1 tested at 0.3 μM, demonstrating that the compounds have significant degrading activity against the estrogen receptor.

[0147] [Table 17]

[0148] Therefore, it is clear that the tested compounds have degradative activity towards the estrogen receptor with IC50 less than 1 μM and degradation levels greater than 50%.

[0149] Thus, the compounds of formula (I) can be used to prepare medicaments, in particular medicaments that are degraders of estrogen receptors.

[0150] Accordingly, also provided herein is a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0151] There is also provided herein a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0152] There is also provided herein a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in therapy, in particular as an estrogen receptor inhibitor and degrader.

[0153] There is also provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment of ovulatory disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0154] A particular embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment of cancer.

[0155] In some embodiments, the cancer is a hormone-dependent cancer.

[0156] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0157] 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.

[0158] In another embodiment, the metastasis is a cerebral metastasis.

[0159] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0160] In another embodiment, the cancer is resistant to anti-hormonal therapy.

[0161] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR or PI3K inhibitors.

[0162] According to another aspect, provided herein is a method of treating the above-noted pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of this method of treatment, the subject is a human.

[0163] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in treating any of the pathological conditions set out above, more particularly useful in treating cancer.

[0164] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound of formula (I). These pharmaceutical compositions also contain an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0165] Said excipients are selected from the conventional excipients known to those skilled in the art according to the desired pharmaceutical form and method of administration.

[0166] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or its base, acid, zwitterion or salt thereof, in unit dosage form, in admixture with conventional pharmaceutical excipients, may be administered to animals and humans for the treatment of the above disorders or diseases.

[0167] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, the compounds of formula (I) can be used in creams, gels, ointments or lotions.

[0168] As an example, a unit dosage form of a compound of formula (I) in tablet form may contain the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Cornstarch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0169] There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. Formula (I): 【Chemical 1】 (In the formula, R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 and R3′ represent a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom or a fluorine atom; R5 and R5' independently represent a hydrogen atom or a fluorine atom; - Y is -CH ２ represents -, -CH=, -CR9=, -O- or -NH-, and R9 is a fluorine atom or (C １ ~C ３ ) represents an alkyl group; － 【Chemistry 2】 represents a single or double bond; p is 0 or 1; X represents -CH=, -N= or -CR"=, and R" is (C １ ~C ３ ) an alkyl group, a halogen atom such as a fluorine atom or a chlorine atom, a cyano group, or a trifluoromethyl group; １ ~C ３ ) represents a fluoroalkyl group; - R6 is a phenyl group optionally substituted with a halogen atom; a cyano group or an —OH group (C １ ~C ６ ) alkyl group; (C １ ~C ６ ) alkylene group; (C １ ~C ６ ) fluoroalkyl group; (C ３ ~C ６ ) cycloalkyl group; (C １ ~C ６ ) an alkoxy group; (C １ ~C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ ~C ４ ) alkylthio group; (C １ ~C ４ ) a fluoroalkylthio group; (C １ ~C ４ a phenyl group optionally substituted with 1 to 3 substituents independently selected from an alkylsulfonyl group; a —COOH group and a —OH group; ■ (C ３ ~C ６ ) cycloalkyl, (C ３ ~C ６ ) the cycloalkyl ring optionally contains unsaturation, (C ３ ~C ６ ) a fused phenyl group selected from a phenyl group fused with a cycloalkyl, １ ~C ３ ) an alkyl group, a hydroxy group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a fused phenyl group optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Hetero (C ４ ~C ６ ) cycloalkyl, and hetero(C ４ ~C ６ ) cycloalkyl ring optionally contains unsaturation, hetero(C ４ ~C ６ ) a phenyl group fused to a cycloalkyl, １ ~C ３ ) an alkyl group, a hydroxy group, a halogen atom, (C １ ~C ６ ) fluoroalkyl group and (C １ ~C ３ ) a phenyl group optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ Bicyclic groups containing 5 to 12 carbon atoms and optionally containing 1 to 2 unsaturations, such as fluorine atoms, —OH groups, (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) fluoroalkyl group, (C １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a bicyclic group optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; Heteroaryl groups containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as pyridyl, pyridone, or pyrrolyl groups, and which do not contain a halogen atom, (C １ ~C ６ ) alkyl group, (C １ ~C ６ ) fluoroalkyl group, (C １ ~C ６ ) an alkoxy group, (C １ ~C ６ ) a heteroaryl group optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group, a cyano group, a carbamoyl group, and an —OH group; a cycloalkyl group containing 3 to 7 carbon atoms, which is saturated or partially saturated, and Fluorine atoms, —OH groups, optionally substituted with —OH groups (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) fluoroalkyl group, (C １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) a fluoroalkoxy group, an oxo group, and 1 or 2 halogen atoms or (C １ ~C ３ ) optionally substituted with an alkyl group (C ３ ~C ６ ) cycloalkyl groups and phenyl groups a cycloalkyl group optionally substituted with 1 to 4 substituents independently selected from: ■ (C ３ ~C ６ ) cycloalkyl (C １ ~C ３ ) alkyl group, which is not a fluorine atom, an —OH group, (C １ ~C ４ ) alkyl group, (C １ ~C ３ ) fluoroalkyl group, (C １ ~C ３ ) optionally substituted on said cycloalkyl with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; ３ ~C ６ ) cycloalkyl (C １ ~C ３ ) alkyl group; 4 to 7-membered heterocycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as tetrahydropyranyl, dihydropyran, or tetrahydrofuranyl groups, which are saturated or partially saturated and contain a fluorine atom, (C １ ~C ３ ) alkyl group, (C １ ~C ３ ) fluoroalkyl group, (C １ ~C ３ ) a fluoroalkoxy group, an oxo group, (C １ ~C ３ ) a 4- to 7-membered heterocycloalkyl group optionally substituted with 1 to 3 substituents independently selected from an alkoxy group and an —OH group; ■ (C １ ~C ６ ) alkyl groups, such as isobutyl or ethylbutyl groups, and １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and —OH groups (C １ ~C ６ ) alkyl group; ■ (C １ ~C ６ ) alkenyl groups, which are not limited to -OH groups; halogen atoms; (C １ ~C ３ ) alkyl group; (C １ ~C ３ ) fluoroalkyl group; (C １ ~C ３ ) an alkoxy group; (C １ ~C ３ ) fluoroalkoxy groups; optionally substituted with 1 to 4 substituents independently selected from —COOH groups and cyano groups (C １ ~C ６ ) alkenyl groups; and Phenyl (C １ ~C ２ ) alkyl groups each containing a halogen atom; １ ~C ３ ) alkyl group; (C １ ~C ３ ) fluoroalkyl group; (C １ ~C ３ ) an alkoxy group; (C １ ~C ３ phenyl (C) optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group; a cyano group; and an —OH group; １ ~C ２ ) alkyl group represents a group selected from R7 independently represents a (C １ ~C ３ ) alkyl group, halogen atom such as fluorine atom, cyano group or trifluoromethyl group １ ~C ３ ) represents a fluoroalkyl group; R8 is a hydrogen atom or (C １ ~C ３ ) alkyl group, or cyclopropyl; and n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

