Disclosed herein are novel fluorinated N-propyl-pyrrolidine derivatives, the processes for their preparation, as well as the therapeutic uses thereof, in particular as anticancer agents via selective antagonism and degradation of estrogen receptors.

The Estrogen Receptors (ER) belong to the steroid/nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation and in target tissues. ERs are in two forms: the estrogen receptor alpha (ERa) and the estrogen receptor beta (ER0) respectively encoded by the ESRI and the ESR2 genes. ERa and ERp are ligand- activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17p-estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA/ER complex interacts with co-regulators to modulate the transcription of target genes.

ERa is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERa signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis.

ERa is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high level of ERa are classified as ERa-positive breast tumors. The etiological role of estrogen in breast cancer is well established and modulation of ERa signaling remains the mainstay of breast cancer treatment for the majority ERa-positive breast tumors. Currently, several strategies for inhibiting the estrogen axis in breast cancer exist, including: 1- blocking estrogen synthesis by aromatase inhibitors that are used to treat early and advanced ERa-positive breast cancer patients; 2- antagonizing estrogen ligand binding to ERa by tamoxifen which is used to treat ERa-positive breast cancer patients in both pre- and post- menopausal setting; 3- antagonizing and downregulating ERa levels by fulvestrant, which is used to treat breast cancer in patients that have progressed despite endocrine therapies such as tamoxifen or aromatase inhibitors. Although these endocrine therapies have contributed enormously to reduction in breast cancer development, about more than one-third of ERa-positive patients display de novo resistance or develop resistance over time to such existing therapies. Several mechanisms have been described to explain resistance to such hormone therapies. For example, hypersensitivity of ERa to low estrogen level in treatment with aromatase inhibitors, the switch of tamoxifen effects from antagonist to agonist effects in tamoxifen treatments or multiple growth factor receptor signaling pathways. Acquired mutations in ERa occurring after initiation of hormone therapies may also play a role in treatment failure and cancer progression. Certain mutations in ERa, particularly those identified in the Ligand Binding Domain (LBD), result in the ability to bind to DNA in the absence of ligand and confer hormone independence in cells harboring such mutant receptors.

Most of the endocrine therapy resistance mechanisms identified rely on ERa- dependent activity. One of the new strategies to counterforce such resistance is to shut down the ERa signaling by removing ERa from the tumor cells using Selective Estrogen Receptors Degraders (SERDs). Clinical and preclinical data showed that a significant number of the resistance pathways can be circumvented by the use of SERDs.

There is still a need to provide SERDs with good degradation efficacy.

Documents WO2017/140669 and W02018/091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)- pyrrolidine derivatives useful as SERDs. However, as detailed hereafter, such compounds do not display an optimized pharmacological profile, especially regarding the limitation of CYP3A4 induction.

The inventors have now found novel compounds able to selectively antagonize and degrade the estrogen receptors (SERDs compounds), for use in cancer treatment.

Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof:

wherein ‐ R1 and R2 independently represent a hydrogen atom or a deuterium atom; ‐ 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 and R5 independently represent a hydrogen atom, a fluorine atom , a -NH ₂ group, a (C1-C3)alkyl group such as a methyl group, a (C1-C3)alkoxy group such as a methoxy group or an ethoxy group, or a -OH group; or R4 and R5 together form an oxo group or R4 and R5 together form a =NOCH ₃ group or a (C ₃ -C ₅ )cycloalkyl group with the carbon atom to which they are attached; ‐ R7 represents a hydrogen atom, a methyl group, a -OH group or a fluorine atom; or alternatively R4 and R7 together form a cyclopropyl group together with the bond to which they are attached, that gives with the adjacent pyrrolidine group an azaspiro[2.4]heptane; ‐ R6 represents a group selected from: ^ a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C ₁ -C ₆ )alkyl group optionally substituted with a cyano group or a -OH group; a (C ₁ -C ₆ )fluoroalkyl group; a (C3-C6)cycloalkyl group; a (C1-C6)alkoxy group; a (C1-C6)fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C ₁ -C ₄ )alkylthio group; a (C ₁ -C ₄ )fluoroalkylthio group; a (C ₁ -C ₄ )alkylsulfonyl group; and a -OH group; ^ a fused phenyl group, selected from phenyl groups fused with a (C3-C6)cycloalkyl, which (C3-C6)cycloalkyl ring optionally comprises an unsaturation and wherein the fused phenyl is optionally substituted with 1 to 3 substituents independently selected from a (C1-C3)alkyl group, a hydroxy group, a halogen atom, a (C1-C6)fluoroalkyl group and a (C1-C3)alkoxy group; ^ a bicyclic group comprising 5 to 12 carbon atoms, optionally comprising 1 to 2 unsaturations; optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a -OH group, a (C1-C3)alkyl group, a (C ₁ -C ₃ )fluoroalkyl group, a (C ₁ -C ₃ )alkoxy group, a (C ₁ -C ₃ )fluoroalkoxy group and an oxo group; ^ a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as a pyridyl group, a pyridone group or a pyrrolyl group, said heteroaryl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C ₁ -C ₆ )alkyl group, a (C ₁ -C ₆ )fluoroalkyl group, a (C ₁ -C ₆ )alkoxy group, a (C1-C6)fluoroalkoxy group, a cyano group, a carbamoyl group and a -OH group; ^ a cycloalkyl group comprising 3 to 7 carbon atoms, said cycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 4 substituents independently selected from: o a fluorine atom, a -OH group, a (C1-C3)alkyl group, a (C ₁ -C ₃ )fluoroalkyl group, a (C ₁ -C ₃ )alkoxy group, a (C ₁ -C ₃ )fluoroalkoxy group, an oxo group, o a (C3-C6)cycloalkyl group and a phenyl group, said (C3-C6)cycloalkyl or phenyl groups being optionally substituted with one or two halogen atom(s) or (C ₁ -C ₃ )alkyl group(s); ^ a (C3-C6)cycloalkyl(C1-C3)alkyl group, optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from: a fluorine atom, a -OH group, a (C ₁ -C ₄ )alkyl group, a (C ₁ -C ₃ )fluoroalkyl group, a (C ₁ -C ₃ )fluoroalkoxy group and an oxo group; ^ a 4 to 7 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl group or a tetrahydrofuranyl, said heterocycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom, a (C1-C3)alkyl group, a (C1-C3)fluoroalkyl group, a (C1-C3)fluoroalkoxy group, an oxo group, a (C1-C3)alkoxy group and a -OH group; ^ a (C ₁ -C ₆ )alkyl group, such as an isobutyl group or an ethylbutyl group, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group and a -OH group; and ^ a phenyl(C ₁ -C ₂ )alkyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C ₁ -C ₃ )alkyl group; a (C ₁ -C ₃ )fluoroalkyl group; a (C ₁ -C ₃ )alkoxy group; a (C ₁ -C ₃ )fluoroalkoxy group; a cyano group; and a -OH group; ‐ X represents -CH ₂ -, -O- , or -S-; ‐ Y represents -CH=, -N= or -CR”=, wherein R” represents a (C ₁ -C ₃ )alkyl group or a halogen atom, such as a fluorine or a chlorine atom, a cyano group, or a (C ₁ -C ₃ )fluoroalkyl group, such as a trifluoromethyl; ‐ R8 independently represents a (C ₁ -C ₃ )alkyl group, such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or a (C ₁ -C ₃ )fluoroalkyl group, such as a trifluoromethyl; ‐ R9 represents a hydrogen atom or a fluorine atom; ‐ R10 and R10’ independently represent a hydrogen atom or a fluorine atom ; ‐ R11 represents a hydrogen atom, or a (C ₁ -C ₃ )alkyl group or a cyclopropyl; ‐ n is 0, 1 or 2, and ‐ m is 0 or 1. The compounds of formula (I) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers. The compounds of formula (I) may be present as well under tautomer forms. The compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Hence, herein are provided compounds of formula (I) or pharmaceutically acceptable salts thereof. These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided. Among suitable salts of the compounds of formula (I), hydrochloride may be cited.

As used herein, the terms below have the following definitions unless otherwise mentioned throughout the instant specification:

- a halogen atom: a fluorine, a chlorine, a bromine or an iodine atom, and in particular a fluorine and a chlorine atom;

- an oxo: a “=O” group;

- an alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms (noted “(Ci-C6)alkyl”). By way of examples, mention may be made of, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, and the like;

- a cycloalkyl group: a monocyclic alkyl group comprising, unless otherwise mentioned, from 3 to 7 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted. By way of examples, mention may be made of, but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, groups and the like, in particular a cyclopentyl, a cyclohexyl, a cycloheptyl, a cycloheptenyl, or a cyclohexenyl;

- a cycloalkylalkyl group: an alkyl group substituted with a cyclic alkyl group as defined above. Mention may be made of, but not limited to: cyclobutylmethyl;

- a heterocycloalkyl group: a 4 to 7-membered cycloalkyl group, saturated or partially unsaturated, comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular being oxygen or nitrogen. By way of examples, mention may be made of, but not limited to: morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, aziridinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, tetrahydropyranyl, and tetrahydrothiopyranyl. The heterocycloalkyl is advantageously tetrahydrofuranyl or tetrahydropyranyl.

- a fluoroalkyl group: an alkyl group as previously defined where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -CH2F, -CHF2, -CH2CHF2, -CH2CH2F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl group. By way of example, mention may be made of trifluoromethyl group or trifluoroethyl group and the like; - an alkoxy group: an -O-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methoxy, ethoxy, propoxy,sopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, andhe like; a fluoroalkoxy group: an -O-alkyl group where the alkyl group is as previously defined and where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -OCH ₂ F, -OCHF ₂ , -OCH ₂ CH ₂ F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group can be named perfluoroalkoxy group. By way of example, mention may be made ofrifluoromethoxy group and the like; a (C1-C4)alkylthio group also named a (C1-C4)alkylsulfanyl group: a -S-alkyl group wherehe alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methylthio, ethylthio, propylthio, isopropylthio, linear, secondary or tertiary butylthio, isobutylthio, and the like; a (C1-C4)alkylsulfonyl group: a -SO2-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limitedo -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ and the like; a (C1-C4)fluoroalkylthio group also named a (C1-C4)fluoroalkylsulfanyl group: a -S-fluoroalkyl group where the fluoroalkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: fluoromethylthio, difluoromethylthio,rifluoromethylthio and the like; a fused phenyl: a bicyclic radical comprising from 7 to 10 carbon atoms and that contains a phenyl moiety. Said phenyl moiety may be fused to a (C ₃ -C ₆ )cycloalkyl group, i.e. the phenyl moiety may share a bond with said (C ₃ -C ₆ )cycloalkyl group. The fused phenyl group may be bound to the rest of the molecule by its phenyl moiety. It may be substituted. Examples are, but are not limited to indanyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl,etrahydronaphthalenyl and the like; - a heteroaryl group: a cyclic 5 to 10-membered aromatic group containing between 2 and 9 carbon atoms and containing between 1 and 3 heteroatoms, such as nitrogen, oxygen or sulfur. Such nitrogen atom may be substituted with an oxygen atom in order to form a -N-0 bond. Such -N-0 bond can be in a form of a N-oxide (-N ⁺ -0‘). Said heteroaryl group may be monocyclic or bicyclic. By way of examples of heteroaryl groups, mention may be made of, but not limited to: thiophene, furan, thiadiazole, thiazole, imidazole, pyridazine, triazine, pyrazine, oxadiazole, pyrazole, isothiazole, oxazole, isoxazole, pyridine, pyrimidine, benzotriazole, benzoxazole, pyrrolo[2,3-b]pyridine, benzimidazole, benzoxadiazole, benzothiazole, benzothiadiazole, benzofuran, indole, isoquinoline, indazole, benzisoxazole, benzisothiazole, pyridone groups and the like. The heteroaryl group is advantageously pyridine, pyrrole, imidazole, pyrazine, furane, thiazole, pyrazole, thiadiazole, pyridazine, pyridone and pyrimidine, and more particularly pyridine, pyridone and pyrrole;

- a bicyclic group, generally comprising 5 to 12 carbon atoms, is a hydrocarbon group selected from groups comprising two rings connected through:

• a single common atom: a “spirobicyclic ring”. Such spiro bicyclic alkyl generally comprises 5 to 11 carbon atoms referring to a “spiro(C5-Cn)bicyclic ring”. The rings may be saturated or partially unsaturated. Such spirobicyclic ring may be unsubstituted or substituted, in particular by at least one (Ci-C3)alkyl group such as methyl or a fluorine. By way of examples of spiro(C5-Cn)bicyclic ring as for the definition of R6, mention may be made of, but not limited to: spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.3]heptene, spiro[2.5]octane and 7-azaspiro[3.5]nonane. The spiro(C5-Cn)bicyclic ring is advantageously spiro[3.3]heptane or spiro[3.3]heptene still for the R6 group.

• two common atoms: In that case the bicyclic group comprises 7 to 12 carbon atoms and optionally comprises 1 to 2 unsaturations. By way of examples of such bicyclic groups, mention may be made of, but not limited to: cis-l,3a,4,5,6,6a-hexahydropentalenyl group, bicyclo[3.1.0]hexan-l-yl and bicyclo[4.1.0]heptanyl.

