Substituted tetrahydroarylhepta [e] indole derivatives, process for preparation thereof and therapeutic use thereof

Abstract

Disclosed herein are compounds having formula (I) or a pharmaceutically acceptable salt thereof: wherein 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-; (AA) represents a single bond or a double bond; p is 0 or 1; x represents-CH =,-N =, or-CR ''=; r6 represents a group selected from the group consisting of phenyl; a fused phenyl group; phenyl fused with a hetero (C4-C6) cyclic hydrocarbon group; a bicyclic group comprising from 5 to 12 carbon atoms; a heteroaryl group; a cyclic hydrocarbon group; (C3-C6) cycloalkyl (C1-C3) alkyl; a 4 to 7 membered heterocyclic hydrocarbon group; (C1-C6) alkyl groups; 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 or a (C1-C3) alkyl group or cyclopropyl group; and n is 0, 1 or 2. Further disclosed are processes for their preparation, pharmaceutical compositions comprising them and the compounds of formula (I) for use as inhibitors and degradation agents of estrogen receptors, in particular in the treatment of ovulation dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation. # imgabs0 #

Description

[0001] Disclosed herein are novel substituted tetrahydrocycloheptenyl indole derivatives, methods for their preparation, and their therapeutic uses, particularly as anticancer agents via selective antagonism and degradation of estrogen receptors.

[0002] Estrogen receptor (ER) belongs to the steroid / nuclear receptor superfamily involved in regulating eukaryotic gene expression, cell proliferation and target tissues. ER is in two forms: estrogen receptor α (ERα) and estrogen receptor β (ERβ) encoded by ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors, which are activated by the hormone estrogen (the most potent estrogen produced in vivo is 17β-estradiol). In the absence of hormones, ER is mainly located in the cytosol of cells. When the hormone estrogen binds to ER, ER migrates from the cytosol of cells to the nucleus, forms a dimer, and then binds to a specific genomic sequence called an estrogen response element (ERE). DNA / ER complexes interact with co-regulators to regulate the transcription of target genes.

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

[0004] ERα is expressed in no more than 10% of normal breast epithelium, but is expressed in approximately 50%-80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is established, and regulation of ERα signaling remains an important approach to breast cancer treatment for most ERα-positive breast tumors. Currently, there are several strategies for inhibiting the estrogen axis in breast cancer, including: 1-Blocking estrogen synthesis through aromatase inhibitors for the treatment of early and advanced ERα-positive breast cancer patients; 2-Antagonizing estrogen ligand binding to ERα through tamoxifen for the treatment of ERα-positive breast cancer patients in both premenopausal and postmenopausal situations; 3-Antagonizing and downregulating ERα levels through Fulvestrant for the treatment of breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have greatly contributed to the reduction of breast cancer development, about more than one-third of ERα-positive patients show resistance to such existing therapies from the beginning or develop resistance over time. Several mechanisms have been described to explain resistance to such hormone therapies. For example, the hypersensitivity of ERα to low estrogen levels in the treatment with aromatase inhibitors, the switching of tamoxifen effects from antagonists to agonist effects or multiple growth factor receptor signaling pathways in tamoxifen treatment. ERα acquired mutations that occur after hormone therapy is initiated can also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand binding domain (LBD), lead to the ability to bind to DNA in the absence of a ligand and confer hormone independence in cells with such mutant receptors.

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

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

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

[0009] The inventors have now discovered novel compounds that are able to selectively antagonize and degrade estrogen receptors (SERD compounds) for use in cancer treatment.

[0010] Disclosed herein are compounds having formula (I) or pharmaceutically acceptable salts thereof:

[0011]

[0012] in:

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

[0014] - R3 and R3' represent a hydrogen atom or a fluorine atom;

[0015] -R4 represents a hydrogen atom or a fluorine atom;

[0016] - R5 and R5' independently represent a hydrogen atom or a fluorine atom;

[0017] -Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C1-C3) alkyl group;

[0018] - represents a single bond or a double bond;

[0019] -p is 0 or 1;

[0020] -X represents -CH=, -N= or -CR"=, wherein R" represents a (C1-C3)alkyl group or a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group;

[0021] -R6 represents a group selected from the following:

[0022] ■ phenyl, which is optionally substituted by 1 to 3 substituents independently selected from the following: a halogen atom; a (C1-C6)alkyl group optionally substituted by 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;

[0023] ■ a fused phenyl group selected from a phenyl group fused to a (C3-C6)cycloalkyl group, the (C3-C6)cycloalkyl ring optionally containing unsaturation and, wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxyl group, a halogen atom, a (C1-C6)fluoroalkyl group and a (C1-C3)alkoxy group;

[0024] ■ a phenyl group fused to a hetero(C4-C6)cycloalkyl group, the hetero(C4-C6)cycloalkyl group ring optionally comprising unsaturation and wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C3)alkyl, hydroxyl, halogen atoms, (C1-C6)fluoroalkyl and (C1-C3)alkoxy;

[0025] ■ a bicyclic group containing 5 to 12 carbon atoms, which optionally contains 1 to 2 degrees of unsaturation; optionally substituted by 1 to 4 substituents independently selected from the group consisting of fluorine atoms, -OH groups, (C1-C3)-alkyl groups, (C1-C3)fluoroalkyl groups, (C1-C3)alkoxy groups, (C1-C3)fluoroalkoxy groups and oxo groups;

[0026] ■ a heteroaryl group containing 2 to 9 carbon atoms and containing 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, the heteroaryl group being optionally substituted by 1 to 3 substituents independently selected from halogen atoms, (C1-C6)alkyl groups, (C1-C6)fluoroalkyl groups, (C1-C6)alkoxy groups, (C1-C6)fluoroalkoxy groups, cyano groups, carbamoyl groups and -OH groups;

[0027] ■ a cycloalkyl group containing 3 to 7 carbon atoms, which is saturated or partially saturated and optionally substituted by 1 to 4 substituents independently selected from:

[0028] o a fluorine atom, an -OH group, a (C1-C3)alkyl group optionally substituted with an -OH group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group, an oxo group, and

[0029] o (C3-C6) cycloalkyl and phenyl, wherein the (C3-C6) cycloalkyl or phenyl is optionally substituted with one or two halogen atoms or (C1-C3) alkyl;

[0030] ■ (C3-C6)cycloalkyl (C1-C3)alkyl, which is optionally substituted on the cycloalkyl by 1 to 4 substituents independently selected from the group consisting of fluorine atoms, -OH groups, (C1-C4)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and oxo groups;

[0031] ■ a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group, a dihydropyranyl group or a tetrahydrofuranyl group, said heterocycloalkyl group being saturated or partially saturated and optionally substituted by 1 to 3 substituents independently selected from the group consisting of 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;

[0032] ■ (C1-C6) alkyl such as isobutyl or ethylbutyl, the alkyl being optionally substituted by 1 to 4 substituents independently selected from the group consisting of fluorine atoms, (C1-C3) alkoxy groups, (C1-C3) fluoroalkoxy groups and -OH groups;

[0033] ■(C1-C6)alkenyl, which is optionally substituted by 1 to 4 substituents independently selected from the group consisting of: -OH group; halogen atom; (C1-C3)alkyl; (C1-C3)fluoroalkyl; (C1-C3)alkoxy; (C1-C3)fluoroalkoxy; -COOH group and cyano group; and

[0034] ■phenyl(C1-C2)alkyl, the phenyl being optionally substituted by 1 to 3 substituents independently selected from the group consisting of: halogen atoms; (C1-C3)alkyl; (C1-C3)fluoroalkyl; (C1-C3)alkoxy; (C1-C3)fluoroalkoxy; cyano; and -OH groups;

[0035] - 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 a trifluoromethyl group;

[0036] - R8 represents a hydrogen atom or a (C1-C3) alkyl group or a cyclopropyl group; and

[0037] -n is 0, 1, or 2.

[0038] The compounds of formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in the form of enantiomers.

[0039] Compounds of formula (I) may also exist in tautomeric forms.

[0040] The compound of formula (I) may exist in the form of a base, an acid, a zwitterion or an addition salt with an acid or a base. Accordingly, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0041] These salts may be prepared with pharmaceutically acceptable acids or bases, although salts of other acids or bases useful, for example, in the purification or isolation of compounds of formula (I) are also provided.

