Novel substituted 4-amino-4-oxo-but-2-enyl derivatives, processes for their preparation and therapeutic uses thereof - Patents.com

Abstract

TIFF2025512050000156.tif68170 Disclosed herein are compounds of formula (I), or a pharma- ceutically acceptable salt thereof: [0033] Formula (I) (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 group; 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 trifluoro R6 represents a group selected from a phenyl group, a fused phenyl group, a bicyclic group, a heteroaryl group, a cycloalkyl group, a (C3-C6)cycloalkyl(C1-C3)alkyl group, a 4- to 7-membered heterocycloalkyl group, and a phenyl(C1-C2)alkyl 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 formula (II); and formula (III). Further disclosed are processes for preparing the above, pharmaceutical compositions containing them as well as said compounds of formula (I) for use in the treatment of diseases in which the estrogen receptor is involved, such as the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

Description

[Technical field]

[0001] Disclosed herein are novel substituted 4-amino-4-oxo-but-2-enyl derivatives, processes for their preparation and their therapeutic use, particularly as anti-cancer agents, via selective antagonism and degradation of the estrogen receptor. [Background technology]

[0002] Estrogen receptors (ER) belong to the steroid / nuclear receptor superfamily that are involved in the control of eukaryotic gene expression, cell growth and differentiation in target tissues. There are two forms of ER: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors that are activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormones, ER is primarily located in the cytosol of cells. When the hormone estrogen binds to ER, ER translocates from the cytosol to the nucleus of the cell, forms dimers, and then binds to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to modulate the transcription of target genes.

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

[0004] ERα is expressed in approximately 50-80% of breast tumors, whereas expression in 10% or less of normal breast epithelium. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The pathogenic role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the backbone of breast cancer treatment for the majority of ERα-positive breast cancers. Currently, there are several strategies to inhibit the estrogen system in breast cancer, such as: 1-blocking estrogen synthesis with aromatase inhibitors, used to treat patients with early and advanced ERα-positive breast cancer; 2-neutralization of estrogen ligands that bind to ERα with tamoxifen, used to treat patients with ERα-positive breast cancer in both pre- and postmenopausal settings; 3-neutralization and downregulation of ERα levels with fulvestrant, used to treat breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have contributed greatly to the reduction of breast cancer incidence, more than about one-third of ERα-positive patients show de-novo resistance or become resistant over time to such existing therapies. Several mechanisms have been described to explain such resistance to hormone therapy, such as hypersensitivity of ERα to low estrogen levels in aromatase inhibitor treatment, switching of tamoxifen effect from antagonistic to agonistic effect in tamoxifen treatment, or multiple growth factor receptor signaling pathways. Acquired mutations in ERα that occur after the initiation of hormone therapy may also be involved in treatment failure and cancer progression. Certain mutations in ERα, especially those identified in the ligand-binding domain (LBD), confer the ability to bind DNA in the absence of ligand, conferring hormone independence in cells with such mutant receptors. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there remains a need to provide potent compounds suitable as ER-directed therapeutics. [Means for solving the problem]

[0007] The inventors have now discovered novel compounds that are selective estrogen receptor covalent antagonists (SERCAs).

[0008] Disclosed herein are compounds of formula (I), or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, 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 group; - 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 trifluoromethyl; - R6, ■ a phenyl group (the phenyl group is optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted by a cyano group or an -OH group; a (C1-C6) fluoroalkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy group; a (C1-C6) fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4) alkylthio group; a (C1-C4) fluoroalkylthio group; a (C1-C4) alkylsulfonyl group and a -OH group); ■ a fused phenyl group selected from a phenyl group fused with a (C3-C6)cycloalkyl, where the (C3-C6)cycloalkyl ring optionally contains unsaturation, and where 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 containing 5 to 12 carbon atoms (optionally containing 1 to 2 unsaturations; optionally substituted with 1 to 4 substituents independently selected from a fluorine atom, an -OH group, a (C1-C3) alkyl group, a (C1-C3) fluoroalkyl group, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group and an oxo group); ■ Heteroaryl groups containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as pyridyl or pyrrolyl groups (the heteroaryl groups are optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) fluoroalkyl groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, cyano groups, carbamoyl groups and -OH groups); ■ Cycloalkyl groups containing 3 to 7 carbon atoms (the cycloalkyl groups are saturated or partially saturated, ○Fluorine atom, -OH group, (C1-C3) alkyl group, (C1-C3) fluoroalkyl group, (C1-C3) alkoxy group, (C 1- C3) a fluoroalkoxy group, an oxo group, (C3-C6)cycloalkyl and phenyl groups, said (C3-C6)cycloalkyl or phenyl groups being optionally substituted with one or two halogen atoms or a (C1-C3)alkyl group; and optionally substituted with 1 to 4 substituents independently selected from: ■ (C3-C6)cycloalkyl(C1-C3)alkyl groups, optionally substituted on the cycloalkyl group with 1 to 4 substituents independently selected from a fluorine atom, an -OH group, a (C1-C4)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group and an oxo group; ■ 4-7 membered heterocycloalkyl groups containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as tetrahydropyranyl or tetrahydrofuranyl groups (the heterocycloalkyl groups are saturated or partially saturated and are optionally substituted with 1 to 3 substituents independently selected from fluorine atoms, (C1-C3) alkyl groups, (C1-C3) fluoro alkyl groups, (C1-C3) fluoro alkoxy groups, oxo groups, (C1-C3) alkoxy groups and -OH groups); ■ (C1-C6) alkyl groups, such as an isobutyl group or an ethylbutyl group (the alkyl groups are 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); ■ Phenyl(C1-C2)alkyl group (the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C1-C3)alkyl group; a (C1-C3)fluoroalkyl group; a (C1-C3)alkoxy group; a (C1-C3)fluoroalkoxy group; a cyano group; and a -OH group) represents a group selected from - X represents -CH2-, -O- or -S-; - n is 0, 1 or 2; - m is 0 or 1; - Z is [ka] represents a group selected from (In the formula, R1 and R2 independently represent a hydrogen atom, a -CH3 group, a -CH2CH3 group or a -CH2CH2OH group, or R1 and R2 together with the nitrogen atom to which R1 and R2 are linked form a 4- to 6-membered heterocycloalkyl group, said heterocycloalkyl group optionally containing further heteroatoms selected from oxygen, nitrogen and sulfur; 〇Y represents -CH2-, -CH=, -CR7=, -O- or -NH-, where R7 represents a fluorine atom or a (C1-C3) alkyl group; 〇 [ka] represents a single bond or a double bond; ○p is 0 or 1).

[0009] Y is [ka] represents a single bond, represents -CH2-, -O- or -NH-, and Y is [ka] When represents a double bond, it represents -CH= or -CR7=.

[0010] The compounds of formula (I) may contain one or more asymmetric carbon atoms and therefore may exist in enantiomeric forms.

[0011] The compounds of formula (I) may also exist in tautomeric forms.