• three or more common atoms: In that case the bicyclic group comprises 6 to 10 carbon atoms, such bicyclic group may be referred to as a “bridged (C6-Cio)cycloalkyl” group, the rings share three or more atoms and the bridge contains at least one atom, for example 1, 2 or 3 atoms and preferentially 1 atom. By way of examples of such bridged cycloalkyl groups, mention may be made of, but not limited to bicyclo[3.2.1]octan-3-yl and bicyclo[2.2. l]heptan-2-yl.

- a zwitterion means: a globally neutral molecule with a positive and a negative electrical charge and having an acidic group and a basic group. In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above, R3 is a -COOH group or a -OH group, more particularly R3 is a -COOH group. In another embodiment, in the compounds of formula (I) as defined above, when m is 1 then X represents -CH ₂ - or -O-. In another embodiment, in the compounds of formula (I) as defined above, X represents -CH ₂ - or -O-, in particular X represents -CH ₂ -. In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 independently represent a hydrogen atom or a fluorine atom, more particularly R4 and R5 both represent a hydrogen atom or R4 and R5 both represent a fluorine atom. In another embodiment, in the compounds of formula (I) as defined above, R4 and R5 both represent a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above, R7 represents a hydrogen atom or a fluorine atom, more particularly a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above: - R4 and R5 independently represent a hydrogen atom, a -NH2 group, a (C1-C3)alkyl group such as a methyl group, a (C ₁ -C ₃ )alkoxy group such as a methoxy group or an ethoxy group, or a -OH group; or R4 and R5 together form an oxo group or R4 and R5 together form a =NOCH3 group or a (C3-C5)cycloalkyl group with the carbon atom to which they are attached, and - R7 represents a hydrogen atom, a methyl group or a -OH group; or alternatively R4 and R7 together form a cyclopropyl group together with the bond to which they are attached, that gives with the adjacent pyrrolidine group an azaspiro[2.4]heptane. In another embodiment, in the compounds of formula (I) as defined above, R6 represents a group selected from: - a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C1-C6)alkyl group optionally substituted with a cyano group or a -OH group; a (C1-C6)fluoroalkyl group; a (C3-C6)cycloalkyl group; a (C1-C6)alkoxy group; a (C1-C6)fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C1-C4)alkylthio group; a (C1-C4)fluoroalkylthio group; a (C ₁ -C ₄ )alkylsulfonyl group; and a -OH group; - a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms dependently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including rbon atoms and heteroatoms, such as a pyridyl group, a pyridone group or a pyrrolyl group, id heteroaryl group being optionally substituted with 1 to 3 substituents independently lected from a halogen atom, a (C1-C6)alkyl group, a (C1-C6)fluoroalkyl group, a C ₁ -C ₆ )alkoxy group, a (C ₁ -C ₆ )fluoroalkoxy group, a cyano group, a carbamoyl group and a OH group; and a cycloalkyl group comprising 3 to 7 carbon atoms, said cycloalkyl group being saturated partially saturated and being optionally substituted with 1 to 4 substituents independently lected from: a fluorine atom, a -OH group, a (C ₁ -C ₃ )alkyl group, a (C ₁ -C ₃ )fluoroalkyl oup, a (C3-C6)cycloalkyl group, a (C1-C3)alkoxy group, a (C1-C3)fluoroalkoxy group, an xo group and a phenyl group optionally substituted with a halogen atom or a (C1-C3)alkyl oup. In another embodiment, in the compounds of formula (I) as defined above, R6 presents a phenyl group, said phenyl group being optionally substituted with 1 to 3 bstituents independently selected from a halogen atom, a (C ₁ -C ₆ )alkyl group and a C ₁ -C ₆ )fluoroalkyl group; more particularly selected from: a fluorine atom, a chlorine atom, methyl group and a trifluoromethyl group. In such embodiment, in particular, at least one the substituents of said phenyl group comprises a halogen atom. In another embodiment, in the compounds of formula (I) as defined above, R6 presents a pyridyl group, said pyridyl group being optionally substituted with 1 to 3 bstituents independently selected from a (C1-C6)alkoxy group, more particularly a ethoxy group. In another embodiment, in the compounds of formula (I) as defined above, R6 presents a saturated or partially saturated cyclohexyl group, more particularly a cyclohexyl oup or a cyclohexenyl group, said saturated or partially saturated cyclohexyl group being ptionally substituted with 1 to 4 substituents independently selected from a (C ₁ -C ₃ )alkyl oup, more particularly with 1 to 4 methyl group(s). In another embodiment, in the compounds of formula (I) as defined above, R3’ and R3” both represent a hydrogen atom.

In another embodiment, in the compounds of formula (I) as defined above, n is 0.

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

In another embodiment, in the compounds of formula (I) as defined above, R9 represents a hydrogen atom.

In another embodiment, in the compounds of formula (I) as defined above, RIO and RIO’ both represent a hydrogen atom; or one of RIO and RIO’ represents a hydrogen atom and the other a fluorine atom.

In another embodiment, in the compounds of formula (I) as defined above, RIO and RIO’ both represent a hydrogen atom.

In another embodiment, in the compounds of formula (I) as defined above, R11 represents a hydrogen atom or a methyl group, more particularly a hydrogen atom.

In another embodiment, in the compounds of formula (I) as defined above, m is 1.

In another embodiment, in the compounds of formula (I) as defined above, R3 is a -COOH group and R6 is a phenyl group comprising one, two or three substitutions independently selected from a chlorine atom, a fluorine atom, a chlorine atom, a methyl group and a trifluoromethyl group, at least one of the substitutions comprising a halogen atom. In such embodiment, R3’ and R3” are in particular hydrogen atoms. Still in such embodiment, Rl, R2, R4, R5, R7, R9 and Rl l are hydrogen atoms. In such embodiment, both RIO and RIO’ are hydrogen atoms or one of RIO and RIO’ is a hydrogen atom and the other is a fluorine atom. Still in such embodiment, Y is -CH=, m is equal to 1 and n is equal to 0. Still in such embodiment, X is a -CH2- group.

Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof:

- 8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S) isomer (1), - 8-(2-chloro-4-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3-yl)methyl)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (2),

- 8-(4,4-dimethylcyclohexyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)methyl)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (3),

- 9-(4-(( 1 -(3 ,3 -difluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-8-(4-fluoro-2- methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (4),

- 9-(4-(( 1 -(3 ,3 -difluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-8-(4-fluoro-2- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid hydrochloride, Isomer 1 (5),

- 8-(3-chloro-2-methylphenyl)-9-(4-((l-(3,3-difluoropropyl)pyr rolidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1 (6),

- 4-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2,3- dihydrobenzo[b]oxepine-8-carboxylic acid hydrochloride, Isomer 1 (7),

- 4-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2,3- dihydrobenzo[b]oxepine-8-carboxylic acid hydrochloride, Isomer 2 (8),

- 8-(2,4-dichlorophenyl)-9-(4-(( 1 -(3 , 3 -difluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-6, 7 - dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (9),

- 8-(2,4-difluorophenyl)-9-(4-((l-(3,3-difluoropropyl)pyrrolid in-3-yl)methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (10),

- 8-(4,4-dimethylcyclohex-l-en-l-yl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1 (11),

- 9-(4-(( 1 -(3 -fluoropropyl)pyrroli din-3 -yl)methyl)phenyl)-8-(2-methyl-3 - (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid hydrochloride, Isomer 1 (12),

- 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((l-(3-fluoropro pyl)pyrrolidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1 (13),

- 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(6 -methoxypyridin-3-yl)-6,7- dihydro-5H- benzo[7]annulene-3-carboxylic acid, Isomer 1 (14), - 8-(3-chloro-2-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3-yl)methyl)phenyl)-

6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (15),

- 8-(3-chloro-2-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3-yl)methyl)phenyl)-

6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (16),

- 8-(4-fluoro-2-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3-yl)methyl)phenyl)-

6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (17),

- 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid, Isomer 1 (18),

- 8-(2,4-difluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (19),

- 8-(3 -fluoro-2-methylphenyl)-9-(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-

6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (20),

- 8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3-yl)methyl)phenyl)-

6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (21),

- 8-(2,4-dichlorophenyl)-9-(4-((3 -fluoro- 1 -(3 -fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid, 2,2,2- trifluoroacetic acid, Isomer 2 (22),

- 8-(2,4-dichlorophenyl)-9-(4-((3 -fluoro- 1 -(3 -fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid, 2,2,2- trifluoroacetic acid, Isomer 1 (23),

- 8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid, (R) Isomer (24),

- 3-(2,4-dichlorophenyl)-4-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2H- thiochromene-7-carboxylic acid hydrochloride, Isomer 1 (25),

- 8-(2,4-dichlorophenyl)-9-(4-(difluoro(l-(3-fluoropropyl)pyrr olidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid, Isomer 1 (26),

- 8-(2-chloro-4-fluorophenyl)-9-(4-(( 1 -(3 ,3 -difluoropropyl )pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1 (27),

- 9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)- 8-(2-methyl-3- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid hydrochloride, Isomer 1 (28), - 8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-ol hydrochloride, Isomer 1 (29),

- 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3 -methyl-2- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid, Isomer 1 (30),

- 8-(2,4-dichlorophenyl)-9-(4-(( 1 -(3 , 3 -difluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-6, 7 - dihydro-5H-benzo[7]annulen-3-ol hydrochloride, Isomer 1 (31),

- 9-(4-(( 1 -(3 ,3 -difluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-8-(4-fluoro-2,6- dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (32),

- 9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)- 8-(2- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid (33),

- 9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)- 8-(3-methyl-2- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid hydrochloride, Isomer 1 (34),

- 8-(4-fluoro-2, 6-dimethylphenyl)-9-(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1 (35),

- 6-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-7,8- dihydronaphthalene-2-carboxylic acid hydrochloride, Isomer 1 (36),

- 8-(4-chlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl) methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (37),

- 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(4 -(trifluoromethyl)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (38),

- 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-8-(3 -(trifluoromethyl)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (39),

- 8-(3-chlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl) methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, Isomer 1 (40),

- 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-me thyl-8-(4- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid, Isomer 1 (41), - 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-me thyl-8-(4- (trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylic acid, Isomer 2 (42),

- 4-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2,3- dihydrobenzo[b]thiepin-8-ol, Isomer 1 (43),

- 4-(2-chlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl) methyl)phenyl)-2,3- dihydrobenzo[b]thiepin-8-ol, Isomer 1 (44).

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

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

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

Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.

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

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

The inventors surprisingly highlighted that compounds of formula (I) display an improved pharmacological profile, especially as CYP3A4 non-inductors in other terms by minimizing CYP3A4 induction, which is not predictable from prior art, in particular in view of WO2017/ 140669 and W02018/091153. The following illustrative part highlights this unexpected property in comparison to chemical compounds representative of the prior art as well as in connection to a large number of compounds of formula (I) of the present invention.

Cytochrome P450 isoform 3A4 (CYP3A4) is involved in the metabolism of about 30% of clinically used drugs from almost all therapeutic categories. The evaluation of CYP3A4 induction potential is thus important for the prediction of drug-drug interactions due to CYP3A4 overexpression. More precisely, low CYP3A4 induction indicates limited undesired drug-drug interactions. In particular, the measurement of the CYP3A4 induction potential of a compound is part of its overall ADME (Absorption, Distribution, Metabolism, Excretion) evaluation.

Another embodiment is thus a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as an inhibitor and degrader of estrogen receptors, which simultaneously displays an improved pharmacological profile, especially demonstrating no CYP3A4 induction, or a weak or intermediary CYP3 A4 induction.

As used herein, the term “no CYP3A4 induction, or weak or intermediary CYP3 A4 induction” with respect to a compound relates respectively to no extent of CYP3 A4 induction, or a weak or moderate extent of CYP3A4 induction which is typically calculated from the results of the test “CYP3A4 induction potential for ADME profile evaluation” in comparison to the reference compound rifampicin and named “% Emax”. Such test is based, for example, on the quantification of CYP3A4 mRNA induction performed by RT-PCR analysis. Said % Emax may be calculated as detailed in the illustrative part under the following formula:

Ecompound: relative fold mRNA expression following treatment with test compound,

Epositive control: relative fold mRNA expression following reference inducer i.e., 10 pM rifampicin,

Evehicie control: relative fold mRNA expression following vehicle treatment i.e., 0.1 % DMSO, and

E is the efficiency of the quantitative PCR. Typically, compounds for which Emax is equal or less than 20% may be considered as compounds showing a weak CYP3A4 induction or no CYP3A4 induction (low risk of drug-drug interactions) and compounds for which Emax is comprised between 20% and 45% may be considered as compounds showing intermediary CYP3A4 induction (limited risk of drug-drug interactions).

Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, especially breast cancer, which simultaneously displays an improved pharmacological profile, typically a low or limited risk of drug-drug interactions, especially demonstrating no CYP3A4 induction, or a weak or intermediary CYP3 A4 induction

Another embodiment is a method of inhibiting and degrading estrogen receptors comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, which displays an improved pharmacological profile, typically a low or limited risk of drug-drug interactions, especially demonstrating no CYP3A4 induction, or a weak or intermediary CYP3A4 induction.

Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, which displays an improved pharmacological profile, typically a low or limited risk of drug-drug interactions, especially demonstrating no CYP3A4 induction, or a weak or intermediary CYP3A4 induction.

