Novel substituted 4-amino-4-oxo-but-2-enyl derivatives, methods for their preparation and therapeutic uses thereof

Description

[0001] Disclosed herein are novel substituted 4-amino-4-oxo-but-2-enyl derivatives, the processes for their preparation, as well as the therapeutic uses thereof, in particular as anticancer agents via selective antagonism and degradation of estrogen receptors.

[0002] The Estrogen Receptors (ER) belong to the steroid / nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation and differentiation in target tissues. ERs are in two forms: the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ) respectively encoded by the ESR1 and the ESR2 genes. ERα and ERβ are ligand-activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA / ER complex interacts with co-regulators to modulate 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 development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis.

[0004] ERα is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high level of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is well established and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority ERα-positive breast tumors. Currently, several strategies for inhibiting the estrogen axis in breast cancer exist, including: 1- blocking estrogen synthesis by aromatase inhibitors that are used to treat early and advanced ERα-positive breast cancer patients; 2- antagonizing estrogen ligand binding to ERα by tamoxifen which is used to treat ERα-positive breast cancer patients in both pre- and post- menopausal setting; 3-antagonizing and downregulating ERα levels by fulvestrant, which is used to treat breast cancer in patients that have progressed despite endocrine therapies such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have contributed enormously to reduction in breast cancer development, about more than one-third of ERα-positive patients display de-novo resistance or develop resistance over time to such existing therapies. Several mechanisms have been described to explain resistance to such hormone therapies. For example, hypersensitivity of ERα to low estrogen level in treatment with aromatase inhibitors, the switch of tamoxifen effects from antagonist to agonist effects in tamoxifen treatments or multiple growth factor receptor signaling pathways. Acquired mutations in ERα occurring after initiation of hormone therapies may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the Ligand Binding Domain (LBD), result in the ability to bind to DNA in the absence of ligand and confer hormone independence in cells harboring such mutant receptors. Further reference may be made to WO2018 / 091153, WO2017 / 140669 and Maximov et al., "J. Med. Chem.", 57(11), 2014, pages 4569-4583.

[0006] Hence, there is still a need to provide potent compounds suitable as ER-directed therapies.

[0007] The inventors have now found novel compounds which are selective estrogen receptors covalent antagonists (SERCA).

[0008] Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof: wherein: R3 represents a hydrogen atom, a -COOH group or a -OH group; R3' and R3" independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom or a cyano group; R4 represents a hydrogen atom, a (C 1 -C 3 )alkyl group or a cyclopropyl; R5 independently represents a (C 1 -C 3 )alkyl group such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or a (C 1 -C 3 )fluoroalkyl group, such as a trifluoromethyl; R6 represents a group selected from: ▪ a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C 1 -C 6 )alkyl group, optionally substituted with a cyano group or a -OH group; a (C 1 -C 6 )fluoroalkyl group; a (C 3 -C 6 )cycloalkyl group; a (C 1 -C 6 )alkoxy group; a (C 1 -C 6 )fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C 1 -C 4 )alkylthio group; a (C 1 -C 4 )fluoroalkylthio group; a (C 1 -C 4 )alkylsulfonyl group and a -OH group; ▪ a fused phenyl group, selected from phenyl groups fused with a (C 3 -C 6 )cycloalkyl, which (C 3 -C 6 )cycloalkyl ring optionally comprises an unsaturation and, wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C 1 -C 3 )alkyl group, a hydroxy group, a halogen atom, a (C 1 -C 6 )fluoroalkyl group and a (C 1 -C 3 )alkoxy group; ▪ a bicyclic group comprising 5 to 12 carbon atoms, optionally comprising 1 to 2 unsaturations; optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a -OH group, a (C 1 -C 3 )alkyl group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )alkoxy group, a (C 1 -C 3 )fluoroalkoxy group and an oxo group; ▪ a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 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 or a pyrrolyl group, said heteroaryl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )fluoroalkyl group, a (C 1 -C 6 )alkoxy group, a (C 1 -C 6 )fluoroalkoxy group, a cyano group, a carbamoyl group and a -OH group; ▪ a cycloalkyl group comprising 3 to 7 carbon atoms, said cycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 4 substituents independently selected from: ∘ a fluorine atom, a -OH group, a (C 1 -C 3 )alkyl group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )alkoxy group, a (C 1 -C 3 )fluoroalkoxy group, an oxo group, ∘ a (C 3 -C 6 )cycloalkyl group, and a phenyl group, said (C 3 -C 6 )cycloalkyl or phenyl groups being optionally substituted with one or two halogen atom(s) or (C 1 -C 3 )alkyl group(s); ▪ a (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl group, optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from: a fluorine atom, a -OH group, a (C 1 -C 4 )alkyl group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )fluoroalkoxy group and an oxo group; ▪ a 4 to 7 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl or a tetrahydrofuranyl group, said heterocycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom, a (C 1 -C 3 )alkyl group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )fluoroalkoxy group, an oxo group, a (C 1 -C 3 )alkoxy group, and a -OH group; ▪ a (C 1 -C 6 )alkyl group, such as an isobutyl group or an ethylbutyl group, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C 1 -C 3 )alkoxy group, a (C 1 -C 3 )fluoroalkoxy group and a -OH group; and ▪ a phenyl(C 1 -C 2 )alkyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C 1 -C 3 )alkyl group; a (C 1 -C 3 )fluoroalkyl group; a (C 1 -C 3 )alkoxy group; a (C 1 -C 3 )fluoroalkoxy group; a cyano group; and a -OH group; X represents -CH 2 -, -O- or -S-; n is 0, 1 or 2; m is 0 or 1; and Z represents a group selected from: ▪ and ▪ wherein: o R1 and R2 independently represent a hydrogen atom, a -CH 3 group, a -CH 2 CH 3 group, or a -CH 2 CH 2 OH group, or R1 and R2 forms a 4 to 6 membered-heterocycloalkyl group with the nitrogen atom to which R1 and R2, are attached, said heterocycloalkyl group optionally comprising an additional heteroatom selected from oxygen, nitrogen and sulfur; o Y represents -CH 2 -, -CH=, -CR7=, -O- or -NH-, wherein R7 represents a fluorine atom or a (C 1 -C 3 )alkyl group; ∘ represents a single bond or a double bond; and o p is 0 or 1.

[0009] Y represents -CH 2 -, -O- or -NH- when represents a single bond and Y represents -CH= or -CR7= when represents a double bond.

[0010] The compounds of formula (I) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers.

[0011] The compounds of formula (I) may be present as well under tautomer forms.

[0012] The compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Hence, herein are provided compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0013] These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided.

[0014] Among suitable salts of the compounds of formula (I), hydrochloride may be cited.

[0015] As used herein, the terms below have the following definitions unless otherwise mentioned throughout the instant specification: a halogen atom: a fluorine, a chlorine, a bromine or an iodine atom, and in particular a fluorine and a chlorine atom; an oxo: a "=O" group; an alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms (noted "(C 1 -C 6 )alkyl"). By way of examples, mention may be made of, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, and the like; a cycloalkyl group: a monocyclic alkyl group comprising, unless otherwise mentioned, from 3 to 7 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted. By way of examples, mention may be made of, but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups and the like, in particular a cyclopentyl, a cyclohexyl, a cycloheptyl, a cycloheptenyl, or a cyclohexenyl; a heterocycloalkyl group: a 4 to 7-membered cycloalkyl group, saturated or partially unsaturated, comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular being oxygen or nitrogen. By way of examples, mention may be made of, but not limited to: morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl, and tetrahydrothiopyranyl. The heterocycloalkyl is advantageously tetrahydrofuranyl or tetrahydropyranyl. a fluoroalkyl group: an alkyl group as previously defined where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -CH 2 F, -CHF 2 , -CH 2 CHF 2 , -CH 2 CH 2 F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl group. By way of example, mention may be made of trifluoromethyl group or trifluoroethyl group and the like; an alkoxy group: an -O-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, and the like; a fluoroalkoxy group: an -O-alkyl group where the alkyl group is as previously defined and where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -OCH 2 F, -OCHF 2 , -OCH 2 CH 2 F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group can be named perfluoroalkoxy group. By way of example, mention may be made of trifluoromethoxy group and the like; a (C 1 -C 4 )alkylthio group also named a (C 1 -C 4 )alkylsulfanyl group: a -S-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, and the like; a (C 1 -C 4 )alkylsulfonyl group: a -SO 2 -alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to -SO 2 CH 3 , -SO 2 CH 2 CH 3 and the like; a (C 1 -C 4 )fluoroalkylthio group also named a (C 1 -C 4 )fluoroalkylsulfanyl group: a -S-fluoroalkyl group where the fluoroalkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: fluoromethylthio, difluoromethylthio, trifluoromethylthio and the like; a fused phenyl group: a bicyclic radical comprising from 7 to 10 carbon atoms and that contains a phenyl moiety. Said phenyl moiety may be fused to a (C 3 -C 6 )cycloalkyl group, i.e. the phenyl moiety may share a bond with said (C 3 -C 6 )cycloalkyl group. The fused phenyl group may be bound to the rest of the molecule by 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, tetrahydronaphthalenyl and the like; a heteroaryl group: a cyclic 5 to 10-membered aromatic group containing between 2 and 9 carbon atoms and containing between 1 and 3 heteroatoms, such as nitrogen, oxygen or sulfur. Such nitrogen atom may be substituted with an oxygen atom in order to form a -NO bond. Such -N-O bond can be in a form of a N-oxide (-N +< -O -< ). Said heteroaryl group may be monocyclic or bicyclic. By way of examples of heteroaryl groups, mention may be made of, but not limited to: thiophene, furan, thiadiazole, thiazole, imidazole, pyridazine, triazine, pyrazine, oxadiazole, pyrazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine, benzotriazole, benzoxazole, pyrrolo[2,3-b]pyridine, benzimidazole, benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridone groups and the like. The heteroaryl group is advantageously pyridine, pyrrole, imidazole, pyrazine, furane, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, and more particularly pyridine, pyridone and pyrrole; a bicyclic group, generally comprising 5 to 12 carbon atoms, is a hydrocarbon group selected from groups comprising two rings connected through: a single common atom: a "spirobicyclic ring". Such spiro bicyclic alkyl generally comprises 5 to 11 carbon atoms referring to a "spiro(C 5 -C 11 )bicyclic ring". The rings may be saturated or partially unsaturated. Such spirobicyclic ring may be unsubstituted or substituted, in particular by at least one (C 1 -C 3 )alkyl group such as methyl or a fluorine. By way of examples of spiro(C 5 -C 11 )bicyclic ring as for the definition of R6, mention may be made of, but 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. The spiro(C 5 -C 11 )bicyclic ring is advantageously spiro[3.3]heptane or spiro[3.3]heptene still for the R6 group. two common atoms: In that case the bicyclic group comprises 7 to 12 carbon atoms and optionally comprises 1 to 2 unsaturations. By way of examples of such bicyclic groups, mention may be made of, but not limited to: cis-1,3a,4,5,6,6a-hexahydropentalenyl group, bicyclo[3.1.0]hexan-1-yl, bicyclo[4.1.0]heptanyl and octahydropentalenyl. three or more common atoms: In that case the bicyclic group comprises 6 to 10 carbon atoms, such bicyclic group may be referred to as a "bridged (C 6 -C 10 )cycloalkyl" group, the rings share three or more atoms and the bridge contains at least one atom, for example 1, 2 or 3 atoms and preferentially 1 atom. By way of examples of such bridged cycloalkyl groups, mention may be made of, but not limited to bicyclo[3.2.1]octan-3-yl and bicyclo[2.2.1]heptan-2-yl. a zwitterion means: a globally neutral molecule with a positive and a negative electrical charge and having an acidic group and a basic group.

[0016] In another embodiment, in the compounds of formula (I) as defined above, Z represents a group:

[0017] According to this embodiment, the compounds of formula (I) as defined above are of formula (I'):

[0018] In another embodiment, in the compounds of formula (I) or (I') as defined above, Y represents -CH 2 -, -CH=, -O- or -NH-.

[0019] In another embodiment, in the compounds of formula (I) or (I') as defined above, Y represents -O-.

[0020] In another embodiment, in the compounds of formula (I) or (I') as defined above, Y represents -CH 2 -.

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

[0022] In another embodiment, in the compounds of formula (I) or (I') as defined above, Y represents -NH-.

[0023] In another embodiment, in the compounds of formula (I) or (I') as defined above, represents a single bond.