[0042] Among suitable salts of the compound of formula (I) there may be mentioned trifluoroacetate.

[0043] As used herein, unless otherwise mentioned throughout this specification, the following terms have the following definitions:

[0044] - halogen atoms: fluorine, chlorine, bromine or iodine atoms, and in particular fluorine and chlorine atoms;

[0045] -Oxo: "=O" group;

[0046] - Alkyl: a straight-chain or branched saturated hydrocarbon aliphatic group, which, unless otherwise specified, contains 1 to 6 carbon atoms (indicated as "(C1-C6)-alkyl"); by way of example, but not limited to, there may be mentioned: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc.;

[0047] -Alkenyl: a straight-chain or branched hydrocarbon aliphatic group, which, unless otherwise indicated, contains 1 to 6 carbon atoms (indicated as "(C1-C6)-alkylene") and at least one degree of unsaturation. By way of example, but not limited to, mention may be made of: vinyl, etc.;

[0048] - Cycloalkyl: saturated or partially unsaturated and unsubstituted or substituted monocyclic hydrocarbon radicals, which, unless otherwise specified, contain 3 to 7 carbon atoms. By way of example, but not limited to, mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, etc., in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl or cyclohexenyl;

[0049] - Heterocycloalkyl: saturated or partially unsaturated 4- to 7-membered cycloalkyl, in particular 4- to 6-membered cycloalkyl, containing 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen. By way of example, but not limited to, mention may be made of: morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxetanyl, diazepanyl, dioxanyl, dihydropyranyl, tetrahydropyranyl and tetrahydrothiopyranyl. Heterocycloalkyl is advantageously tetrahydrofuranyl or tetrahydropyranyl;

[0050] -Fluoroalkyl: an alkyl group as defined previously, wherein the alkyl group is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, -CH2F, -CHF2, CH2CHF2, -CH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be named as a perfluoroalkyl group. By way of example, trifluoromethyl or trifluoroethyl, etc. may be mentioned;

[0051] - Alkoxy: -O-alkyl, wherein alkyl is as defined previously. By way of example, but not limited to, there may be mentioned: methoxy; ethoxy; propoxy; isopropoxy; linear butoxy, sec-butoxy or tert-butoxy; isobutoxy; pentyloxy or hexyloxy, etc.;

[0052] -Fluoroalkoxy: -O-alkyl, wherein alkyl is as defined previously and wherein alkyl is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl is replaced by a fluorine atom. By way of example, -OCH2F, -OCHF2, -OCH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl are replaced by fluorine atoms, the fluoroalkoxy may be named as perfluoroalkoxy. By way of example, trifluoromethoxy, etc. may be mentioned;

[0053] -(C1-C4)alkylthio, which is also named (C1-C4)alkylsulfanyl: -S-alkyl, wherein alkyl is as defined previously. By way of example, but not limited to, there may be mentioned: methylthio, ethylthio, propylthio, isopropylthio, straight-chain secondary or tert-butylthio, isobutylthio, etc.;

[0054] -(C1-C4)alkylsulfonyl: -SO2-alkyl, wherein alkyl is as defined above. For example, -SO2CH3, -SO2CH2CH3, etc. may be mentioned but are not limited thereto;

[0055] -(C1-C4)fluoroalkylthio, which is also named (C1-C4)fluoroalkylsulfanyl: -S-fluoroalkyl, wherein the fluoroalkyl group is as defined above. For example, there can be mentioned but are not limited to: fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.;

[0056] - Fused phenyl: a bicyclic radical comprising 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 bound to the rest of the molecule via its phenyl moiety. It may be substituted. Examples are, but are not limited to, indanyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, tetrahydronaphthyl, etc.;

[0057] -phenyl fused to hetero(C4-C6)cycloalkyl: a bicyclic radical comprising 7 to 10 carbon atoms and containing a phenyl moiety. The phenyl moiety may be fused to the hetero(C4-C6)cycloalkyl, i.e. the phenyl moiety may share a bond with the hetero(C4-C6)cycloalkyl. The fused phenyl may be bound to the rest of the molecule via its phenyl moiety. It may be substituted. Examples are, but are not limited to, chromanyl, in particular chroman-8-yl, etc.;

[0058] -Heteroaryl: A cyclic 5- to 10-membered aromatic group containing between 2 and 9 carbon atoms and between 1 and 3 heteroatoms such as nitrogen, oxygen or sulfur. Such nitrogen atoms may be replaced by oxygen atoms to form -NO bonds. Such -NO bonds may be in the form of N-oxides (-N + -O - ) in the form of. The heteroaryl group may be monocyclic or bicyclic. As examples of heteroaryl groups, mention may be made, but is 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, benzooxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridone groups and the like. Heteroaryl groups are advantageously pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, and more particularly pyridine, pyridone and pyrrole;

[0059] - Bicyclic radicals generally containing from 5 to 12 carbon atoms are hydrocarbon radicals chosen from radicals containing two rings connected by:

[0060] ■ Single common atom: "spiro bicyclic". Such spiro bicyclic alkyl groups usually contain 5 to 11 carbon atoms and refer to "spiro (C5-C 11 The ring may be saturated or partially unsaturated. Such a spiro bicyclic ring may be unsubstituted or substituted, in particular by at least one (C1-C3) alkyl group such as methyl, or fluorine. Regarding the definition of R6, as a spiro (C5-C 11 ) Examples of 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. Still for the R6 group, spiro(C5-C 11 ) the bicyclic ring is advantageously spiro[3.3]heptane or spiro[3.3]heptene;

[0061] ■ two common atoms. In this case, the bicyclic radical contains 7 to 12 carbon atoms and optionally 1 to 2 degrees of unsaturation. As examples of such bicyclic radicals, mention may be made, without limitation, of cis-1,3a,4,5,6,6a-hexahydropentalenyl, bicyclo[3.1.0]hex-1-yl, bicyclo[4.1.0]heptanyl and octahydropentalenyl; or

[0062] ■ Three or more common atoms. In this case, the bicyclic group contains 6 to 10 carbon atoms and such a bicyclic group may be referred to as a "bridged (C6-C 10 )cycloalkyl", the rings have three or more atoms in total and the bridge contains at least one atom, such as 1, 2 or 3 atoms and preferably 1 atom. As examples of such bridged cycloalkyls, mention may be made, but are not limited to, bicyclo[3.2.1]octan-3-yl and bicyclo[2.2.1]hept-2-yl;

[0063] - Zwitterion means: a generally neutral molecule having both positive and negative charges and possessing both acidic and basic groups.

[0064] In another embodiment, in the compound having formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0065] In another embodiment, in the compound of formula (I) as defined above, R3 and R3' are hydrogen atoms.

[0066] In another embodiment, in the compound of formula (I) as defined above, R4, R5 and R5' represent a hydrogen atom.

[0067] In another embodiment, in the compounds of formula (I) as defined above, X represents -CH=.

[0068] In another embodiment, in the compound of formula (I) as defined above, Y is -CH2-, -CH=, -O- or -NH-.

[0069] In another embodiment, in the compound of formula (I) as defined above, R7 represents a hydrogen atom and n is 1.

[0070] In another embodiment, in the compound of formula (I) as defined above, R6 represents a phenyl group, which is optionally substituted by 1 to 3 substituents independently selected from the following: a fluorine atom; a chlorine atom; a (C1-C4) alkyl group optionally substituted by an OH group, such as a methyl or ethyl group; a trifluoromethyl group; a (C1-C4) alkoxy group, such as a methoxy group; a cyano group; a -COOH group and a -OH group.

[0071] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a pyridyl group optionally substituted with 1 to 3 substituents independently selected from fluorine atoms and (C1-C6)alkoxy groups, more particularly methoxy groups.

[0072] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a saturated or partially saturated cyclohexyl group, which is optionally substituted with 1 to 2 fluorine atoms.

[0073] In another embodiment, in the compound of formula (I) as defined above, R6 represents a saturated or partially saturated 6-membered heterocyclic hydrocarbon group containing an oxygen atom, such as dihydropyranyl.

[0074] In another embodiment, in the compounds of formula (I) as defined above, R8 represents a hydrogen atom.