[0012] The compounds of formula (I) can exist in the form of a base, an acid, a zwitterion, or an addition salt with an acid or a base. Accordingly, there is provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0013] These salts may be prepared using pharma- ceutically acceptable acids or bases, although other acid or base salts 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), mention may be made of the hydrochloride salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As used herein, the following terms have the following definitions throughout the specification, unless otherwise stated. halogen atoms: fluorine, chlorine, bromine or iodine atoms, and in particular fluorine and chlorine atoms; - Oxo: the "=O" group; - alkyl group: unless otherwise stated, an aliphatic group based on a linear or branched saturated hydrocarbon containing 1 to 6 carbon atoms (hence "(C1-C6) alkyl"). Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, etc.; - cycloalkyl group: a saturated or partially unsaturated unsubstituted or substituted monocyclic alkyl group containing 3 to 7 carbon atoms, unless otherwise stated, examples which may be mentioned, but are not limited to, are: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl groups, such as in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl or cyclohexenyl; - Heterocycloalkyl group: a saturated or partially unsaturated 4- to 7-membered cycloalkyl group containing 1 to 2 heteroatoms, independently selected from oxygen, nitrogen and sulfur, in particular oxygen or nitrogen. Examples may include, but are not limited to: morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl and tetrahydrothiopyranyl. Heterocycloalkyl is preferably tetrahydrofuranyl or tetrahydropyranyl. - Fluoroalkyl group: an alkyl group as defined above, in which the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. Examples may include -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be named as a perfluoroalkyl group. Examples may include a trifluoromethyl group or a trifluoroethyl group; - alkoxy group: -O-alkyl group, where the alkyl group is as defined above. Examples that may be mentioned, but are not limited to, are: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; -Fluoroalkoxy group: -O-alkyl group, where the alkyl group is as previously defined, and the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is substituted with a fluorine atom. Examples may include -OCH2F, -OCHF2, -OCH2CH2F, and the like. When all hydrogen atoms belonging to the alkyl group are substituted with fluorine atoms, the fluoroalkoxy group may be named a perfluoroalkoxy group. Examples may include trifluoromethoxy group, and the like; - (C1-C4) alkylthio groups are also named (C1-C4) alkylsulfanyl groups: -S-alkyl groups, where the alkyl group is as defined above. Examples may include, but are not limited to: methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, etc.; -(C1-C4) alkylsulfonyl group: -SO2-alkyl group, where the alkyl group is as defined above. Examples may include, but are not limited to, -SO2CH3, -SO2CH2CH3, etc.; - (C1-C4)fluoroalkylthio group, also named (C1-C4)fluoroalkylsulfanyl group: -S-fluoroalkyl group, in which the fluoroalkyl group is as defined above. Examples may include, but are not limited to: fluoromethylthio, difluoromethylthio, trifluoromethylthio, etc.; - Fused phenyl group: a bicyclic group containing 7-10 carbon atoms and containing a phenyl moiety. The phenyl moiety may be fused to a (C3-C6) cycloalkyl group, i.e. the phenyl moiety may share a bond with the (C3-C6) cycloalkyl group. The fused phenyl group may be bonded to the rest of the molecule 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, etc.; - Heteroaryl group: a cyclic 5-10 membered aromatic group containing 2-9 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen or sulfur. Such nitrogen atoms may be replaced by oxygen atoms to form -NO bonds. Such -NO bonds can be referred to as N-oxides (-N + -O - ) form. Said heteroaryl group may be monocyclic or bicyclic. Examples of heteroaryl groups may include, but are not limited to, thiophene, furan, thiadiazole, thiazole, imidazole, pyridazine, triazine, pyrazine, oxadiazole, pyrazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine, benzotriazole, benzoxazole, pyrrolo[2,3-b]pyridine, benzimidazole, benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridone groups, etc. Heteroaryl groups are preferably pyridine, pyrrole, imidazole, pyrazine, furan, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, and more specifically pyridine, pyridone and pyrrole; - bicyclic radicals, which generally contain from 5 to 12 carbon atoms, are hydrocarbon radicals selected from the radicals containing two rings linked through: A single common atom: a "spiro-bicyclic ring". Such spiro-bicyclic alkyls are generally called "spiro (C5-C 11 The term spiro (C5-C6) bicyclic ring refers to a "spiro (C6-C7) bicyclic ring". The ring may be saturated or partially unsaturated. Such spiro bicyclic rings may be unsubstituted or substituted, in particular by at least one (C1-C3) alkyl group such as methyl or fluorine. With respect to the definition of R6, spiro (C5-C6) bicyclic rings refer to a "spiro (C5-C6) bicyclic ring". 11 Examples of spiro(C5-C6) bicyclic rings may include, but are not limited to, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.3]heptene, spiro[2.5]octane, and 7-azaspiro[3.5]nonane. 11 Advantageously, the bicyclic ring is furthermore a spiro[3.3]heptane or spiro[3.3]heptene with respect to the R6 group. 2 common atoms: in this case the bicyclic group contains 7 to 12 carbon atoms and optionally contains 1 to 2 unsaturations. Examples of such bicyclic groups include, but are not limited to, cis-1,3a,4,5,6,6a-hexahydropentalenyl, bicyclo[3.1.0]hexan-1-yl, bicyclo[4.1.0]heptanyl and octahydropentalenyl. 3 or more common atoms: In this case, the bicyclic group contains 6 to 10 carbon atoms, and such a bicyclic group is called a "bridged (C6-C 10 (cycloalkyl) groups, where the rings share three or more atoms and the bridge contains at least one atom, e.g., 1, 2 or 3 atoms and preferentially 1 atom. Examples of such bridged cycloalkyl groups can include, but are not limited to, bicyclo[3.2.1]octan-3-yl and bicyclo[2.2.1]heptan-2-yl. - Zwitterion refers to an overall neutral molecule that carries a positive and a negative charge and has acidic and basic groups.

[0016] In another embodiment, in the compound of formula (I) as defined above, Z is a group: [ka] Represents.

[0017] According to this embodiment, the compound of formula (I) as defined above has the formula (I'): [ka] It is a compound of the formula:

[0018] In another embodiment, in the compound of formula (I) or (I') as defined above, Y represents -CH2-, -CH=, -O- or -NH-.

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

[0020] In another embodiment, in a compound of formula (I) or (I') as defined above, Y represents -CH2-.

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

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

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

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

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

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

[0027] In another embodiment, in the compound of formula (I) as defined above, Z is a group: [ka] Represents.

[0028] According to this embodiment, the compound of formula (I) as defined above is a compound of formula (I″): [ka] It is.

[0029] In another embodiment, in the compounds of formula (I), (I') or (I'') as defined above, R1 and R2 are -CH3 groups.

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

[0031] In another embodiment, in the compound 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 a compound of formula (I), (I') or (I'') as defined above, X represents -CH2-.

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

[0036] In another embodiment, in the compound 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 compound of formula (I), (I') or (I'') as defined above, n is 0.

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

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

[0041] In another embodiment, in the compound of formula (I), (I') or (I'') as defined above, R6 is ■ a phenyl group (the phenyl group is optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6) alkyl group optionally substituted by a cyano group or an -OH group; a (C1-C6) fluoroalkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy group; a (C1-C6) fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4) alkylthio group; a (C1-C4) fluoroalkylthio group; a (C1-C4) alkylsulfonyl group and a -OH group); or ■ Heteroaryl groups containing 2 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and containing at least 5 atoms including carbon atoms and heteroatoms, such as a pyridyl group or a pyrrolyl group (the heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C1-C6) alkyl group, a (C1-C6) fluoroalkyl group, a (C1-C6) alkoxy group, a (C1-C6) fluoroalkoxy group, a cyano group, a carbamoyl group, and a -OH group). Represents.

[0042] In another embodiment, in the compound 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 (C1-C6) alkyl group optionally substituted with a cyano group or an -OH group; a (C1-C6) fluoroalkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy group; a (C1-C6) fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4) alkylthio group; a (C1-C4) fluoroalkylthio group; a (C1-C4) alkylsulfonyl group and a -OH group.

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

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

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

[0046] In another embodiment, in the compound of formula (I), (I') or (I'') as defined above, R6 represents a heteroaryl group containing 2 to 9 carbon atoms and containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as a pyridyl group or a pyrrolyl group, wherein said heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from halogen atoms, (C1-C6) alkyl groups, (C1-C6) fluoroalkyl groups, (C1-C6) alkoxy groups, (C1-C6) fluoroalkoxy groups, cyano groups, carbamoyl groups and -OH groups.

[0047] In another embodiment, in the compound 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 (C1-C6)alkoxy group, more particularly selected from a fluorine atom and a methoxy group.

[0048] In another embodiment, in the compound of formula (I) or (I'), R3 is a -COOH group and R6 is a phenyl group substituted with one or two substituents independently selected from a chlorine atom, a fluorine atom and a methyl group. In such an embodiment, R3' and R3'' are in particular hydrogen atoms. Also in such an embodiment, R4 is a hydrogen atom, X is a -CH2- group, m is equal to 1 and n is equal to 0. In such an embodiment, R1 and R2 are -CH3 groups, Y is -O-; [ka] represents a single bond and p is equal to 1.

[0049] In another embodiment, in the compound of formula (I) or (I''), R3 is a -COOH group and R6 is a phenyl group substituted with one or two substituents independently selected from a chlorine atom, a fluorine atom and a methyl group. In such an embodiment, R3' and R3'' are in particular hydrogen atoms. Also in such an embodiment, R4 is a hydrogen atom, X is a -CH2- group, m is equal to 1 and n is equal to 0. In such an embodiment, R1 and R2 are -CH3 groups.

[0050] Among the compounds of formula (I), (I') or (I'') described herein, mention may be made in particular of the following compounds, or a pharma- ceutically acceptable salt thereof, in particular the 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-carvone 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]oxepin-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 pharma- ceutically acceptable salt thereof, for use in therapy, in particular as an inhibitor and degrader of the estrogen receptor.

[0052] Another embodiment is a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, in particular breast cancer.

[0053] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0054] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0055] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0056] Another embodiment is a pharmaceutical composition comprising as an active ingredient an effective dose of a compound selected from the above list, or a pharma- ceutically acceptable salt thereof, and also at least one pharma- ceutically acceptable excipient.

[0057] The compounds of formula (I), (I') or (I'') may be prepared by the following process.