[0024] In another embodiment, in the compounds of formula (I) or (I') as defined above, represents a double bond.

[0025] In another embodiment, in the compounds of formula (I) or (I') as defined above, p is 1.

[0026] In another embodiment, in the compounds of formula (I) or (I') as defined above, p is 0.

[0027] In another embodiment, in the compounds of formula (I) as defined above, Z represents a group:

[0028] According to this embodiment, the compounds of formula (I) as defined above are of formula (I"):

[0029] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R1 and R2 are a -CH 3 group.

[0030] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R3 is a -COOH group.

[0031] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R3 is a -OH group.

[0032] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R3 is a hydrogen atom.

[0033] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R3' and R3" represent a hydrogen atom.

[0034] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, X represents -CH 2 -.

[0035] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, X represents -O-.

[0036] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, X represents -S-.

[0037] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R4 represents a hydrogen atom.

[0038] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, n is 0.

[0039] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, m is 1.

[0040] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, m is 0.

[0041] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R6 represents: ▪ a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C 1 -C 6 )alkyl group, optionally substituted with a cyano group or a -OH group; a (C 1 -C 6 )fluoroalkyl group; a (C 3 -C 6 )cycloalkyl group; a (C 1 -C 6 )alkoxy group; a (C 1 -C 6 )fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C 1 -C 4 )alkylthio group; a (C 1 -C 4 )fluoroalkylthio group; a (C 1 -C 4 )alkylsulfonyl group and a -OH group; or ▪ a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 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 or a pyrrolyl group, said heteroaryl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )fluoroalkyl group, a (C 1 -C 6 )alkoxy group, a (C 1 -C 6 )fluoroalkoxy group, a cyano group, a carbamoyl group and a -OH group.

[0042] In another embodiment, in the compounds of formula (I) , (I') or (I") as defined above, R6 represents a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C 1 -C 6 )alkyl group, optionally substituted with a cyano group or a -OH group; a (C 1 -C 6 )fluoroalkyl group; a (C 3 -C 6 )cycloalkyl group; a (C 1 -C 6 )alkoxy group; a (C 1 -C 6 )fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C 1 -C 4 )alkylthio group; a (C 1 -C 4 )fluoroalkylthio group; a (C 1 -C 4 )alkylsulfonyl group and a -OH group.

[0043] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R6 represents a phenyl group, said phenyl group being optionally substituted with 1 or 2 substituents independently selected from a chlorine atom, a fluorine atom and a methyl group.

[0044] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R6 represents a phenyl group.

[0045] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R6 represents a phenyl group, said phenyl group being substituted with 1 or 2 substituents independently selected from a chlorine atom, a fluorine atom, and a methyl group.

[0046] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R6 represents heteroaryl group comprising 2 to 9 carbon atoms and comprising from 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 or a pyrrolyl group, said heteroaryl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )fluoroalkyl group, a (C 1 -C 6 )alkoxy group, a (C 1 -C 6 )fluoroalkoxy group, a cyano group, a carbamoyl group and a -OH group.

[0047] In another embodiment, in the compounds of formula (I), (I') or (I") as defined above, R6 represents a pyridyl group, said pyridyl group being substituted by two substituents independently selected from a halogen atom and a (C 1 -C 6 )alkoxy group, and more particularly selected from a fluorine atom and a methoxy group.

[0048] In another embodiment, in the compounds of formula (I) or (I'), R3 is a -COOH group and R6 is a phenyl group substituted with 1 or 2 substituents independently selected from a chlorine atom, a fluorine atom, and a methyl group. In such embodiment, R3' and R3" are in particular hydrogen atoms. Still in such embodiment, R4 is a hydrogen atom, X is a -CH 2 - group, m is equal to 1 and n is equal to 0. In such embodiment, R1 and R2 are a -CH 3 group, Y is -O-, represents a single bond, and p is equal to 1.

[0049] In another embodiment, in the compounds of formula (I) or (I"), R3 is a -COOH group, R6 is a phenyl group substituted with 1 or 2 substituents independently selected from a chlorine atom, a fluorine atom and a methyl group. In such embodiment, R3' and R3" are in particular hydrogen atoms. Still in such embodiment, R4 is a hydrogen atom, X is a -CH 2 -group, m is equal to 1 and n is equal to 0. In such an embodiment, R1 and R2 are a -CH 3 group.

[0050] Among the compounds of formula (I), (I') or (I") described herein, mention may be made in particular of the following compounds or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof: (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7] annulene-3-carboxylic acid, (1) (S,E)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) (S,E)-8-(4-chloro-2-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) (S,E)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) (S,E)-8-(3-chloro-4-methylphenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2,4-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) (S,E)-8-(2-chlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2-fluoro-6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) (S,E)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid, (13) (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1, (18) (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2, (19) 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) (E)-8-(2,4-dichlorophenyl)-9-(4-(2-((4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide, (23) (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid, (24) (S,E)-6-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid, (25) (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide, (26) (S,E)-4-(3-(4-(4-(2,4-dichlorophenyl)-8-hydroxy-2,3-dihydrobenzo[b]thiepin-5-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide, (27).

[0051] 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.

[0052] 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.

[0053] Another embodiment is a pharmaceutical composition comprising as active principle 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.

[0054] The compounds of the formula (I), (I') or (I") can be prepared by the following processes.

[0055] The compounds of the formula (I), (I') or (I") and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known by the skilled person in the art. In addition, solvents, temperatures and other reaction conditions presented below may vary as deemed appropriate to the skilled person in the art.

[0056] General below methods for the preparation of compounds of formula (I), (I') or (I") optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formula (I), (I') or (I") as described below.

[0057] The following abbreviations and empirical formulae are used: BASTDeoxo-Fluor BOC 2 Odi-ter-butyldicarbonate Cs 2 CO 3 Cesium carbonate COCarbon monoxide DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCMDichloromethane DIEADiisopropylethylamine DMFN,N-dimethylformamide DMAPDimethylaminopyridine DMSODimethyl sulfoxide Et 2 ODiethyl ether EtOAcEthyl acetate EtOHEthanol H 2 Hydrogen HATU2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) HBTU(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HClHydrochloric acid HPLCHigh performance liquid chromatography K 2 CO 3 Potassium carbonate KHMDSPotassium bis(trimethylsilyl)amide KOAcPotassium acetate KOHPotassium hydroxide KOPhPotassium phenolate LiHMDSLithium bis(trimethylsilyl)amide LiOHLithium hydroxide MeCNAcetonitrile MeOHMethanol MeTHF2-Methyltetrahydrofuran MgSO 4 MgSO 4 MTBEMethyl tert-butyl ether n-BuLin-Butyllithium Na 2 SO 4 Sodium sulfate NaBH 4 Sodium borohydride NaClSodium chloride NaHSodium hydride NaHCO 3 Sodium bicarbonate NaHSO 3 Sodium bisulfate NaOHSodium hydroxide NH 4 ClAmmonium chloride NH 4 OHAmmonium hydroxide Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(0) Pd / CPalladium on carbon Pd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc) 2 Palladium acetate Pd(PPh 3 ) 2 Cl 2 bis (triphenylphosphine) palladium(II) dichloride PhOKPotassium phenolate PPh 3 Triphenylphosphine RTRoom temperature SCXStrong cation exchange SFCSupercritical Fluid Chromatography TEATriethylamine TFATrifluoroacetic acid THFTetrahydrofuran XANTPHOS(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0058] According to SCHEME 1a, in which R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, R1, R2, R3, R3', R3", R4, R5, X, Y, m, n, p and are defined as described above, and R6 is a phenyl or heteroaryl group, compound 1A can be converted in STEP 1 to compound 1B by treatment with aryl or heteroaryl bromide or iodide in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) Pd 2 (dba) 3 , and a phosphine such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (XANTPHOS) in solution in toluene by heating up to reflux of solvent, in presence of a base such as K 2 CO 3 or Cs 2 CO 3 . Alternative way to prepare compound 1B, wherein R6 can be any of the groups defined above for R6 in formula (I) or (I'), is described in SCHEME 1f below.

[0059] Compound 1B can be converted in STEP 2 to compound 1C by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or NaH, or KHMDS at -50°C, in a solvent such as MeTHF.

[0060] Compound 1C can be converted in STEP 3 to compound 1D by treatment for example with bis(pinacolato)diboron, and with a palladium catalyst, for example bis (triphenylphosphine)palladium(II) dichloride Pd(PPh 3 ) 2 Cl 2 , and a phosphine, such as triphenylphosphine, in solution in toluene by heating up to reflux of solvent, in presence of a base such as KOPh.

[0061] Compound 1F can be prepared in a Suzuki coupling reaction either between compound 1D and compound 1E in STEP 4 or between compounds 1C and compound 1E' in STEP 5 using for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0062] When R3a is -COOMe, -COOEt, or a protected -OH such as O-pivaloyl, deprotection can be performed in STEP 6 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in THF or dioxane. When R3 is -COOH, extraction of the product could give the sodium or lithium salt of compound of formula (I) or (I'). The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound of formula (I) or (I'). The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound (I) or (I'). The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound (I) or (I').

[0063] According to SCHEME 1b in which R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, and R1, R2, R3, R3', R3", R4, R5, R6, X, Y, m, n, and p are defined as described above, compound 1C can be converted in STEP 1 to compound 1H by treatment with compound 1G using for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0064] Compound 1H can be converted in STEP 2 to compound 1I by treatment with trifluoromethanesulfonic anhydride in the presence of pyridine in DCM.

[0065] Compound 1I can be converted in STEP 3 to compound 1L (Y = -NH-) in a Buchwald coupling reaction with compound 1J in dioxane at 130°C using for example xantphos / palladium acetate (Pd(OAc) 2 ) as catalytic system.

[0066] Compound 1H can be converted in STEP 4 to compound 1L (Y = -O-) by reaction with compound 1K (A = Br or I) in presence of a base such as Cs 2 CO 3 in DMF or MeCN, or under Mitsunobu conditions, when (A = -OH), using for example N,N,N',N'-tetramethylazodicarboxamide and triphenylphosphine as coupling agents in THF as a solvent.

[0067] Compound 1L can be converted in STEP 5 to compound 1M by treatment with TFA in DCM or HCl in dioxane.

[0068] Compound 1M can be converted in STEP 6 to compound 1F' by treatment with compound 1N, in presence of a base such as DIEA in DMF or MeCN.

[0069] When R3a is -COOMe, -COOEt, or a protected -OH such as O-pivaloyl, deprotection can be performed in STEP 7 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in THF or dioxane. When R3 is -COOH, extraction of the product can give the sodium or lithium salt of compound of formula (I) or (I'). The acidification with an aqueous solution of HCl 2N to pH 6-7 can give the neutral form of compound of formula (I) or (I'). The acidification with an aqueous solution of HCl 2N to pH 1-2 can give the hydrochloride salt of compound of formula (I) or (I'). The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound of formula (I) or (I').

[0070] According to SCHEME 1c Part-1 and Part-2 in which R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, and R1, R2, R3, R3', R3", R4, R5, R6, X, Y, m, n and p are defined as described above, compound 1O can be converted in STEP 1 to compound 1P by treatment with compound 1G using for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0071] Compound 1P can be converted in STEP 2 to compound 1Q by treatment with trifluoromethanesulfonic anhydride in the presence of pyridine in DCM.

[0072] Compound 1Q can be converted in STEP 3 to compound 1R (Y = -NH-) in a Buchwald coupling reaction with compound 1J in dioxane at 130°C using for example xantphos / palladium acetate (Pd(OAc) 2 as catalytic system.

[0073] Compound 1P can be converted in STEP 4 to compound 1R (Y = -O-) by reaction with compound 1K (A = -Br or -I) in presence of a base such as cesium carbonate (Cs 2 CO 3 ) in DMF or MeCN, or under Mitsunobu conditions, when (A = -OH), using for example N,N,N',N'-tetramethylazodicarboxamide and triphenylphosphine as coupling agents in THF as a solvent.

[0074] Compound 1R can be converted in STEP 5 to compound 1S by treatment with for example pyridinium tribromide in DCM or THF at room temperature followed by treatment of the obtained residue with TFA in DCM or HCl in dioxane.

[0075] Compound 1S can be converted in STEP 6 to compound 1T by treatment with compound 1N, in the presence of a base such as DIEA in DMF or MeCN.

[0076] Compound 1T can be converted in STEP 7 to compound 1U by treatment for example with bis(pinacolato)diboron, and with a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride Pd(PPh 3 ) 2 Cl 2 , and a phosphine such as triphenylphosphine in solution in toluene by heating up to reflux of solvent in presence of a base such as KOPh or AcOK.