[0075] Among the compounds of formula (I) described herein, the following compounds or their pharmaceutically acceptable salts, in particular their hydrochlorides, may be mentioned in particular:

[0076] -7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (1),

[0077] -7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (2),

[0078] -7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (3),

[0079] -(S)-7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (4),

[0080] -(S)-7-(4,4-difluorocyclohex-1-en-1-yl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (5),

[0081] -2,6-difluoro-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenol (6),

[0082] -7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (7),

[0083] -7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (8),

[0084] -7-(2,3-dimethoxyphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (9),

[0085] -6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (10),

[0086] -3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzonitrile (11),

[0087] -2-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzonitrile (12),

[0088] -4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzonitrile (13),

[0089] -6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(2-methoxypyridin-4-yl)-3,8,9,10-tetrahydrohepta[e]indole (14),

[0090] -6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(6-methoxypyridin-3-yl)-3,8,9,10-tetrahydrohepta[e]indole (15)

[0091] -7-(3,6-dihydro-2H-pyran-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (16),

[0092] -(E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)prop-2-en-1-ol (17),

[0093] -(E)-4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)-2-methylbut-3-en-2-ol (18),

[0094] -(3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenyl)methanol (19),

[0095] -(4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenyl)methanol (20),

[0096] -2-(3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenyl)ethan-1-ol (21),

[0097] -3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzoic acid (22),

[0098] -4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzoic acid, 2,2,2-trifluoroacetic acid (23),

[0099] -(E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)acrylic acid (24),

[0100] -3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)propan-1-ol (25),

[0101] -7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (26),

[0102] -N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine (27),

[0103] -(S)-N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine (28), and

[0104] -(Z)-7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (29).

[0105] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use in therapy, especially as an inhibitor and degrader of estrogen receptors.

[0106] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, especially breast cancer.

[0107] Another embodiment is a method of inhibiting and degrading estrogen receptors, which comprises administering a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof to a subject, especially a human, in need thereof.

[0108] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy 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.

[0109] 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.

[0110] 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.

[0111] The compound having the formula (I) can be prepared by the following method.

[0112] Compounds of formula (I) and other related compounds with different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0113] The following general methods for preparing compounds having formula (I), optionally modified by use of appropriate reagents, and conditions for introducing the various moieties found in formula (I) are described below.

[0114] The following abbreviations and empirical formulas are used:

[0115] MeCN Acetonitrile

[0116] NH4Cl Ammonium chloride

[0117] Pd(dppf)Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride

[0118] CO2 Carbon dioxide

[0119] Cs2CO3 Cesium carbonate

[0120] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0121] DCM Dichloromethane

[0122] Et2O Ether

[0123] DMF N,N-Dimethylformamide

[0124] DMSO Dimethyl sulfoxide

[0125] Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[0126] EtOH

[0127] EtOAc Ethyl acetate

[0128] H2 Hydrogen

[0129] HCl

[0130] LiHMDS Lithium bis(trimethylsilyl)amide

[0131] LiOH Lithium Hydroxide

[0132] MeOH Methanol

[0133] MgSO4 Magnesium sulfate

[0134] 2-MeTHF 2-Methyltetrahydrofuran

[0135] Pd / C Palladium / Carbon

[0136] Pd(OAc)2 Palladium acetate

[0137] Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride

[0138] PtO2 Platinum Oxide

[0139] AcOK Potassium Acetate

[0140] KHMDS Potassium bis(trimethylsilyl)amide

[0141] K2CO3 Potassium carbonate

[0142] KOH Potassium Hydroxide

[0143] PG Protecting Group

[0144] NaHCO3 Sodium bicarbonate

[0145] NaBH4 Sodium borohydride

[0146] NaH Sodium hydride

[0147] NaOH Sodium hydroxide

[0148] Na2SO4 Sodium sulfate

[0149] SCX Strong Cation Exchange

[0150] SFC Supercritical Fluid Chromatography

[0151] TEA Triethylamine

[0152] TFA Trifluoroacetic acid

[0153] THF Tetrahydrofuran

[0154] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0155] room temperature room temperature

[0156] Option 1a Parts 1 and 2 : Preparation of compounds of formula (I) - General method

[0157] Option 1a – Part 1 :

[0158]

[0159] Option 1a – Part 2 :

[0160]

[0161] According to Scheme 1a - Part 1 and Part 2, 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 tosyl, benzenesulfonamide, methoxymethylamine, ethoxymethylamine or 1-adamantylcarbamate, compound 1A can be converted to compound 1B in step 1 by treating with an aryl or heteroaryl bromide or iodide in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)Pd2(dba)3 and a phosphine such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (XANTPHOS) in solution in toluene by heating to solvent reflux in the presence of a base such as K2CO3 or Cs2CO3. An alternative way to prepare compound 1B, wherein R6 can be any group as defined above for R6 in formula (I), is described in Scheme 1g below.

[0162] 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.

[0163] Compound 1C can be converted to compound 1G in step 4 by, for example, treating compound 1F with a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2 and a phosphine such as triphenylphosphine in toluene by heating to solvent reflux in the presence of a base such as KOPh.

[0164] Compound 1D can be prepared in a 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)Cl2) complexed with DCM in a solvent such as a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0165] Alternatively, compound 1G can be converted to compound 1K in step 6 in a Suzuki coupling reaction with compound 1J using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux. Compound 1K can be converted to compound 1L in step 7 by treatment with TFA in solution in DCM or HCl in solution in dioxane. Compound 1L can be converted to compound 1D in step 8 by treatment with compound 1M (wherein W is Br, I or OSO2R, where R=CH3, PhMe, CF3 or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate at 70°C in DMF, or in the presence of sodium hydroxide or potassium hydroxide at room temperature in THF, or in the presence of aqueous sodium hydroxide in DCM at room temperature.

[0166] PG of compound 1D can be deprotected in step 9 to compound I using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter GM Wuts, John Wiley & Sons Inc). In particular, when PG is a tosyl or benzenesulfonamide group, deprotection can be accomplished by, for example, treatment with an aqueous solution of potassium hydroxide in methanol. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be performed in the presence of, for example, an aqueous solution of HCl. When PG is an adamantyl carbamate group, deprotection can be achieved by, for example, treatment with an aqueous solution of NaOH.

[0167] When Y═CH, compound I can be reduced by hydrogenation in step 10 using a catalyst such as Pd / C or platinum oxide (PtO 2 ) under hydrogen (H 2 ) pressure to give the corresponding saturated compound I′.

[0168] Alternatively, when Y═CH, compound I′ can be prepared by hydrogenating compound 1D in step 11 using a catalyst such as Pd / C or platinum oxide (PtO 2 ) under hydrogen (H 2 ) pressure, followed by deprotection of compound 1D′ using appropriate conditions depending on PG as listed above.

[0169] Option 1b Parts 1 and 2 : Preparation of compounds of formula (I') - General method Option 1b – Part 1 :

[0170]

[0171] Option 1b – Part 2 :

[0172]

[0173] According to Scheme 1b - Part 1 and Part 2, 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 tert-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 treating with trifluoromethanesulfonic anhydride in the presence of pyridine as a base in a solution in DCM.

[0174] Compound 1N can be converted to compound 1P in step 3 by, for example, treating compound 1F with a palladium catalyst such as bis(triphenylphosphine)palladium(II) chloride Pd(PPh3)2Cl2 and a phosphine such as triphenylphosphine in toluene by heating to solvent reflux in the presence of a base such as KOPh.

[0175] Compound 10 can be prepared in a Suzuki coupling reaction between compounds 1P and 1H' in step 4 or between compounds 1N and 1E' in step 2, using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0176] Compound 10 can be converted to compound 1Q in step 5 by treatment with pyridinium tribromide, for example in DCM or THF at room temperature.

[0177] Compound 1Q can be converted to compound 1R in step 7 by, for example, treating compound 1F with a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2 and a phosphine such as triphenylphosphine in toluene by heating to solvent reflux in the presence of a base such as KOPh.