[0058] Compounds of formula (I), (I') or (I'') and other related compounds having different substituents are synthesized using the techniques and materials described below or using methods and materials otherwise known to those of skill in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those of skill in the art.

[0059] The following general methods for preparing 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 formula (I), (I') or (I'') as described below.

[0060] The following abbreviations and empirical formulas are used: BAST Deoxo-Fluor BOC2O Di-tert-butyl dicarbonate Cs2CO3 Cesium carbonate CO Carbon monoxide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIEA Diisopropylethylamine DMF N,N-Dimethylformamide DMAP Dimethylaminopyridine DMSO Dimethyl sulfoxide Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol H2 Hydrogen HATU 2-(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 HCl Hydrochloric acid HPLC High Performance Liquid Chromatography K2CO3 Potassium Carbonate KHMDS Potassium bis(trimethylsilyl)amide KOAc Potassium Acetate KOH Potassium hydroxide KOPh Potassium Phenolate LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium hydroxide MeCN Acetonitrile MeOH Methanol MeTHF 2-Methyltetrahydrofuran MgSO4MgSO4 MTBE Methyl tert-butyl ether n-BuLi n-Butyl lithium Na2SO4 Sodium Sulfate NaBH4 Sodium borohydride NaCl Sodium chloride NaH Sodium hydride NaHCO3 Sodium bicarbonate NaHSO3 Sodium hydrogen sulfate NaOH Sodium hydroxide NH4Cl Ammonium chloride NH4OH Ammonium hydroxide Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd / C Palladium Carbon Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2Palladium Acetate Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride PhOK Potassium phenolate PPh3 Triphenylphosphine RT room temperature SCX Strong Cation Exchange SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0061] Scheme 1a: Preparation of Compounds of Formula (I) or (I') - General Process [ka] According to Scheme 1a, R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, or a protected -OH, such as O-pivaloyl, and is preferably selected from R1, R2, R3, R3', R3'', R4, R5, X, Y, m, n, p, and [ka] is defined as above, R6 is a phenyl group or a heteroaryl group, compound 1A can be converted to compound 1B in step 1 by treatment with an aryl or heteroaryl bromide or iodide in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0)Pd2(dba)3 and a phosphine such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos) in solution in toluene by heating to the reflux temperature of the solvent in the presence of a base such as K2CO3 or Cs2CO3. An alternative method for preparing compound 1B, where R6 can be any of the groups defined above for R6 in formula (I) or (I'), is described below in scheme 1f.

[0062] Compound 1B can be converted to compound 1C in step 2 by treatment with N,N-bis(trifluoromethylsulfonyl)aniline in the presence of a base such as DBU or NaH or KHMDS at -50°C in a solvent such as MeTHF.

[0063] Compound 1C can be converted to compound 1D in step 3 by treatment with, for example, bis(pinacolato)diboron and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2 and a phosphine, such as triphenylphosphine, in a solution in toluene by heating to the reflux temperature of the solvent in the presence of a base, such as KOPh.

[0064] Compound 1F can be prepared in a Suzuki coupling reaction either between compound 1D in step 4 and compound 1E or between compound 1C in step 5 and compound 1E' using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complexed with DCM, as catalyst in a mixture of dioxane and water by heating to the reflux temperature of the solvent and in the presence of a base, such as cesium carbonate (CsCO).

[0065] When R3a is -COOMe, -COOEt or protected -OH such as O-pivaloyl, deprotection can be carried out 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 can provide the sodium or lithium salt of the compound of formula (I) or (I'). Acidification with an aqueous solution of HCl 2N to pH 6-7 can provide the neutral form of the compound of formula (I) or (I'). Acidification with an aqueous solution of HCl 2N to pH 1-2 can provide the hydrochloride salt of compound (I) or (I'). Purification of the eluate using HPLC in the presence of formic acid or trifluoroacetic acid can provide the formate or trifluoroacetate salt of compound (I) or (I').

[0066] Scheme 1b: Preparation of Compounds of Formula (I) and (I') - General Process [ka] According to scheme 1b, where R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, or a protected -OH, such as O-pivaloyl, and R1, R2, R3, R3', R3'', R4, R5, R6, X, Y, m, n and p are defined as above, compound 1C can be converted to compound 1H in step 1 by treatment with compound 1G using, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, as catalyst, in a mixture of dioxane and water, and in the presence of a base, such as cesium carbonate (Cs2CO3), by heating to the reflux temperature of the solvent.

[0067] Compound 1H can be converted to compound 1I in step 2 by treatment with trifluoromethanesulfonic anhydride in the presence of pyridine in DCM.

[0068] Compound 1I can be converted to compound 1L (Y=-NH-) in step 3 in a Buchwald coupling reaction with compound 1J in dioxane at 130° C. using, for example, Xantphos / palladium acetate (Pd(OAc)2) as a catalytic system.

[0069] Compound 1H can be converted to compound 1L (Y=-O-) in step 4 by reaction with compound 1K (A=Br or I) in the presence of a base such as Cs2CO3 in DMF or MeCN, or under Mitsunobu conditions in the case of (A=-OH), using, for example, N,N,N',N'-tetramethylazodicarboxamide and triphenylphosphine as coupling agents in THF as solvent.

[0070] Compound 1L can be converted to compound 1M in step 5 by treatment with TFA in DCM or HCl in dioxane.

[0071] Compound 1M can be converted to compound 1F' in step 6 by treatment with compound 1N in the presence of a base such as DIEA in DMF or MeCN.

[0072] When R3a is -COOMe, -COOEt or a protected -OH such as O-pivaloyl, deprotection can be achieved in step 7 by treatment with aqueous sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in THF or dioxane. When R3 is -COOH, extraction of the product can provide the sodium or lithium salt of the compound of formula (I) or (I'). Acidification with aqueous HCl 2N to pH 6-7 can provide the neutral form of the compound of formula (I) or (I'). Acidification with aqueous HCl 2N to pH 1-2 can provide the hydrochloride salt of the compound of formula (I) or (I'). Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluate provides the formate or trifluoroacetate salt of the compound of formula (I) or (I').

[0073] Scheme 1c - Part 1: Preparation of Compounds of Formula (I) or (I') - General Process [ka] Scheme 1c - Part 2 [ka] According to scheme 1c part-1 and part-2, where R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, etc. or a protected -OH, such as O-pivaloyl, and R1, R2, R3, R3', R3'', R4, R5, R6, X, Y, m, n and p are defined as above, compound 1O can be converted to compound 1P in step 1 by treatment with compound 1G using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, in a mixture of dioxane and water, by heating to the reflux temperature of the solvent, and in the presence of a base, such as cesium carbonate (Cs2CO3).

[0074] Compound 1P can be converted to compound 1Q in step 2 by treatment with trifluoromethanesulfonic anhydride in the presence of pyridine in DCM.

[0075] Compound 1Q can be converted to compound 1R (Y=-NH-) in step 3 in a Buchwald coupling reaction with compound 1J in dioxane at 130° C. using, for example, Xantphos / palladium acetate (Pd(OAc)2) as a catalytic system.

[0076] Compound 1P can be converted to compound 1R (Y=-O-) in step 4 by reaction with compound 1K (A=-Br or -I) in the presence of a base such as cesium carbonate (Cs2CO3) in DMF or MeCN or under Mitsunobu conditions in the case of (A=-OH) using, for example, N,N,N',N'-tetramethylazodicarboxamide and triphenylphosphine as coupling agents in THF as solvent.

[0077] Compound 1R can be converted to compound 1S in step 5 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature, followed by treatment of the resulting residue with TFA in DCM or HCl in dioxane.

[0078] Compound 1S can be converted to compound 1T in step 6 by treatment with compound 1N in the presence of a base such as DIEA in DMF or MeCN.

[0079] Compound 1T can be converted to compound 1U in step 7 by treatment with, for example, bis(pinacolato)diborane and a palladium catalyst, for example, bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine, for example, triphenylphosphine, in a solution in toluene by heating to the reflux temperature of the solvent in the presence of a base, such as KOPh or AcOK.

[0080] Compound 1F' can be prepared in a Suzuki coupling reaction either between 1U and R6Br or R6I or R6OTf in step 8 or between compound 1T and R6B(OR')2 or R6BF3K in step 9, using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, in a mixture of dioxane and water by heating to the reflux temperature of the solvent and in the presence of a base, such as, for example, cesium carbonate (Cs2CO3). (wherein -B(OR')2 is a boronic acid or pinacolato ester and R6 is as defined above).