[0077] Compound 1F' can be prepared in a Suzuki coupling reaction either between 1U and R6Br or R6I or R6OTf in STEP 8 or between compounds 1T and R6B(OR') 2 or R6BF 3 K, wherein -B(OR') 2 is a boronic acid or a pinacolate ester and R6 is as above defined, in STEP 9 using for example [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0078] When R3a is -COOMe, -COOEt, or a protected -OH such as O-pivaloyl, deprotection can be performed in STEP 10 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in THF or dioxane. When R3 is -COOH, extraction of the product could give the sodium or lithium salt of compound of formula (I) or (I'). The acidification with an aqueous solution of HCl 2N to pH 6-7 can give the neutral form of compound of formula (I) or (I'). The acidification with an aqueous solution of HCl 2N to pH 1-2 can give the hydrochloride salt of compound of formula (I) or (I'). The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound of formula (I) or (I').

[0079] According to SCHEME 1d, in which R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, and R3, R3', R3", R4, R5, X, m, n and p are defined as described above, compound 1O can be converted in STEP 1 to compound 1O' by treatment for example with bis(pinacolato)diboron, and with a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride Pd(PPh 3 ) 2 Cl 2 , and a phosphine such as triphenylphosphine in solution in toluene by heating up to reflux of solvent in presence of a base such as KOPh or AcOK.

[0080] Compound 1W can be prepared in a Suzuki coupling reaction either between compounds 1O and 1V in STEP 2 or between compounds 1O' and 1V' in STEP 2' in the presence of a palladium catalyst, for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0081] Compound 1W can be converted in STEP 3 to compound 1S by treatment with for example pyridinium tribromide in DCM or THF at room temperature.

[0082] According to SCHEME 1e, in which X, m, R3', R3", R3a = CO 2 Me and R4 are defined as described above, compound 1O could be prepared as follows: compound 1X (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted in STEP 1 to compound 1Y by treatment with trifluoromethanesulfonic anhydride, in solution in DCM, in the presence of pyridine as a base.

[0083] Compound 1Y can be converted in STEP 2 to compound 1Z by carbonylation with carbon monoxide, in solution in DMF and MeOH, in the presence of a palladium catalyst, for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM.

[0084] Compound 1Z can be converted in STEP 3 to compound 1O wherein R3a = CO 2 Me by treatment with trifluoromethanesulfonic anhydride, in solution in DCM, in the presence of pyridine as a base.

[0085] According to SCHEME 1f, in which R3a is a hydrogen atom or a carboxylic ester such as COOMe, COOEt, or protected OH such as O-pivaloyl for example, R3', R3", R, X and m are defined as described above, compound 1B can alternatively be prepared as follows: compound 1A can be converted in STEP 1 to compound 1Aa by treatment with pyridinium tribromide in DCM or THF at room temperature for example.

[0086] Compound 1Aa can be converted in STEP 2 to compound 1Ab by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0087] Compound 1Ac can be prepared in STEP 3 in a Suzuki coupling reaction between compounds 1Ab and R 6 B(OR') 2 or R 6 BF 3 K using for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, as catalyst, in a mixture of toluene and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0088] Compound 1Ac can be converted in STEP 4 to compound 1B by hydrolysis with aqueous HCl solution by heating in methanol and DCM for example.

[0089] According to SCHEME 1g, in which R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, and R1, R2, R3, R3', R3", R4, R5, R6, X, m and n are defined as described above, compound 1D can be converted in STEP 1 to compound 2A by treatment with compound 1Z using for example [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (Cs 2 CO 3 ), by heating up to reflux of solvent.

[0090] Compound 2A can be converted to compound 2B in STEP 2 by treatment with TFA in DCM.

[0091] When R3a is -COOMe, -COOEt, or a protected -OH such as O-pivaloyl, deprotection can be performed in STEP 3 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in THF or dioxane. When R3 is -COOH, extraction of the product could give the sodium or lithium salt of compound of formula (I) or (I"). The acidification with an aqueous solution of HCl 2N to pH 6-7 could give the neutral form of compound of formula (I) or (I"). The acidification with an aqueous solution of HCl 2N to pH 1-2 could give the hydrochloride salt of compound of formula (I) or (I"). The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound of formula (I) or (I").

[0092] Herein is also provided a process for preparing a compound of formula (I) or (I') as defined above, wherein a compound of formula 1F: wherein R1, R2, R3', R3", R4, R5, R6, m, n, p, X, Y and are as defined above and R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, is converted to compound of formula (I) or (I'), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in THF or dioxane.

[0093] Herein is also provided a process for preparing a compound of formula (I) or (I') as described above, wherein a compound of formula 1F': wherein R1, R2, R3, R3', R3", R4, R5, R6, m, n, p, X and Y are as described above, and R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, is converted to compound of formula (I) or (I'), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in THF or dioxane , said step being optionally preceded by a step for obtaining compound 1F', wherein a compound of formula 1T: wherein R1, R2, R3', R3", R4, R5, m, n, p, X and Y are as described above, is submitted to a Suzuki coupling with a boronic reagent R6B(OR') 2 , wherein -B(OR') 2 is a boronic acid or a pinacolate ester and R6 is defined above.

[0094] Herein are also provided the intermediates compounds selected from compounds of formula 1T, 1F, 1F' and 2B, or any of its pharmaceutically acceptable salt, and wherein R1, R2, R3', R3", R4, R5, R6, m, n, p, X, Y and are as defined above and R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl.

[0095] Herein is further provided the intermediate compound of formula 1E, or any of its pharmaceutically acceptable salt: wherein R1, R2, R5, Y, n, p and are as described above.

[0096] The present application also describes the intermediate compound of formula 1D, or any of its pharmaceutically acceptable salt: wherein R3a, R3', R3", X, m, R4 and R6 are as described above.

[0097] In another aspect, herein is also provided a process for the preparation of a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula IF as defined above, optionally followed by a purification step.

[0098] Said purification step may for example consist, as illustrated in step 2 of example 1 herein after, in an acidification step, for example with an aqueous solution of hydrochloric acid.