[0178] Compound 1D' can be prepared in a Suzuki coupling reaction between compound 1Q and a suitable boronic reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacol ester and R6 is as defined above) in step 6 or between compound 1R and R6Br or R6I or R6OTf (and R6 is as defined above) in step 8, using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0179] PG of compound 1D' can be deprotected in step 9 to compound I' using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter GM Wuts, John Wiley & Sons Inc). In particular, when PG is a tosyl or benzenesulfonamide group, deprotection can be achieved by, for example, treatment with an aqueous solution of potassium hydroxide in methanol. When PG is a tert-butylcarbamate group, deprotection can be carried out in the presence of, for example, an aqueous solution of TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be carried out in the presence of, for example, an aqueous solution of HCl. When PG is an adamantyl carbamate group, deprotection can be achieved by, for example, treatment with an aqueous solution of NaOH.

[0180] Alternatively, PG of compound 1Q can be deprotected in step 10 to compound 1S using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter GM Wuts, John Wiley & Sons Inc). In particular, when PG is a tosyl or benzenesulfonamide group, deprotection can be accomplished by, for example, treatment with an aqueous solution of potassium hydroxide in methanol. When PG is a tert-butylcarbamate group, deprotection can be performed in the presence of, for example, an aqueous solution of TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be performed in the presence of, for example, an aqueous solution of HCl. When PG is an adamantyl carbamate group, deprotection can be achieved by, for example, treatment with an aqueous solution of NaOH.

[0181] The deprotection step may be followed by treating the obtained compound 1S in step 11 with a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacol ester and R6 is as defined above), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux. When R6 is a substituted partially unsaturated cycloalkyl, partially unsaturated heterocycloalkyl or acyclic alkenyl, compound I' can be reduced by, for example, hydrogenation with a catalyst such as Pd / C at a temperature of up to 70°C under a hydrogen pressure of about 5 bar to give the corresponding saturated compound I'.

[0182] Solution 1c : Preparation of compounds of formula (I) - General method

[0183]

[0184] According to Scheme 1c, 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 toluenesulfonyl group, a benzenesulfonamide group, a tert-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group or a 1-adamantylcarbamate group, compound 1N can be converted to compound 1U in step 1 in a Suzuki coupling reaction with compound 1T using, for example, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0185] Compound 1U can be converted to compound 1V in step 2 by treatment with sodium nitrite followed by sodium iodide in a solvent such as a mixture of water and acetonitrile.

[0186] Compound 1V can be converted to compound 1W in step 3 by treatment with pyridinium tribromide, for example in DCM or THF at room temperature.

[0187] Compound 1W can be converted to compound 1Y in step 4 by a coupling reaction with one of compounds 1X under coupling reaction conditions.

[0188] Compound 1Y can be converted to compound 1D in step 5 in a Suzuki coupling reaction with a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacol ester and R6 is as defined above) using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0189] PG of compound 1D can be deprotected in step 6 to compound I using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter GM Wuts, John Wiley & Sons Inc). In particular, when PG is a tosyl or benzenesulfonamide group, deprotection can be accomplished by, for example, treatment with an aqueous solution of potassium hydroxide in methanol. When PG is a tert-butylcarbamate group, deprotection can be performed in the presence of, for example, an aqueous solution of TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be performed in the presence of, for example, an aqueous solution of HCl. When PG is an adamantyl carbamate group, deprotection can be achieved by, for example, treatment with an aqueous solution of NaOH.

[0190] Alternatively, PG of compound 1Y can be deprotected in step 7 to compound 1Z using methods known in the literature (Protective Groups in Organic Synthesis, Theodora W. Greene, Peter GM Wuts, John Wiley & Sons Inc). In particular, when PG is a tosyl or benzenesulfonamide group, deprotection can be accomplished by, for example, treatment with an aqueous solution of potassium hydroxide in methanol. When PG is a tert-butylcarbamate group, deprotection can be performed in the presence of, for example, an aqueous solution of TFA. When PG is a methoxymethylamine group or an ethoxymethylamine group, deprotection can be performed in the presence of, for example, an aqueous solution of HCl. When PG is an adamantyl carbamate group, deprotection can be achieved by, for example, treatment with an aqueous solution of NaOH.

[0191] The deprotection step can be followed by treating the obtained compound 1Z in step 8 with a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacol ester and R6 is as defined above), using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0192] Scheme 1d: Alternative preparation of compounds of formula (1D) - General method

[0193]

[0194] According to Scheme 1d, 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 toluenesulfonyl group, a benzenesulfonamide group, a p-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.

[0195] Compound 2A can be converted to compound 2B in step 2 by treatment with TFA or HCl.

[0196] 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, where R = CH3, PhMe, CF3 or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent.

[0197] Compound 1Y can be converted to compound 2C in step 5 by, for example, treating compound 1F with a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2 and a phosphine such as triphenylphosphine in toluene in a solution by heating to solvent reflux in the presence of a base such as KOPh.

[0198] Compound 1D can be prepared in a Suzuki coupling reaction between compound 1Y and a suitable boron reagent R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacol ester and R6 is as defined above) in step 4 or between compound 2C and R6Br or R6I or R6OTf (and R6 is as defined above) in step 6, using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst, in a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0199] Option 1e : Preparation of compounds of formula (1A') - General method

[0200]

[0201] According to Scheme 1e, wherein R3 and R3' are as defined above and PG is tosyl, 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.

[0202] Compound 2E can be converted to compound 2G in step 2 by treatment with compound 2F in the presence of a base such as KHMDS in a Wittig reaction.

[0203] Compound 2H can be prepared by hydrogenating compound 2G in step 3 under hydrogen (H2) pressure using a catalyst such as Pd / C.

[0204] Compound 2H can be converted to compound 2J in step 4 by treatment with a base such as LiOH.

[0205] Compound 1A' can be prepared by treating compound 2J with Eaton's reagent.

[0206] Scheme 1f : Preparation of compounds of formula (1A) - General method

[0207]

[0208] According to Scheme 1f, wherein R3, R3' and R8 are as defined above and PG is a protecting group (PG) such as tosyl, compound 1A' can be converted to compound 2K in step 1 by treatment with pyridinium tribromide.

[0209] Compound 2K can be converted to compound 2L in step 2 by treatment with a base such as DBU.

[0210] 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.

[0211] Scheme 1g: Alternative preparation of compounds of formula (1B) - General method

[0212]

[0213] According to Scheme 1g, wherein R3, R3', R6 and R8 are as defined above and PG is a protecting group (PG) such as tosyl, 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.

[0214] 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.

[0215] Compound 2O can be prepared in step 3 in a Suzuki coupling reaction between compound 2N and R6B(OR')2 (wherein -B(OR')2 is a boronic acid or pinacol ester) or R6BF3K (and R6 is as defined above) using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM as a catalyst in a mixture of toluene and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0216] Compound 20 can be converted to compound 1B in step 4, for example, by hydrolysis with aqueous HCl by heating in methanol and DCM.

[0217] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1D is converted to a compound of formula (I) by a deprotection step

[0218]

[0219] Wherein R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, and Y is as defined above, and PG is a protecting group such as toluenesulfonyl, benzenesulfonamide, tert-butylcarbamate, methoxymethylamine, ethoxymethylamine or 1-adamantylcarbamate, the deprotection step is optionally followed by a hydrogenation step under hydrogen (H2) pressure with a catalyst such as Pd / C or platinum oxide (PtO2) to obtain is a single bond,

[0220] The deprotection step may be preceded by a step of obtaining compound 1D, wherein the compound of formula 1C

[0221]

[0222] wherein R3, R3', R6 and R8 are as defined above and PG is a protecting group as defined above, or compound 1G

[0223]

[0224] wherein R3, R3', R6 and R8 are as defined above and PG is as defined above, respectively with compound 1E

[0225]

[0226] Where R1, R2, R4, R5, R5', R7, n, p, X, and Y is as defined above

[0227] or with compound 1H

[0228]

[0229] Where R1, R2, R4, R5, R5', R7, n, p, X, and Y are as defined above, reacted in a Suzuki coupling step using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM in a solvent such as a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

[0230] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein is a single bond, wherein the compound having formula 1D' may alternatively be deprotected

[0231]

[0232] 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 toluenesulfonyl group, a benzenesulfonamide group, a tert-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group or a 1-adamantylcarbamate group,

[0233] Or a compound having formula 1S

[0234]

[0235] wherein R1, R2, R3, R3', R4, R5, R5', R7, R8, n, p, X and Y are as defined above, with a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed 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 to reflux of the solvent,

[0236] The alternative step may be preceded by a step of obtaining a compound of formula 1D' or a compound of formula 1S, respectively, by: respectively making a compound of formula 1Q

[0237]

[0238] 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 as defined above,

[0239] Reaction with a boron reagent R6B(OR')2 to obtain the compound of formula 1D', wherein -B(OR')2 is a boronic acid or a pinacol ester and R6 is as defined above,

[0240] or

[0241] A deprotection step, in particular treatment with an aqueous solution of potassium hydroxide in methanol, affords the compound of formula 1S.