[0081] When R3a is -COOMe, -COOEt or a protected -OH such as O-pivaloyl, deprotection can be carried out 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 can provide the sodium or lithium salt of the compound of formula (I) or (I'). Acidification with an aqueous solution of HCl 2N to pH 6-7 can provide the neutral form of the compound of formula (I) or (I'). Acidification with an aqueous solution of HCl 2N to pH 1-2 can provide the hydrochloride salt of the compound of formula (I) or (I'). Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of the compound of formula (I) or (I').

[0082] Scheme 1d: Alternative method for the preparation of compounds of formula (1S) - General process [ka] According to scheme 1d, where R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, or a protected -OH, such as O-pivaloyl, and R3, R3', R3'', R4, R5, X, m, n and p are defined as above, compound 1O can be converted in step 1 to compound 1O' by treatment with, for example, bis(pinacolato)diborane in solution in toluene, by heating to the reflux temperature of the solvent in the presence of a base, such as KOPh or AcOK, and with a palladium catalyst, such as bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Cl2, and a phosphine, such as triphenylphosphine.

[0083] 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, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complexed with DCM, in a mixture of dioxane and water by heating to the reflux temperature of the solvent and in the presence of a base, such as cesium carbonate (CsCO).

[0084] Compound 1W can be converted to compound 1S in step 3 by treatment with, for example, pyridinium tribromide in DCM or THF at room temperature.

[0085] Scheme 1e: Preparation of compounds of formula (1O) where R3a = CO2Me - General process [ka] According to scheme 1e, where X, m, R3', R3'', R3a = CO2Me and R4 are defined as above, compound 1O can be prepared as follows: Compound 1X (commercially available or prepared according to WO2017140669 and WO2018091153) can be converted to compound 1Y in step 1 by treatment with trifluoromethanesulfonic anhydride in solution in DCM in the presence of pyridine as a base.

[0086] Compound 1Y can be converted to compound 1Z in step 2 by carbonylation with carbon monoxide in a solution in DMF and MeOH in the presence of a palladium catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM.

[0087] Compound 1Z can be converted to compound 1O (wherein R3a = CO2Me) in step 3 by treatment with trifluoromethanesulfonic anhydride in solution in DCM in the presence of pyridine as a base.

[0088] Scheme 1f: Alternative preparation of compounds of formula (1B) - General process [ka] According to scheme 1f, where R3a is a hydrogen atom or a carboxylic acid ester, such as COOMe, COOEt, or a protected OH, such as O-pivaloyl, and R3', R3'', R, X, and m are defined as above, compound 1B can alternatively be prepared as follows: compound 1A can be converted to compound 1Aa in step 1, for example by treatment with pyridinium tribromide in DCM or THF at room temperature.

[0089] Compound 1Aa can be converted to compound 1Ab in step 2 by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

[0090] Compound 1Ac can be prepared in step 3 in a Suzuki coupling reaction between compound 1Ab and R6B(OR')2 or R6BF3K using, as a catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, in a mixture of toluene and water by heating to the reflux temperature of the solvent and in the presence of a base, for example, cesium carbonate (Cs2CO3).

[0091] Compound 1Ac can be converted to compound 1B in step 4 by hydrolysis with aqueous HCl solution, for example by heating in methanol and DCM.

[0092] Scheme 1g: Preparation of Compounds of Formula (i) or (i'') - General Process [ka] According to scheme 1g, where R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, or a protected -OH, such as O-pivaloyl, and R1, R2, R3, R3', R3'', R4, R5, R6, X, m and n are defined as above, compound 1D can be converted to compound 2A in step 1 by treatment with compound 1Z using, as catalyst, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), complexed with DCM, in a mixture of dioxane and water, by heating to the reflux temperature of the solvent, and in the presence of a base, such as cesium carbonate (Cs2CO3).

[0093] Compound 2A can be converted to compound 2B in step 2 by treatment with TFA in DCM.

[0094] When R3a is -COOMe, -COOEt or a protected -OH such as O-pivaloyl, deprotection can be achieved in step 3 by treatment with aqueous sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in THF or dioxane. When R3 is -COOH, extraction of the product can provide the sodium or lithium salt of the compound of formula (I) or (I''). Acidification with aqueous HCl 2N to pH 6-7 can provide the neutral form of the compound of formula (I) or (I''). Acidification with aqueous HCl 2N to pH 1-2 can provide the hydrochloride salt of the compound of formula (I) or (I''). Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of the compound of formula (I) or (I'').

[0095] Also provided herein is a process for preparing a compound of formula (I) or (I') as defined above, comprising the step of preparing a compound of formula 1F: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R6, m, n, p, X, Y and [ka] is as defined above and R is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, etc. or a protected -OH, such as O-pivaloyl, is converted to a compound of formula (I) or (I') in the presence of a source of hydroxide ions, such as NaOH or LiOH, in a solution in THF or dioxane.

[0096] Also provided herein is a process for preparing a compound of formula (I) or (I') as above, comprising the step of preparing a compound of formula 1F': [ka] wherein R1, R2, R3, R3', R3'', R4, R5, R6, m, n, p, X and Y are as defined above and R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt or a protected -OH, such as O-pivaloyl, is converted to a compound of formula (I) or (I') in the presence of a hydroxide ion source, such as NaOH or LiOH, in a solution in THF or dioxane, optionally preceded by a step to obtain compound 1F', wherein compound 1T of formula [ka] (wherein R1, R2, R3', R3'', R4, R5, m, n, p, X and Y are as described above.) is subjected to Suzuki coupling with a boron reagent R6B(OR')2, where -B(OR')2 is a boronic acid or pinacolatoyl ester and R6 is defined above.

[0097] Provided herein is an intermediate compound selected from compounds of formula 1T, 1F, 1F', and 2B, or any of its pharma- ceutically acceptable salts: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R6, m, n, p, X, Y and [ka] is as defined above, and R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, etc. or a protected -OH, such as O-pivaloyl, etc. are also provided.

[0098] Provided herein is an intermediate compound of formula 1E or any of its pharma- ceutically acceptable salts: [ka] (Wherein, R1, R2, R5, Y, n, P and [ka] is as described above) is further provided.

[0099] The present application also relates to an intermediate compound of formula 1D, or any of its pharma- ceutically acceptable salts: [ka] (wherein R3a, R3', R3'', X, m, R4 and R6 are as defined above) are also described.

[0100] In another aspect, there is also provided herein a process for the preparation of a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection process of a compound of formula IF as defined above, optionally followed by a purification step.

[0101] Said purification step may for example consist in an acidification step, for example with an aqueous solution of hydrochloric acid, as exemplified in step 2 of Example 1 herein.

[0102] At 400 and 500 MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, and chemical shifts (σ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) are referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0103] 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 DAD210-400 nm and a flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1x30 mm, mobile phase H2O+0.1% HCOH / CH3CN+0.1% HCOH.

[0104] [Table 1]

[0105]

Table 2

[0106]

Table 3

[0107]

Table 4

[0108]

Table 5

[0109]

Table 6

[0110]

Table 7

[0111]

Table 8

[0112]

Table 9

[0113]

Table 10

[0114]

Table 11

[0115] [Table 12]

[0116] [Table 13]

[0117] The following examples describe the preparation of some compounds of formula (I) described herein. The number of compounds exemplified below corresponds to those given in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0118] In the following examples, unless the source of a starting product is specified, it is to be understood that said product is a known compound.

[0119] 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 [ka] Step 1: Methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] 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 Cs2CO3 (44.32 g, 135.88 mmol). The reaction mixture was stirred at RT for 30 min. Water (500 ml) and EtOAc (500 ml) were added. The organic phase was dried over MgSO4, 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+):295

[0120] Step 2: Tert-butyl (S)-3-(4-(3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine-1-carboxylate [ka] 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 PPh3 (8.91 g, 33.97 mmol). The reaction mixture was stirred at RT for 18 h. EtOAc (500 ml) and water (250 ml) were added. The organic phase was separated, dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue 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. LC / MS(m / z,MH+):464

[0121] Step 3: Methyl (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] 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 h. Concentrated aqueous NaHCO3 was added. After decantation, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. To the resulting residue was added dioxane (100 ml) and HCl 4 N in dioxane (30.42 ml, 121.67 mmol). After stirring at RT for 30 min, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified on a 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. LC / MS(m / z,MH+):442

[0122] Step 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 [ka] 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 h. EtOAc (200 ml) and concentrated aqueous NaCl solution (50 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue 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. LC / MS(m / z,MH+):582

[0123] Step 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 [ka] 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 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH (100 / 00 to 90 / 10) to afford 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. LC / MS(m / z,MH+):526