[0099] The 1< H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0100] The liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210-400 nm and flash Acquity UPLC CSH C18 1.7 µm, dimension 2.1x30 mm, mobile phase H 2 O + 0.1% HCO 2 H / CH 3 CN + 0.1% HCO 2 H. Table 1a: (the first column Ex corresponds to the compound and example number) Ex Structure Name 1 (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid2 (S,E)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid3 (S,E)-8-(4-chloro-2-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid4 (S,E)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid5 (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid6 (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid7 (S,E)-8-(3-chloro-4-methylphenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid8 (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2,4-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid9 (S,E)-8-(2-chlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid10 (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2-fluoro-6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid11 (S,E)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid12 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid13 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1)14 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid15 (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid16 (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid17 (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid18 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 119 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 220 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid21 (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid22 (E)-8-(2,4-dichlorophenyl)-9-(4-(2-((4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid23 (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide24 (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid25 (S,E)-6-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid26 (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide27 (S,E)-4-(3-(4-(4-(2,4-dichlorophenyl)-8-hydroxy-2,3-dihydrobenzo[b]thiepin-5-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide Table 1b: Ex Preparation Method NMR MASS: LC / MS (m / z, MH+):1A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.03 (m, 1 H), 2.14 - 2.37 (m, 5 H), 2.80 - 2.97 (m, 4 H), 3.00 (s, 3 H), 3.05 (s, 3 H), 3.09 - 3.21 (m, 2 H), 3.41 - 3.49 (m, 2 H), 4.78 (br t, J=6 Hz, 1 H), 6.49 - 6.58 (m, 3 H), 6.74 (d, J=8 Hz, 2 H), 6.84 - 7.08 (m, 4 H), 7.34 (d, J=2 Hz, 1 H), 7.84 (dd, J=8, 2 Hz, 1 H), 7.98 (d, J=2 Hz, 1 H)6052A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.02 (m, 1 H), 2.13 - 2.38 (m, 5 H), 2.75 - 2.96 (m, 4 H), 3.00 (s, 3 H), 3.05 (s, 3 H), 3.11 (m, 2 H), 3.34 - 3.52 (m, 2 H), 4.78 (m, 1 H), 6.45 - 6.59 (m, 3 H), 6.68 - 6.92 (m, 4 H), 6.96 (br d, J=8 Hz, 1 H), 6.99 - 7.14 (m, 2 H), 7.84 (br d, J=8 Hz, 1 H), 7.98 (s, 1 H)5893A1H NMR (400 MHz, CDCl 3 ) δ ppm 1.87 - 2.54 (m, 6 H), 2.69 - 3.16 (m, 12 H), 3.32 - 3.54 (m, 2 H), 4.79 (m, 1 H), 6.48 - 6.59 (m, 3 H), 6.75 (d, J=9 Hz, 2 H), 6.84 - 7.05 (m, 5 H), 7.83 (dd, J=8, 2 Hz, 1 H), 7.97 (d, J=1 Hz, 1 H)5894A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.00 (m, 1 H), 2.12 - 2.36 (m, 5 H), 2.74 - 3.17 (m, 12 H), 3.34 - 3.51 (m, 2 H), 4.76 (br s, 1 H), 6.46 - 6.56 (m, 3 H), 6.75 (d, J=8 Hz, 2 H), 6.84 - 7.07 (m, 5 H), 7.85 (d, J=8 Hz, 1 H), 7.99 (s, 1 H)5895A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.02 (m, 1 H), 2.11 - 2.31 (m, 8 H), 2.75 - 3.18 (m, 12 H), 3.34 - 3.52 (m, 2 H), 4.78 (br t, J=6 Hz, 1 H), 6.44 - 6.60 (m, 3 H), 6.71 - 6.82 (m, 4 H), 6.87 (dt, J=15, 6 Hz, 1 H), 6.92 - 7.07 (m, 2 H), 7.83 (d, J=8 Hz, 1 H), 7.97 (d, J=1 Hz, 1 H)5696A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.01 (m, 1 H), 2.12 - 2.44 (m, 5 H), 2.64 - 3.23 (m, 12 H), 3.33 - 3.51 (m, 2 H), 4.78 (m, 1 H), 6.43 - 6.61 (m, 3 H), 6.69 - 6.80 (m, 2 H), 6.88 (dt, J=15, 6 Hz, 1 H), 6.95 (d, J=8 Hz, 1 H), 7.08 - 7.23 (m, 5 H), 7.82 (s, 1 H), 7.97 (d, J=1 Hz, 1 H)5377A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.03 (m, 1 H), 2.13 - 2.36 (m, 8 H), 2.79 - 2.98 (m, 5 H), 3.00 (s, 3 H), 3.06 (s, 3 H), 3.11 (m, 1 H), 3.31 - 3.56 (m, 2 H), 4.80 (m, 1 H), 6.48 - 6.61 (m, 3 H), 6.76 (d, J=8 Hz, 2 H), 6.85 - 7.01 (m, 4 H), 7.15 (d, J=2 Hz, 1 H), 7.83 (dd, J=8, 2 Hz, 1 H), 7.96 (d, J=2 Hz, 1 H)5858A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.01 (m, 1 H), 2.09 - 2.15 (m, 3 H), 2.16 - 2.29 (m, 8 H), 2.70 - 2.95 (m, 5 H), 3.00 (s, 3 H), 3.03 - 3.15 (m, 4 H), 3.32 - 3.48 (m, 2 H), 4.75 (m, 1 H), 6.43 - 6.58 (m, 3 H), 6.69 (d, J=9 Hz, 2 H), 6.79 - 7.05 (m, 5 H), 7.83 (dd, J=8, 2 Hz, 1 H), 7.97 (d, J=2 Hz, 1 H)5659A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.01 (m, 1 H), 2.15 - 2.37 (m, 5 H), 2.75 - 2.96 (m, 5 H), 3.00 (s, 3 H), 3.05 (s, 3 H), 3.11(m, 1 H), 3.31 - 3.51 (m, 2 H), 4.76 (m, 1 H), 6.48 - 6.56 (m, 3 H), 6.76 (d, J=8 Hz, 2 H), 6.87 (dt, J=15, 6 Hz, 1 H), 6.98 (d, J=8 Hz, 1 H), 7.04 - 7.13 (m, 3 H), 7.32 (d, J=9 Hz, 1 H), 7.84 (dd, J=8, 2 Hz, 1 H), 7.98 (d, J=2 Hz, 1 H)57110A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.02 (m, 1 H), 2.13 - 2.33 (m, 5 H), 2.78 - 2.96 (m, 5 H), 3.00 (s, 3 H), 3.05 (s, 3 H), 3.10 (br dd, J=11, 6 Hz, 1 H), 3.35 - 3.51 (m, 2 H), 3.88 (s, 3 H), 4.79 (m, 1 H), 6.45 (dd, J=8, 1 Hz, 1 H), 6.51 (d, J=15 Hz, 1 H), 6.55 - 6.62 (m, 2 H), 6.75 - 6.82 (m, 2 H), 6.88 (dt, J=16, 6 Hz, 1 H), 6.95 (d, J=8 Hz, 1 H), 7.35 (m, 1 H), 7.83 (dd, J=8, 2 Hz, 1 H), 7.97 (d, J=2 Hz, 1 H)58611A1H NMR (400 MHz, CDCl 3 ) δ ppm 2.01 (m, 1 H), 2.28 (s, 8 H), 2.80 - 3.18 (m, 12 H), 3.32 - 3.53 (m, 2 H), 4.77 (m, 1 H), 6.46 - 6.56 (m, 3 H), 6.77 (d, J=9 Hz, 2 H), 6.83 - 6.92 (m, 2 H), 6.92 - 7.00 (m, 2 H), 7.14 (s, 1 H), 7.83 (dd, J=8, 2 Hz, 1 H), 7.97 (d, J=2 Hz, 1 H)58512B1H NMR (500 MHz, DMSO-d6) δ ppm 2.07 - 2.22 (m, 4 H), 2.85 (s, 3 H), 2.89 (br d, J=4 Hz, 2 H), 2.92 - 2.98 (m, 2 H), 3.02 (s, 3 H), 3.21 (d, J=2 Hz, 2 H), 3.68 - 3.76 (m, 2 H), 4.71 (quin, J=6 Hz, 1 H), 6.48 (s, 2 H), 6.61 (d, J=9 Hz, 2 H), 6.75 (d, J=9 Hz, 2 H), 6.78 (br d, J=8 Hz, 1 H), 7.19 (d, J=8 Hz, 1 H), 7.27 (dd, J=8, 2 Hz, 1 H), 7.59 (d, J=2 Hz, 1 H), 7.74 (br d, J=7 Hz, 1 H), 7.89 (s, 1 H)59113B1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 - 2.26 (m, 4 H), 2.76 - 2.86 (m, 2 H), 2.88 (s, 3 H), 2.92 - 3.01 (m, 3 H), 3.04 (s, 3 H), 3.73 - 3.85 (m, 2 H), 3.91 (br s, 2 H), 4.12 (br s, 2 H), 6.43 (m, 1 H), 6.73 - 6.86 (m, 4 H), 6.98 (d, J=8 Hz, 2 H), 7.18 - 7.28 (m, 2 H), 7.59 (d, J=2 Hz, 1 H), 7.75 (dd, J=8, 2 Hz, 1 H), 7.93 (d, J=2 Hz, 1 H), 10.01 (br s, 1 H), 12.89 (br s, 1 H)58914B1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 - 2.29 (m, 4 H), 2.86 (s, 3 H), 2.89 - 2.98 (m, 2 H), 3.03 (s, 3 H), 3.19 - 3.25 (m, 2 H), 3.94 (br s, 2 H), 4.09 (br s, 2 H), 6.09 (t, J=2 Hz, 1 H), 6.47 - 6.57 (m, 2 H), 6.78 - 6.92 (m, 5 H), 7.19 - 7.29 (m, 2 H), 7.58 (d, J=2 Hz, 1 H), 7.74 (dd, J=8, 2 Hz, 1 H), 7.91 (d, J=2 Hz, 1 H)58715B1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1 H), 2.00 - 2.28 (m, 5 H), 2.39 - 3.25 (m, 12 H), 3.36(m hidden, 2 H), 4.77 (br t, J=6 Hz, 1 H), 6.51 - 6.60 (m, 2 H), 6.63 - 6.69 (m, 2 H), 6.71 - 6.77 (m, 2 H), 6.88 (d, J=8 Hz, 1 H), 7.20 (d, J=9 Hz, 1 H), 7.28 (d, J=8 Hz, 1 H), 7.59 (d, J=2 Hz, 1 H), 7.76 (dd, J=8, 2 Hz, 1 H), 7.91 (d, J=2 Hz, 1 H), 12.20 (br s, 1 H)60516B1H NMR (400 MHz, DMSO-d6) δ ppm 0.84 (m, 1 H), 1.28 (m, 1 H), 2.00 - 2.27 (m, 4 H), 2.51 - 3.35 (m partially hidden, 14 H), 4.13 (m hidden , 1 H), 5.75 - 6.13 (m, 1 H), 6.36 (d, J=9 Hz, 2 H), 6.54 - 6.66 (m, 4 H), 6.90 (d, J=8 Hz, 1 H), 7.20 (d, J=8 Hz, 1 H), 7.29 (dd, J=8, 2 Hz, 1 H), 7.59 (d, J=2 Hz, 1 H), 7.75 (dd, J=8, 2 Hz, 1 H), 7.90 (d, J=2 Hz, 1 H), 12.85 (br s, 1 H)60417B1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (m, 1 H), 2.05 - 2.20 (m, 5 H), 2.34 (m, 1 H), 2.43 (m, 1 H), 2.60 (m, 1 H), 2.72 (m, 1 H), 2.80 - 2.91 (m, 5 H), 3.00 (s, 3 H), 3.13 - 3.23 (m, 2 H), 3.76 (m, 1 H), 5.74 (br d, J=7 Hz, 1 H), 6.29 (d, J=9 Hz, 2 H), 6.50 - 6.63 (m, 4 H), 6.91 (d, J=8 Hz, 1 H), 7.19 (d, J=8 Hz, 1 H), 7.27 (dd, J=8, 2 Hz, 1 H), 7.57 (d, J=2 Hz, 1 H), 7.74 (dd, J=8, 2 Hz, 1 H), 7.87 (d, J=2 Hz, 1 H), 11.29 - 13.81 (m, 1 H)60418B1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (m, 1 H), 1.86 (m, 1 H), 2.11 - 2.23 (m, 4 H), 2.42 - 3.91 (m, 9 H), 2.86 (s, 3 H), 2.90 - 2.96 (m, 2 H), 3.02 (s, 3 H), 6.57 (td, J=15, 6 Hz, 1 H), 6.66 - 6.78 (m, 1 H), 6.78 (d, J=8 Hz, 2 H), 6.86 (d, J=8 Hz, 1 H), 6.99 (d, J=8 Hz, 2 H), 7.18 (d, J=8 Hz, 1 H), 7.25 (dd, J=8, 2 Hz, 1 H), 7.57 (d, J=2 Hz, 1 H), 7.75 (dd, J=8, 2 Hz, 1 H), 7.91 (d, J=2 Hz, 1 H), 10.58 - 13.98 (m, 1 H)60319B1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (m, 1 H), 1.77 (m, 1 H), 2.01 - 2.22 (m, 5 H), 2.25 - 2.55 (m, 6 H), 2.85 (s, 3 H), 2.86 - 2.95 (m, 2 H), 3.00 (s, 3 H), 3.07 - 3.21 (m, 2 H), 6.51 (d, J=15 Hz, 1 H), 6.56 (td, J=15, 6 Hz, 1 H), 6.75 (d, J=8 Hz, 2 H), 6.80 (br d, J=8 Hz, 1 H), 6.96 (d, J=8 Hz, 2 H), 7.17 (d, J=8 Hz, 1 H), 7.24 (dd, J=8, 2 Hz, 1 H), 7.58 (s, 1 H), 7.72 (br d, J=7 Hz, 1 H), 7.89 (br s, 1 H)60320B1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 - 2.26 (m, 4 H), 2.55 - 2.61 (m, 4 H), 2.86 (s, 3 H), 2.90 - 2.97 (m, 2 H), 3.01 (s, 3 H), 3.27 (m partially hidden, 2 H), 3.35 (m partially hidden, 2 H), 6.22 (br s, 1 H), 6.53 - 6.65 (m, 2 H), 6.81 (d, J=8 Hz, 2 H), 6.87 (d, J=8 Hz, 1 H), 6.98 (d, J=9 Hz, 2 H), 7.20 (m, 1 H), 7.29 (m, 1 H), 7.58 (d, J=2 Hz, 1 H), 7.75 (dd, J=8, 2 Hz, 1 H), 7.92 (d, J=2 Hz, 1 H), 12.20 - 13.74 (m, 1 H)60121B1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 - 2.21 (m, 4 H), 2.72 - 2.81 (m, 2 H), 2.83 - 2.92 (m, 5 H), 3.02 (s, 3 H), 3.12 - 3.21 (m, 2 H), 3.63 (br t, J=7 Hz, 2 H), 3.88 (m, 1 H), 6.04 (d, J=7 Hz, 1 H), 6.25 (d, J=9 Hz, 2 H), 6.43 - 6.50 (m, 2 H), 6.50 - 6.56 (m, 2 H), 6.88 (d, J=8 Hz, 1 H), 7.18 (d, J=8 Hz, 1 H), 7.27 (dd, J=8, 2 Hz, 1 H), 7.57 (d, J=2 Hz, 1 H), 7.72 (dd, J=8, 2 Hz, 1 H), 7.87 (d, J=2 Hz, 1 H), 11.52 - 13.92 (m, 1 H)59022B1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 - 2.24 (m, 4 H), 2.88 (s, 3 H), 2.95 (t, J=8 Hz, 2 H), 3.05 (s, 3 H), 3.15 - 3.21 (m, 2 H), 3.69 (m, 2 H), 4.08 - 4.21 (m, 2 H), 6.60 (m, 1 H), 6.73 - 6.84 (m, 5 H), 6.87 (d, J=8 Hz, 1 H), 7.22 - 7.32 (m, 2 H), 7.60 (d, J=2 Hz, 1 H), 7.76 (dd, J=8, 2 Hz, 1 H), 7.92 (s, 1 H), 8.30 - 9.69 (m, 1 H)59723C1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (m, 1 H), 2.02 - 2.11 (m, 2 H), 2.13 - 2.28 (m, 3 H), 2.37 - 2.44 (m, 1 H), 2.57 (br d, J=2 Hz, 1 H), 2.64 - 2.82 (m, 4 H), 2.86 (s, 3 H), 3.00 (s, 3 H), 3.19 (d, J=5 Hz, 2 H), 4.76 (m, 1 H), 6.49 - 6.77 (m, 9 H), 7.14 (d, J=9 Hz, 1 H), 7.23 (br d, J=8 Hz, 1 H), 7.54 (d, J=2 Hz, 1 H), 9.42 (s, 1 H)57724A1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (m, 1 H), 2.22 (m, 1 H), 2.37 - 2.43 (m, 2 H), 2.60 (m, 1 H), 2.61 - 2.73 (m, 2 H), 2.79 (m, 1 H), 2.85 (s, 3 H), 3.00 (s, 3 H), 3.20 (d, J=6 Hz, 2 H), 4.49 - 4.63 (m, 2 H), 4.77 (br s, 1 H), 6.52 - 6.65 (m, 2 H), 6.69 (d, J=9 Hz, 2 H), 6.77 (d, J=9 Hz, 2 H), 6.87 (d, J=9 Hz, 1 H), 7.09 (d, J=8 Hz, 1 H), 7.27 (br d, J=8 Hz, 1 H), 7.59 - 7.66 (m, 3 H), 12.29 - 14.22 (m, 1 H)25A1H NMR (400 MHz, DMSO-d6) δ ppm 1.74 (m, 1 H), 2.24 (m, 1 H), 2.36 - 2.74 (m partially hidden, 5 H), 2.82 (m, 1 H), 2.86 (s, 3 H), 2.99 - 3.07 (m, 5 H), 3.21 (d, J=5 Hz, 2 H), 4.80 (br s, 1 H), 6.53 - 6.62 (m, 2 H), 6.76 (m, 3 H), 6.94 (br d, J=8 Hz, 2 H), 7.12 (d, J=8 Hz, 1 H), 7.23 (m, 1 H), 7.55 (d, J=1 Hz, 1 H), 7.68 (br d, J=8 Hz, 1 H), 7.82 (s, 1 H), 11.58 - 13.62 (m, 1 H)26C1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (m, 1 H), 2.04 - 2.28 (m, 5 H), 2.42 (m, 1 H), 2.56 (m, 1 H), 2.63 - 2.72 (m, 2 H), 2.74 - 2.91 (m, 5 H), 3.00 (s, 3 H), 3.19 (d, J=5 Hz, 2 H), 4.75 (m, 1 H), 6.49 - 6.61 (m, 2 H), 6.64 (d, J=10 Hz, 2 H), 6.73 (d, J=8 Hz, 2 H), 6.77 (dd, J=8, 1 Hz, 1 H), 7.13 - 7.29 (m, 4 H), 7.32 (dd, J=7, 1 Hz, 1 H), 7.57 (d, J=2 Hz, 1 H)45027C1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (m, 1 H), 2.19 (m, 1 H), 2.35 - 2.44 (m, 2 H), 2.56 (m, 1 H), 2.62 - 2.73 (m, 2 H), 2.78 (m, 1 H), 2.85 (s, 3 H), 3.00 (s, 3 H), 3.08 (m, 1 H), 3.19 (d, J=5 Hz, 2 H), 3.44 (m, 1 H), 4.74 (m, 1 H), 6.34 (d, J=3 Hz, 1 H), 6.52 - 6.63 (m, 2 H), 6.64 - 6.76 (m, 5 H), 7.09 (d, J=8 Hz, 1 H), 7.25 (dt, J=8, 2 Hz, 1 H), 7.43 (d, J=8 Hz, 1 H), 7.64 (d, J=2 Hz, 1 H), 9.55 (s, 1 H)595

[0101] The examples which follow describe the preparation of some compounds of formula (I) described herein. The numbers of the compounds exemplified below match those given in the Tables 1a and 1b above. All reactions are performed under inert atmosphere, unless otherwise stated.