Another embodiment is a method of treating cancer comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, which displays an improved pharmacological profile, typically a low or limited risk of drug-drug interactions, especially demonstrating no CYP3A4 induction, or a weak or intermediary CYP3A4 induction.

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

General below methods for the preparation of compounds of formula (I) optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formula (I) are described below.

The following abbreviations and empirical formulae are used:

ADME Absorption, Distribution, Metabolism and Excretion

AIBN Azobisisobutyronitrile

MeCN Acetonitrile

NH4CI Ammonium chloride

CO Carbon monoxide

DDI Drug-Drug Interaction

BAST Deoxo-Fluor

CS2CO3 Cesium carbonate

CYP3A4 Cytochrome P450 (CYP) 3A4

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DCM Di chloromethane

Et2O Diethyl ether

DIEA Diisopropylethylamine

DMF N,N-dimethylformamide

DMAP Dimethylaminopyridine

DMSO Dimethyl sulfoxide

BoczO di-ter-butyldicarbonate

EtOH Ethanol

EtOAc Ethyl acetate

H2 Hydrogen

HC1 Hydrochloric acid

IsoPrOH Isopropanol

LiHMDS Lithium bis(trimethylsilyl)amide

LiOH Lithium hydroxide MeOH Methanol

MgSO ₄ Magnesium sulfate

MeTHF 2-Methyltetrahydrofuran

Pd/C Palladium on carbon

KOAc Potassium acetate

KHMDS Potassium bis(trimethylsilyl)amide

K2CO3 Potassium carbonate

NaBH ₄ Sodium borohydride

NaHCCh Sodium bicarbonate

NaH Sodium hydride

NaOH Sodium hydroxide

Na ₂ SO ₄ Sodium sulfate

NaHSCh Sodium bi sulfate sex Strong cation exchange

PCR Polymerase Chain Reaction

Pd(dppf)C12 [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(PPh ₃ ) ₂ C12 bis (triphenylphosphine) palladium(II) dichloride

Pd ₂ (dba)3 tris(dibenzylideneacetone)dipalladium(0)

PhOK Potassium phenolate

SFC Supercritical Fluid Chromatography

TEA Tri ethyl amine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

PPh ₃ Triphenylphosphine

RT Room temperature

RT-PCR Reverse Transcriptase PCR SCHEME la Parts 1 and 2: Preparation of compounds of the formula (I) - General process

SCHEME la - Part - 1 : SCHEME la - Part - 2:

STEP 4 According to SCHEME la - Part - 1 and Part - 2, in which R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt, or protected OH such as O-pivaloyl, Rl, R2, R3, R3’, R3”, R4, R5, R6, R7, R8, R9, RIO, RIO’, Rl 1, n, m, X and Y are as defined above, compound 1A (prepared according to WO2017140669 when X = C), can be converted in STEP 1 to compound 1C by treatment with compound IB in the presence of a palladium catalyst, for example bis(triphenylphosphine) palladium(II) di chloride Pd(PPhs)2C12, and a phosphine such as triphenylphosphine in solution in toluene by heating up to reflux of solvent in presence of a base such as KOPh. Compound 1C can be converted in STEP 2 to compound IE by treatment with compound ID in a Suzuki coupling reaction using for example [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)C12), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent.

Alternatively, compound IE can be obtained in STEP 1’ by Suzuki coupling between compound 1A and compound ID’ using for example [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)C12), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent.

Compound IE, can be converted in STEP 3 to compound IF by treatment for example with pyridinium tribromide in DCM or THF at room temperature.

This bromo derivative intermediate IF can then be subjected in STEP 4 to a second Suzuki coupling with a suitable boronic reagent R6B(OR’)2, wherein -B(OR’)2 is a boronic acid or a pinacolate ester and R6 is defined as above, using for example Pd(dppf)C12, complex with DCM, as catalyst, in a mixture of dioxane and water as solvent and in the presence of a base, for example CS2CO3, at room temperature or by heating up to reflux to give compound 1G. When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced by hydrogenation with a catalyst such as Pd/C under hydrogen pressure (H2) around 5 bars for example at temperature up to 70°C to give the corresponding saturated compound 1G.

Alternatively, compound IF can be subjected to a photocatalyzed coupling reaction with R6Br, where R6 is an alkyl group, a cycloalkyl or a spiro bicyclic alkyl as defined above, using catalysts such as (Ir[dF(CF3)ppy]2(dtbpy))PFe and nickel(II) chloride ethylene glycol dimethyl ether complex in presence of tris(trimethylsilyl)silane and bases such as 4,4'-di-tert-butyl-2,2’-bipyridine and sodium carbonate to give the corresponding compound 1G.

Compound 1G can be converted in STEP 5 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH).

Compound IF can be converted in STEP 6 to compound IFa in the presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). This compound IFa can be converted in STEP 7 to compound I through Suzuki conditions using a suitable boronic reagent R6B(OR’)2, wherein -B(0R’)2 is a boronic acid or a pinacolate ester and R6 is as above defined, using for example Pd(dppf)C12, complex with DCM, as catalyst, in a mixture of dioxane and water as solvent and in the presence of a base, for example CS2CO3, at room temperature or by heating up to reflux of solvents.

When R6 is a substituted cycloalkene, heterocycloalkene or aliphatic ethylene, it may be reduced by hydrogenation with a catalyst, such as Pd/C under hydrogen (H2) pressure around 5 bars, for example at temperature up to 70°C, to give the corresponding saturated compound I. When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, deprotection can be performed in STEP 5 by treatment with an aqueous solution of sodium hydroxide (NaOH) 2N or lithium hydroxide (LiOH) in MeOH. When R3 is COOH, extraction of the product can give the sodium salt of compound I. The acidification with an aqueous solution of HC1 2N to pH 6-7 can give the neutral form of compound I. The acidification with an aqueous solution of HC1 2N to pH 1-2 can give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound I.

SCHEME lb: Alternative preparation of compounds of the formula (IE)

Compound 1A Compound 1E'

Compound 1Ea According to SCHEME lb, in which R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt or protected OH with O-pivaloyl for example, and Rl, R2, R3, R3’, R3”, R4, R5, R7, R8, R9, RIO, RIO’, Rl l, n, m, X and Y are as defined above, compound IE’ can be prepared in a Suzuki coupling reaction either between compounds 1C and IDa in STEP 1 or between compounds 1A and IDa’ in STEP 1’ in the presence of a palladium catalyst, for example

[l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) (Pd(dppf)Ch), complex with DCM, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent. Compound IE’ can be converted in STEP 2 to compound IE in presence of TFA followed by the treatment with compound lEa, wherein W is Cl, Br or I or OS2R with R = CH3, PhMe, CF3 or CF2CF2CF2CF3 in presence of a base such as potassium carbonate in DMF as a solvent.

SCHEME 1c: Preparation of compounds of the formula (I) - General process

Compound I

Compound 1G

According to SCHEME 1c, in which R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt, or protected OH such as O-pivaloyl; R11 is a hydrogen atom and Rl, R2, R3, R3’, R3”, R4, R5, R6, R7, R8, R9, RIO, RIO’, n, m, X and Y are as defined above, compound IF can be converted in STEP 1 to compound 1H by treatment for example with compound IB and with a palladium catalyst, for example bis(triphenylphosphine)palladium(II) dichloride Pd(PPh3)2Ch, and a phosphine such as triphenylphosphine in toluene by heating up to reflux of solvent in presence of a base such as KOPh

Compound 1G wherein R6 is phenyl or heteroaryl can be prepared in a Suzuki coupling reaction between compounds 1H and either R6Br or R6I or R6OTf in STEP 2 using for example [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)C12), complex with DCM as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent. When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compound 1G can be converted in STEP 3 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a -COOH group, extraction of the product can give the sodium salt of compound I. The acidification with an aqueous solution of HC1 2N to pH 6-7 can give the neutral form of compound I. The acidification with an aqueous solution of HC1 2N to pH 1-2 can give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound I.

SCHEME Id - Part- 1 : Preparation of compounds of the formula (I) - General process Compound 1J

SCHEME Id - Part-2

According to SCHEME ld -Part-1 andPart-2, in which R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt or protected OH such as O-pivaloyl, Rl l is a hydrogen atom, R6 is a phenyl group or a heteroaryl group, Rl, R2, R3, R3’, R3”, R4, R5, R7, R8, R9, RIO, RIO’, n, m, X and Y are as defined above, compound II can be converted in STEP 1 to compound 1J by treatment with aryl or heteroaryl bromide or iodide in the presence of a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), in solution in toluene or xylene by heating up to reflux of solvent, in presence of a base such as K2CO3 or CS2CO3. Alternative way to prepare compound 1 J, wherein R6 can be any of the groups defined above for R6 in formula (I), is described in SCHEME 1g below.

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

Compound IK can be converted in STEP 3 to compound IL by treatment for example with compound IB, and with a palladium catalyst, for example bis (triphenylphosphine) palladium(II) dichloride Pd(PPh3)2Ch, and a phosphine such as triphenylphosphine in solution in toluene by heating up to reflux of solvent, in presence of a base such as KOPh.

Compound 1G can be prepared in a Suzuki coupling reaction between compounds IL and ID in STEP 4 using for example [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Ch), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent.

Alternatively, compound IL can be converted in STEP 6 to compound IN in a Suzuki coupling reaction with compound IM using for example [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12), complex with DCM, as catalyst, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent.

Compound IN can be reduced to compound 10 in STEP 7 by hydrogenation with a catalyst, such as PtO2 under hydrogen (H2) pressure, around 2 bars for example, at room temperature.

When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compounds 1G or 10 can be converted in STEP 5 or STEP 8 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a -COOH group, extraction of the product can give the sodium salt of compound I. The acidification with an aqueous solution of HC1 2N to pH 6-7 can give the neutral form of compound I. The acidification with an aqueous solution of HC1 2N to pH 1-2 can give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound I.

SCHEME le: Preparation of compounds of the formula (I) - General process

Compound I

According to SCHEME le, in which R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt or protected OH such as O-pivaloyl, and Rl, R2, R3, R3’, R3”, R4, R5, R6, R7, R8, R9, RIO, RIO’, Rl l, n, m, X and Y are as defined above, compound IK can be converted in STEP 1 to compound 1G by treatment with compound ID’ in the presence of a palladium catalyst, for example [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Ch), complex with DCM, in a mixture of dioxane and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent.

When R3a is COOMe, COOEt, or a protected OH such as O-pivaloyl, compound 1G can be converted in STEP 2 to compound of formula (I) in presence of a source of hydroxide ions such as NaOH in solution in methanol (MeOH). When R3 represents a -COOH group, extraction of the product can give the sodium salt of compound I. The acidification with an aqueous solution of HC1 2N to pH 6-7 can give the neutral form of compound I The acidification with an aqueous solution of HC1 2N to pH 1-2 can give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound I.

SCHEME If: Preparation of compounds of the formula (1A) wherein R3a = CCbMe -

General process

According to SCHEME If, in which X, m, R3’, R3” and Rl l are as defined above, compound 1A can be commercially available or prepared as follows: compound IP (commercially available or prepared according to WO2017140669 and W02018091153) can be converted in STEP 1 to compound IQ by treatment with trifluoromethanesulfonic anhydride, in solution in DCM, in the presence of pyridine as a base. Compound IQ can be converted in STEP 2 to compound II’ by carbonylation with carbon monoxide, in solution in DMF and MeOH, in the presence of a palladium catalyst, for example [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12), complex with DCM. Compound H’can be converted in STEP 3 to compound 1 A wherein R3a =

CCbMe by treatment with trifluoromethanesulfonic anhydride, in solution in DCM, in the presence of pyridine as a base

SCHEME 1g: Alternative preparation of compounds of the formula (1J) - General process

STEP 1 2

Compound 11 Compound 1 R

Compound 1J

According to SCHEME 1g, in which R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl for example, R3’, R3”, R6, R11, X and m are as defined above, compound 1J can alternatively be prepared as follows: compound II can be converted in STEP 1 to compound 1R by treatment with pyridinium tribromide in DCM or THF at room temperature for example.

Compound 1R can be converted in STEP 2 to compound IS by deprotonation with a base such as LiHMDS in THF followed by treatment with acetic anhydride.

Compound IT can be prepared in STEP 3 in a Suzuki coupling reaction between compounds 1 S and ReB(OR’)2 or Rr.BFsK wherein -B(0R’)2 is a boronic acid or a pinacolate ester and R6 is as above defined, using for example [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (Pd(dppf)C12), complex with DCM, as catalyst, in a mixture of toluene and water and in the presence of a base, for example cesium carbonate (CS2CO3), by heating up to reflux of solvent.

Compound IT can be converted in STEP 4 to compound 1J by hydrolysis with aqueous HC1 solution by heating in methanol and DCM for example.

Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1G wherein Rl, R2, R3’, R3”, R4, R5, R6, R7, R8, R9, RIO, RIO’, R11, n, m, X and Y are defined above and R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt, or protected OH such as O-pivaloyl, is converted to compound of formula (I), in presence of a source of hydroxide ions, such as NaOH in solution in methanol, said step being optionally preceded by a step of obtaining compound 1G, wherein a compound of formula IF

wherein Rl, R2, R3’, R3”, R4, R5, R7, R8, R9, RIO, RIO’, Rl l, n, m, X and Y are as defined above and R3a is as defined above, is subjected to a Suzuki coupling with a boronic reagent R6-B(OR’)2, wherein -B(OR’)2 is a boronic acid or a pinacolate ester and R6 is as defined above.

Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula IFa wherein Rl, R2, R3, R3’, R3”, R4, R5, R7, R8, R9, RIO, RIO’, Rl 1, n, m, X and Y are as defined above, is submitted to a Suzuki coupling a boronic reagent R6-B(OR’)2, wherein -B(OR’)2 is a boronic acid or a pinacolate ester and R6 is as defined above, said step being optionally preceded by a step for obtaining compound IFa, wherein a compound of formula IF

wherein Rl, R2, R3’, R3”, R4, R5, R7, R8, R9, RIO, RIO’, Rl l, n, m, X and Y are as defined above and R3a is as defined above, is converted to a compound IFa in the presence of a source of hydroxide ions, such as NaOH in solution in methanol.

Herein are also provided the intermediate compounds selected from compounds of formula IE, IF, 1G and IFa, or any of its pharmaceutically acceptable salt, wherein Rl, R2, R3, R3’, R3”, R4, R5, R6, R7, R8, R9, RIO, RIO’, Rl l, n, m, X and Y are as defined above and R3a is a hydrogen atom, a carboxylic ester such as COOMe, COOEt, or protected OH such as O-pivaloyl. Herein are further provided the intermediate compounds of formula ID and ID’ , or any of their pharmaceutically acceptable salt wherein Rl, R2, R4, R5, R7, R8, R9, RIO, RIO’, n and Y are as defined above.

In another aspect, herein is also provided a process for the preparation of a compound of formula (I), wherein R3 is a -COOH group, comprising a deprotection step of a compound of formula 1G as defined above, optionally followed by a purification step.

Said purification step may for example consist, as illustrated in step 2 of example 1 hereinafter, in an acidification step, for example with an aqueous solution of hydrochloric acid.

Herein is further provided the intermediate compound of formula IL, or any of its pharmaceutically acceptable salt wherein R3a, R3’, R3”, X, m and R6 are as defined above and Rl l is a hydrogen atom.

The ^X H NMR Spectra at 400 and 500 MHz were performed on a Broker Avance DRX-400 and Broker Avance DPX-500 spectrometer, respectively, with the chemical shifts

(8 in ppm) in the solvent dimethyl solfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coopling constants (J) are given in Hertz.

The liqoid chromatography/mass spectra (LC/MS) were obtained on a UPLC Acqoity Waters instiument, light scattering detector Sedere and SQD Waters mass spectrometer osing UV detection DAD 210-400 nm and flash Acqoity UPLC CSH C18 1.7 pm, dimension 2.1x30 mm, mobile phase H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H.

The following tables la and lb comprise respectively specific compoonds of formnla (I) (name and stroctore) in accordance with the present disclosore as well their characterization ( ^X HNMR and liqoid chromatography/mass).

Table la: Table lb;

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

In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds.

Intermediates:

Intermediate 1: 3-(4-Bromobenzyl)-l-(3-fluoropropyl)pyrrolidine, Isomer 1 and Isomer 2

To a solution of commercially available 3-(4-bromobenzyl)pyrrolidine (35.0 g, 145 mmol) and TEA (29 5 g, 292 mmol) in DCM (250 ml) was added DMAP (1.78 g, 14.57 mmol) and BOC2O (33.4 g, 153 mmol) at RT and the suspension was stirred at RT for 12 hours. The reaction mixture was quenched by addition of water (300 ml) and extracted with DCM (100 ml). The organic phase was washed with brine (200 ml), dried over NaiSCU filtered and concentrated under reduced pressure and the residue obtained was purified by flash chromatography, eluting with a gradient of petroleum ether / ethyl acetate: from 98/02 to 50/50 to give 37 g (73%) of tert-butyl 3 -(4-bromobenzyl)pyrrolidine- 1 -carboxylate as a light yellow oil.

The mixture of isomers of tert-butyl 3-(4-bromobenzyl)pyrrolidine-l-carboxylate (37 g, 107 mmol) was separated by preparative SFC (column: DAICEL CHIRALCEL OJ (250 x 50 mm, 10pm); supercritical CO2 80% / [0.1% NH4OH EtOH] 20%) to give 17 g of tert-butyl 3-(4-bromobenzyl)pyrrolidine-l-carboxylate Isomer 1 and 17 g of tert-butyl 3-(4- bromobenzyl)pyrrolidine-l -carboxylate Isomer 2.

LC/MS (m/z, MH+): 340 Step 2: 3-(4-Bromobenzyl)pyrrolidine hydrochloride, Isomer 1

To a solution of tert-butyl 3-(4-bromobenzyl)pyrrolidine-l-carboxylate Isomer 1 (17.0 g, 50.0 mmol) in EtOAc (160 ml) was added a 4N solution of HC1 in dioxane (50 ml, 200 mmol) and the mixture was stirred at RT for 2 hours. The solution was concentrated under vacuum to give compound 17 g (crude) of 3-(4-bromobenzyl)pyrrolidine hydrochloride, Isomer 1.

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

Step 3: 3-(4-Bromobenzyl)-l-(3-fluoropropyl)pyrrolidine, Isomer 1

To a mixture of 3-(4-bromobenzyl)pyrrolidine hydrochloride, Isomer 1 (12 g, 43.4 mmol) and K2CO3 in DMF (84 ml) was added l-fluoro-3 -iodo-propane (8.56 g, 45.55 mmol) and the mixture was heated to 80°C for 2 hours. The reaction mixture was quenched by addition of water (400 ml) and extracted twice with EtOAc (200 ml). The combined organic phases were washed with brine (200 ml), dried over Na2SOr, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / MeOH from 100/00 to 90/10 to give 10 g (76%) of 3-(4-bromobenzyl)- l-(3-fluoropropyl)pyrrolidine, Isomer 1.

LC/MS (m/z, MH+): 300 Step 2’: 3-(4-Bromobenzyl)pyrrolidine hydrochloride, Isomer 2

Step 2’ of Intermediate 1 Isomer 2 was prepared following a similar procedure to that of step 2 of Intermediate 1 Isomer 1 from tert-butyl 3 -(4-bromobenzyl)pyrrolidine-l -carboxylate Isomer 2 to give 16 g (crude) of 3-(4-bromobenzyl)pyrrolidine hydrochloride, Isomer 2.

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

Step 3’: 3-(4-Bromobenzyl)-l-(3-fluoropropyl)pyrrolidine, Isomer 2

Step 3’ of Intermediate 1 Isomer 2 was prepared following a similar procedure to that of step 3 of Intermediate 1 Isomer 1 from 3-(4-bromobenzyl)pyrrolidine hydrochloride, Isomer 2 to give 9.95 g (55%) of 3-(4-bromobenzyl)-l-(3-fluoropropyl)pyrrolidine, Isomer 2.

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

Intermediate 2: Methyl 9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro- 5H- benzo [7] annul ene-3 -carb oxy 1 ate

A mixture of methyl 9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]an nulene- 3-carboxylate (15 g, 42.82 mmol) (prepared according to WO2017140669), Pd(PPh3)2Ch (1.53 g, 2.14 mmol), PPhs (674.87 mg, 2.57 mmol), bis(pinacolato)diboron (144.08 g, 52.67 mmol) and PhOK (8.04 g, 60.80 mmol) in toluene (150 ml) was heated to 75°C for 1.5 hours. The yellow suspension becomes orange then brown. After cooling to room temperature, DCM (150 ml) and water (150 ml) were added, and decantation was done by hydrophobic column. The organic phase was concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of heptane/DCM: from 85/15 to 20/80 to give 10.1 g (72%) of methyl 9-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-c arboxylate as a white solid. LC/MS (m/z, MH+): 329

Intermediate 3: Methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-

2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

Intermediate 3 was prepared following a similar procedure to that of Intermediate 2 from methyl 8-(2,4-dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6, 7-dihydro-5H- benzo[7]annulene-3 -carboxylate (prepared according to W02020/049153) to give 4.23 g (30% yield) of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2- yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a white solid.

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

Intermediate 4: 3-[(4-Bromophenyl)methyl]-3-fluoro-l-(3-fluoropropyl)pyrroli dine

Isomer 1 and Isomer 2

Step 1: Tert-butyl 3 -(4-bromobenzoyl)-3-fluoro-pyrrolidine-l -carboxylate

To a solution of commercially available tert-butyl 3-(4-bromobenzoyl)pyrrolidine-l- carboxylate (130 g, 367 mmol) in THF (1.00 L) was added LiHMDS (1 M, 514 ml) at -70 °C. The reaction mixture was stirred at -70°C for 1 hour. N-(Benzenesulfonyl)-N-fluoro- benzenesulfonamide (150 g, 477 mmol) in THF (500 ml) was added to the mixture above at -70 °C. The reaction mixture was stirred at -70 °C for 1 hour then it was poured into aqueous NH4CI solution (500 ml), extracted with EtOAc 900 ml (3x300 ml), dried over Na2SO4, filtered and concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of Petroleum ether/EtOAc from 10/1 to 4/1 to give 130 g (95%) of tert-butyl 3 -(4-bromobenzoyl)-3-fluoro-pyrrolidine-l -carboxylate.

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

Step 2: Tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]-3-fluoro-pyrrolidine-l- carboxylate

To a solution of tert-butyl 3 -(4-bromobenzoyl)-3-fluoro-pyrrolidine-l -carboxylate (130 g, 349 mmol) in MeOH (1 L) was added NaBH4 (19.8 g, 524 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by addition of water (20 ml) at 0 °C, and then diluted with water (400 ml) and the organic phase was removed. The aqueous layer was extracted with EtOAc (3x400 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 130 g (crude) of tert-butyl 3-[(4-bromophenyl)- hydroxy-methyl]-3-fluoro-pyrrolidine-l-carboxylate as light yellow oil.

LC/MS (m/z, MH+): 374 Step 3: Tert-butyl 3-[(4-bromophenyl)-methylsulfanylcarbothioyloxy-methyl]-3-fl uoro- pyrrolidine- 1 -carboxylate

To a solution of tert-butyl 3-[(4-bromophenyl)-hydroxy-methyl]-3-fluoro-pyrrolidine-l- carboxylate (86 g, 230 mmol) and imidazole (78.2 mg, 1.15 mmol) in THF (900 ml) was added NaH (13.8 g, 345 mmol, 60% purity) at 10 °C. The reaction mixture was stirred at 10 °C for 30 minutes. Carbon disulfide (35 g, 460 mmol, 27.8 ml) was added to the mixture and the reaction mixture was stirred at 25 °C for 30 minutes. Methyl iodide (58.7 g, 414 mmol, 25.8 ml) was added to the above mixture and the reaction mixture was stirred at RT for 30 minutes. The reaction mixture was poured into NH4CI solution (200 ml). The organic phase was separated, washed with EtOAc (3x200 ml), dried over NazSOi, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of Petroleum ether/EtOAc from 90/10 to 70/30 to give 102 g (96%) of tert-butyl 3-[(4-bromophenyl)-methylsulfanylcarbothioyloxy-methyl]-3-fl uoro- pyrrolidine-1 -carboxylate as light yellow oil.

LC/MS (m/z, MH+): 374

Step 4: Tert-butyl 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine-l-carboxylate

To a solution of tert-butyl 3-[(4-bromophenyl)-methylsulfanylcarbothioyloxy-methyl]-3- fluoro-pyrrolidine-1 -carboxylate (25.5 g, 54.9 mmol) in toluene (250 ml) was added tributyl stannane (29.6 g, 102 mmol, 26.9 ml) and AIBN (721 mg, 4.39 mmol). The reaction mixture was stirred at 90 °C for 2 hours. After cooling to RT, the reaction mixture was poured into water (1 L), extracted with EtOAc (3x100 ml), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of Petroleum ether/EtOAc from 90/10 to 70/30 to give 17.25 g (88%) of tert-butyl 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine-l- carboxylate as light yellow solid.

LC/MS (m/z, MH+): 358

Step 5: 3-[(4-Bromophenyl)methyl]-3-fluoro-pyrrolidine, hydrochloride

Step 5 of Intermediate 4 was prepared following a similar procedure to that of step 2 of Intermediate 1 Isomer 1 from tert-butyl 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine-l- carboxylate to give 32 g (crude) of 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine, hydrochloride.

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

Step 6: 3-[(4-Bromophenyl)methyl]-3-fluoro-l-(3-fluoropropyl)pyrroli dine

To a solution of 3-[(4-bromophenyl)methyl]-3-fluoro-pyrrolidine, hydrochloride (32.0 g, 109 mmol) in THF (220 ml) was added NaOH (5 M, 109 ml) and l-fluoro-3-iodo-propane (20.4 g, 109 mmol). The reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was poured into water (100 ml), extracted with EtOAc (300 ml), dried over NazSOi, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 98/02 to 90/10 to give 28 g (crude) which was further purified by preparative HPLC (column: Agela DuraShell C18 250x70mm, 10pm; mobile phase: gradient of MeCN in water (0.05%NH40H+10mM NH4HCO3) from 43% to 67% in 20min) to give 12 g (35%) of 3-[(4-bromophenyl)methyl]- 3 -fluoro- 1 -(3 -fluoropropyl)pyrrolidine .