[0242] Also provided herein are intermediate compounds selected from compounds of Formula 1D, 1K, 1L, 1D', 1O, 1Q, 1S, 1R, 1Y, 1Z, 2A and 2C, or any one of their pharmaceutically acceptable salts,

[0243]

[0244]

[0245]

[0246] 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 as defined above, such as tosyl.

[0247] At 400 and 500MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, with chemical shifts (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0248] Liquid chromatography / mass spectrometry (LC / MS) was obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210-400 nm and fast Acquity UPLC CSHC18 1.7 μm, size 2.1×30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H.

[0249] Tables 1a and 1b below contain specific compounds (names and structures) of formula (I) according to the present disclosure and their characterizations ( 1 H NMR and liquid chromatography / mass spectrometry).

[0250] Table 1a:

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] Table 1b:

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] The following examples describe the preparation of some of the compounds of formula (I) described herein. The quantities of the compounds exemplified below match those given in Table 1 above. Unless otherwise specified, all reactions were performed under an inert atmosphere.

[0267] In the following examples, when the origin of the starting product is not specified, it is understood that the product is a known compound.

[0268] Intermediates:

[0269] Intermediate 1: 3-Tosyl-7,8,9,10-tetrahydrohepta[e]indol-6(3H)-one

[0270]

[0271] Step 1: 1-Tosyl-1H-indole-4-carbaldehyde

[0272]

[0273] To the mixture of indole-4-carboxaldehyde (60g, 413mmol) in DCM (100ml), tetrabutylammonium hydrogen sulfate (14g, 41.3mmol) and NaOH (82.7g, 2.07mol) in water (80ml) are added. Then, 4-methylbenzenesulfonyl chloride (86.7g, 455mmol) in DCM (200ml) is added. The mixture is vigorously stirred for 2h at room temperature. After decantation, the organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (eluted with 70 / 30 petroleum ether / EtOAc), to obtain 110g (89%) of 1-toluenesulfonyl-1H-indole-4-carboxaldehyde in the form of light yellow solid.

[0274] LC / MS (m / z, MH+): 300

[0275] Step 2: Ethyl 5-(1-tosyl-1H-indol-4-yl)pent-4-enoate

[0276]

[0277] At -78 ° C, to a suspension of (4-ethoxy-4-oxobutyl) triphenylphosphonium bromide (252g, 551mmol) in anhydrous THF (1350ml), a 1M solution of bis(trimethylsilyl) amide potassium 1M in THF (551ml, 826.5mmol) was added dropwise. The mixture was stirred for 1.5h at -78 ° C. A solution of 1-tosyl-1H-indole-4-carboxaldehyde (110g, 367.47mmol) in anhydrous THF (450ml) was added. The reaction mixture was stirred for 2h at -78 ° C and the temperature was allowed to warm to room temperature. After stirring overnight, the reaction mixture was poured onto a saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue obtained was purified by flash chromatography (eluting with 70 / 30 petroleum ether / EtOAc) to give 103 g (71%) of ethyl 5-(1-tosyl-1H-indol-4-yl)pent-4-enoate as a white solid.

[0278] LC / MS (m / z, MH+): 398

[0279] Step 3: Ethyl 5-(1-tosyl-1H-indol-4-yl)pentanoate

[0280]

[0281] In a Parr apparatus, 10% Pd / C (3.5 g, 1.58 mmol, 10% purity) was added to a solution of ethyl 5-(1-tosyl-1H-indol-4-yl)pent-4-enoate (35 g, 88.05 mmol) in EtOH (350 ml). The mixture was placed in 6 bar hydrogen for 2 h, then filtered, washed with DCM, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluted with petroleum ether / EtOAc with a gradient of 70 / 30 to 95 / 05 to 70 / 30) to give 24.7 g (66%) of ethyl 5-(1-tosyl-1H-indol-4-yl)pentanoate as a colorless oil.

[0282] LC / MS (m / z, MH+): 400

[0283] Step 4: 5-(1-Tosyl-1H-indol-4-yl)pentanoic acid

[0284]

[0285] 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, then poured onto ice-cold 1N HCl aqueous solution (50 ml) and extracted twice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give 56 g (79%) of 5-(1-tosyl-1H-indol-4-yl)pentanoic acid.

[0286] LC / MS (m / z, MH+): 372

[0287] Step 5: 3-Tosyl-7,8,9,10-tetrahydroarylhepta[e]indol-6(3H)-one

[0288]

[0289] The mixture of 5-(1-tosyl-1H-indol-4-yl)pentanoic acid (56g, 150.76mmol) and Eaton's reagent (538g, 2.26mol, 354ml) is heated to 50°C for 12h. The mixture is poured into ice-cold water (3000ml) and extracted with DCM (600ml). After decantation, the organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (eluting with heptane / EtOAc of 100 / 00 to 70 / 30 gradient) to obtain 10.1g (18%) of 3-tosyl-7,8,9,10-tetrahydroaromatic heptanoic [e] indole-6 (3H) -one.

[0290] LC / MS (m / z, MH+): 354

[0291] Intermediate 2: 3-Tosyl-3,8,9,10-tetrahydrohepta[e]indol-6-yl trifluoromethanesulfonate

[0292]

[0293] Trifluoromethanesulfonic acid anhydride (6.79 g, 24.1 mmol) was added to a solution of 3-tosyl-7,8,9,10-tetrahydrohepta[e]indol-6(3H)-one (intermediate 1) (4.37 g, 12.4 mmol) and pyridine (1.5 ml, 19 mmol) in DCM (120 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into a mixture of water and ice (100 ml). After decantation, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with 50 / 50 heptane / DCM) to obtain 5.5 g (91%) of trifluoromethanesulfonic acid 3-tosyl-3,8,9,10-tetrahydrohepta[e]indol-6-yl ester.

[0294] LC / MS (m / z, MH+): 486

[0295] Intermediate 3: (S)-7-bromo-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0296]

[0297] Step 1: (S)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0298]

[0299] A mixture of 3-tosyl-3,8,9,10-tetrahydroarheptano[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), Cs2CO3 (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. DCM (20ml) and water (10ml) are added to the obtained residue. After decantation, the organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (eluting with heptane / EtOAc of 100 / 00 to 00 / 100 gradient) to obtain 955mg (85%) of (S)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydroarylhepta[e]indole.

[0300] LC / MS (m / z, MH+): 559

[0301] Step 2: (S)-7-Bromo-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0302]

[0303] To a mixture of (S)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole (50 mg, 0.09 mmol) in DCM (2 ml) cooled at 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 MgSO4 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-tetrahydrohepta[e]indole.

[0304] LC / MS (m / z, MH+): 637

[0305] Intermediate 4: 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0306]

[0307] Step 1: 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0308]

[0309] Step 1 of Intermediate 4 was prepared following a procedure similar to that of Step 1 of Intermediate 3 from 3-tosyl-3,8,9,10-tetrahydrohepta[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 WO 2022084280) to give 6.4 g (88%) of 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole.

[0310] LC / MS (m / z, MH+): 543

[0311] Step 2: 7-Bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0312]

[0313] Intermediate 4, step 2 was prepared following a procedure similar to that of Intermediate 3, step 2 from 6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole and pyridinium tribromide to give 6 g (82%) of

[0314] 7-Bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydroarylhepta[e]indole.

[0315] LC / MS (m / z, MH+): 621

[0316] Intermediate 5: 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole

[0317]

[0318] To a mixture of 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[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 h. 1 N HCl was added until pH 9. EtOAc (80 ml) and water (5 ml) were added. After decantation, the organic phase was dried over MgSO4 and concentrated under reduced pressure, and the residue obtained was purified by flash chromatography (eluting with DCM / MeOH with a gradient 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-tetrahydrohepta[e]indole.