[0102] In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds.Intermediates: Intermediate 1: Methyl (S,E)-8-bromo-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0103] Step 1: Methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0104]

[0105] To a mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (23.8 g, 67.94 mmol) (prepared according to WO2017140669), (4-hydroxyphenyl)boronic acid (10.85 g, 74.73 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (4.48 g, 6.11 mmol) in dioxane (200 ml) and water (70 ml) was added Cs 2 CO 3 (44.32 g, 135.88 mmol). The reaction mixture was stirred for 30 minutes at RT. Water (500 ml) and EtOAc (500 ml) were added. The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of EtOAc and n-heptane (20 / 80; v / v) to give 17.36 g (87%) of methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH+): 295Step 2: Tert-butyl (S)-3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate

[0106]

[0107] To a mixture of methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (5 g, 17 mmol), tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (3.82 g, 20.38 mmol) and N,N,N',N'-tetramethylazodicarboxamide (5.97 g, 33.97 mmol) in THF (100 ml) was added PPh 3 (8.91 g, 33.97 mmol). The reaction mixture was stirred at RT for 18 hours. EtOAc (500 ml) and water (250 ml) were added. The organic phase was separated, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH (100 / 00 to 98 / 02), to give 5.9 g (75%) of tert-butyl (S)-3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate.

[0108] LC / MS (m / z, MH+): 464Step 3: Methyl (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0109]

[0110] To a solution of tert-butyl (S)-3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate (5.9 g, 12.73 mmol) in DCM (340 ml) was added pyridinium tribromide (4.48 g, 14 mmol). The reaction mixture was stirred at RT for 18 hours. A concentrated aqueous solution of NaHCO 3 was added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure. To the residue obtained was added dioxane (100 ml) and HCl in dioxane 4 N (30.42 ml, 121.67 mmol). After 30 minutes of stirring at RT, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified on strong cation exchange (SCX) column to give 4.95 g (92%) of methyl (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0111] LC / MS (m / z, MH+): 442Step 4: Methyl (S,E)-8-bromo-9-(4-((1-(4-(tert-butoxy)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0112]

[0113] A mixture of methyl (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (2.34 g, 5.29 mmol), DIEA (1.37 g, 10.58 mmol) and tert-butyl (E)-4-bromobut-2-enoate (1.29 g, 5.29 mmol) in THF (40 ml) was stirred at RT for 18 hours. EtOAc (200 ml) and concentrated aqueous solution of NaCl (50 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH (100 / 00 to 98 / 02), to give 1.6 g (52%) of methyl (S,E)-8-bromo-9-(4-((1-(4-(tert-butoxy)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo [7]annulene-3-carboxylate.

[0114] LC / MS (m / z, MH+): 582Step 5: (S,E)-4-(3-(4-(8-Bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)but-2-enoic acid

[0115]

[0116] To a solution of methyl (S,E)-8-bromo-9-(4-((1-(4-(tert-butoxy)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (2.4 g, 4.12 mmol) in DCM (4 ml) was added TFA (3.17 ml, 41.2 mmol). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH (100 / 00 to 90 / 10), to give 1.5 g (69%) of (S,E)-4-(3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)but-2-enoic acid.

[0117] LC / MS (m / z, MH+): 526Step 6: Methyl (S,E)-8-bromo-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0118]

[0119] A mixture of (S,E)-4-(3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)but-2-enoic acid (1.5 g, 2.85 mmol) DMF (10 ml), DIEA (1.1 g, 8.53 mmol) and HATU (1.3 g, 3.42 mmol) was stirred at RT for 10 minutes. Dimethylamine 2M in THF (2.14 ml, 4.27 mmol) was added and the reaction mixture was stirred at RT for 2 hours. EtOAc (50 ml) and water (50 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with DCM / acetone 25 / 75 to give 1.58 g (100%) of methyl (S,E)-8-bromo-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0120] LC / MS (m / z, MH+): 553Intermediate 2: (E)-4-Bromo-N,N-dimethyl-but-2-enamide

[0121]

[0122] To a mixture of (E)-4-bromobut-2-enoic acid (20 g, 121.23 mmol) in DCM (50 ml) cooled at 0°C were added DIEA (17.24 g, 133.35 mmol) and HBTU (46.71 g, 145.47 mmol). The reaction mixture was stirred for 30 minutes at 0°C. The reaction mixture was cooled at - 10°C, then was added dropwise dimethylamine 2M in THF (75.77 ml, 151.53 mmol). The reaction mixture was stirred at 0°C for 2 hours. DCM (150 ml) and water (150 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of heptane / EtOAc from 100 / 00 to 00 / 100 to give 9.33 g (40%) of (E)-4-bromo-N,N-dimethyl-but-2-enamide.

[0123] LC / MS (m / z, MH+): 192Intermediate 3: Methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0124]

[0125] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2020 / 049153) (15 g, 30.29 mmol) in toluene (300 ml), Pd(PPh 3 ) 2 Cl 2 (0.87 g, 1.21 mmol), PPh 3 (0.64 g, 2.42 mmol), bis(pinacolato)diboron (19.23 g, 75.71 mmol) and PhOK (8.43 g, 60.57 mmol) was heated to 75°C for 24 h. After cooling to RT, EtOAc (300 mL) and water (300 mL) were added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of heptane / EtOAc (from 100 / 00 to 90 / 10) to give 11.73 g (82%) of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid.

[0126] LC / MS (m / z, MH+): 473Intermediate 4: (E)-4-[3-(4-Bromophenoxy)azetidin-1-yl]-N,N-dimethyl-but-2-enamide

[0127] Step 1: Tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate

[0128]

[0129] A mixture of 4-bromphenol (5 g, 29 mmol), 1-boc-3-iodoazetidine (12 g, 43 mmol) and Cs 2 CO 3 (19 g, 58 mmol) in DMF (50 ml) was heated at 65°C for 6 hours. After cooling to RT, addition of EtOAc (200 ml) and water (200 ml). After decantation, the organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100 / 00 to 99 / 01 to give 9.33 g (98%) of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate.

[0130] LC / MS (m / z, MH+): 328Step 2: 3-(4-Bromophenoxy)azetidine

[0131]

[0132] To a solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (5.85 g, 17.8 mmol) in DCM (60 ml) was added dropwise TFA (13.2 ml, 178 mmol). The reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH / NH 4 OH from 100 / 00 / 00 to 38 / 17 / 2 to give 3.51 g (83%) of 3-(4-bromophenoxy)azetidine.

[0133] LC / MS (m / z, MH+): 228Step 3: (E)-4-[3-(4-Bromophenoxy)azetidin-1-yl]-N,N-dimethyl-but-2-enamide

[0134]

[0135] A mixture of 3-(4-bromophenoxy)azetidine (151 mg, 0.66 mmol), DIEA (171 mg, 1.32 mmol) and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) (127 mg, 0.66 mmol) in MeCN (4 ml) was stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue obtained, EtOAc (20 ml) and water (5 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH (100 / 00 to 95 / 05), to give 151 mg (68%) of (E)-4-[3-(4-bromophenoxy)azetidin-1-yl]-N,N-dimethyl-but-2-enamide.

[0136] LC / MS (m / z, MH+): 339Intermediate 5: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0137]

[0138] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) (116 mg, 0.24 mmol), (E)-4-[3-(4-bromophenoxy)azetidin-1-yl]-N,N-dimethyl-but-2-enamide (Intermediate 4) (75 mg, 0.22 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (21 mg, 0.029 mmol), Cs 2 CO 3 (185 mg, 0.57 mmol) in dioxane (4 ml) and water (1 ml) was heated to reflux for 4 hours. The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure. After cooling to RT, EtOAc (20 ml) and water (5 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with with a gradient of DCM / MeOH (100 / 00 to 95 / 05) to give 41.6 mg (31%) methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a yellow solid.

[0139] LC / MS (m / z, MH+): 605Intermediate 6: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0140] Step 1: Methyl 9-(4-(azetidin-3-ylmethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0141]

[0142] Step 1 of Intermediate 6 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and 3-[(4-bromophenyl)methyl]azetidine, 4-methylbenzenesulfonic acid to give 350 mg (34%) methyl 9-(4-(azetidin-3-ylmethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0143] LC / MS (m / z, MH+): 492Step 2: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0144]

[0145] A mixture of methyl 9-(4-(azetidin-3-ylmethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (200 mg, 0.41 mmol), DIEA (68 mg, 0.53 mmol) and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) (78 mg, 0.41 mmol) in DMF (4 ml) was stirred at RT for 3 hours. EtOAc (10 ml), diethyl ether (10 ml) and water (20 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (100 / 00 to 00 / 100), then a gradient of EtOAc / MeOH (100 / 00 to 90 / 10) and then DCM / MeOH (90 / 10) to give 110 mg (45%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0146] LC / MS (m / z, MH+): 603Intermediate 7: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0147] Step 1: Tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate

[0148] Method 1:

[0149] To a solution of (4-bromobenzyl)triphenylphosphonium bromide (79.2 g, 155 mmol) in DMF (400 mL) was added NaH (6.18 g, 155 mmol, 60% purity in weight) at 0°C. The mixture was stirred at 0°C for 15 min. To this reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (24.1 g, 141 mmol) in DMF (160 mL). The reaction mixture was stirred at 20°C for 9 hours. The reaction mixture was quenched by addition of saturated aqueous solution of NH 4 Cl (100 mL) at 0°C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 60.0 g (crude) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a yellow solid.

[0150] LC / MS (m / z, MH+): 324Method 2:

[0151] A mixture of tert-butyl 3-methyleneazetidine-1-carboxylate (12.5 g, 73.9 mmol), 1-bromo-4-iodobenzene (23 g, 81.3 mmol), K 2 CO 3 (20.4 g, 148 mmol), tetrabutylammonium bromide (23.8 g, 73.9 mmol) and palladium(II) acetate (1.66 g, 7.39 mmol) in DMF (125 mL) was heated to 60°C for 16 hours. After cooling to RT, EtOAc (500 ml) and water (500 mL) were added. After decantation, the organic phase was washed twice with water (500 ml), dried over MgSO 4 , filtered, concentrated under reduced pressure and purified by flash chromatography, eluting with DCM to give 20.7 g (86%) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a beige solid.

[0152] LC / MS (m / z, MH+): 324Step 2: Tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate

[0153]

[0154] Step 2 of Intermediate 7 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate to give 1.46 g (80%) of tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate.

[0155] LC / MS (m / z, MH+): 590Step 3: Methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid

[0156]

[0157] Step 3 of Intermediate 7 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate to give 1.58 g (crude) of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-SH-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid which was used as such in the next step.