LC/MS (m/z, MH+): 318

Step 7: 3-[(4-Bromophenyl)methyl]-3-fluoro-l-(3-fluoropropyl)pyrroli dine Isomer 1 and

Isomer 2

The mixture of isomers of 3-[(4-bromophenyl)methyl]-3-fluoro-l-(3- fluoropropyl)pyrrolidine was separated by preparative SFC (column: DAICEL CHIRALPAK IG (250x30mm, 10pm); supercritical CO2 75% / MeOH 25%) to give 5 g of 3-[(4-bromophenyl)methyl]-3-fluoro-l-(3-fluoropropyl)pyrroli dine Isomer 1 and 5 g of 3- [(4-bromophenyl)methyl]-3 -fluoro- 1 -(3 -fluoropropyl)pyrrolidine Isomer 2.

LC/MS (m/z, MH+): 318

Intermediate 5: (4-Bromophenyl)-[l-(3-fluoropropyl)pyrrolidin-3-yl]methanone , racemic mixture

Step 1: (4-Bromophenyl)-pyrrolidin-3-yl-methanone, hydrochloride, racemic mixture

Step 1 of Intermediate 5 was prepared following a similar procedure to that of step 2 of Intermediate 1 Isomer 1 from tert-butyl 3-(4-bromobenzoyl)pyrrolidine-l-carboxylate, racemic mixture to give 76 g (crude) of (4-bromophenyl)-pyrroli din-3 -yl-methanone hydrochloride, racemic mixture.

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

Step 2: (4-Bromophenyl)-[l-(3-fluoropropyl)pyrrolidin-3-yl]methanone , racemic mixture

Step 2 of Intermediate 5 was prepared following a similar procedure to that of step 6 of Intermediate 4 from (4-bromophenyl)-pyrrolidin-3-yl-methanone hydrochloride, racemic mixture to give 28 g (93%) of (4-bromophenyl)-[l-(3-fluoropropyl)pyrrolidin-3- yl]methanone, racemic mixture.

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

Intermediate 6: 3-[(4-Bromophenyl)-difluoro-methyl]-l-(3-fluoropropyl)pyrrol idine

Isomer 1 and Isomer 2

Step 1: Tert-butyl 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine-l-carboxylate , racemic mixture

To a solution of tert-butyl 3 -(4-bromobenzoyl)pyrrolidine-l -carboxylate, racemic mixture (20 g, 56.5 mmol) was added bis(2-methoxyethyl)aminosulfur trifluoride BAST (100 ml). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with NaHCCh (1000 ml) and extracted with EtOAc (300 ml). The organic phase was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of Petroleum ether/Ethyl acetate from 98/02 to 00/100 to give 19 g (89%) of tert-butyl 3-[(4- bromophenyl)-difluoro-methyl]pyrrolidine- 1 -carboxylate, racemic mixture.

LC/MS (m/z, MH+): 376

Step 2: 3-[(4-Bromophenyl)-difluoro-methyl]pyrrolidine hydrochloride, racemic mixture

Step 2 of Intermediate 6 was prepared following a similar procedure to that of step 2 of Intermediate 1 Isomer 1 from tert-butyl 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine-l- carboxylate, racemic mixture to give 20 g (99%) of 3-[(4-bromophenyl)-difluoro- methyl]pyrrolidine, hydrochloride, racemic mixture.

LC/MS (m/z, MH+): 276

Step 3: 3-[(4-Bromophenyl)-difluoro-methyl]-l-(3-fluoropropyl)pyrrol idine, racemic mixture

Step 3 of Intermediate 6 was prepared following a similar procedure to that of step 3 of Intermediate 1 Isomer 1 from 3-[(4-bromophenyl)-difluoro-methyl]pyrrolidine hydrochloride, racemic mixture to give 15 g (62%) of 3-[(4-bromophenyl)-difluoro-methyl]- l-(3-fluoropropyl)pyrrolidine, racemic mixture.

LC/MS (m/z, MH+): 336 Step 4: 3-[(4-Bromophenyl)-difluoro-methyl]-l-(3-fluoropropyl)pyrrol idine Isomer 1 and

Isomer 2

The mixture of isomers of 3-[(4-bromophenyl)-difluoro-methyl]-l-(3- fluoropropyl)pyrrolidine was separated by preparative SFC (column: DAICEL

CHIRALPAK AD (250 x 50 mm, 10pm); supercritical CO ₂ 85% / [0.1% NH4OH MeOH] 15%) to give 5.2 g (21%) of 3-[(4-bromophenyl)-difluoro-methyl]-l-(3- fluoropropyl)pyrrolidine Isomer 1 and 5.2 g (21%) of 3-[(4-bromophenyl)-difluoro-methyl]- l-(3-fluoropropyl)pyrrolidine Isomer 2. LC/MS (m/z, MH+): 336

Intermediate 7: Methyl 8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 Step 1: Methyl 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7- dihydro-5H- benzo[7]annulene-3 -carboxylate Isomer 1

A mixture of methyl 9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro- 5H- benzo[7]annulene-3 -carboxylate (Intermediate 2) (9.09 g, 27.7 mmol), 3-[(4- bromophenyl)methyl]-l-(3-fluoropropyl)pyrrolidine, Isomer 1 (Intermediate 1, Isomer 1) (7.55 g, 25.1 mmol) (15 g, 52.41 mmol), Pd(dppf)C12 complex with DCM (1.23 g, 1.51 mmol), CS2CO3 (20.49 g, 62.89 mmol) in dioxane (75 ml) and water (30 ml) was heated to reflux for 4 hours. After cooling to room temperature, DCM (80 ml) and water (80 ml) were added, and decantation was done by hydrophobic column. The organic phase was concentrated under reduced pressure and the residue obtained was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 8.44 g (80%) of methyl 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7- dihydro- 5H-benzo[7]annulene-3-carboxylate Isomer 1 as an orange viscous oil.

LC/MS (m/z, MH+): 422

Step 2: Methyl 8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1

To a mixture of methyl 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (8.58 g, 20.4 mmol) in DCM (90 ml) was added pyridinium tribromide (8.46 g, 26.5 mmol). The reaction mixture was stirred for 2 hours at room temperature. Water (100 ml) and DCM (150 ml) were added and pH was adjusted to 10 with concentrated solution of NaHCCh and K2CO3. The aqueous phase was washed 3 times with DCM and the gathered organic phases were dried over MgSCh, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH: from 100/00 to 95/05 to give 6.1 g (60%) of methyl 8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1.

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

Intermediate 8: 3-[(4-Bromophenyl)methyl]-l-(3,3-difluoropropyl)pyrrolidine, Isomer 1

Step 1: 3-[(4-Bromophenyl)methyl]pyrrolidine, 2,2,2-trifluoroacetic acid, Isomer 1

To a solution of tert-butyl 3-[(4-bromophenyl)methyl]pyrrolidine-l -carboxylate Isomer 1 (2.11 g, 5.6 mmol) in DCM (50 ml) was added TFA (30 ml) and the mixture was stirred at RT for 4 hours. The solution was concentrated under vacuum and the residue obtained was treated with LtzO. The solid formed was filtered and dried to give 1.98 g (90%) of 3-[(4- bromophenyl)methyl]pyrrolidine, 2,2,2-trifluoroacetic acid, Isomer 1.

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

Step 2: 3,3-Difluoropropyl 4-methylbenzenesulfonate

To a solution of 3,3-difluoroprapan-l-ol (500 mg, 5.2 mmol) in THF (10 ml) cooled at 0°C was added NaH (229 mg, 5.72 mmol, 60% purity) and the mixture was stirred at 0°C for 1 hour. Then 4-methylbenzensulfonyl chloride (1.04 g, 5.46 mmol) was added. After 1 hour of stirring at RT, a concentrated solution of NH4Q (20 ml) was added and the mixture was extracted with EtOAc (3x50 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with DCM to give 1.03 g (79%) of 3, 3 -difluoropropyl 4- methylbenzenesulfonate.

LC/MS (m/z, MH+): 251

Step 3: 3-[(4-Bromophenyl)methyl]-l-(3,3-difluoropropyl)pyrrolidine, Isomer 1

To a mixture of 3-[(4-bromophenyl)methyl]pyrrolidine, 2,2,2-trifluoroacetic acid Isomer 1 (1.2 g, 3.39 mmol) and K2CO3 in MeCN (30 ml) was added 3, 3 -difluoropropyl 4- methylbenzenesulfonate (1.02 g, 4.07 mmol) and the mixture was heated at 80°C for 2 hours. The reaction mixture was quenched by addition of concentrated solution of NH4CI (50 ml) and extracted with EtOAc (3x50 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM / EtOAc from 100/00 to 00/100 to give 607 mg (56%) of 3-[(4-bromophenyl)methyl]-l-(3,3-difluoropropyl)pyrrolidine, Isomer 1. LC/MS (m/z, MH+): 318 Intermediate 9 : 1 -(3 -Fluoropropyl)-3 -[ [4-(4,4, 5 , 5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)phenyl]methyl]pyrrolidine, Isomer 1

A mixture of 3-[(4-bromophenyl)methyl]-l-(3-fluoropropyl)pyrrolidine, Isomer 1 (Intermediate 1 Isomer 1) (640 mg, 2.13 mmol), Pd(PPli3)2C12 (109 mg, 0.15 mmol), bis(pinacolato)diboron (704 mg, 2.77 mmol) and AcOK (523 mg, 5.33 mmol) in dioxane (10 ml) was heated to reflux for 2 hours. After cooling, the reaction mixture was filtered on dicalite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography, eluting with a gradient of DCM/MeOH: from 100/00 to 90/10 to give 270 mg (36%) of l-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2- yl)phenyl]methyl]pyrrolidine, Isomer 1.

LC/MS (m/z, MH+): 348

Intermediate 10: l-(3,3-Difluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-l,3,2-diox aborolan-2- yl)phenyl]methyl]pyrrolidine, Isomer 1

Intermediate 10 was prepared following a similar procedure to that of Intermediate 9 from 3-[(4-bromophenyl)methyl]-l-(3,3-difluoropropyl)pyrrolidine, Isomer 1 (Intermediate 8) to give 114.8 mg (87%) of l-(3,3-difluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]methyl]pyrrolidine, Isomer 1.

LC/MS (m/z, MH+): 366 Intermediate 11: Methyl 8-bromo-9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1 Step 1: Methyl 9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)phenyl)- 6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate, Isomer 1

Step 1 of Intermediate 11 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from 3-[(4-bromophenyl)methyl]-l-(3,3-difluoropropyl)pyrrolidine, Isomer 1 (Intermediate 8) and methyl 9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-

5H-benzo[7]annulene-3-carboxylate (Intermediate 2) to give 252 mg (59%) of methyl 8- bromo-9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl)ph enyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate, Isomer 1.

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

Step 2: Methyl 8-bromo-9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl) phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1

Step 2 of Intermediate 11 was prepared following a similar procedure to that Step 2 of Intermediate 7 from methyl 8-bromo-9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1 to give 212 mg (71%) of methyl 8-bromo-9-(4-((l-(3,3-difluoropropyl)pyrrolidin-3-yl)methyl) phenyl)-

6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1.

LC/MS (m/z, MH+): 518

Intermediate 12: 8-(2,4-Dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6, 7-dihydro- 5H-benzo[7]annulen-3-yl pivalate

Step 1: 6-(2,4-Dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo [7]annulen-5-one

A mixture of l-bromo-2,4-dichloro-benzene (890 mg, 3.94 mmol), 2-methoxy-6, 7,8,9- tetrahydro-5H-benzo[7]annulen-5-one (500 mg, 2.63 mmol), CS2CO3 (2.03 g, 10.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.304 g, 0.53 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.3 g, 0.53 mmol) in xylene (10 ml) was heated to reflux for 16 hours. After cooling to room temperature, water (50 ml) and Et2O (50 ml) were added. The organic phase was dried over MgSCU, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of cyclohexane/EtOAc from 100/00 to 95/05 to give 470 mg (42%) of 6-(2,4- dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annu len-5-one.

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

Step 2: 6-(2,4-Dichlorophenyl)-2 -hydroxy-6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen-5-one

A mixture of 6-(2,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzo [7]annulen-5- one (470 mg, 1.23 mmol) and aluminium chloride (395 mg, 2.96 mmol) in toluene (8 ml) was heated at 90°C for 2 hours. After cooling to room temperature, water (20 ml) and EtOAc (50 ml) were added. The organic phase was separated, dried over MgSOr, filtered and concentrated under reduced pressure The residue obtained was purified by flash chromatography, eluting with a gradient of cyclohexane/EtOAc from 100/00 to 80/20 to give 165 mg (42%) of 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H- benzo[7]annulen-5-one.

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

Step 3: 6-(2,4-Dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]a nnulen-2-yl pivalate

A mixture of 6-(2,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo [7]annulen-5- one (163 mg, 0.51 mmol), potassium carbonate (77 mg, 0.56 mmol) and pivaloyl chloride (67 mg, 0.56 mmol) in acetone (5 ml) was heated at 40°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by flash chromatography with a gradient of cyclohexane/EtOAc from 100/00 to 90/10 to give 205 mg (96%) of 6-(2,4-dichlorophenyl)- 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl pivalate.