2. 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. 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R3 and R3' are hydrogen atoms.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that R4, R5 and R5' represent a hydrogen atom.

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

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

7. A compound of formula (I) according to any one of claims 1 to 6, characterized in that R7 represents a hydrogen atom and n is 1, or a pharmaceutically acceptable salt thereof.

8. R6 represents a phenyl group, said phenyl group being optionally substituted with a fluorine atom; a chlorine atom; an OH group, such as a methyl or ethyl group (C １ ~C ４ ) alkyl group; trifluoromethyl group; methoxy group, etc. １ ~C ４ 8. The compound of formula (I) according to any one of claims 1 to 7, characterized in that it is optionally substituted by 1 to 3 substituents independently selected from: an alkoxy group; a cyano group; a -COOH group and a -OH group.

9. R6 represents a pyridyl group, and the pyridyl group contains a fluorine atom and (C １ ~C ６ 8. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that they are optionally substituted with 1 to 3 substituents independently selected from alkoxy groups, more particularly methoxy groups.

10. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a saturated or partially saturated cyclohexyl group, said cyclohexyl group being optionally substituted with 1 to 2 fluorine atoms.

11. Compounds of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a saturated or partially saturated 6-membered heterocycloalkyl group containing an oxygen atom, such as dihydropyranyl.