[0319] LC / MS (m / z, MH+): 467

[0320] Intermediate 6: 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indol-6-yl trifluoromethanesulfonate

[0321]

[0322] Step 1: 7-(3-chloro-2-methylphenyl)-3-tosyl-7,8,9,10-tetrahydrohepta[e]indol-6(3H)-one

[0323]

[0324] A mixture of 3-tosyl-7,8,9,10-tetrahydroarheptano[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), 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 obtained 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-tetrahydroarylhepta[e]indol-6(3H)-one.

[0325] LC / MS (m / z, MH+): 478

[0326] Step 2: 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indol-6-yl trifluoromethanesulfonate

[0327]

[0328] To a mixture of 7-(3-chloro-2-methylphenyl)-3-tosyl-7,8,9,10-tetrahydroarheptano[e]indol-6(3H)-one (1.44g, 3mmol) in THF (25ml) cooled at -72°C, N,N-bis(trifluoromethylsulfonyl)aniline (1.4g, 3.92mmol) was added. Then, KHMDS 0.7M in THF (6ml, 3.91mmol) was added dropwise at -72°C. The reaction mixture was stirred at -70°C for 30 minutes. The cooling bath was removed and the temperature was allowed to rise to room temperature. The reaction mixture was stirred at room temperature for 18h. EtOAc (50ml) and water (30ml) were added to the reaction mixture. After decantation, the organic phase was dried over MgSO4 and concentrated under reduced pressure, and the residue obtained was purified by flash chromatography (elution with heptane / DCM with a gradient from 100 / 00 to 60 / 40) to give 540 mg (29%) of 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydroarheptano[e]indol-6-yl trifluoromethanesulfonate.

[0329] LC / MS (m / z, MH+): 610

[0330] Intermediate 7: (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine

[0331]

[0332] Step 1: (4-Bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid

[0333]

[0334] 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 room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was triturated with Et2O. The formed solid was filtered to give 17 g (81%) of (4-bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid.

[0335] LC / MS (m / z, MH+): 254

[0336] Step 2: (4-Bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone

[0337]

[0338] A mixture of (4-bromophenyl)-pyrrolidin-3-yl-methanone, 2,2,2-trifluoroacetic acid (9.45 g, 25.67 mmol), K2CO3 (10.64 g, 77 mmol), 1-fluoro-3-iodo-propane (5.07 g, 26.95 mmol) in MeCN (200 ml) was heated at 80° C. for 3 h. The reaction mixture was quenched by the addition of a saturated solution of NH4Cl (200 ml) and extracted with EtOAc (3×200 ml). The organic phase was washed with brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue obtained was purified by flash chromatography (eluting with DCM / MeOH with a gradient of 100 / 00 to 50 / 50 to 90 / 10) to give 6.34 g (78%) of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanone.

[0339] LC / MS (m / z, MH+): 314

[0340] Step 3: (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol

[0341]

[0342] 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 NaBH4 (2.28 g, 60.21 mmol) and the mixture was stirred at room temperature for 2 hours. A concentrated solution of NH4Cl (100 ml) and EtOAc (300 ml) were added. After decantation, the organic phase was washed with brine (200 ml), dried over Na2SO4, 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 as is in the next step.

[0343] LC / MS (m / z, MH+): 316

[0344] Step 4: 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine, cis and trans isomers

[0345]

[0346] At 0 ℃, sulfuric acid (35ml) was added dropwise to a mixture of (4-bromophenyl)-[1-(3-fluoropropyl)pyrrolidin-3-yl]methanol (5.16g, 16.33mmol) and water (10ml). The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of ice and water (500ml). Powdered NaHCO was added to pH 9. EtOAc (300ml) was added and the organic phase was dried over NaSO, filtered, concentrated under reduced pressure, and the obtained residue was purified by flash chromatography (eluted with DCM / EtOAc of a gradient of 100 / 00 to 00 / 100) to obtain 4.13g (85%) of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine as a mixture of cis and trans isomers.

[0347] Step 5: (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine

[0348]

[0349] 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 CO2 mobile phase with 30% of 0.1% TEA in MeOH solution as a co-solvent. The temperature was set at 40° C. and the back pressure regulator was set at 100 bar to give 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.

[0350] LC / MS (m / z, MH+): 298

[0351] Step 6: (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine

[0352]

[0353] A mixture of (3Z)-3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine (200 mg, 0.67 mmol) in dioxane (4 ml), Pd(PPh3)2Cl2 (38 mg, 0.07 mmol), bis(pinacolato)diboron (221 mg, 0.87 mmol) and AcOK (164 mg, 1.68 mmol) was heated under reflux for 2 hours. After cooling, the reaction mixture was filtered on celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with DCM / EtOAc / EtOH with a gradient of 100 / 00 / 00 to 75 / 20 / 05) to give 160 mg (69%) of (3Z)-1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]pyrrolidine.

[0354] LC / MS (m / z, MH+): 346

[0355] Intermediate 8: (S)-1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine

[0356]

[0357] Step 1: (S)-N-(4-bromophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine

[0358]

[0359] A mixture of 1-bromo-4-iodobenzene (2.5 g, 8.8 mmol), Pd(OAc)2 (200 mg, 0.88 mmol), Xantphos (720 mg, 1.2 mmol), Cs2CO3 (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 under 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 MgSO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography (eluting with DCM / MeOH with a gradient from 100 / 00 to 95 / 05) to give 0.56 g (21%) of (S)-N-(4-bromophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine.

[0360] LC / MS (m / z, MH+): 301

[0361] Step 2: (S)-1-(3-Fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine

[0362]

[0363] Intermediate 8, step 2 was prepared following a procedure analogous to that of Intermediate 7, step 6 from (S)-N-(4-bromophenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine and bis(pinacolato)diboron 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.

[0364] LC / MS (m / z, MH+): 349

[0365] Intermediate 9: 1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-3-amine

[0366]

[0367] Step 1: tert-Butyl 3-((4-bromophenyl)amino)azetidine-1-carboxylate

[0368]

[0369] Intermediate 10, step 1 was prepared following a procedure similar to that of Intermediate 8, step 1 from 1-bromo-4-iodobenzene and tert-butyl 3-aminoazetidine-1-carboxylate to give 2.11 g (37%) of tert-butyl 3-((4-bromophenyl)amino)azetidine-1-carboxylate.

[0370] LC / MS (m / z, MH+): 327

[0371] Step 2: N-(4-bromophenyl)azetidine-3-amine

[0372]

[0373] Intermediate 9, step 2 was prepared following a procedure analogous to that of Intermediate 7, step 1 from tert-butyl 3-((4-bromophenyl)amino)azetidine-1-carboxylate to afford 0.88 g (93%) of N-(4-bromophenyl)azetidine-3-amine after workup on SCX.

[0374] LC / MS (m / z, MH+): 227

[0375] Step 3: N-(4-bromophenyl)-1-(3-fluoropropyl)azetidine-3-amine

[0376]

[0377] A mixture of N-(4-bromophenyl)azetidine-3-amine (880mg, 3.9mmol), 1-fluoro-3-iodopropane (874mg, 4.6mmol) and NaOH (620mg, 15.5mmol) in THF (9ml) was stirred at room temperature for 24h. In the reaction mixture, water (5ml) and EtOAc (10ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure, and the obtained residue was purified by flash chromatography (eluted with DCM / MeOH of a gradient of 100 / 00 to 95 / 05) to obtain 338mg (30%) of N-(4-bromophenyl)-1-(3-fluoropropyl)azetidine-3-amine.

[0378] LC / MS (m / z, MH+): 287

[0379] Step 4: 1-(3-Fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-amine

[0380]

[0381] Step 4 of Intermediate 9 was prepared following a procedure similar to that of Step 6 of Intermediate 7 from N-(4-bromophenyl)-1-(3-fluoropropyl)azetidine-3-amine and bis(pinacolato)diboron to afford 140 mg (36%) of 1-(3-fluoropropyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-3-amine.