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

Step 4: 8-(2,4-Dichlorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6, 7-dihydro-5H- benzo[7]annulen-3-yl pivalate

To a solution of 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]a nnulen-2-yl pivalate (197 mg, 0.48 mmol) in THF (5 ml) was added KHMDS (1 M, 0.58 ml, 0.58 mmol) at -50°C under Ar atmosphere. The mixture was stirred for 30 min and 1,1,1 -trifluoro-N- phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (173 mg, 0.49 mmol) was added to the resulting mixture. The reaction mixture was slowly warmed up to 20°C and stirred for 90 minutes. The reaction mixture was quenched with saturated aqueous citric acid solution, then diluted with H2O and extracted twice with Et2O. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography with a gradient of cyclohexane/EtOAc from 100/00 to 90/10 to give 160 mg (61%) of 8-(2,4-dichlorophenyl)-9- (((trifhioromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annu len-3-yl pivalate.

LC/MS (m/z, MH+): 537

Intermediate 13: Methyl 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate

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

To a mixture of 8-hydroxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one (4.2 g, 23.57 mmol) (prepared according to W02018091153) and pyridine (2.82 g, 2.89 ml, 35.36 mmol) in DCM (120 ml) cooled at -20°C was dropwise added trifluoromethanesulfonic anhydride (8.14 g, 6 ml, 28.28 mmol). The reaction mixture was stirred at 0°C for 30 minutes. Water (50 ml) was added. The organic phase was separated and washed with an aqueous saturated solution of NaHCCh (50 ml). The organic phase was dried over MgSCU, filtered, and concentrated under reduced pressure to give 7.30 g (100%) of 5-oxo-2,3,4,5- tetrahydrobenzo[b]oxepin-8-yl trifluorom ethanesulfonate.

LC/MS (m/z, MH+): 311

Step 2: Methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate

To a solution of 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)C12 complex with DCM (1.10 g, 1.43 mmol). The suspension was degassed and purged three times with CO. The mixture was stirred under CO (5 bars) at 75 °C for 2 hours. The reaction mixture 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 residue obtained was purified by flash chromatography eluting with a gradient of heptane/ethyl acetate: from 85/15 to 80/20 to give 4.6 g (88%) methyl 5-oxo-2, 3,4,5- tetrahydrobenzo[b]oxepine-8-carboxylate.

LC/MS (m/z, MH+): 221

Step 3: Methyl 4-(2,4-dichlorophenyl)-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepi ne-8- carboxylate

Step 3 of Intermediate 13 was prepared following a similar procedure to that of step 1 of Intermediate 12 from methyl 5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate and 1- bromo-2,4-di chloro-benzene to give 1.13 g (67%) of methyl 4-(2,4-dichlorophenyl)-5-oxo- 2,3,4,5-tetrahydrobenzo[b]oxepine-8-carboxylate.

LC/MS (m/z, MH+): 365

Step 4: Methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2, 3- dihy drob enzo [b ] oxepine- 8 -carb oxy late

Step 4 of Intermediate 13 was prepared following a similar procedure to that of step 4 of Intermediate 12 from methyl 4-(2,4-dichlorophenyl)-5-oxo-2, 3,4,5- tetrahydrobenzo[b]oxepine-8-carboxylate to give 0.48 g (31%) of methyl 4-(2,4- dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihyd robenzo[b]oxepine-8- carboxylate.

LC/MS (m/z, MH+): 496

Step 5: Methyl 4-(2,4-dichlorophenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2-yl)-2,3- dihy drob enzo [b ] oxepine- 8 -carb oxy late

Step 5 of Intermediate 13 was prepared following a similar procedure to that of Intermediate 2 from methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2, 3- dihydrobenzo[b]oxepine-8-carboxylate to give 260 mg (61%) of methyl 4-(2,4- dichlorophenyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2,3- dihydrobenzo[b]oxepine-8-carboxylate.

LC/MS (m/z, MH+): 271

Intermediate 14: Methyl 3-bromo-4-(4-((l-(3-fluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-2H-thiochromene-7-carboxylate

Step 1: 4-Oxothiochroman-7-yl trifluoromethanesulfonate

Step 1 of Intermediate 14 was prepared following a similar procedure to that of step 1 of Intermediate 13 from 7-hydroxythiochroman-4-one (prepared according to W02018091153) to give 1.14 g (33%) of 4-oxothiochroman-7-yl trifluoromethanesulfonate. LC/MS (m/z, MH+): 313

Step 2: Methyl 4-oxothiochromane-7-carboxylate

Step 2 of Intermediate 14 was prepared following a similar procedure to that of step 2 of Intermediate 13 from 4-oxothiochroman-7-yl trifluoromethanesulfonate to give 0.61 g (76%) of methyl 4-oxothiochromane-7-carboxylate.

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

Step 3: Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxy late

Step 3 of Intermediate 14 was prepared following a similar procedure to that of step 4 of Intermediate 12 from methyl 4-oxothiochromane-7-carboxylate to give 199 mg (41%) of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxy late.

LC/MS (m/z, MH+): 355

Step 4: Methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-thiochrom ene-7- carboxylate

Step 4 of Intermediate 14 was prepared following a similar procedure to that of Intermediate 2 from methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2H-thiochromene-7-carboxy late to give 1 g (35%) of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-thiochrom ene-7- carboxylate.

LC/MS (m/z, MH+): 333

Step 5: Methyl 4-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-t hiochromene- 7-carboxylate

Step 5 of Intermediate 14 was prepared following a similar procedure to that of step 1 of Intermediate 7 from methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H- thiochromene-7-carboxylate and 3-[(4-bromophenyl)methyl]-l-(3- fluoropropyl)pyrrolidine, Isomer 1 (Intermediate 1, Isomer 1) to give 120 mg (47%) of methyl 4-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-t hiochromene-7- carboxylate, Isomer 1.

LC/MS (m/z, MH+): 426

Step 6: Methyl 3-bromo-4-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-2H- thiochromene-7-carboxylate, Isomer 1

Step 6 of Intermediate 14 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 4-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H- thiochromene-7-carboxylate to give 140 mg (64%) of methyl 3-bromo-4-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2H-thiochromene- 7-carboxylate, Isomer 1. LC/MS (m/z, MH+): 504

Intermediate 15: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8- dihydronaphthalene-2-carboxylate

Step 1: Methyl 2-(2,4-dichlorophenyl)-l-oxo-tetralin-6-carboxylate

Step 1 of Intermediate 15 was prepared following a similar procedure to that of step 1 of Intermediate 12 from methyl l-oxotetralin-6-carboxylate and l-bromo-2,4-di chlorobenzene to give 459 mg (19%) of methyl 4-(2,4-dichlorophenyl)-5-oxo-2, 3,4,5- tetrahydrobenzo[b]oxepine-8-carboxylate.

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

Step 2: Methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8- dihydronaphthalene-2-carboxylate

Step 2 of Intermediate 15 was prepared following a similar procedure to that of step 2 of Intermediate 12 from methyl 2-(2,4-dichlorophenyl)-l-oxo-tetralin-6-carboxylate 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 Intermediate 16: Methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7] annul ene-3 -carboxylate

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

Step 1 of Intermediate 16 was prepared following a similar procedure to that of step 1 of Intermediate 12 from methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate and l-bromo-2,4-difluoro-benzene to give 2.55 g (34%) of methyl 6-(2,4-difluorophenyl)- 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.

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

Step 2: Methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6, 7-dihydro-5H- benzo [7] annul ene-3 -carb oxy 1 ate

To a suspension of NaH (545 mg, 13.62 mmol, 60% purity in wheight) in Me-THF (22 ml) cooled at 5°C was added DBU (277 mg, 0.27 ml, 1.82 mmol) followed by a solution of methyl 6-(2,4-difluorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annul ene-2-carboxylate (3 g, 9.08 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (4.2 g, 11.81 mmol) in THF (25 ml). The cooling bath was removed to allow the temprature to warm up to RT. A mixture of acetic acid (0.4 ml) and water (32 ml) was dropwise added, followed by water (100 ml) and EtOAc (150 ml). After decantation, the organic phase was dried over MgSCh, filtered and concentrated under reduced pressure The residue obtained was purified by flash chromatography, eluting with DCM/heptane 50/50 to give 2.77 g (66%) of methyl 8-(2,4- difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihyd ro-5H-benzo[7]anmilene-3- carboxylate.

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

Step 3: Methyl 8-(2,4-difluorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2-yl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate

Step 3 of Intermediate 16 was prepared following a similar procedure to that of Intermediate 2 from methyl 8-(2,4-difluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6, 7-dihydro-5H- benzo[7]annulene-3 -carboxylate to give 1.89 g (72%) of methyl 8-(2,4-difluorophenyl)-9- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H -benzo[7]annulene-3- carboxylate.

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

Intermediate 17: Methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7] annul ene-3 -carboxylate

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

Step 1 of Intermediate 17 was prepared following a similar procedure to that of step 1 of Intermediate 12 from l-bromo-2-methyl-4-fluoro-benzene to give 700 mg (47%) of methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benz o[7]annulene-2- carboxylate.

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

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

Step 2 of Intermediate 17 was prepared following a similar procedure to that of step 2 of Intermediate 16 from methyl 6-(2-methyl-4-fluorophenyl)-5-oxo-6, 7,8,9- tetrahydrobenzo[7]annulene-2-carboxylate to give 7.86 g (82%) of methyl 8-(2-methyl-4- fluorophenyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro -5H-benzo[7]annulene-3- carboxylate.

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

Step 3: Methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2-dio xaborolan-2- yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

Step 3 of Intermediate 17 was prepared following a similar procedure to that of Intermediate 2 from methyl 8-(2-methyl-4-fluorophenyl)-9-(((trifluoromethyl)sulfonyl)ox y)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate to give 3.93g (43%) of methyl 8-(2-methyl-4- fluorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylate.

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

Intermediate 18: tert-Butyl 3-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]methyl]pyrrolidine-l-carboxylate, Isomer 1 Intermediate 18 was prepared following a similar procedure to that of Intermediate 9 from tert-butyl 3-(4-bromobenzyl)pyrrolidine-l-carboxylate Isomer 1 (Step 1 of Intermediate 1) to give 2.53 g (74%) of tert-butyl 3-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]methyl]pyrrolidine-l-carboxylate, Isomer 1.

LC/MS (m/z, MH+): 388 Intermediate 19: Methyl 8-(2-methyl-4-fluorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxy late, Isomer 1

Step 1: Methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carbo xylate

To a mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (9.42 g, 43.2 mmol) in DCM (400 mL) was portionwise added pyridinium tribromide (16.12 g, 45.4 mmol). The reaction mixture was stirred overnight at room temperature. Water (500 ml) and ether (1 L) were added. The organic phase was separated and washed twice with water, dried over MgSCU, filtered and concentrated under reduced pressure to give 14.4 g (90%) of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carbo xylate. LC/MS (m/z, MH+): 297

Step 2: Methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate

To a solution of methyl 6-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2- carboxylate (10 g, 33.66 mmol) in acetonitrile (100 mL) was added DABCO (7.4 mL, 67.32 mmol). The reaction mixture was heated to 55°C for 2.5 hours under Ar. Ether and IN HC1 were added. The organic phase was separated and washed twice with water, with brine, dried over MgSOi, filtered and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane/ EtOAc 85/15 to give 1.88 g (26%) of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate. LC/MS (m/z, MH+): 217

Step 3: Methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carb oxylate, racemic mixture

To a solution of methyl 5-oxo-8,9-dihydro-5H-benzo[7]annulene-2-carboxylate (1.88 g, 8.6 mmol) in THF (30 mL) under Ar at 0°C was added a 0.328 M cuprate solution (35 mL, 11.5 mmol) prepared by addition of 15 mL of a 1.6 N solution of methyl lithium in ether to a suspension of 2.5 g of Cui (13 mmol) in 25 mL of ether under Ar at 0°C. The reaction mixture was stirred for 30 minutes at 0°C. Ether (200 mL) and IN HC1 (200 mL) were added. The organic phase was separated and the aqueous phase extracted with ether. The combined organic phases were washed with water, dried over MgSCk, filtered and concentrated under reduced pressure. The resulting residue was then purified by flash chromatography eluting with a mixture of cyclohexane/ EtOAc 95/5 to give 1.95 g (86%) of methyl 7-methyl-5-oxo- 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate as a racemic mixture.

LC/MS (m/z, MH+): 233

Step 4: Methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate, racemic mixture

Step 4 of Intermediate 19 was prepared following a similar procedure to that of step 4 of Intermediate 12 from methyl 7-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2- carboxylate to give 2.5 g (86%) of methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.

LC/MS (m/z, MH+): 365

Step 5: Tert-butyl 3-(4-(3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]an nulen- 9-yl)benzyl)pyrrolidine-l-carboxylate, Isomer 1

Step 5 of Intermediate 19 was prepared following a similar procedure to that of step 1 of Intermediate 7 from methyl 7-methyl-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylate and tert-Butyl 3-[[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]methyl]pyrrolidine-l -carboxylate, Isomer 1 (Intermediate 18) to give 1.02 g (76%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H- benzo[7]annulen-9-yl)benzyl)pyrrolidine-l -carboxylate, Isomer 1.

