NOVEL SUBSTITUTED TETRAHYDROISOQUINOLINE-6- CARBOXYLIC ACID DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC USES THEREOF Disclosed herein are novel substituted tetrahydroisoquinoline-6-carboxylic acid 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 (ERα) and the estrogen receptor beta (ERβ) respectively encoded by the ESR1 and the ESR2 genes. ERα and ERβ are ligand- activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA/ER complex interacts with co-regulators to modulate the transcription of target genes. ERα is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERα signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis. ERα is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high level of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is well established and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority ERα-positive breast tumors. Currently, several strategies for inhibiting the estrogen axis in breast cancer exist, including: 1- blocking estrogen synthesis by aromatase inhibitors that are used to treat early and advanced ERα-positive breast cancer patients; 2- antagonizing estrogen ligand binding to ERα by tamoxifen which is used to treat ERα-positive breast cancer patients in both pre- and post- menopausal setting; 3- antagonizing and downregulating ERα levels by fulvestrant, which is used to treat breast cancer in patients that have progressed despite endocrine therapies such as tamoxifen or aromatase inhibitors. Although these endocrine therapies have contributed enormously to reduction in breast cancer development, about more than one-third of ERα-positive patients display de novo resistance or develop resistance over time to such existing therapies. Several mechanisms have been described to explain resistance to such hormone therapies. For example, hypersensitivity of ERα to low estrogen level in treatment with aromatase inhibitors, the switch of tamoxifen effects from antagonist to agonist effects in tamoxifen treatments or multiple growth factor receptor signaling pathways. Acquired mutations in ERα occurring after initiation of hormone therapies may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the Ligand Binding Domain (LBD), result in the ability to bind to DNA in the absence of ligand and confer hormone independence in cells harboring such mutant receptors. Most of the endocrine therapy resistance mechanisms identified rely on ERα- dependent activity. One of the new strategies to counterforce such resistance is to shut down the ERα signaling by removing ERα 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 WO2018/091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)- pyrrolidine derivatives useful as SERDs. 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’ and R3” independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; - R4 represents a hydrogen atom or a fluorine atom; - R5 and R5’ independently represent a hydrogen atom or a fluorine atom; - Y represents -CH2-, -CH=, -CR9=, -O- or -NH-, wherein R9 represents a fluorine atom or a (C ₁ -C ₃ )alkyl group; - represents a single bond or a double bond; - p is 0 or 1; - X represents -CH=, -N= or -CR”=, wherein R” represents a (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; - R7 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; - n is 0, 1 or 2; and - R6 represents a (C1-C6)alkyl group, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C ₁ -C ₃ )alkoxy group, a (C ₁ -C ₃ )fluoroalkoxy group, a cyclopropyl group, an oxetanyl group, and a -OH group; - R8 represents a hydrogen atom, a (C1-C3)alkyl group, a -CH2F group, a -CHF2 group, a -CF ₃ group, or a (C ₃ -C ₄ )cycloalkyl group. 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 alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms (noted “(C1-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 4 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted; - a fluoroalkyl group: an alkyl group as previously defined where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -CH ₂ F, -CHF ₂ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be named perfluoroalkyl group. By way of example, mention may be made of trifluoromethyl group or trifluoroethyl group and the like; - an alkoxy group: an -O-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, and the like; - a fluoroalkoxy group: an -O-alkyl group where the alkyl group is as previously defined and where the alkyl group is substituted with at least one fluorine atom. In other terms, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, mention may be made of -OCH ₂ F, -OCHF ₂ , -OCH ₂ CH ₂ F and the like. When all the hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkoxy group can be named perfluoroalkoxy group. By way of example, mention may be made of trifluoromethoxy group and the like; - a 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’ represents a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above, R3” represents a hydrogen atom. 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, R4 represents a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above, R5 and R5’ both represent a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above, p is 0. In another embodiment, in the compounds of formula (I) as defined above, p is 1. In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH2-, -CH=, -O- or -NH-. In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH ₂ -. 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, Y represents -O-. In another embodiment, in the compounds of formula (I) as defined above, Y represents -NH-. In another embodiment, in the compounds of formula (I) as defined above, R7 is a halogen atom, and preferably a fluorine 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, n is 1. In another embodiment, in the compounds of formula (I) as defined above, n is 2. In another embodiment, in the compounds of formula (I) as defined above, R7 represents a fluorine atom and n is 1 or 2. In another embodiment, in the compounds of formula (I) as defined above, R8 represents a (C ₁ -C ₆ )alkyl group, and preferably represents a methyl group. In another embodiment, in the compounds of formula (I) as defined above, X represents -N= or -CR”=, wherein R” represents a halogen atom, preferably a fluorine atom. In another embodiment, in the compounds of formula (I) as defined above, X represents -N=. In another embodiment, in the compounds of formula (I) as defined above, X represents -CR”=, wherein R” represents a halogen atom, preferably a fluorine atom. In another embodiment, in the compounds of formula (I) as defined above, X represents -CR”=, wherein R” represents a hydrogen atom. In another embodiment, in the compounds of formula (I) as defined above, R6 represents a (C ₁ -C ₆ )alkyl group, said (C ₁ -C ₆ )alkyl group being optionally substituted with 1 to 3 fluorine atom, preferably said (C1-C6)alkyl group being substituted with 2 or 3 fluorine atom. In another embodiment, in the compounds of formula (I) as defined above, R6 represents a -CH2-CF3 group or a -CH2-CF2-CH3 group. In another embodiment, in the compounds of formula (I) as defined above, represents a single bond. In another embodiment, represents a double bond. In another embodiment, in the compounds of formula (I) as defined above, p is equal to 1 when Y represents -CH2-, -O- or -NH-. In another embodiment, in the compounds of formula (I) as defined above, p is equal to 1. 