12. Compounds of formula (I) according to any one of claims 1 to 11, wherein R8 represents a hydrogen atom.

13. The following compounds: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (1), 7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (2), 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (3), (S)-7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (4), (S)-7-(4,4-difluorocyclohex-1-en-1-yl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (5), 2,6-difluoro-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenol (6), 7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (7), 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (8), 7-(2,3-dimethoxyphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (9), 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (10), 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzonitrile (11), 2-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzonitrile (12), 4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzonitrile (13), 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(2-methoxypyridin-4-yl)-3,8,9,10-tetrahydrocyclohepta[e]indole (14), 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(6-methoxypyridin-3-yl)-3,8,9,10-tetrahydrocyclohepta[e]indole (15), 7-(3,6-dihydro-2H-pyran-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (16), (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)prop-2-en-1-ol (17), (E)-4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)-2-methylbut-3-en-2-ol (18), (3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenyl)methanol (19), (4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenyl)methanol (20), 2-(3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)phenyl)ethan-1-ol (21), 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzoic acid (22), 4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)benzoic acid, 2,2,2-trifluoroacetic acid (23), (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)acrylic acid (24), 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-7-yl)propan-1-ol (25), 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (26), N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine (27), (S)—N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrocyclohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (28), and (Z)-7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrocyclohepta[e]indole (29) 13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in particular a trifluoroacetate salt thereof, characterized in that it is selected from:

14. A process for preparing a compound of formula (I) according to any one of claims 1 to 13, comprising reacting a compound of formula 1D 【Chemistry 3】 (In the formula, R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, 【Chemistry 4】 and Y are as defined in any one of claims 1 to 12, and PG is a protecting group such as a tosyl group, a benzenesulfonamide group, a methoxymethylamine, an ethoxymethylamine or a 1-adamantylcarbamate group. is converted to a compound of formula (I) by a deprotection step, optionally followed by deprotection with hydrogen (H ２ ) Pd / C or platinum oxide (PtO ２ ) followed by a catalytic hydrogenation step, 【Chemistry 5】 is a single bond, The deprotection step is optionally preceded by a step to obtain compound 1D, 【Chemistry 6】 wherein R3, R3′, R6 and R8 are as defined above, and PG is a protecting group such as defined above. or compound 1G 【Chemistry 7】 wherein R3, R3′, R6 and R8 are as defined above, and PG is as defined above. In the Suzuki coupling step, either of the compounds 1E 【Chemistry 8】 (In the formula, R1, R2, R4, R5, R5', R7, n, p, X, 【Chemistry 9】 and Y is as defined above. or compound 1H 【Chemistry 10】 (In the formula, R1, R2, R4, R5, R5', R7, n, p, X, 【Chemistry 11】 and Y is as defined above. and a catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl ２ ) complex with DCM in a solvent such as a mixture of dioxane and water and a base such as cesium carbonate (Cs ２ CO ３ ) by heating to reflux of the solvent.

15. A process for preparing a compound of formula (I) according to any one of claims 1 to 13, wherein the compound of formula (I) is as defined above, 【Chemistry 12】 is a single bond, and instead, 【Chemistry 13】 wherein R1, R2, R3, R3′, R4, R5, R5′, R6, R7, R8, n, p, X and Y are as defined in any one of claims 1 to 12, and PG is a protecting group such as a tosyl group, a benzenesulfonamide group, a t-butylcarbamate group, a methoxymethylamine, an ethoxymethylamine or a 1-adamantylcarbamate group. is deprotected, or Formula 1S 【Chemistry 14】 (wherein R1, R2, R3, R3′, R4, R5, R5′, R7, R8, n, p, X and Y are as defined above). The compound of formula (I) can be used as a catalyst, for example, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl ２ ) with DCM in a solvent such as a mixture of dioxane and water and in the presence of a base such as cesium carbonate by heating the solvent to reflux, Optionally, before said alternative step, a step of obtaining a compound of formula 1D' or a compound of formula 1S, respectively, 【Chemistry 15】 wherein R1, R2, R3, R3′, R4, R5, R5′, R6, R7, R8, n, p, X and Y are as defined above, and PG is a protecting group such as defined above. is reacted with the boronic acid reagent R6B(OR') ２ (In the formula, -B(OR') ２ is a boronic acid or pinacolato ester, and R6 is as defined above) to give a compound of formula 1D'; or The process is preceded by a deprotection step, in particular by treatment with aqueous potassium hydroxide in methanol, to obtain said compound of formula 1S.

16. Formulas 1D, 1K, 1L, 1D', 1O, 1Q, 1S, 1R, 1Y, 1Z, 2A and 2C 【Chemistry 16】 【Chemistry 17】 (In the formula, R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, 【Chemistry 18】 and Y are as defined in any one of claims 1 to 12, and PG is a protecting group such as a tosyl group, a benzenesulfonamide group, a t-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group or a 1-adamantylcarbamate group, in particular a tosyl group. or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

19. A compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use as an inhibitor and degrader of estrogen receptors.

20. 14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for use in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

21. 21. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to claim 20 for use in the treatment of cancer.

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