LC/MS (m/z, MH+): 476

Step 6: Methyl 7-methyl-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylate, 2,2,2-trifluoroacetic acid, Isomer 1

Step 6 of Intermediate 19 was prepared following a similar procedure to that of step 1 of Intermediate 8 from 3-(4-(3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H- benzo[7]annulen-9-yl)benzyl)pyrrolidine-l -carboxylate, Isomer 1 to give 753 mg (100%) of methyl 7-methyl-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H- benzo[7]annulene-3- carboxylate, 2,2,2-trifluoroacetic acid, Isomer 1.

LC/MS (m/z, MH+): 376 Step 7: Methyl 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-me thyl-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1

To a solution of methyl 7-methyl-9-(4-(pyrrolidin-3-ylmethyl)phenyl)-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylate, 2,2,2-trifluoroacetic acid, Isomer 1 (753 mg, 1.538 mmol) in DCM (15 ml) was added NaOH (0.5 N, 7 ml) and, after 5 minutes, l-fluoro-3 -iodopropane (0.166 ml, 1.692 mmol). The reaction mixture was stirred at RT overnight. After decantation, the organic phase was dried over Na2SC>4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 90/10 to give 446 mg (67%) of methyl 9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7-methyl-6,7-dih ydro-5H-benzo[7]annulene- 3-carboxylate, Isomer 1.

LC/MS (m/z, MH+): 436 Step 8: Methyl 8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-7- methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 Step 8 of Intermediate 19 was prepared following a similar procedure to that of step 2 of Intermediate 7 from methyl 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7- methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 to give 372 mg (71%) of methyl 8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-7-methyl-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1.

LC/MS (m/z, MH+): 514

Intermediate 20 : 4-Bromo-5 -(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2, 3 - dihydrobenzo[b]thiepin-8-ol, Isomer 1

Step 1: tert-Butyl 3-(4-(8-(pivaloyloxy)-2,3-dihydrobenzo[b]thiepin-5- yl)benzyl)pyrrolidine-l -carboxylate, Isomer 1

Step 1 of Intermediate 20 was prepared following a similar procedure to that of Step 1 of Intermediate 7 from 5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]thiepi n-8-yl pivalate (prepared according to W02018091153) and tert-butyl 3-[[4-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)phenyl]methyl]pyrroli dine- 1 -carboxylate, Isomer 1 (Intermediate 18) to give 810 mg (86%) of tert-butyl 3-(4-(8-(pivaloyloxy)-2,3-dihydrobenzo[b]thiepin-5- yl)benzyl)pyrrolidine-l -carboxylate, Isomer 1.

LC/MS (m/z, MH+): 522

Step 2: 5-(4-(Pyrrolidin-3-ylmethyl)phenyl)-2,3-dihydrobenzo[b]thiep in-8-yl pivalate, 2,2,2-trifluoroacetic acid, Isomer 1

Step 2 of Intermediate 20 was prepared following a similar procedure to that of Step 1 of Intermediate 8 from tert-butyl 3-(4-(8-(pivaloyloxy)-2,3-dihydrobenzo[b]thiepin-5- yl)benzyl)pyrrolidine-l -carboxylate, Isomer 1 to give 1.1 g (crude) of 5-(4-(pyrrolidin-3- ylmethyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-yl pivalate, 2,2,2-trifluoroacetic acid, Isomer 1.

LC/MS (m/z, MH+): 422

Step 3 : S-(4-(( 1 -(3 -Fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2,3 - dihydrobenzo[b]thiepin-8-yl pivalate, Isomer 1

Step 3 of Intermediate 20 was prepared following a similar procedure to that step 3 of Intermediate 1 from 5-(4-(pyrrolidin-3-ylmethyl)phenyl)-2,3-dihydrobenzo[b]thiep in-8-yl pivalate, 2,2,2-trifluoroacetic acid, Isomer 1 to give 490 mg (66%) of 5-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo [b]thiepin-8-yl pivalate,

Isomer 1.

LC/MS (m/z, MH+): 482

Step 4 : 4-Bromo-5 -(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2, 3 - dihydrobenzo[b]thiepin-8-yl pivalate, Isomer 1

Step 4 of Intermediate 20 was prepared following a similar procedure to that Step 2 of Intermediate 7 from 5-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3- dihydrobenzo[b]thiepin-8-yl pivalate, Isomer 1 to give 360 mg (63%) of 4-bromo-5-(4-((l- (3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2,3-dihydrobe nzo[b]thiepin-8-yl pivalate, Isomer 1.

LC/MS (m/z, MH+): 560

Step 5 : 4-Bromo-5 -(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2, 3 - dihydrobenzo[b]thiepin-8-ol, Isomer 1

A mixture of 4-bromo-5-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-2,3- dihydrobenzo[b]thiepin-8-yl pivalate, Isomer 1 (360 mg, 0.64 mmol) in MeOH (7 ml) and NaOH IN (2 ml, 2 mmpl) was stirred at room temperature for 30 minutes. After addition of HC1 IN (2 ml), the reaction mixture was concentrated under reduced pressure. To the residue obtained, addition of DCM (60 ml) and water (20 ml). After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 360 mg (crude) of 4-bromo-5 -(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2, 3 - dihydrobenzo[b]thiepin-8-ol, Isomer 1.

LC/MS (m/z, MH+): 476

Examples

Method A:

Example 1: 8-(2,4-Dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid, (S) Isomer

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1

A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-l,3,2-dioxabor olan-2- yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 3) (101 mg, 214.75 pmol), 3-(4-bromobenzyl)-l-(3-fluoropropyl)pyrrolidine, Isomer 1 (Intermediate 1 Isomer 1) (65.8 mg, 219.14 pmol), CS2CO3 (178.5 mg, 536.9 pmol), and Pd(dppf)Ch, complex with DCM (18 mg, 21 pmol) in dioxane (1 ml) and water (0.4 ml) was heated to reflux 1 hour. Water (2 ml) and DCM (5 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was treated on SCX column. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 94 mg (77%) of methyl 8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)met hyl)phenyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate, Isomer 1.

LC/MS (m/z, MH+): 566

Step 2: 8-(2,4-Dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (S) Isomer

To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1 (94 mg, 165.8 pmol) in MeOH (0.50 ml) and THF (0.5 ml) was added a solution of NaOH IN (0.5 ml) and the reaction mixture was heated to reflux for 1 hour. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 2 with HC1 IN. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by SFC (Flash DCPAK B 5 pm; 250x30 mm; supercritical CO2 75% / MeOH 25% / TEA 0.1% at 120 ml/min) to give 65.46 mg (71%) of 8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-b enzo[7]annulene-3- carboxylic acid, (S) Isomer.

Method B: 8-(2-Chloro-4-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride,

Isomer 1

Step 1: Methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1

A mixture of methyl 8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phen yl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate, Isomer 1 (Intermediate 7) (98 mg, 195.8 pmol), (2-chloro-4-fluoro-phenyl)boronic acid (35 mg, 203 pmol), CS2CO3 (175 mg, 537 pmol), and Pd(dppf)Ch, complex with DCM (16 mg, 19 pmol) in dioxane (1 ml) and water (0.4 ml) was heated at 70°C for 1 hour. After cooling to room temperature, Water (2 ml) and DCM (5 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was treated on SCX column to give 85 mg (79%) of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1.

LC/MS (m/z, MH+): 550 Step 2: 8-(2-Chloro-4-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride,

Isomer 1

To a solution of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate Isomer 1 (85 mg, 154.5 pmol) in MeOH (1 ml) and THF (1 ml) was added NaOH IN (15 mg, 465 pmol) and the reaction mixture was heated to reflux for 40 minutes. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 2 with HC1 IN. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by SFC (Flash DCPAK B 5 pm; 250 x30 mm; supercritical CO2 70% / MeOH 30% / TEA 0.1% at 120 ml/min) to give 26.47 mg (30%) of 8-(2-chloro-4-fluorophenyl)-9-(4- ((l-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihyd ro-5H-benzo[7]annulene-3- carboxylic acid hydrochloride, Isomer 1.

Method C:

36: 6-(2,4-Dichlorophenyl)-5-(4-((l (3 -fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, Isomer 1

Step 1: Methyl 6-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate, Isomer 1 A mixture of methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-7,8- dihydronaphthalene-2-carboxylate (Intermediate 15) (177 mg, 367 pmol), l-(3- fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2- yl)phenyl]methyl]pyrrolidine, Isomer 1 (Intermediate 9) (98 mg, 282 pmol), CS2CO3 (230 mg, 705 pmol), and Pd(dppf)C12, complex with DCM (14 mg, 17 pmol) in dioxane (2 ml) and water (0.8 ml) was heated to 50°C for 40 minutes. Water (2 ml) and DCM (4 ml) were added. After separation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a solution of MeOH in DCM (95/05, v/v) to give 33 mg (21%) of methyl 6-(2,4-dichlorophenyl)-5-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-7,8-dihydronapht halene-2-carboxylate, Isomer 1.

LC/MS (m/z, MH+): 552

Step 2: 6-(2,4-Dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-

7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, Isomer 1

Step 2 of Example 36 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 6-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylate Isomer 1 to give 34 mg (100%) of 6-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-7,8- dihydronaphthalene-2-carboxylic acid hydrochloride, Isomer 1.

Method D: Example 3; 8-(4,4-Dimethylcyclohexyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1

Step 1: Methyl 8-(4,4-dimethylcyclohex-l-en-l-yl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1

Step 1 of Example 3 was prepared following a similar procedure to that of step 1 of Example 2 from 2-(4,4-dimethyl-l-cyclohexen-l-yl)-4,4,5,5-tetramethyl-l,3,2 -dioxaborolane to give 99 mg (22%) of methyl 8-(4,4-dimethylcyclohex-l-en-l-yl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-b enzo[7]annulene-3- carboxylate, Isomer 1.

LC/MS (m/z, MH+): 530.

Step 2: Methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1

A mixture of methyl 8-(4,4-dimethylcyclohex-l-en-l-yl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-b enzo[7]annulene-3- carboxylate, Isomer 1 (99 mg, 187 pmol), Pd/C 10% (21 mg, 200 pmol) in EtOH (6.5 ml) and EtOAc (4 ml) was hydrogenated at 50°C and 5 bars of H2 for 20 hours. The reaction mixture was filtered The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (Amylose-1 5pM; 250x30 mm; heptane / IsoPrOH / TEA 95/05/0.1) to give 35 mg (35%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-b enzo[7]annulene-3- carboxylate, Isomer 1.

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

Step 3: 8-(4,4-Dimethylcyclohexyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride,

Isomer 1

Step 3 of Example 3 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ate, Isomer 1 to give 35 mg (97%) of 8-(4,4-dimethylcyclohexyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyl ic acid hydrochloride, Isomer 1.

Method E: 4-(2,4-Dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, Isomer 1

Example 43 was prepared following a similar procedure to that of Step 1 of Example 2 from 4-bromo-5 -(4-(( 1 -(3 -fluoropropyl)pyrrolidin-3 -yl)methyl)phenyl)-2, 3 - dihydrobenzo[b]thiepin-8-ol, Isomer 1 (Intermediate 20) and 2,4-dichlorophenylboronic acid to give 120 mg (70%) of 4-(2,4-dichlorophenyl)-5-(4-((l-(3-fluoropropyl)pyrrolidin-3 - yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepin-8-ol, Isomer 1.

The compounds according to table 1 above were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.

Test: Estrogen receptor degradation activity

Said test involves measuring the in vitro degradation activity of the compounds of the Table la.

The measurements of the degradation activities were made using a breast cancer cell ERa in cell western assay as described hereunder.

MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/ 30 pL per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound was added to the cells in 2.5pL at final concentrations ranging from 0.3-0.0000018 pM (in table 2), or 0.1 pM for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 pL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 pL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 pL anti-ER rabbit monoclonal antibody (Thermo scientific MAI -39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking buffer but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween- 20) and incubated at 37 °C for 60 minutes in LI-COR (0.1% tween-20) containing goat antirabbit antibody Alexa 488 (1 : 1000) and Syto-64 a DNA dye (2 pM final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech). Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ERa and DNA respectively.

The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or ICso) in nM.

The % of ERa levels decrease were determined as follows: % inhibition = 100 * (1- (sample - fulvestrant: DMSO - fulvestrant)). The Table 2 below indicates the estrogen receptor degradation activity results for the compounds of Table la tested at 0.3 pM, and demonstrates that said compounds have a significant degradation activity on estrogen receptors. Table 2:

It is therefore apparent that the tested compounds have degradation activities for estrogen receptors, with IC50 less than 1 pM and with degradation levels greater than 40%, especially greater than 45% or 50%, and equal to or greater than 60% or 80% for most compounds. The compounds of formula (I) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors.

Test; CYP3A4 induction potential for ADME profile evaluation

Said test evaluates the potential induction effect of the tested compounds on CYP3 A4 gene expression in primary cultures of human hepatocytes from one or two donors with established concentration-dependent response to the reference inducer, rifampicin.

Material and Methods

Compounds and Chemicals:

Rifampicin and dimethylsulfoxide (DMSO) were purchased from Sigma- Aldrich (St. Louis, MO). All other chemicals and reagents used were obtained from usual commercial sources and were of the highest commercially available grade.