[0124] Step 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 [ka] 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) in DMF (10 ml), DIEA (1.1 g, 8.53 mmol) and HATU (1.3 g, 3.42 mmol) was stirred at RT for 10 min. Dimethylamine 2M in THF (2.14 ml, 4.27 mmol) was added and the reaction mixture was stirred at RT for 2 h. EtOAc (50 ml) and water (50 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and the resulting residue 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. LC / MS(m / z,MH+):553

[0125] Intermediate 2(E)-4-Bromo-N,N-dimethyl-but-2-enamide [ka] To a mixture of (E)-4-bromobut-2-enoic acid (20 g, 121.23 mmol) in DCM (50 ml) cooled at 0° C. was added DIEA (17.24 g, 133.35 mmol) and HBTU (46.71 g, 145.47 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled at −10° C. and then dimethylamine 2M in THF (75.77 ml, 151.53 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 h. DCM (150 ml) and water (150 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of 100 / 00 to 00 / 100 heptane / EtOAc to give 9.33 g (40%) of (E)-4-bromo-N,N-dimethyl-but-2-enamide. LC / MS(m / z,MH+):192

[0126] Intermediate 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 [ka] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (prepared according to WO 2020 / 049153) (15 g, 30.29 mmol), Pd(PPh3)2Cl2 (0.87 g, 1.21 mmol), PPh3 (0.64 g, 2.42 mmol), bis(pinacolato)diborane (19.23 g, 75.71 mmol) and PhOK (8.43 g, 60.57 mmol) in toluene (300 ml) 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 Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc (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. LC / MS(m / z,MH+):473

[0127] Intermediate 4(E)-4-[3-(4-bromophenoxy)azetidin-1-yl]-N,N-dimethyl-but-2-enamide [ka] Step 1: Tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate [ka] A mixture of 4-bromophenol (5 g, 29 mmol), 1-boc-3-iodoazetidine (12 g, 43 mmol) and Cs2CO3 (19 g, 58 mmol) in DMF (50 ml) was heated at 65° C. for 6 h. After cooling to RT, EtOAc (200 ml) and water (200 ml) were added. After decantation, the organic phase was dried over MgSO4, 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. LC / MS(m / z,MH+):328

[0128] Step 2: 3-(4-bromophenoxy)azetidine [ka] To a solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (5.85 g, 17.8 mmol) in DCM (60 ml) was added TFA (13.2 ml, 178 mmol) dropwise. The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH / NH4OH from 100 / 00 / 00 to 38 / 17 / 2 to give 3.51 g (83%) of 3-(4-bromophenoxy)azetidine. LC / MS(m / z,MH+):228

[0129] Step 3: (E)-4-[3-(4-bromophenoxy)azetidin-1-yl]-N,N-dimethyl-but-2-enamide [ka] 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 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue were added EtOAc (20 ml) and water (5 ml). After decantation, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure and the resulting residue 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. LC / MS(m / z,MH+):339

[0130] Intermediate 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 [ka] 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), Cs2CO3 (185 mg, 0.57 mmol) in dioxane (4 ml) and water (1 ml) was heated to reflux for 4 h. The organic phase was dried over MgSO4, 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 Na2SO4, 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 95 / 05) to give 41.6 mg (31%) of 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. LC / MS(m / z,MH+):605

[0131] Intermediate 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 [ka] Step 1: Methyl 9-(4-(azetidin-3-ylmethyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1 of intermediate 6 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and 3-[(4-bromophenyl)methyl]azetidine, 4-methylbenzenesulfonic acid following the same procedure as intermediate 5 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. LC / MS(m / z,MH+):492

[0132] Step 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 [ka] 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 h. EtOAc (10 ml), diethyl ether (10 ml) and water (20 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure and the resulting residue 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), then a gradient of 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. LC / MS(m / z,MH+):603

[0133] Intermediate 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 [ka] Step 1: Tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate [ka]

[0134] Method 1: 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 wt% purity) 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 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 ml) at 0° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 60.0 g (crude) of tert-butyl 3-(4-bromobenzylidene)azetidine-1-carboxylate as a yellow solid. LC / MS(m / z,MH+):324

[0135] Method 2: A mixture of tert-butyl 3-methyleneazetidine-1-carboxylate (12.5 g, 73.9 mmol), 1-bromo-4-iodobenzene (23 g, 81.3 mmol), K2CO3 (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 h. 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 MgSO4, 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. LC / MS(m / z,MH+):324

[0136] Step 2: Tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate [ka] Step 2 of intermediate 7 was prepared following a procedure similar 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]annulene-9-yl)benzylidene)azetidine-1-carboxylate. LC / MS(m / z,MH+):590

[0137] Step 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 [ka] Step 3 of intermediate 7 was prepared following a similar procedure as step 2 of intermediate 4 from tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-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-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid, used directly in the next step. LC / MS(m / z,MH+):490

[0138] Step 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 [ka] To a mixture of 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 (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 0.5N (2 ml, 1.13 mmol). The reaction mixture was stirred at RT for 18 h. After decantation, the organic phase was purified by flash chromatography using a gradient of EtOAc / MeOH (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. LC / MS(m / z,MH+):601

[0139] Intermediate 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 [ka] Step 1: Tert-butyl (3S)-3-(4-bromoanilino)pyrrolidine-1-carboxylate [ka] 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 Cs2CO3 (17 g, 53 mmol) in dioxane (50 ml) was heated at reflux for 5 h. After cooling to RT, EtOAc (100 ml) and water (100 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (88 / 12 to 00 / 100) to give 5 g (82%) of tert-butyl (3S)-3-(4-bromoanilino)pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):341

[0140] Step 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 [ka] Step 2 of intermediate 8 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and tert-butyl (3S)-3-(4-bromoanilino)pyrrolidine-1-carboxylate following a similar procedure as for intermediate 5 to give 98 mg (11%) of tert-butyl (S)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):607

[0141] Step 3: Methyl (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 3 of intermediate 8 was prepared from tert-butyl (S)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)pyrrolidine-1-carboxylate following a procedure similar to step 2 of intermediate 4 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. LC / MS(m / z,MH+):507

[0142] Step 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 [ka] Step 4 of intermediate 8 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):618

[0143] Intermediate 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 [ka] Step 1: Tert-butyl (3R)-3-(4-bromophenoxy)pyrrolidine-1-carboxylate [ka] Step 1 of intermediate 9 was prepared following a similar procedure to 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. LC / MS(m / z,MH+):342

[0144] Step 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 [ka] Step 2 of intermediate 9 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and tert-butyl (3R)-3-(4-bromophenoxy)pyrrolidine-1-carboxylate following a similar procedure as for intermediate 5 to give 321 mg (36%) of tert-butyl (R)-3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenoxy)pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):608

[0145] Step 3: Methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 3 of intermediate 9 was prepared from tert-butyl (R)-3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenoxy)pyrrolidine-1-carboxylate following a procedure similar to step 2 of intermediate 4 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. LC / MS(m / z,MH+):508

[0146] Step 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 [ka] Step 4 of intermediate 9 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):619

[0147] Intermediate 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 [ka] Step 1: Tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]pyrrolidine-1-carboxylate [ka] To a mixture of commercially available tert-butyl 3-(4-bromobenzoyl)pyrrolidine-1-carboxylate (5.82 g, 16.44 mmol) in MeOH (180 ml) was added NaBH4 (1.866 g, 49.33 mmol) and the mixture was stirred at RT for 2 h. A concentrated aqueous solution of NH4Cl (100 ml) and EtOAc (300 ml) was added. After decantation, the organic phase was washed with brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5.8 g (crude) tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]pyrrolidine-1-carboxylate. LC / MS(m / z,MH+):356

[0148] Step 2: (3Z)-3-[(4-bromophenyl)methylene]pyrrolidine [ka] 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., sulfuric acid (42 ml) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured into a mixture of ice and water (500 ml). Powdered NaHCO3 was added until pH 9, followed by EtOAc (300 ml), the organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.97 g (51%) of 3-[(4-bromophenyl)methylene]pyrrolidine as a mixture of (Z) and (E) isomers. The mixture of (Z) and (E) isomers of 3-[(4-bromophenyl)methylene]-1-(3-fluoropropyl)pyrrolidine was separated on a column Chiralcel OZ 20 μm (0.46×25 cm) eluting with heptane / EtOH / TEA (95 / 5 / 0.1) to give 641 mg of the (Z) isomer (3Z)-3-[(4-bromophenyl)methylene]pyrrolidine and 953 mg of the (E) isomer (3E)-3-[(4-bromophenyl)methylene]pyrrolidine. LC / MS(m / z,MH+):238

[0149] Step 3: Methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylidenemethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 3 of intermediate 10 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and (3Z)-3-[(4-bromophenyl)methylene]pyrrolidine following the same procedure as for intermediate 5 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. LC / MS(m / z,MH+):504