[0382] LC / MS (m / z, MH+): 335

[0383] Intermediate 10: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine

[0384]

[0385] Step 1: tert-Butyl 3-(4-bromophenoxy)azetidine-1-carboxylate

[0386]

[0387] A mixture of 4-bromophenol (40 g, 231 mmol), 3-iodoazetidine-1-carboxylic acid tert-butyl ester (65.5 g, 231 mmol), CsCO (151 g, 462 mmol) in DMF (400 ml) was stirred at room temperature for 12 h. Water (500 ml) and EtOAc (300 ml) were added to the reaction mixture. After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure to obtain 30 g (crude) of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate, which was used as is in the next step.

[0388] LC / MS (m / z, MH+): 328

[0389] Step 2: 3-(4-bromophenoxy)azetidine, 2,2,2-trifluoroacetic acid

[0390]

[0391] Intermediate 10, step 2 was prepared following a similar procedure to that of Intermediate 7, step 1 from tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate to afford 20 g (crude) of 3-(4-bromophenoxy)azetidine, 2,2,2-trifluoroacetic acid, which was used as such in the next step.

[0392] LC / MS (m / z, MH+): 228

[0393] Step 3: 3-(4-bromophenoxy)-1-(3-fluoropropyl)azetidine

[0394]

[0395] 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 obtained residue was purified by flash chromatography (eluting with petroleum ether / EtOAc with a gradient of 97 / 03 to 00 / 100) to obtain 9 g (53%) of N-(4-3-(4-bromophenoxy)-1-(3-fluoropropyl)azetidine.

[0396] LC / MS (m / z, MH+): 288

[0397] Step 4: 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine

[0398]

[0399] Step 4 of Intermediate 10 was prepared following a procedure similar to that of Step 6 of Intermediate 7 from 3-(4-bromophenoxy)-1-(3-fluoropropyl)azetidine and bis(pinacolato)diboron to give 140 mg (36%) of 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)azetidine.

[0400] LC / MS (m / z, MH+): 336

[0401] Examples

[0402] Method A:

[0403] Example 1 :7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole

[0404]

[0405] Step 1: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0406]

[0407] A mixture of 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydroarheptano[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 minutes. 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 residue obtained was purified by flash chromatography (elution with cyclohexane / EtOAc gradient from 100 / 00 to 00 / 100) to give 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-tetrahydroarylhepta[e]indole.

[0408] LC / MS (m / z, MH+): 651

[0409] Step 2: 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole

[0410]

[0411] A mixture of 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydroarheptano[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, 1 N HCl was added to reduce pH to 7. Then, EtOAc (50 ml), ether (50 ml) and water (20) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography (elution with DCM / MeOH with a gradient from 100 / 00 to 80 / 20) to give 58 mg (72%) of 7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole.

[0412] Method B:

[0413] Example 2 :7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole

[0414]

[0415] Example 2 was prepared following a procedure similar to that of Step 1 of Example 1 from 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (Intermediate 5) and (3-fluoro-2-methoxy-4-pyridinyl)boronic acid 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-tetrahydrohepta[e]indole.

[0416] Example 17 :(E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)prop-2-en-1-ol

[0417]

[0418] Example 17 was prepared following a procedure analogous to that of Step 1 of Example 1 from 7-bromo-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (Intermediate 5) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol to afford 119 mg (50%) of (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)prop-2-en-1-ol.

[0419] Method C:

[0420] Example 3 :7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole

[0421]

[0422] Step 1: 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole

[0423]

[0424] Step 1 of Example 3 was prepared following a procedure similar to that of Step 1 of Example 1 from 7-(3-chloro-2-methylphenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[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 WO2022084298) to give 180 mg (61%) of 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidine-3-ylidene)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole.

[0425] LC / MS (m / z, MH+): 665

[0426] Step 2: 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole

[0427]

[0428] Step 2 of Example 3 was prepared following a procedure similar to that of Step 2 of Example 1 from 7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-tosyl-3,8,9,10-tetrahydrohepta[e]indole 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-tetrahydrohepta[e]indole.

[0429] Method D:

[0430] Example 25 :3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)propan-1-ol

[0431]

[0432] A mixture of (E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydroarheptano[e]indol-7-yl)prop-2-en-1-ol (Example 17) (100 mg, 0.22 mmol), Pd / C 10% (24 mg, 0.024 mmol) in EtOAc (5 ml) and EtOH (8 ml) was hydrogenated at room temperature under H (1 bar) for 15 h. The reaction mixture was filtered on celite and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash chromatography (eluting with DCM / MeOH with a gradient from 100 / 00 to 90 / 10) to give 70 mg (70%) of 3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydroarhepta[e]indol-7-yl)propan-1-ol.

[0433] The compounds according to Table 1 above were subjected to pharmacological testing for determining their degradation effect on estrogen receptors.

[0434] Test: Estrogen receptor degradation activity

[0435] The test involves measuring the in vitro degradation activity of the compounds of Table 1.

[0436] Degradation activity of ERα was measured using breast cancer cells in a cellular Western blot assay as described below.

[0437] MCF7 cells (ATCC) were seeded in phenol red-free MEMα medium (Invitrogen) containing 5% charcoal dextran treated FBS at a concentration of 10,000 cells / 30 μL / well in 384-well microplates (collagen coated). The next day, 9 points of each compound were added to the cells in a final concentration of 0.3-0.0000018 μM (Table 2) or 0.1 μM Fulvestrant (used as a positive control) in 2.5 μL cells at a continuous 1:5 dilution. 4 hours after compound addition, cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature, and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight in a cold room with 50 μL of anti-ER rabbit monoclonal antibody (Thermoscientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells treated with blocking buffer but without antibody were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated at 37°C for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64a DNA dye (2 μM final concentration). The cells were then washed 3 times in PBS and scanned in an ACUMEN detector (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0438] In this test, the degradation activity of estrogen receptor is determined by the concentration that degrades 50% of the estrogen receptor (or IC 50 ) is given in nM.

[0439] The % reduction in ERa levels was determined as follows: % inhibition = 100*(1-(sample - fulvestrant:DMSO-fulvestrant)).

[0440] The following Table 2 shows the estrogen receptor degradation activity results of the compounds of Table 1 tested at 0.3 μM, and demonstrates that the compounds have significant degradation activity on the estrogen receptor.

[0441] Table 2 :

[0442]

[0443]

[0444] Therefore, it is obvious that the tested compounds have degradation activity on estrogen receptors, with IC50 less than 1 μM and degradation level greater than 50%. Therefore, the compounds of formula (I) can be used to prepare medicaments, especially medicaments as degraders of estrogen receptors.

[0445] Therefore, also provided herein is a medicament comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0446] Also provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0447] Also provided herein are compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, particularly as inhibitors and degraders of estrogen receptors.

[0448] Also provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[0449] A particular aspect is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0450] In embodiments, the cancer is a hormone-dependent cancer.

[0451] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular the cancer is an estrogen receptor alpha dependent cancer.

[0452] 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.

[0453] In another embodiment, the metastasis is a brain metastasis.

[0454] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0455] In another embodiment, the cancer is resistant to anti-hormone therapy.

[0456] In further embodiments, the compounds of formula (I) are used as single agents or in combination with other agents such as CDK4 / 6, mTOR or PI3K inhibitors.

[0457] According to another aspect, provided herein is a method of treating the above indicated pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.

[0458] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of any of the above indicated pathological conditions, more particularly useful for the treatment of cancer.

[0459] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0460] The excipients are selected from the customary excipients known to those skilled in the art, depending on the desired pharmaceutical form and method of administration.

[0461] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the above active ingredient of formula (I) or its base, acid, zwitterion or salt thereof can be administered to animals and humans in a unit administration form, as a mixture with conventional pharmaceutical excipients for the treatment of the above disorders or diseases.

[0462] Suitable unit administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the compounds of formula (I) can be used in creams, gels, ointments or lotions.