[0158] LC / MS (m / z, MH+): 490Step 4: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0159]

[0160] To a mixture of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-SH-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid (303 mg, 0.50 mol), (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) (106 mg, 0.55 mmol) in DCM (4 ml) was added NaOH 0.5 N (2 ml, 1.13 mmol). The reaction mixture was stirred at RT for 18 hours. After decantation, the organic phase was purified by flash chromatography using a gradient of EtOAc / MeOH (from 100 / 00 to 90 / 10) to give 126 mg (42%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0161] LC / MS (m / z, MH+): 601Intermediate 8: Methyl (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0162] Step 1: Tert-butyl (3S)-3-(4-bromoanilino)pyrrolidine-1-carboxylate

[0163]

[0164] A mixture of 1-bromo-4-iodo-benzene (5 g, 18 mmol), (S)-1-Boc-3-aminopyrrolidine (6.6 g, 35 mmol), palladium(II) acetate (400 mg, 1.8 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.4 g, 2.5 mmol) and Cs 2 CO 3 (17 g, 53 mmol) in dioxane (50 ml) was heated at reflux for 5 hours. After cooling to RT, EtOAc (100 ml) and water (100 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered, concentrated under reduced pressure and purified by flash chromatography, eluting with a gradient of cyclohexane / EtOAc (from 88 / 12 to 00 / 100) to give 5 g (82%) of tert-butyl (3S)-3-(4-bromoanilino)pyrrolidine-1-carboxylate.

[0165] LC / MS (m / z, MH+): 341Step 2: Tert-butyl (S)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate

[0166]

[0167] Step 2 of Intermediate 8 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl (3S)-3-(4-bromoanilino)pyrrolidine-1-carboxylate to give 98 mg (11%) of tert-butyl (S)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate.

[0168] LC / MS (m / z, MH+): 607Step 3: Methyl (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0169]

[0170] Step 3 of Intermediate 8 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl (S)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate to give 49 mg (43%) of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0171] LC / MS (m / z, MH+): 507Step 4: Methyl (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0172]

[0173] Step 4 of Intermediate 8 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 39 mg (72%) of methyl (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0174] LC / MS (m / z, MH+): 618Intermediate 9: Methyl (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0175] Step 1: Tert-butyl (3R)-3-(4-bromophenoxy)pyrrolidine-1-carboxylate

[0176]

[0177] Step 1 of Intermediate 9 was prepared following a similar procedure to that of Step 2 of Intermediate 1 from 4-bromophenol and tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate to give 9.26 g (93%) of tert-butyl (3R)-3-(4-bromophenoxy)pyrrolidine-1-carboxylate.

[0178] LC / MS (m / z, MH+): 342Step 2: Tert-butyl (R)-3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate

[0179]

[0180] Step 2 of Intermediate 9 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl (3R)-3-(4-bromophenoxy)pyrrolidine-1-carboxylate to give 321 mg (36%) of tert-butyl (R)-3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate.

[0181] LC / MS (m / z, MH+): 608Step 3: Methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0182]

[0183] Step 3 of Intermediate 9 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl (R)-3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate to give 220 mg (85%) of methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0184] LC / MS (m / z, MH+): 508Step 4: Methyl (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0185]

[0186] Step 4 of Intermediate 9 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 113 mg (43%) of methyl (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0187] LC / MS (m / z, MH+): 619Intermediate 10: Methyl 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0188] Step 1: Tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]pyrrolidine-1-carboxylate

[0189]

[0190] To a mixture of commercially available tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate (5.82 g, 16.44 mmol) in MeOH (180ml) was added NaBH 4 (1.866 g, 49.33 mmol) and the mixture was stirred at RT for 2 hrs. A concentrated aqueous solution of NH 4 Cl (100 ml) and EtOAc (300 ml) were added. After decantation, the organic phase was washed with brine (200 ml), dried over Na 2 SO 4 filtered and concentrated under reduced pressure to give 5.8 g (crude) of tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]pyrrolidine-1-carboxylate.

[0191] LC / MS (m / z, MH+): 356Step 2: (3Z)-3-[(4-bromophenyl)methylene]pyrrolidine

[0192]

[0193] To a mixture of tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]pyrrolidine-1-carboxylate (5.8 g, 16.29 mmol) and water (12 ml) at 0°C was dropwise added sulfuric acid (42 ml). The cooling bath was removed, and the reaction mixture was stirred for 1 hour at RT. The reaction mixture was poured into a mixture of ice and water (500 ml). Powder NaHCO 3 was added to pH 9 followed by EtOAc (300 ml) and the organic phase was separated and dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give 1.97 g (51%) 3-[(4-bromophenyl)methylene]pyrrolidine as a mixture of (Z) and (E) isomers.

[0194] The mixture of (Z) and (E) isomers of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine was separated on column Chiralcel OZ 20 µm (0.46x25cm), eluting with heptane / EtOH / TEA (95 / 5 / 0.1) to give 641 mg of (Z) isomer (3Z)-3-[(4-bromophenyl)methylene]pyrrolidine and 953 mg of (E) isomer (3E)-3-[(4-bromophenyl)methylene]pyrrolidine.

[0195] LC / MS (m / z, MH+): 238Step 3: Methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylidenemethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0196]

[0197] Step 3 of Intermediate 10 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and (3Z)-3-[(4-bromophenyl)methylene]pyrrolidine to give 97 mg (30%) of methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylidenemethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0198] LC / MS (m / z, MH+): 504Step 4: Methyl 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0199]

[0200] Step 4 of Intermediate 10 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylidenemethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 106 mg (49%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0201] LC / MS (m / z, MH+): 615Intermediate 11: Methyl 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0202] Step 1: (E)-4-[2-(4-Bromophenoxy)ethylamino]-N,N-dimethyl-but-2-enamide

[0203]

[0204] Step 1 of Intermediate 11 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from 2-(4-bromophenoxy)ethanamine, hydrochloride and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 327 mg (36%) of (E)-4-[2-(4-bromophenoxy)ethylamino]-N,N-dimethyl-but-2-enamide.

[0205] LC / MS (m / z, MH+): 327Step 2: Tert-butyl N-[2-(4-bromophenoxy)ethyl]-N-[(E)-4-(dimethylamino)-4-oxo-but-2-enyl]carbamate

[0206]

[0207] To a mixture of (E)-4-[2-(4-bromophenoxy)ethylamino]-N,N-dimethyl-but-2-enamide (460 mg, 1.40 mmol) and DIEA (0.48 ml, 2.81 mmol) in DCM (5 ml) cooled at 0°C was added di-tert-butyl dicarbonate (368 mg, 1.69 mmol). The cooling bath was removed and the reaction mixture was stirred for 5 hours at RT. Water (5 ml) and DCM (10 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100 / 00 to 98 / 02 to give 414 mg (69%) tert-butyl N-[2-(4-bromophenoxy)ethyl]-N-[(E)-4-(dimethylamino)-4-oxo-but-2-enyl]carbamate.

[0208] LC / MS (m / z, MH+): 427Step 3: Methyl (E)-9-(4-(2-((tert-butoxycarbonyl)(4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0209]

[0210] Step 3 of Intermediate 11 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl N-[2-(4-bromophenoxy)ethyl]-N-[(E)-4-(dimethylamino)-4-oxo-but-2-enyl]carbamate to give 261 mg (39%) of methyl (E)-9-(4-(2-((tert-butoxycarbonyl)(4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0211] LC / MS (m / z, MH+): 693Step 4: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-(2-((4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0212]

[0213] Step 4 of Intermediate 11 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from methyl (E)-9-(4-(2-((tert-butoxycarbonyl)(4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 114 mg (52%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-(2-((4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0214] LC / MS (m / z, MH+): 593Intermediate 12: Methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0215] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo [7] annulene-3-carboxylate

[0216]

[0217] To a mixture of methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO2020 / 049153) (5 g, 10 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.7 g, 12 mmol mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.74 g, 1 mmol) in dioxane (40 ml) and water (10 ml) was added Cs 2 CO 3 (6.6 g, 20 mmol). The reaction mixture was heated to reflux for 24 hours. Water (100 ml) and EtOAc (200 ml) were added. The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (from 89 / 11 to 00 / 100) to give 3.8 g (87%) of methyl 8-(2,4-dichlorophenyl)-9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0218] LC / MS (m / z, MH+): 439Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0219]

[0220] To a mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (2 g, 4.6 mmol) in DCM (20 ml) cooled at 0°C were added pyridine (0.65 ml, 8.2 mmol) and trifluoromethanesulfonic anhydride (2.3 g, 8.1 mmol). The reaction mixture was stirred at 0°C for 15 minutes and RT for 2 hours. DCM (50 ml) and water (20 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered, concentrated under reduced pressure, and purified by flash chromatography, eluting with a gradient of cyclohexane / EtOAc (from 86 / 14 to 90 / 10) to give 2.31 g (89%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0221] LC / MS (m / z, MH+): 571Intermediate 13: Methyl (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0222] Step 1: Tert-butyl (R)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate

[0223]

[0224] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 12) (0.715 g, 1.25 mmol), (R)-1-Boc-3-aminopyrrolidine (0.589 g, 3.16 mmol), palladium(II) acetate (28 mg, 0.125 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (101 mg, 0.175 mmol) and Cs 2 CO 3 (1.22 g, 3.75 mmol) in dioxane (10 ml) was heated to reflux for 5 hours. After cooling to RT, EtOAc (50 ml) and water (50 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered, concentrated under reduced pressure and purified by flash chromatography, eluting with a gradient of cyclohexane / EtOAc (from 87 / 13 to 00 / 100) to give 207 mg (19%) of tert-butyl (R)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine- 1-carboxylate.

[0225] LC / MS (m / z, MH+): 607Step 2: Methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0226]

[0227] Step 2 of Intermediate 13 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl (R)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-1-carboxylate to give 136 mg (82%) of methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0228] LC / MS (m / z, MH+): 507Step 3: Methyl (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0229]

[0230] Step 3 of Intermediate 13 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 80 mg (51%) of methyl (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0231] LC / MS (m / z, MH+): 618Intermediate 14: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0232] Step 1: Tert-butyl 3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)azetidine-1-carboxylate

[0233]

[0234] Step 1 of Intermediate 14 was prepared following a similar procedure to that of Step 1 of Intermediate 13 from methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 12) and tert-butyl 3-aminoazetidine-1-carboxylate to give 372 mg (60%) of 1-tert-butyl 3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)azetidine-1-carboxylate.

[0235] LC / MS (m / z, MH+): 594Step 2: Methyl 9-(4-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0236]

[0237] Step 2 of Intermediate 14 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl 3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenyl)amino)azetidine-1-carboxylate to give 226 mg (74%) of methyl 9-(4-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0238] LC / MS (m / z, MH+): 494Step 3: Methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0239]

[0240] Step 3 of Intermediate 14 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl 9-(4-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 107 mg (39%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0241] LC / MS (m / z, MH+): 604Intermediate 15: methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 1

[0242] Step 1: Tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate Isomer 1 and Isomer 2

[0243]

[0244] To a solution of commercially available 3-[(4-bromophenyl)methyl]pyrrolidine (35.0 g, 145 mmol) and TEA (29.5 g, 292 mmol) in DCM (250 ml) was added DMAP (1.78 g, 14.57 mmol) and Boc 2 O (33.4 g, 153 mmol) at RT and the suspension was stirred at RT for 12 hours. The reaction mixture was quenched by addition of water (300 ml) and extracted with DCM (100 ml). The organic phase was washed with brine (200 ml), dried over Na 2 SO 4 filtered and concentrated under reduced pressure and the residue obtained was purified by flash chromatography, eluting with a gradient of petroleum ether / ethyl acetate: from 98 / 02 to 50 / 50 to give 37 g (73%) of racemic tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate as a light yellow oil.

[0245] The racemic tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate (37 g, 107 mmol) was separated by preparative SFC (column: DAICEL CHIRALCEL OJ (250x50mm,10µm); CO 2 mobile phase with 20% of a solution of 0.1% NH 4 OH in EtOH) to give 17 g of tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate Isomer 1 and 17 g of tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate Isomer 2.

[0246] LC / MS (m / z, MH+): 340Step 2: tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate , Isomer 1

[0247]

[0248] Step 2 of Intermediate 15 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate, Isomer 1 to give 470 mg (53%) of tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate , Isomer 1.

[0249] LC / MS (m / z, MH+): 606Step 3: methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 1

[0250]

[0251] Step 3 of Intermediate 15 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate , Isomer 1 to give 341 mg (87%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 1.

[0252] LC / MS (m / z, MH+): 506Step 4: methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 1

[0253]

[0254] Step 4 of Intermediate 15 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 229 mg (56%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 1.