[0150] Step 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 [ka] Step 4 of intermediate 10 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):615

[0151] Intermediate 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 [ka] Step 1: (E)-4-[2-(4-bromophenoxy)ethylamino]-N,N-dimethyl-but-2-enamide [ka] Step 1 of intermediate 11 was prepared from 2-(4-bromophenoxy)ethanamine, hydrochloride and (E)-4-bromo-N,N-dimethyl-but-2-enamide (intermediate 2) following a procedure similar to step 3 of intermediate 4 to give 327 mg (36%) of (E)-4-[2-(4-bromophenoxy)ethylamino]-N,N-dimethyl-but-2-enamide. LC / MS(m / z,MH+):327

[0152] Step 2: Tert-butyl N-[2-(4-bromophenoxy)ethyl]-N-[(E)-4-(dimethylamino)-4-oxo-but-2-enyl]carbamate [ka] 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 at RT for 5 h. Water (5 ml) and DCM (10 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100 / 00 to 98 / 02 to give 414 mg (69%) of tert-butyl N-[2-(4-bromophenoxy)ethyl]-N-[(E)-4-(dimethylamino)-4-oxo-but-2-enyl]carbamate. LC / MS(m / z,MH+):427

[0153] Step 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 [ka] 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 Step 3 of intermediate 11 was prepared following a similar procedure to intermediate 5 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. LC / MS(m / z,MH+):693

[0154] Step 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 [ka] Step 4 of intermediate 11 was prepared 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 following a procedure similar to step 2 of intermediate 4 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. LC / MS(m / z,MH+):593

[0155] Intermediate 12: Methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] 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 WO 2020 / 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 Cs2CO3 (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 MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (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. LC / MS(m / z,MH+):439

[0156] Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] 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. was 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 min and at RT for 2 h. DCM (50 ml) and water (20 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (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. LC / MS(m / z,MH+):571

[0157] Intermediate 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 [ka] 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 [ka] 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 Cs2CO3 (1.22 g, 3.75 mmol) in dioxane (10 ml) was heated to reflux for 5 h. After cooling to RT, EtOAc (50 ml) and water (50 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography eluting with a gradient of cyclohexane / EtOAc (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. LC / MS(m / z,MH+):607

[0158] Step 2: Methyl (R)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 2 of intermediate 13 was prepared from tert-butyl (R)-3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)pyrrolidine-1-carboxylate following a procedure similar to step 2 of intermediate 4 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. LC / MS(m / z,MH+):507

[0159] Step 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 [ka] Step 3 of intermediate 13 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):618

[0160] Intermediate 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 [ka] 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 [ka] Step 1 of intermediate 14 was prepared 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 following a procedure similar to step 1 of intermediate 13 to give 372 mg (60%) of 1-tert-butyl 3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)azetidine-1-carboxylate. LC / MS(m / z,MH+):594

[0161] Step 2: Methyl 9-(4-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] Step 2 of intermediate 14 was prepared from tert-butyl 3-((4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)phenyl)amino)azetidine-1-carboxylate following a procedure similar to step 2 of intermediate 4 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. LC / MS(m / z,MH+):494

[0162] Step 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 [ka] Step 3 of intermediate 14 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):604

[0163] Intermediate 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 [ka] Step 1: Tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate isomer 1 and isomer 2 [ka] 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) at RT was added DMAP (1.78 g, 14.57 mmol) and Boc2O (33.4 g, 153 mmol) and the suspension was stirred at RT for 12 h. 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 Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of petroleum ether / ethyl acetate 98 / 02 to 50 / 50 to give 37 g (73%) of racemic tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate as a pale yellow oil.

[0164] Racemic tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-1-carboxylate (37 g, 107 mmol) was separated by preparative SFC (column: DAICEL CHIRALCEL OJ (250x50 mm, 10 μm); mobile phase with 20% CO in 0.1% NHOH 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. LC / MS(m / z,MH+):340

[0165] Step 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 [ka] Step 2 of intermediate 15 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate, isomer 1 following a similar procedure to intermediate 5 to give 470 mg (53%) of tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1. LC / MS(m / z,MH+):606

[0166] Step 3: Methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 1 [ka] Step 3 of intermediate 15 was prepared from tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 1 following a similar procedure as step 2 of intermediate 4 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. LC / MS(m / z,MH+):506

[0167] Step 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 [ka] Step 4 of intermediate 15 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):617

[0168] Intermediate 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 [ka] 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 [ka] Step 1 of intermediate 16 was prepared from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (intermediate 3) and tert-butyl 3-(4-bromobenzyl)pyrrolidine-1-carboxylate, isomer 2 following a similar procedure as for intermediate 5 to give 390 mg (44%) of tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 2. LC / MS(m / z,MH+):606

[0169] Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, isomer 2 [ka] Step 3 of intermediate 16 was prepared from tert-butyl 3-(4-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulene-9-yl)benzyl)pyrrolidine-1-carboxylate, isomer 2 following a procedure similar to step 2 of intermediate 4 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. LC / MS(m / z,MH+):506

[0170] Step 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 [ka] Step 3 of intermediate 16 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):617

[0171] Intermediate 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]oxepin-8-carboxylate [ka] Step 1: 5-Oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate [ka] To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to WO2018091153) and pyridine (2.82 g, 2.89 ml, 35.36 mmol) in DCM (120 ml) cooled at -20°C, trifluoromethanesulfonic anhydride (8.14 g, 6 ml, 28.28 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 min. Water (50 ml) was added. The organic phase was separated and washed with a saturated aqueous solution of NaHCO3 (50 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):311

[0172] Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate [ka] To a solution of compound 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl trifluoromethanesulfonate (7.4 g, 23.85 mmol) in DMF (30 ml) and MeOH (15 ml) was added DIEA (3.15 g, 4.16 ml, 23.85 mmol) and Pd(dppf)Cl2DCM complex (1.10 g, 1.43 mmol), the suspension was degassed and purged with CO three times. The mixture was stirred under CO (5 bars) at 75 °C for 2 h. 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 Na2SO4, filtered, concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with a gradient of heptane / ethyl acetate: 85 / 15 to 80 / 20 to give 4.6 g (88%) of methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z,MH+):221

[0173] Step 3: Methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate [ka] Mixture of 1-bromo-2,4-difluoro-benzene (4.21 g, 18.1 mmol), methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate (2 g, 9.1 mmol), Cs2CO3 (11.92 g, 36.58 mmol) in toluene (12 ml). After addition of Xantphos (1.1 g, 1.8 mmol) and Pd2(dba)3 (0.83 g, 0.91 mmol), the reaction mixture was heated to reflux for 18 h. After cooling to RT, water (250 ml) and DCM (20 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc 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]oxepin-8-carboxylate. LC / MS(m / z,MH+):365

[0174] Step 4: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] To a suspension of NaH (361 mg, 9.04 mmol, 60 wt% purity) 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]oxepin-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 and the temperature was allowed to rise to RT. The reaction mixture was stirred at RT for 4 h. A mixture of acetic acid (0.14 ml) and water (20 ml) was added dropwise, followed by water (60 ml) and EtOAc (60 ml). After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue 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]oxepin-8-carboxylate. LC / MS(m / z,MH+):496

[0175] Step 5: Methyl (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate [ka] Step 5 of intermediate 17 was prepared following a procedure similar to step 1 of intermediate 12 from methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepin-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]oxepin-8-carboxylate. LC / MS(m / z,MH+):510

[0176] Step 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]oxepin-8-carboxylate [ka] Step 6 of intermediate 17 was prepared from methyl (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]oxepin-8-carboxylate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (intermediate 2) following a procedure similar to step 3 of intermediate 4 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]oxepin-8-carboxylate. LC / MS(m / z,MH+):621

[0177] Intermediate 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 [ka] Step 1: Methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate [ka] Step 1 of intermediate 18 was prepared from methyl 1-oxotetralin-6-carboxylate following a procedure similar to step 3 of intermediate 17 to give 459 mg (19%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-8-carboxylate. LC / MS(m / z,MH+):349

[0178] Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate [ka] Step 2 of intermediate 18 was prepared from methyl 2-(2,4-dichlorophenyl)-1-oxo-tetralin-6-carboxylate following a procedure similar to step 4 of intermediate 17 to give 0.48 g (31%) of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8-dihydronaphthalene-2-carboxylate. LC / MS(m / z,MH+):481

[0179] Step 3: Methyl (S)-6-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-7,8-dihydronaphthalene-2-carboxylate [ka] Step 3 of intermediate 18 was prepared following a procedure similar to 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. LC / MS(m / z,MH+):494

[0180] Step 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 [ka] Step 4 of intermediate 18 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):605

[0181] Method 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 [ka] 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 [ka] 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), Cs2CO3 (309 mg, 0.95 mmol), Pd(dppf)Cl2 complex with DCM (33 mg, 45.17 μmol) in dioxane (3.36 ml) and water (0.84 ml) was heated to 100° C. under microwave irradiation for 30 min. After cooling to RT, DCM (10 ml) and water (2 ml) were added. After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of 75 / 25 to 50 / 50 DCM / acetone to give 119 mg (43%) 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. LC / MS(m / z,MH+):619

[0182] Step 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 [ka] 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 h. DCM (5 ml) and HCl 1N were added until pH 7. After decantation, the organic phase was dried over Na2SO4, 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.