[0463] As an example, a unit administration form of a compound of formula (I) in the form of a tablet may comprise the following components:

[0464]

[0465]

[0466] There may be specific cases where higher or lower doses are appropriate. According to routine practice, the appropriate dose for the patient is determined by the physician according to the mode of administration and the weight and response of each patient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: - 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-, wherein R9 represents a fluorine atom or a (C1-C3) alkyl group; - represents a single bond or a double bond; -p is 0 or 1; -X represents -CH=, -N= or -CR"=, wherein R" represents a (C1-C3)alkyl group or a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group; -R6 represents a group selected from the following: ■ phenyl, which is optionally substituted by 1 to 3 substituents independently selected from the following: a halogen atom; a (C1-C6)alkyl group optionally substituted by 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; ■ a fused phenyl group selected from a phenyl group fused to a (C3-C6)cycloalkyl group, the (C3-C6)cycloalkyl ring optionally containing unsaturation and, wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxyl group, a halogen atom, a (C1-C6)fluoroalkyl group and a (C1-C3)alkoxy group; ■ a phenyl group fused to a hetero(C4-C6)cycloalkyl group, the hetero(C4-C6)cycloalkyl group ring optionally comprising unsaturation and wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C1-C3)alkyl, hydroxyl, halogen atoms, (C1-C6)fluoroalkyl and (C1-C3)alkoxy; ■ a bicyclic group containing 5 to 12 carbon atoms, which optionally contains 1 to 2 degrees of unsaturation; optionally substituted by 1 to 4 substituents independently selected from the group consisting of fluorine atoms, -OH groups, (C1-C3)-alkyl groups, (C1-C3)fluoroalkyl groups, (C1-C3)alkoxy groups, (C1-C3)fluoroalkoxy groups and oxo groups; ■ a heteroaryl group containing 2 to 9 carbon atoms and containing 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, the heteroaryl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom, a (C1-C6)alkyl group, a (C1-C6)fluoroalkyl group, 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 optionally substituted by 1 to 4 substituents independently selected from: o a fluorine atom, an -OH group, a (C1-C3)alkyl group optionally substituted with an -OH group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group, an oxo group, and o (C3-C6) cycloalkyl and phenyl, wherein the (C3-C6) cycloalkyl or phenyl is optionally substituted with one or two halogen atoms or (C1-C3) alkyl; ■ (C3-C6)cycloalkyl (C1-C3)alkyl, which is optionally substituted on the cycloalkyl by 1 to 4 substituents independently selected from the group consisting of fluorine atoms, -OH groups, (C1-C4)alkyl, (C1-C3)fluoroalkyl, (C1-C3)fluoroalkoxy and oxo groups; ■ a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group, a dihydropyranyl group or a tetrahydrofuranyl group, said heterocycloalkyl group being saturated or partially saturated and optionally substituted by 1 to 3 substituents independently selected from the group consisting of 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 such as isobutyl or ethylbutyl, the alkyl being optionally substituted by 1 to 4 substituents independently selected from the group consisting of fluorine atoms, (C1-C3) alkoxy groups, (C1-C3) fluoroalkoxy groups and -OH groups; ■(C1-C6)alkenyl, which is optionally substituted by 1 to 4 substituents independently selected from the group consisting of: -OH group; halogen atom; (C1-C3)alkyl; (C1-C3)fluoroalkyl; (C1-C3)alkoxy; (C1-C3)fluoroalkoxy; -COOH group and cyano group; and ■phenyl(C1-C2)alkyl, the phenyl being optionally substituted by 1 to 3 substituents independently selected from the group consisting of: halogen atoms; (C1-C3)alkyl; (C1-C3)fluoroalkyl; (C1-C3)alkoxy; (C1-C3)fluoroalkoxy; cyano; and -OH groups; - 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 a trifluoromethyl group; - R8 represents a hydrogen atom or a (C1-C3) alkyl group or a cyclopropyl group; and -n is 0, 1, or 2.

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

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

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

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Y is -CH2-, -CH=, -O- or -NH-.

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

8. A compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a phenyl group, which is optionally substituted by 1 to 3 substituents independently selected from the following: a fluorine atom; a chlorine atom; a (C1-C4) alkyl group optionally substituted by an OH group, such as a methyl or ethyl group; a trifluoromethyl group; a (C1-C4) alkoxy group, such as a methoxy group; a cyano group; a -COOH group and a -OH group.

9. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a pyridyl group which is optionally substituted by 1 to 3 substituents independently selected from fluorine atoms and (C1-C6)alkoxy groups, more particularly methoxy groups.

10. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a saturated or partially saturated cyclohexyl group which is optionally substituted by 1 to 2 fluorine atoms.

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

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

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular a trifluoroacetate thereof, according to any one of claims 1 to 12, characterized in that: The compound is selected from the following compounds: --7-(4-fluoro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (1), -7-(3-fluoro-2-methoxypyridin-4-yl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (2), -7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (3), -(S)-7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[e]indole (5), -2,6-difluoro-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenol (6), -7-(2,4-dichlorophenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (7), -7-(3-chloro-2-methylphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (8), -7-(2,3-dimethoxyphenyl)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (9), -6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indole (10), -3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzonitrile (11), -2-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzonitrile (12), -4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[e]indole (14), -6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-(6-methoxypyridin-3-yl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[e]indole (16), -(E)-3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[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-tetrahydrohepta[e]indol-7-yl)phenyl)methanol (19), -(4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenyl)methanol (20), -2-(3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)phenyl)ethan-1-ol (21), -3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[e]indol-7-yl)benzoic acid (22), -4-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[e]indol-7-yl)acrylic acid (24), -3-(6-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[e]indole (26), -N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrohepta[e]indol-6-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine (27), -(S)-N-(4-(7-(3-chloro-2-methylphenyl)-3,8,9,10-tetrahydrohepta[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-tetrahydrohepta[e]indole (29).

14. A method for preparing a compound of formula (I) as claimed in any one of claims 1 to 13, wherein The compound of formula 1D is converted into a compound of formula (I) by a deprotection step Wherein R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, and Y is as defined in any one of claims 1 to 12, and PG is a protecting group such as tosyl, benzenesulfonamide, methoxymethylamine, ethoxymethylamine or 1-adamantylcarbamate, the deprotection step being optionally followed by a hydrogenation step under hydrogen (H2) pressure with a catalyst such as Pd / C or platinum oxide (PtO2) to obtain is a single bond, The deprotection step may be preceded by a step of obtaining compound 1D, wherein the compound of formula 1C wherein R3, R3', R6 and R8 are as defined above and PG is a protecting group as defined above, or compound 1G wherein R3, R3', R6 and R8 are as defined above and PG is as defined above, respectively with compound 1E Where R1, R2, R4, R5, R5', R7, n, p, X, and Y is as defined above or with compound 1H Where R1, R2, R4, R5, R5', R7, n, p, X, and Y are as defined above, reacted in a Suzuki coupling step using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed with DCM in a solvent such as a mixture of dioxane and water and in the presence of a base such as cesium carbonate (Cs2CO3) by heating to solvent reflux.

15. A method for preparing a compound of formula (I) as claimed in any one of claims 1 to 13, wherein Deprotecting a compound of formula (I) as defined above, wherein is a single bond, wherein the compound having formula 1D' may alternatively be deprotected 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 toluenesulfonyl group, a benzenesulfonamide group, a tert-butylcarbamate group, a methoxymethylamine, an ethoxymethylamine or a 1-adamantylcarbamate group, Or a compound having formula 1S wherein R1, R2, R3, R3', R4, R5, R5', R7, R8, n, p, X and Y are as defined above, with a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) complexed 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 to reflux of the solvent, The alternative step may be preceded by a step of obtaining a compound of formula 1D' or a compound of formula 1S, respectively, by: respectively making a compound of formula 1Q 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 as defined above, Reaction with a boron reagent R6B(OR')2 to obtain the compound of formula 1D', wherein -B(OR')2 is a boronic acid or a pinacol ester and R6 is as defined above, or A deprotection step, in particular treatment with an aqueous solution of potassium hydroxide in methanol, affords the compound of formula 1S.

16. A compound selected from compounds of Formula 1D, 1K, 1L, 1D', 1O, 1Q, 1S, 1R, 1Y, 1Z, 2A and 2C, or any one of their pharmaceutically acceptable salts, Wherein R1, R2, R3, R3', R4, R5, R5', R6, R7, R8, n, p, X, and Y is 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 tert-butylcarbamate group, a methoxymethylamine group, an ethoxymethylamine group or a 1-adamantylcarbamate group, in particular a tosyl group.

17. A medicament, characterized in that: The medicament comprises a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises 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) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for use as an inhibitor and degrader of estrogen receptors.

20. 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 ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

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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