[0255] LC / MS (m / z, MH+): 617Intermediate 16: methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 2

[0256] Step 1: tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate , Isomer 2

[0257]

[0258] Step 1 of Intermediate 16 was prepared following a similar procedure to that of Intermediate 5 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) and tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate, Isomer 2 to give 390 mg (44%) of tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate , Isomer 2.

[0259] LC / MS (m / z, MH+): 606Step 2: methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 2

[0260]

[0261] Step 3 of Intermediate 16 was prepared following a similar procedure to that of Step 2 of Intermediate 4 from tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)pyrrolidine-1-carboxylate , Isomer 2 to give 320 mg (98%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 2.

[0262] LC / MS (m / z, MH+): 506Step 3: methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 2

[0263]

[0264] Step 3 of Intermediate 16 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 2 and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 23 mg (53%) of methyl (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate , Isomer 2.

[0265] LC / MS (m / z, MH+): 617Intermediate 17: Methyl (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate

[0266] Step 1: 5-Oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-yl trifluoromethanesulfonate

[0267]

[0268] To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepine-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO2018091153) and pyridine (2.82 g, 2.89 ml, 35.36 mmol) in DCM (120 ml) cooled at -20°C was dropwise added trifluoromethanesulfonic anhydride (8.14 g, 6 ml, 28.28 mmol). The reaction mixture was stirred at 0°C for 30 minutes. Water (50 ml) was added. The organic phase was separated and washed with an aqueous saturated solution of NaHCO 3 (50 ml). The organic phase was dried over MgSO 4 , filtered, and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-yl trifluoromethanesulfonate.

[0269] LC / MS (m / z, MH+): 311Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate

[0270]

[0271] To a solution of compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-yl trifluoromethanesulfonate (7.4 g, 23.85 mmol) in DMF (30 ml) and MeOH (15 ml) was added DIEA (3.15 g, 4.16 ml, 23.85 mmol) and Pd(dppf)Cl 2 complex with DCM (1.10 g, 1.43 mmol), the suspension was degassed and purged three times with CO. The mixture was stirred under CO (5 bars) at 75 °C for 2 hours. The reaction was filtered through celite. The filtrate was diluted with water (400 ml) and extracted three times with EtOAc (300 ml). The combined organic phases were dried over Na 2 SO 4 , filtered, concentrated under reduced pressure, and the residue obtained was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: from 85 / 15 to 80 / 20 to give 4.6 g (88%) methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate.

[0272] LC / MS (m / z, MH+): 221Step 3: Methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate

[0273]

[0274] A mixture of 1-bromo-2,4-difluoro-benzene (4.21 g, 18.1 mmol), methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate (2 g, 9.1 mmol), Cs 2 CO 3 (11.92 g, 36.58 mmol) in toluene (12 ml). After addition of XANTPHOS (1.1 g, 1.8 mmol) and Pd 2 (dba) 3 (0.83 g, 0.91 mmol), the reaction mixture was heated to reflux for 18 hours. After cooling to RT, water (250 ml) and DCM (20 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of Heptane / EtOAc from 100 / 00 to 90 / 10 to give 1.85 g (56%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate.

[0275] LC / MS (m / z, MH+): 365Step 4: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-8-carboxylate

[0276]

[0277] To a suspension of NaH (361 mg, 9.04 mmol, 60% purity in wheight) in Me-THF (17 ml) cooled at -2°C was added DBU (183 mg, 0.18 ml, 1.21 mmol) followed by a solution of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate (2.2 g, 6.02 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (2.80 g, 7.83 mmol) in THF (15 ml). The cooling bath was removed to allow the temperature to warm up to RT. The reaction mixture was stirred at RT for 4 hours. A mixture of acetic acid (0.14 ml) and water (20 ml) was dropwise added, followed by water (60 ml) and EtOAc (60 ml). After decantation, the organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with DCM / heptane 70 / 30 to give 1.31 g (44%) of methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.

[0278] LC / MS (m / z, MH+): 496Step 5: Methyl (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate

[0279]

[0280] Step 5 of Intermediate 17 was prepared following a similar procedure to that of Step 1 of Intermediate 12 from methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-8-carboxylate and (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (prepared according to WO2017140669) to give 530 mg (67%) of methyl (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.

[0281] LC / MS (m / z, MH+): 510Step 6: Methyl (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate

[0282]

[0283] Step 6 of Intermediate 17 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 423 mg (66%) of (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate.

[0284] LC / MS (m / z, MH+): 621Intermediate 18: Methyl (S,E)-6-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate

[0285] Step 1: Methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate

[0286]

[0287] Step 1 of Intermediate 18 was prepared following a similar procedure to that of step 3 of Intermediate 17 from methyl 1-oxotetralin-6-carboxylate to give 459 mg (19%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate.

[0288] LC / MS (m / z, MH+): 349Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate

[0289]

[0290] Step 2 of Intermediate 18 was prepared following a similar procedure to that of step 4 of Intermediate 17 from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate to give 0.48 g (31%) of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate.

[0291] LC / MS (m / z, MH+): 481Step 3: Methyl (S)-6-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate

[0292]

[0293] Step 3 of Intermediate 18 was prepared following a similar procedure to that of Step 1 of Intermediate 12 from methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate and (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (prepared according to WO2017140669) to give 290 mg (45%) of methyl (S)-6-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate.

[0294] LC / MS (m / z, MH+): 494Step 4: Methyl (S,E)-6-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate

[0295]

[0296] Step 4 of Intermediate 18 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from methyl (S)-6-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 127 mg (36%) of methyl (S,E)-6-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate.

[0297] LC / MS (m / z, MH+): 605Method A Example 1: (S,E)-8-(2,4-Dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0298] Step 1: Methyl (R)-8-(2,4-dichlorophenyl)-9-(3-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0299]

[0300] A mixture of methyl (S,E)-8-bromo-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 1) (250 mg, 0.45 mmol), 2,4-dichlorophenylboronic acid (103 mg, 0.54 mmol), Cs 2 CO 3 (309 mg, 0.95 mmol), Pd(dppf)Cl 2 complex with DCM (33 mg, 45.17 umol), in dioxane (3.36 ml) and water (0.84 ml) was heated to 100°C under microwaved irradiation for 30 minutes. After cooling to RT, DCM (10 ml) and water (2 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 filtered and concentrated under reduced pressure and the residue obtained was purified by flash chromatography, eluting with a gradient of DCM / acetone from 75 / 25 to 50 / 50 to give 119 mg (43%) methyl (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0301] LC / MS (m / z, MH+): 619Step 2: (S,E)-8-(2,4-Dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0302]

[0303] To a mixture of methyl (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (115 mg, 0.186 mmol) in dioxane (2 ml) and water (2 ml) was added LiOH (12 mg, 0.50 mmol) and the reaction mixture was stirred at RT for 18 hours. DCM (5 ml) and HCl 1N were added till pH 7. After decantation, the organic phase was dried over Na 2 SO 4 filtered and concentrated under reduced pressure to give 73 mg (65%) of (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.Method B Example 16: (S,E)-8-(2,4-Dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0304]

[0305] To a mixture of methyl (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 8) (35 mg, 0.057 mmol) in dioxane (0.3 ml) was added LiOH 1N (0.15 ml, 0.15 mmol) and the reaction mixture was stirred at RT for 5 hours. DCM (5 ml) and a saturated solution of NH4Cl (5 ml) were added. After decantation, the organic phase was dried over Na 2 SO 4 filtered and concentrated under reduced pressure to give 21 mg (61%) of (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.Method C Example 23: (S,E)-4-(3-(4-(8-(2,4-Dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0306] Step 1: (S)-9-(4-(Pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate

[0307]

[0308] Step 1 of Example 23 was prepared following a similar procedure to that of Step 1 of Intermediate 12 from 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (prepared according to WO2017140669) and (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (prepared according to WO2017140669) to give 640 mg (65%) of (S)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.

[0309] LC / MS (m / z, MH+): 406Step 2: (S)-8-Bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate

[0310]

[0311] To a solution of (S)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (640 mg, 1.58 mmol) in DCM (20 ml) was added pyridinium tribromide (656 mg, 2.05 mmol). The reaction mixture was stirred at RT for 2 hours. A concentrated aqueous solution of NaHCO 3 was added. After decantation, the organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography, eluting with a gradient of DCM / MeOH from 95 / 05 to 90 / 10 to give 550 mg (72%) of (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.

[0312] LC / MS (m / z, MH+): 484Step 3: (S)-8-(2,4-Dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate

[0313]

[0314] Step 3 of Example 23 was prepared following a similar procedure to that of Step 1 of Example 1 from (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate and 2,4-dichlorophenylboronic acid to give 200 mg (32%) of (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.

[0315] LC / MS (m / z, MH+): 550Step 4: (S,E)-8-(2,4-Dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate

[0316]

[0317] Step 4 of Example 23 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from (S)-3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 110 mg (40%) of (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.

[0318] LC / MS (m / z, MH+): 661Step 5: (S,E)-4-(3-(4-(8-(2,4-Dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0319]

[0320] Step 5 of Example 23 was prepared following a similar procedure to that of Example 16 from (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate to give 15 mg (16%) of (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide.Example 26: (S,E)-4-(3-(4-(8-(2,4-Dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0321] Step 1: 6,7-Dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate

[0322]

[0323] To a mixture of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.3 g, 8.1 mmol) in DCM (30 ml) cooled at 0°C were added pyridine (0.98 ml, 12 mmol) and trifluoromethanesulfonic anhydride (4.6 g, 16 mmol). The reaction mixture was stirred at 0°C for 15 minutes and RT for 2 hours. DCM (50 ml) and cold water (30 ml) were added. After decantation, the organic phase was dried over MgSO 4 , filtered, concentrated under reduced pressure to give 2.4 g (99%) of 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate.

[0324] LC / MS (m / z, MH+): 293Step 2: (S)-3-(4-(6,7-Dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine

[0325]

[0326] Step 2 of Example 26 was prepared following a similar procedure to that of Step 1 of Intermediate 12 from 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate and (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (prepared according to WO2017140669) to give 1.2 g (49%) of (S)-3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine.

[0327] LC / MS (m / z, MH+): 306Step 3: (S)-3-(4-(8-Bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine

[0328]

[0329] Step 3 of Example 26 was prepared following a similar procedure to that of Step 2 of Example 23 from (S)-3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine and pyridinium tribromide to give 1.48 g (98%) of (S)-3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine.

[0330] LC / MS (m / z, MH+): 384Step 4: (S)-3-(4-(8-(2,4-Dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine

[0331]

[0332] Step 4 of Example 26 was prepared following a similar procedure to that of Step 1 of Example 1 from (S)-3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine and 2,4-dichlorophenylboronic acid to give 1.2 g (69%) of (S)-3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine.

[0333] LC / MS (m / z, MH+): 450Step 5: (S,E)-4-(3-(4-(8-(2,4-Dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0334]

[0335] Step 5 of Example 26 was prepared following a similar procedure to that of Step 3 of Intermediate 4 from (S)-3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 370 mg (46%) of (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide.Example 27: (S,E)-4-(3-(4-(4-(2,4-Dichlorophenyl)-8-hydroxy-2,3-dihydrobenzo[b]thiepin-5-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0336] Step 1: (S)-5-(4-(Pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate

[0337]

[0338] Step 1 of Example 27 was prepared following a similar procedure to that of Step 1 of Intermediate 12 from 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate (prepared according to WO2018091153) and (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (prepared according to WO2017140669) to give 210 mg (62%) of (S)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate.

[0339] LC / MS (m / z, MH+): 424Step 2: (S)-4-Bromo-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate

[0340]

[0341] Step 2 of Example 27 was prepared following a similar procedure to that of Step 3 of Example 23 from (S)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate and pyridinium tribromide to give 300 mg (crude) of (S)-4-bromo-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate.

[0342] LC / MS (m / z, MH+): 502Step 3: (S)-4-(2,4-Dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate

[0343]

[0344] Step 3 of Example 27 was prepared following a similar procedure to that of Step 1 of Example 1 from (S)-4-bromo-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate and 2,4-dichlorophenylboronic acid to give 83 mg (29%) of (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate.

[0345] LC / MS (m / z, MH+): 568Step 4: (S,E)-4-(2,4-Dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate

[0346]

[0347] Step 4 of Example 27 was prepared following a similar procedure to that of Step 3 of Intermediate 4 (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (Intermediate 2) to give 61 mg (61%) of (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate.