[0183] 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 [ka] 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 h. DCM (5 ml) and a saturated solution of NH4Cl (5 ml) were added. After decantation, the organic phase was dried over Na2SO4, 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.

[0184] 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 [ka] Step 1: (S)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Step 1 of Example 23 was prepared following a procedure similar to 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. LC / MS(m / z,MH+):406

[0185] Step 2: (S)-8-Bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] To a solution of (S)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate (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 h. A concentrated aqueous solution of NaHCO3 was added. After decantation, the organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of 95 / 05 to 90 / 10 DCM / MeOH to give 550 mg (72%) of (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate. LC / MS(m / z,MH+):484

[0186] Step 3: (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate [ka] Step 3 of Example 23 was prepared from (S)-8-bromo-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate and 2,4-dichlorophenylboronic acid following the same procedure as step 1 of Example 1 to obtain 200 mg (32%) of (S)-8-(2,4-dichlorophenyl)-9-(4-(pyrrolidin-3-yloxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ylpivalate. LC / MS(m / z,MH+):550

[0187] Step 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 [ka] Step 4 of example 23 was prepared 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) following a procedure similar to step 3 of intermediate 4 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. LC / MS(m / z,MH+):661

[0188] Step 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 [ka] Step 5 of example 23 was prepared 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 following a procedure similar to that of example 16 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.

[0189] 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 [ka] Step 1: 6,7-Dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate [ka] 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. was 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 min and at RT for 2 h. DCM (50 ml) and cold water (30 ml) were added. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 2.4 g (99%) of 6,7-dihydro-5H-benzo[7]annulen-9-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):293

[0190] Step 2: (S)-3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine [ka] Step 2 of Example 26 was prepared following a procedure similar to 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. LC / MS(m / z,MH+):306

[0191] Step 3: (S)-3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine [ka] Step 3 of example 26 was prepared from (S)-3-(4-(6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine and pyridinium tribromide following a procedure similar to step 2 of example 23 to give 1.48 g (98%) of (S)-3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine. LC / MS(m / z,MH+):384

[0192] Step 4: (S)-3-(4-(8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine [ka] Step 4 of example 26 was prepared from (S)-3-(4-(8-bromo-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine and 2,4-dichlorophenylboronic acid following a procedure similar to step 1 of example 1 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. LC / MS(m / z,MH+):450

[0193] Step 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 [ka] Step 5 of example 26 was prepared 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) following a procedure similar to step 3 of intermediate 4 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.

[0194] 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 [ka] Step 1: (S)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate [ka] Step 1 of Example 27 was prepared following a procedure similar to Step 1 of Intermediate 12 from 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate (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-ylpivalate. LC / MS(m / z,MH+):424

[0195] Step 2: (S)-4-Bromo-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate [ka] Step 2 of example 27 was prepared from (S)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate and pyridinium tribromide following the same procedure as step 3 of example 23 to obtain 300 mg (crude) of (S)-4-bromo-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate. LC / MS(m / z,MH+):502

[0196] Step 3: (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate [ka] Step 3 of Example 27 was prepared from (S)-4-bromo-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate and 2,4-dichlorophenylboronic acid following a procedure similar to that of Step 1 of Example 1 to give 83 mg (29%) of (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate. LC / MS(m / z,MH+):568

[0197] Step 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 [ka] Step 4 of example 27 was prepared from (S)-4-(2,4-dichlorophenyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ylpivalate and (E)-4-bromo-N,N-dimethyl-but-2-enamide (intermediate 2) following a procedure similar to step 3 of intermediate 4 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-ylpivalate. LC / MS(m / z,MH+):679

[0198] Step 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 [ka] Step 5 of example 27 was prepared 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-ylpivalate (intermediate 2) following a procedure similar to that of example 16 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

[0199] The compounds listed in Table 1a above were subjected to the pharmacological tests described below.

[0200] Test: In vitro antiproliferative assay Said test involves determining the in vitro antiproliferative activity of the compounds of Table 1a.

[0201] Antiproliferative activity measurements were performed using MCF7-WT (ATCC), MCF7-Y537S and HCC1428-LTED cells as described herein below.

[0202] 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 at 37°C and 5% CO2.

[0203] On day 2, compounds were tested in triplicate in a 10-point dose response (1:3 serial dilution with the highest concentration starting at 300 nM); DMSO (negative control) at the upper limit and staurosporine (1 μM) (positive control) at the lower limit were also included. MCF7-WT cells were then supplemented with a final 0.1 nM b-estradiol. After cells were treated, the assay plate was returned to the incubator at 37°C and 5% CO2.

[0204] Cell viability was measured according to the vendor's recommendations (CellTiter-Glo, Promega) on day 8. Relative IC50 measurements were calculated using a four-parameter logistic derived Levenburg Marquardt algorithm (IDBS XL model 205fit in A-base) as follows:

[0205] Table 2 below shows the antiproliferative activity results for the compounds of Table 1a.

[0206] [Table 14]

[0207] Thus, it is clear that the tested compounds have antiproliferative activity in both wild-type and mutant cell lines as tested above. As shown in Table 2, the compounds described herein exhibit IC50 activity of less than 1 μM, generally less than 500 nM.

[0208] Thus, the compounds of formula (I) may be used for the preparation of medicaments, in particular antiproliferative agents, as well as medicaments useful in the treatment of diseases in which the estrogen receptor is involved.

[0209] Thus, also provided herein is a medicament comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0210] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above, for use as a medicament.

[0211] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above for use in therapy, in particular in the treatment of diseases in which the estrogen receptor is involved.

[0212] There is also provided herein a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0213] A particular embodiment is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined above, for use in the treatment of cancer.

[0214] In one embodiment, the cancer is a hormone-dependent cancer.

[0215] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0216] In another embodiment, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer and lung cancer or metastases thereof.

[0217] In another embodiment, the metastasis is a brain metastasis.

[0218] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0219] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0220] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR or PI3K inhibitors.

[0221] According to another aspect, there is provided herein a method of treating a pathological condition as indicated above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0222] There is also provided herein the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament useful for treating any of the pathological conditions set out above, more particularly useful for the treatment of cancer.

[0223] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions also contain an effective dose of at least one compound of formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0224] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the conventional excipients known to those skilled in the art.

[0225] The active ingredient of formula (I) above, or its base, acid, zwitterion or salt thereof, in unit dosage form, in admixture with conventional pharmaceutical excipients, may be administered to animals and humans for the treatment of the above disorders or diseases in pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration.

[0226] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, ocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, it is possible to use the compounds of formula (I) in creams, gels, ointments or lotions.