Cell Media for Cryopreserved Human Hepatocytes:

The thawing (UCRM™) and plating (UPCM™) media were purchased from In Vitro ADMET Laboratories (Bethesda, MD). The culture medium was composed of Williams Medium E with 2mM Glutamax, 0.1 pM dexamethasone, 1% ITS (10 pg/mL Insulin, 5.5 pg/mL Transferrin, 6.7 ng/mL Sodium Selenite, 50 pg/mL gentamycin (all purchased from Sigma-Aldrich).

Thawing Procedures for cryopreserved human hepatocytes:

Briefly, the vials containing the cryopreserved cells were removed from liquid nitrogen storage, thawed in a 37°C water bath (75 - 90 seconds), and then quickly poured into prewarmed 50 rnL UCRM™, centrifuged 10 min at 100 g, and re-diluted in UPCM™ (IV AL), so-called plating medium.

Human Hepatocyte Cell Culture and Treatment:

Before seeding, cell viability was estimated using the Trypan blue dye exclusion test. Hepatocytes were seeded on collagen Lcoated 96-well plates at a density of 70 000 cells/well in 100 pL of plating medium for at least 4 hours under a humidified atmosphere of CCh/air (5 %/95 %), at 37°C. After the cell attachment period, the plating medium was removed, and the hepatocytes were treated daily for 2 consecutive days (approximately 48 hours), with 100 pL per well of fresh culture medium containing either the vehicle control (0.1 % DMSO) or the investigated compounds at four concentrations 0 3, 1, 3 and 10 pM, or rifampicin, the reference inducer at 10 pM. All incubations were performed in duplicates.

Ten mM stock solutions of the different compounds were diluted to obtain 0.3, 1 and 3 mM daughter solutions. The day of the experiment, stock solutions were diluted 1000-fold in the incubation/culture medium to achieve final concentrations of 0.3, 1, 3 and 10 pM.

The quality of hepatocyte cultures prior to test compounds incubations was assessed by light microscopy. The morphology of the cultured cells, as well as the attachment efficiency and confluence, were observed and recorded daily. Only monolayers with minimum 80 % confluency were used for further assessments.

Assessment of Test Compounds Cytotoxicity :

Microscopical examination of hepatocyte morphology was used to evaluate cytotoxicity during incubation of each test compound. Moreover, to quantify the potential cytotoxic effects of the compounds in each experiment, a cytotoxicity assessment was also performed using the Resazurin Cell Viability Assay Kit (Abeam).

Induction Assay and Measurement of gene expression:

After the 48-hour incubation period with the test compounds, the cell culture medium was removed, and the cells were lysed to release the RNA for CYP3A4 gene expression assessment. Quantification of CYP3A4 mRNA induction was performed by RT- PCR analysis.

Total RNA was extracted from hepatocytes using the King Fisher™ Flex Purification System with the MagMAX mirVana Total RNA Isolation kit (Thermo Fisher Scientific, USA). RNA was quantified by fluorimetry using the Quantifluor RNA System (Promega, USA) and cDNAs were synthesized from 0.1 pg total RNA using the iScript Reverse Transcription Supermix for RT-qPCR from Biorad (France) at 42°C for 30 min. cDNA samples were then diluted in water (1 :5) and 5 pL of each sample was used for realtime PCR amplification by using the SYBR Green kit from Biorad (France). The following program was used: a denaturation step at 95°C for 30 sec, and 40 cycles of PCR (denaturation, 95°C, 10 sec and annealing and extension, 58°C, 1 min). In all cases, the quality of the PCR product was assessed by monitoring a fusion step at the end of the run Human forward and reverse primer sequences used were: 5’-CCT-GGC-ACC-CAG-CAC- AAT-3’ and 5’-GGG-CCG GAC-TCG-TCA-TAC-3’ for actin, 5’- CAC-AAA-CG-GAG- GCC-TTT-TG-3’ and 5’- ATC-CAT-GCT-GTA-GGC-CCC-AA-3’ for CYP3A4

Cq (quantification cycle) values were determined using a multi-variable, nonlinear regression model to individual well traces and then using this model an optimal Cq value was computed. Cq values are inversely proportional to the amount of target nucleic acid in the sample (i.e., lowest Cq level corresponds to the greatest amount of target nucleic acid in the sample). Cq of reference gene (in this study human actin) was also used as positive control of quantitative PCR.

Calculation and ratings:

The extent of induction or % of Emax, resulting from treatment with test compounds was calculated under the following formula:

Ecomcound : relative fold mRNA expression following treatment with test compound,

Epositive control : relative fold mRNA expression following reference inducer i.e., 10 pM rifampicin,

Evehicie control : relative fold mRNA expression following vehicle treatment i.e., 0.1 % DMSO,

E is the efficiency of the quantitative PCR.

The fold induction of test compounds over the level of vehicle control mRNA expression may also be determined and is calculated under the following formula:

Fold induction (FI) over vehicle control = Ecompound / Evehicie control with Evehicie control for mRNA expression set to 1. The ratings to flag test compounds as inducer are based on % of Emax relative to rifampicin and are in the following table 3:

Table 3:

Example A: Comparative biological activities of compounds (Cl) as disclosed in WO2017/140669 and (C2) in the scope of W02018/091153

(Cl) corresponds to the compound of example 51 of WO2017/140669 and (C2) corresponds to a compound in the scope ofW02018/091153, both compounds (Cl) and (C2) being out of the scope of the present invention.

Compound (Cl) has been synthetized according to example 51 of WO2017/140669. Compound (Cl) displays an oxygen as a linker between north phenyl part and pyrrolidinyl part.

Compound (C2) is not specifically disclosed in W02018/091153 but generally covered. It has been synthetized according to scheme 3a described in W02018/091153. Compound (C2) displays a nitrogen as a linker between north phenyl part and pyrrolidinyl part.

Example A.I: Preparation of compound (C2)

Compound (C2): (S)-8-(2,4-Dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyli c acid

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

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 [l,T-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 for 30 minutes at RT. Water (500 ml) and EtOAc (500 ml) were added. The organic phase was dried over MgSCU, 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

Step 2: Methyl 9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylate

To a mixture of methyl 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulene-3- carboxylate (5.02 g, 17.1 mmol) in DCM (100 mL) cooled at 0°C were added pyridine (2.5 mL, 30.91 mmol) and trifluoromethanesulfonic anhydride (8.55 g, 30.32 mmol). The reaction mixture was stirred at 0°C for 30 minutes and RT for 1 hour. DCM (50 mL) and cold water (100 mL) were added, and decantation was done by hydrophobic column. The organic phase was concentrated under reduced pressure to give 7.2 g (99%) of methyl 9-(4- (((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo [7]annulene-3-carboxylate which was used in the next step without further purification.

LC/MS (m/z, MH+): 427

Step 3: Tert-butyl (S)-3-((4-(3-(methoxycarbonyl)-6,7-dihydro-5 H-benzo[7]annulen-9- yl)phenyl)amino)pyrrolidine-l -carboxylate

A mixture of methyl 9-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H- benzo[7]annulene-3 -carboxylate (2.81 g, 6.59 mmol), tert-butyl (S)-3 -aminopyrrolidine- 1- carboxylate (2.45 g, 13.18 mmol), palladium(II) acetate (148 mg, 0.66 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.53 g, 0.92 mmol) and CS2CO3 (6.44 g, 19.77 mmol) in dioxane (27 mb) was heated to 140°C for 2 hours under microwave irradiation. After cooling to RT, dichloromethane and water were added, and decantation was done by hydrophobic column. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of heptane / EtOAc (from 100/00 to 70/30) to give 0.8 g (26%) of tert-butyl (S)-3-((4-(3- (methoxycarbonyl)-6,7-dihydro-5 H-benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-l- carboxylate.

Step 4: Methyl (S)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[ 7]annulene- 3 -carboxylate Step 4 of compound (C2) was prepared following a similar procedure to that of step 2 of Intermediate 1 Isomer 1 from tert-butyl (S)-3-((4-(3-(methoxycarbonyl)-6,7-dihydro-5 H- benzo[7]annulen-9-yl)phenyl)amino)pyrrolidine-l -carboxylate to give 1.64 g (71%) of methyl (S)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro-5H-benzo[ 7]annulene-3- carboxylate.

LC/MS (m/z, MH+): 363

Step 5: Methyl (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6 ,7-dihydro-

5H-benzo[7]annulene-3-carboxylate

Step 5 of compound (C2) was prepared following a similar procedure to that of step 3 of Intermediate 1 Isomer 1 from methyl (S)-9-(4-(pyrrolidin-3-ylamino)phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate to give 2.17 g (100%) of methyl (S)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-6,7-dihydro-5H-be nzo[7]annulene-3- carboxylate.

Step 6: Methyl (S)-8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)amino)p henyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate

Step 6 of compound (C2) was prepared following a similar procedure to that Step 2 of Intermediate 7 from methyl (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 1.51 g (56%) of methyl (S)-8- bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl) -6,7-dihydro-5H- benzo[7]annulene-3-carboxylate. LC/MS (m/z, MH+): 501 tep 7: Methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolid in-3- l)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylat e tep 7 was prepared following a similar procedure to that of Step 1 of Example 2 from methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)p henyl)-6,7-dihydro- H-benzo[7]annulene-3-carboxylate and 2,4-dichlorophenylboronic acid to give 182 mg 100%) of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolid in-3- l)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylat e. C/MS (m/z, MH+): 567 tep 8: (S)-8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolid in-3- l)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (compound (C2)) tep 8 of compound (C2) was prepared following a similar procedure to that of step 2 of xample 1 from methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolid in-3- l)amino)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylat e to give 71 mg (100%) f (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolid in-3-yl)amino)phenyl)-6,7- ihydro-5H-benzo[7]annulene-3-carboxylic acid. C/MS (m/z, MH+): 553. H NMR (400 MHz, DMSO-d6) δ ppm 1.44 - 1.58 (m, 1 H), 1.70 - 1.90 (m, 2 H), 2.03 - .22 (m, 5 H), 2.29 (dd, J=9, 5 Hz, 1 H), 2.39 - 2.62 (m, 5 H), 2.76 (dd, J=9, 7 Hz, 1 H), 2.84 2.94 (m, 2 H), 3.68 - 3.86 (m, 1 H), 4.47 (dt, J=47, 6 Hz, 2 H), 5.75 (br d, J=6 Hz, 1 H), .29 (d, J=9 Hz, 2 H), 6.52 (d, J=9 Hz, 2 H), 6.92 (d, J=8 Hz, 1 H), 7.19 (d, J=8 Hz, 1 H), 7.24 - 7.33 (m, 1 H), 7.58 (d, J=2 Hz, 1 H), 7.74 (dd, J=8, 1.8 Hz, 1 H), 7.88 (d, J= 2 Hz, 1 H). Example A.2: Test: Estrogen receptor degradation activity of compound (C2) Preliminary, the estrogen receptor degradation activity of the compound (C2) was tested following the same biological conditions as described above under “Test: strogen receptor degradation activity”. Table 4 % In Table 4, compound (C2), tested at 0.3 µM, presents a significant degradation activity on estrogen receptors. In addition, as described in WO2017/140669, compound (C1) also displays a significant degradation activity on estrogen receptors (data not shown). Example A.3: Test: CYP 3A4 induction potential for ADME profile evaluation of the compounds of example 1, (C1) and (C2). The Table 5 below shows comparative data regarding CYP3A4 induction of a compound of the present invention (example 1) with respect to compounds (C1) and (C2) under the test described above. Table 5 )

Compounds of example 1, (Cl) and (C2) are structurally close since they present same south part regarding the annulene ring and substituents, same north part with the fluoropropyl-pyrrolidine lateral chain, and differ only in the nature of the linkers between north phenyl part and pyrrolidinyl part. However, as shown in table 5, compound of example 1 of the invention demonstrates no CYP3A4 induction, in other terms has no CYP3A4 inductive effect, and thus displays an improved ADME profile compared to compounds (Cl) and (C2). Hence, example 1 of the invention surprisingly displays an improved pharmacological profile, with a low risk of inducing drug-drug interactions, compared to prior art compounds (Cl) and (C2). Such results were not predictable from prior art.

Example B; CYP3A4 induction potential of other compounds of the invention

Other compounds of the invention described above in table la were evaluated in the test “CYP3A4 induction potential”; results are presented in Table 6.

Table 6 I l l

The CYP3A4 induction potential results in Table 6 indicate that various compounds of the invention demonstrate no CYP3A4 induction, or a weak or intermediary CYP3A4 induction. Various examples of the invention thus display an improved pharmacological profile, with much lower risks of drug-drug interactions compared to compounds (Cl) and (C2).

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

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

Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors, in particular displaying an improved pharmacological profile, typically a low or limited risk of drug-drug interactions, especially demonstrating no CYP3A4 induction, or a weak or intermediary CYP3A4 induction.

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

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

In an embodiment, the cancer is a hormone dependent cancer.

In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer. In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

In another embodiment, the metastasis is a cerebral metastasis.

In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERa positive breast cancer).

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

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

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

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

Herein are also provided the pharmaceutical compositions comprising as active principle a compound of formula (I). These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

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

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

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

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

Compound of formula (I) 50.0 mg

Mannitol 223.75 mg

Sodium croscarmellose 6.0 mg

Corn starch 15.0 mg

Hydroxypropylmethylcellulose 2.25 mg

Magnesium stearate 3.0 mg

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