[0348] LC / MS (m / z, MH+): 679Step 5: (S,E)-4-(3-(4-(4-(2,4-Dichlorophenyl)-8-hydroxy-2,3-dihydrobenzo[b]thiepin-5-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide

[0349]

[0350] Step 5 of Example 27 was prepared following a similar procedure to that of Example 16 from (S,E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate (Intermediate 2) to give 25 mg (47%) of (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide.Examples:

[0351] The compounds according to Table 1a above were subjected to pharmacological tests as presented below.Test: In vitro anti-proliferation assay

[0352] Said test involves measuring the in vitro anti-proliferation activity of the compounds of the Table 1a.

[0353] The measurements of the anti-proliferation activities were made using MCF7-WT (ATCC), MCF7-Y537S and HCC1428-LTED cells as described hereunder.

[0354] On Day 1, MCF7-WT and MCF7-Y537S (Mol Cancer Ther. 2021 20(2):250-262), and HCC1428-LTED (J Clin Invest. 2010;120(7):2406-2413) cells, were seeded at 2000 (WT and LTED) and 500 (Y537S) cells / well in phenol red free IMEM (Corning, 110-026-CV) with 5% Charcoal stripped-FBS and incubated overnight 37°C and 5% CO 2 .

[0355] On day 2, compounds were tested in triplicate in 10-point dose response (1:3 serial dilutions with a top concentration starting 300nM); DMSO for upper limit (negative control) and staurosporine (1uM) for lower limit (positive control) were also included. MCF7-WT cells were then supplemented with final 0.1 nM b-estradiol. After treating the cells, the assay plates were transferred back in the incubator at 37°C and 5% CO 2 .

[0356] On day 8, cell viability was measured per vendor recommendations (Cell Titer-Glo, Promega). Relative IC50 measurements were calculated as follow using a 4-parameter logistic derived from Levenburg Marquardt algorithm (IDBS XL Model 205 fit within Abase).

[0357] The Table 2 below indicates the anti-proliferation activity results for the compounds of Table 1a. Table 2: Viability Screen Results Compound No. MCF7 WT IC50 (nM) MCF7 Y537S IC50 (nM) HCC 1428 IC50 (nM) 1145000.72105000.43241670.7422500253760.26145000.7728500283870.294870.21085000.31122040.112126500313390.01141010.40.415531865163717433171013811826590.319920.70.22041500121285002.122111840.62326230.03241605004.4253005001726211930.4272.9330.02

[0358] It is therefore apparent that the tested compounds have anti-proliferation activities, in both wild-type and mutated cell lines as tested above. As shown in Table 2, the compounds described herein display IC50 activities lower than 1 µM, typically 500 nM or lower activities.

[0359] The compounds of formula (I) can therefore be used for preparing medicaments, especially antiproliferative medicaments, as well as medicaments useful in the treatment of diseases wherein the estrogen receptor is involved.

[0360] Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

[0361] Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use as medicines.

[0362] Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salt thereof, for use in therapy, especially in diseases wherein the estrogen receptor is involved.

[0363] Herein are also provided the compounds of formula (I) defined above, or a pharmaceutically acceptable salts thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[0364] A particular aspect is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0365] In an embodiment, the cancer is a hormone dependent cancer.

[0366] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor α dependent cancer.

[0367] In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

[0368] In another embodiment, the metastasis is a cerebral metastasis.

[0369] In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERα positive breast cancer).

[0370] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0371] In a further embodiment, the compound of formula (I) is as used as single agent or in combination with other agents such as CDK4 / 6, mTOR or PI3K inhibitors.

[0372] Herein is also described the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer.

[0373] Herein are also provided the pharmaceutical compositions comprising as active principle a compound of formula (I). 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.

[0374] The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0375] In the pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.

[0376] The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants. For topical application it is possible to use the compounds of formula (I) in creams, gels, ointments or lotions.

[0377] As an example, a unit administration form of a compound of formula (I) in tablet form may comprise the following components: Compound of formula (I)50.0 mgMannitol223.75 mgSodium croscarmellose6.0 mgCorn starch15.0 mgHydroxypropylmethylcellulose2.25 mgMagnesium stearate3.0 mg

[0378] There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: wherein: - R3 represents a hydrogen atom, a -COOH group or a -OH group; - R3' and R3" independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom or a cyano group; - R4 represents a hydrogen atom, a (C1-C3)alkyl group or a cyclopropyl; - R5 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; - R6 represents a group selected from: ▪ a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6)alkyl group, optionally substituted with a cyano group or a -OH group; a (C1-C6)fluoroalkyl group; a (C3-C6)cycloalkyl group; a (C1-C6)alkoxy group; a (C1-C6)fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4)alkylthio group; a (C1-C4)fluoroalkylthio group; a (C1-C4)alkylsulfonyl group and a -OH group; ▪ a fused phenyl group, selected from phenyl groups fused with a (C3-C6)cycloalkyl, which (C3-C6)cycloalkyl ring optionally comprises an unsaturation and, wherein the fused phenyl group is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group and a (C1-C3)alkoxy group; ▪ a bicyclic group comprising 5 to 12 carbon atoms, optionally comprising 1 to 2 unsaturations; optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a -OH group, a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group and an oxo group; ▪ a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 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 or a pyrrolyl group, said heteroaryl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C6)alkyl group, a (C1-C6)fluoroalkyl group, a (C1-C6)alkoxy group, a (C1-C6)fluoroalkoxy group, a cyano group, a carbamoyl group and a -OH group; ▪ a cycloalkyl group comprising 3 to 7 carbon atoms, said cycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 4 substituents independently selected from: ∘ a fluorine atom, a -OH group, a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group, an oxo group, ∘ a (C3-C6)cycloalkyl group, and a phenyl group, said (C3-C6)cycloalkyl or phenyl groups being optionally substituted with one or two halogen atom(s) or (C1-C3)alkyl group(s); ▪ a (C3-C6)cycloalkyl(C1-C3)alkyl group, optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from: a fluorine atom, a -OH group, a (C1-C4)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group and an oxo group; ▪ a 4 to 7 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl or a tetrahydrofuranyl group, said heterocycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom, a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, an oxo group, a (C1-C3)alkoxy group, and a -OH group; ▪ a (C1-C6)alkyl group, such as an isobutyl group or an ethylbutyl group, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group and a -OH group; and ▪ a phenyl(C1-C2)alkyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and a -OH group; - X represents -CH2-, -O- or -S-; - n is 0, 1 or 2; - m is 0 or 1; and - Z represents a group selected from: ▪ and ▪ wherein: ∘ R1 and R2 independently represent a hydrogen atom, a -CH3 group, a -CH2CH3 group, or a -CH2CH2OH group, or R1 and R2 forms a 4 to 6 membered-heterocycloalkyl group with the nitrogen atom to which R1 and R2, are attached, said heterocycloalkyl group optionally comprising an additional heteroatom selected from oxygen, nitrogen and sulfur; ∘ Y represents -CH2-, -CH=, -CR7=, -O- or -NH-, wherein R7 represents a fluorine atom or a (C1-C3)alkyl group; ∘ represents a single bond or a double bond; and ∘ p is 0 or 1.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is of formula (I'):

3. The compound of formula (I) or (I') according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that Y represents -CH2-, -CH=, - O- or -NH-, and preferably Y represents -O-.

4. The compound of formula (I) or (I') according to any one of claim 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that represents a single bond.

5. The compound of formula (I) or (I') according to any one of claim 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that p is 1.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is of formula (I''):

7. The compound of formula (I), (I') or (I") according to any one of claim 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are a -CH3 group.

8. The compound of formula (I), (I') or (I") according to any one of claim 1 to 7, or a pharmaceutically acceptable salt thereof, characterized in that R3 is a -COOH group.

9. The compound of formula (I), (I') or (I") according to any one of claim 1 to 8, or a pharmaceutically acceptable salt thereof, characterized in that R3' and R3" represent a hydrogen atom.

10. The compound of formula (I), (I') or (I") according to any one of claim 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that R4 represents a hydrogen atom.

11. The compound of formula (I), (I') or (I") according to any one of claim 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that X represents -CH2-.

12. The compound of formula (I), (I') or (I") according to any one of claim 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that n is 0.

13. The compound of formula (I), (I') or (I'') according to anyone of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein m is 1.

14. The compound of formula (I), (I') or (I") according to any one of claim 1 to 13, or a pharmaceutically acceptable salt thereof, characterized in that R6 represents a phenyl group, said phenyl group being optionally substituted with 1 or 2 substituents independently selected from a chlorine atom, a fluorine atom and a methyl group.

15. The compound of formula (I), (I') or (I") according to any one of claim 1 to 13, or a pharmaceutically acceptable salt thereof, characterized in that R6 represents a pyridyl group, said pyridyl group being substituted by two substituents independently selected from a halogen atom and a (C1-C6)alkoxy group, and more particularly selected from a fluorine atom and a methoxy group.

16. The compound of formula (I), (I') or (I'') according to anyone of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof, characterized in that said compound is selected from the following compounds: - (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7] annulene-3-carboxylic acid, (1) - (S,E)-8-(2-chloro-4-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) - (S,E)-8-(4-chloro-2-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) - (S,E)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) - (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) - (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) - (S,E)-8-(3-chloro-4-methylphenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) - (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2,4-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) - (S,E)-8-(2-chlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) - (S,E)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-8-(2-fluoro-6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) - (S,E)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) - (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) - (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid, (13) - (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) - (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) - (S,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) - (R,E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7] annulene-3-carboxylic acid, (17) - (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1, (18) - (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2, (19) - 8-(2,4-dichlorophenyl)-9-(4-((Z)-(1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) - (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) - (E)-8-(2,4-dichlorophenyl)-9-(4-(2-((4-(dimethylamino)-4-oxobut-2-en-1-yl)amino)ethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) - (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide, (23) - (S.E)-4-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid, (24) - (S,E)-6-(2,4-dichlorophenyl)-5-(4-((1-(4-(dimethylamino)-4-oxobut-2-en-1-yl)pyrrolidin-3-yl)oxy)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid, (25) - (S,E)-4-(3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide, (26) - (S,E)-4-(3-(4-(4-(2,4-dichlorophenyl)-8-hydroxy-2,3-dihydrobenzo[b]thiepin-5-yl)phenoxy)pyrrolidin-1-yl)-N,N-dimethylbut-2-enamide, (27).

17. A process for preparing a compound of formula (I) or (I') as defined in anyone of claims 1 to 5 and 7 to 16, or a pharmaceutically acceptable salt thereof, wherein a compound of formula 1F: wherein R1, R2, R3', R3", R4, R5, R6, m, n, p, X, Y and are as defined in any of claims 1, 3 to 5 and 7 to 15, and R3a is a hydrogen atom or a carboxylic ester such as -COOMe, - COOEt, or protected -OH such as O-pivaloyl for example, is converted to compound of formula (I) or (I'), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in THF or dioxane .

18. A process for preparing a compound of formula (I) or (I') as defined in anyone of claims 1 to 5 and 7 to 16, or a pharmaceutically acceptable salt thereof, wherein a compound of formula 1F': wherein R1, R2, R3', R3", R4, R5, R6, m, n, p, X and Y are as defined in any of claims 1, 3 to 5 and 7 to 15, and R3a is a hydrogen atom or a carboxylic ester such as -COOMe, -COOEt, or protected -OH such as O-pivaloyl for example, is converted to compound of formula (I) or (I'), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in THF or dioxane , said step being optionally preceded by a step for obtaining compound 1F', wherein a compound of formula 1T: wherein R1, R2, R3', R3", R4, R5, m, n, p, X and Y are as defined in any of claims 1, 3 to 5 and 7 to 15 and R3a is as defined above, is subjected to a Suzuki coupling with a boronic reagent R6B(OR')2, wherein -B(OR')2 is a boronic acid or a pinacolate ester and R6 is as defined in any of claims 1, 14 or 15.

19. Intermediate compounds selected from compounds of formula 1T, 1F, 1F' and 2B, or any of its pharmaceutically acceptable salt, and wherein R1, R2, R3', R3", R4, R5, R6, m, n, p, X, Y and are as defined in any of claims 1, 3 to 5 and 7 to 15 and R3a is a hydrogen atom or a carboxylic ester such as -COOMe, - COOEt, or protected -OH such as O-pivaloyl.

20. Intermediate compound of formula 1E, or any of its pharmaceutically acceptable salt: wherein R1, R2, R5, Y, n, p and are as defined in any of claims 1, 3 to 5, 7 and 12.

21. A medicament, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

23. A compound of formula (I) according to any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

24. A compound of formula (I) for use according to claim 23, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.