[0227] As an example, a unit dosage form of a compound of formula (I) in the form of a tablet may contain the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Cornstarch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0228] There may be particular cases in which higher or lower dosages are appropriate. According to normal practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. A compound of formula (I), or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, 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 is a hydrogen atom, (C １ -C ３ ) an alkyl group or a cyclopropyl group; R5 is a (C) group such as a methyl group. １ -C ３ ) an alkyl group, a halogen atom such as a fluorine atom, a cyano group, or a trifluoromethyl group, etc. １ -C ３ ) independently represent a fluoroalkyl group; - R6 is A phenyl group (the phenyl group is optionally substituted with a halogen atom, a cyano group, or an —OH group (C １ -C ６ ) alkyl group; (C １ -C ６ ) fluoroalkyl group; ３ -C ６ ) a cycloalkyl group; １ -C ６ ) an alkoxy group; １ -C ６ ) a fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; (C １ -C ４ ) an alkylthio group; １ -C ４ ) a fluoroalkylthio group; １ -C ４ ) optionally substituted with 1 to 3 substituents independently selected from alkylsulfonyl groups and —OH groups; ■ (C ３ -C ６ ) a fused phenyl group selected from a phenyl group fused to a cycloalkyl, ３ -C ６ ) the cycloalkyl ring optionally contains unsaturation, and the fused phenyl group is １ -C ３ ) an alkyl group, a hydroxyl group, a halogen atom, (C １ -C ６ ) fluoroalkyl group and (C １ -C ３ ) optionally substituted with 1 to 3 substituents independently selected from alkoxy groups; ■ optionally containing 1 to 2 unsaturations; Fluorine atom, —OH group, (C １ -C ３ ) alkyl group, (C １ -C ３ ) a fluoroalkyl group, １ -C ３ ) an alkoxy group, (C １ -C ３ ) a bicyclic group containing 5 to 12 carbon atoms, optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; Heteroaryl groups containing 2 to 9 carbon atoms, 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as pyridyl or pyrrolyl groups (the heteroaryl groups are not limited to halogen atoms, (C １ -C ６ ) alkyl group, (C １ -C ６ ) a fluoroalkyl group, １ -C ６ ) an alkoxy group, (C １ -C ６ ) optionally substituted with 1 to 3 substituents independently selected from fluoroalkoxy groups, cyano groups, carbamoyl groups, and —OH groups; Cycloalkyl groups containing 3 to 7 carbon atoms (the cycloalkyl groups are saturated or partially saturated and optionally 〇Fluorine atom, -OH group, (C １ -C ３ ) alkyl group, (C １ -C ３ ) a fluoroalkyl group, １ -C ３ ) an alkoxy group, (C １－ C ３ ) a fluoroalkoxy group, an oxo group, ○ (C ３ -C ６ ) cycloalkyl groups and phenyl groups (see above (C ３ -C ６ ) Cycloalkyl or phenyl groups contain 1 or 2 halogen atoms or (C １ -C ３ ) optionally substituted with an alkyl group and substituted with 1 to 4 substituents independently selected from ■ (C ３ -C ６ ) Cycloalkyl(C １ -C ３ ) alkyl group, optionally containing a fluorine atom, an —OH group, (C １ -C ４ ) alkyl group, (C １ -C ３ ) a fluoroalkyl group, １ -C ３ ) substituted on said cycloalkyl with 1 to 4 substituents independently selected from fluoroalkoxy and oxo groups; ■ 4- to 7-membered heterocycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen and sulfur, such as tetrahydropyranyl or tetrahydrofuranyl groups (the heterocycloalkyl groups are saturated or partially saturated, and optionally contain fluorine atoms, (C １ -C ３ ) alkyl group, (C １ -C ３ ) a fluoroalkyl group, １ -C ３ ) a fluoroalkoxy group, an oxo group, (C １ -C ３ ) substituted with 1 to 3 substituents independently selected from alkoxy groups and —OH groups; ■ (C １ -C ６ ) alkyl groups, such as isobutyl or ethylbutyl groups (the alkyl groups may be fluorine atoms, (C １ -C ３ ) an alkoxy group, (C １ -C ３ ) optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups and —OH groups; and ■ Phenyl (C １ -C ２ ) an alkyl group (the phenyl group is a halogen atom; (C １ -C ３ ) alkyl group; (C １ -C ３ ) fluoroalkyl group; １ -C ３ ) an alkoxy group; １ -C ３ ) optionally substituted with 1 to 3 substituents independently selected from a fluoroalkoxy group; a cyano group; and a —OH group. represents a group selected from - X is -CH ２ represents -, -O- or -S-; - n is 0, 1 or 2; m is 0 or 1; - Z is 【Chemistry 2】 represents a group selected from (In the formula, R1 and R2 are independently a hydrogen atom, -CH ３ group, -CH ２ CH ３ group or -CH ２ CH ２ represents an OH group, or R1 and R2 together with the nitrogen atom to which R1 and R2 are attached form a 4-6 membered heterocycloalkyl group, said heterocycloalkyl group optionally containing further heteroatoms selected from oxygen, nitrogen and sulfur; ○Y is -CH ２ represents -, -CH=, -CR7=, -O- or -NH-, where R7 is a fluorine atom or (C １ -C ３ ) represents an alkyl group; 〇 【Chemistry 3】 represents a single bond or a double bond; ○p is 0 or 1).

2. Formula (I'): 【Chemistry 4】 2. A compound of formula (I) according to claim 1, characterized in that it is: or a pharma- ceutically acceptable salt thereof.

3. Y is -CH ２ A compound of formula (I) or (I') according to claim 1 or 2, characterised in that Y represents -, -CH=, -O- or -NH-, preferably Y represents -O-, or a pharma- ceutically acceptable salt thereof. 【Request 4】 【Chemistry 5】 A compound of formula (I) or (I') according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, characterized in that represents a single bond.

5. A compound of formula (I) or (I') according to any one of claims 1 to 4, characterized in that p is 1, or a pharma- ceutically acceptable salt thereof.

6. Formula (I″): 【Chemistry 6】 2. A compound of formula (I) according to claim 1, characterized in that it is: or a pharma- ceutically acceptable salt thereof.

7. R1 and R2 are CH ３ 7. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, characterized in that:

8. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, characterized in that R3 is a -COOH group.

9. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, characterized in that R3' and R3'' represent a hydrogen atom.

10. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, characterized in that R4 represents a hydrogen atom.

11. X is -CH ２ -, or a pharma- ceutically acceptable salt thereof. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 10, characterized in that it represents -.

12. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 11, characterized in that n is 0, or a pharma- ceutically acceptable salt thereof.

13. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

14. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 13, characterized in that R6 represents a phenyl group, said phenyl group being optionally substituted with one or two substituents independently selected from a chlorine atom, a fluorine atom and a methyl group, or a pharma- ceutically acceptable salt thereof.

15. R6 represents a pyridyl group, and the pyridyl group is selected from the group consisting of a halogen atom and (C １ -C ６ 14. A compound of formula (I), (I') or (I'') according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein the compound is substituted by two substituents independently selected from an alkoxy group, more particularly selected from a fluorine atom and a methoxy group.

16. The following compound: - (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-carvone 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]oxepin-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) A compound of formula (I), (I') or (I'') according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, in particular the hydrochloride thereof, characterized in that it is selected from:

17. Formula 1F: 【Chemistry 7】 (In the formula, R1, R2, R3', R3'', R4, R5, R6, m, n, p, X, Y and 【Chemistry 8】 is as defined in any one of claims 1, 3-5 and 7-15, and R3a is a hydrogen atom or a carboxylic acid ester, e.g. -COOMe, -COOEt etc or a protected -OH, e.g. O-pivaloyl etc), is converted to a compound of formula (I) or (I'), e.g. in the presence of a hydroxide ion source, e.g. NaOH or LiOH in a solution in THF or dioxane, or a pharma- ceutically acceptable salt thereof.

18. A process for preparing a compound of formula (I) or (I') as defined in any one of claims 1 to 5 and 7 to 16, or a pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula 1F': 【Chemistry 9】 wherein R1, R2, R3', R3'', R4, R5, R6, m, n, p, X and Y are as defined in any one of claims 1, 3 to 5 and 7 to 15, and R3a is a hydrogen atom or a carboxylic acid ester, such as -COOMe, -COOEt, or a protected -OH, such as O-pivaloyl, is converted to a compound of formula (I) or (I') in the presence of a hydroxide ion source, such as NaOH or LiOH, in a solution in THF or dioxane, said step being optionally preceded by a step to obtain a compound 1F', in which a compound of formula 1T: 【Chemistry 10】 (wherein R1, R2, R3', R3'', R4, R5, m, n, p, X and Y are as defined in any one of claims 1, 3 to 5 and 7 to 15, and R3a is as defined above). is the boron reagent R6B(OR') ２ The compound is subjected to Suzuki coupling with -B(OR') ２ is a boronic acid or pinacolato ester and R6 is as defined in any of claims 1, 14 or 15.

19. An intermediate compound selected from compounds of formula 1T, 1F, 1F', and 2B, or any of the pharma- ceutically acceptable salts thereof. 【Chemistry 11】 (In the formula, R1, R2, R3', R3'', R4, R5, R6, m, n, p, X, Y and 【Chemistry 12】 is as defined in any one of claims 1, 3 to 5 and 7 to 15, and R3a is a hydrogen atom, or a carboxylic acid ester, such as -COOMe, -COOEt, or a protected -OH, such as O-pivaloyl.

20. An intermediate compound of formula 1E, or any of its pharma- ceutically acceptable salts: 【Chemistry 13】 (Wherein, R1, R2, R5, Y, n, P and 【Chemistry 14】 is as defined in any one of claims 1, 3 to 5, 7 and 12).

21. A medicament comprising a compound of formula (I) according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

23. 17. A compound of formula (I) as defined in any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

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

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