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: - (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)amino)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline -6-carboxylic acid, (1) - (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)amino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid, (2) - (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) amino)phenyl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carb oxylic acid, (3) - (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)oxy)phenyl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylic acid, (4) - (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carb oxylic acid, (5) - (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid, (6) - (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylic acid, (7) - (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, (8) - (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3-ylidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino line-6-carboxylic acid, (9) - (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3-ylidene)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid, (10) - (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-y l)methyl)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylic acid, 50/50 mixture of diastereomers (11). 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 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 formula are used: MeCN Acetonitrile NH4Cl Ammonium chloride BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II ) n-BuLi n-Butyllithium CO Carbon monoxide CO2 Carbon dioxide Cs ₂ CO ₃ Cesium carbonate DCE Dichloroethane DCM Dichloromethane SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMAP Dimethylaminopyridine DMSO Dimethyl sulfoxide EtOAc Ethyl acetate HPLC High performance liquid chromatography H ₂ Hydrogen HCl Hydrochloric acid IsoPrOH Isopropanol LG Leaving group LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium sulfate Pd/C Palladium on carbon PtO2 Platinum oxide K2CO3 Potassium carbonate K ₃ PO ₄ Potassium phosphate NaHCO3 Sodium bicarbonate NaCl Sodium chloride NaOH Sodium hydroxide SFC Supercritical Fluid Chromatography tBuBrettPhos Dimethoxy-2′,4′,6′-tris(1-methylethyl) [1,1′-biphenyl]-2- yl]bis(1,1-dimethylethyl)phosphine tBuBrettPhos Pd G ₃ [(2-Di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate TMAD Tetramethylazodicarboxamide TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran PPh ₃ Triphenylphosphine RT Room temperature SCHEME 1a Parts 1 and 2: Preparation of compounds of the formula (I) – General process SCHEME 1a – Part - 1: SCHEME 1a – Part - 2: ( )p C ^{ompound I'} According to SCHEME 1a – Part 1 and Part 2, in which R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, are defined as described above, compound 1A can be converted in by treatment with compound R6-LG, wherein LG is a suitable leaving group, for example a halogen atom, such as iodo, bromo or chloro or trifluoromethanesulfonate, in the presence of a suitable base, such as diisopropylethylamine (DIPEA) in a suitable solvent, such as DMF. Compound 1B can be converted in STEP 2 to compound 1D by treatment with compound 1C in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example dichloroethane (DCE) by heating up to reflux of solvent. Alternatively, compound 1D can be obtained by treatment of compound 1B with compound 1E in STEP 3 in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example DCE, by heating up to reflux of solvent, followed by a coupling reaction in STEP 4 between obtained compound 1F and one of compounds 1G under coupling reaction conditions. If necessary, phenol group of compound 1F could be protected by a protecting group such as a pivaloyl group. Compound 1D can be converted in STEP 5 to compound 1H by treatment with triflation reagent, such as trifluoromethanesulfonic anhydride or 1,1,1-trifluoro-N-phenyl- N-(trifluoromethylsulfonyl)methanesulfonamide, in the presence of a base, such as triethylamine (TEA) or dimethylaminopyridine (DMAP), in a solvent such as DCM. Compound 1H can be converted in STEP 6 to compound 1J by carbonylation with carbon monoxide (CO), in solution in MeOH, in the presence of a palladium catalyst, for example palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl ₂ ), complex with DCM. Compound 1J can be converted in STEP 7 to compound I by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound I. The acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound I. The acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound I. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound I. When Y = CH=, compound I may be reduced by hydrogenation in STEP 8 with a catalyst, such as Pd/C or platinum oxide (PtO ₂ ) under hydrogen (H ₂ ) pressure to give the corresponding saturated compound I’. Alternatively, when Y = CH=, compound 1J’ could be prepared by hydrogenation of compound 1J in STEP 9 with a catalyst, such as Pd/C or platinum oxide (PtO2) under hydrogen (H2) pressure followed by the treatment of obtained compound 1J’ with an aqueous solution of NaOH or LiOH in MeOH or THF to give compound I’. Extraction of the product could give the sodium or lithium salt of compound I’. The acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound I’. The acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound I’. The purification using HPLC in presence of formic acid or trifluoroacetic acid in the eluent could give the formate or trifluoroacetate salt of compound I’. SCHEME 1b: Alternative process to prepare Intermediate 1D

According to SCHEME 1b, in which R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X, Y and are defined as described above, compound 1F can be converted in STEP 1 to compound 1L by treatment, in a coupling reaction, with one of compounds 1G’ under coupling reaction conditions. If necessary, phenol group of compound 1F could be protected by a protecting group such as pivaloyl group. Alternatively, compound 1L can be obtained in STEP 2 by treatment of compound 1B with compound 1K in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example DCE, by heating up to reflux of solvent. Compound 1L can be converted in STEP 3 to compound 1M by treatment with TFA or HCl. Compound 1M can be converted in STEP 4 to compound 1D by the treatment with compound 1N, wherein W is Cl, Br or I or OSO2R with R = CH3, PhMe, CF3 or CF ₂ CF ₂ CF ₂ CF ₃ in the presence of a base such as potassium carbonate (K ₂ CO ₃ ) in DMF as a solvent. Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1J: ( )p are defined as , presence a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound of formula 1J, wherein a compound of formula 1H: ( )p are defined as carbon monoxide (CO), in solution in MeOH, in the presence of a palladium catalyst. Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1F: wherein R3’, R3’’, R6, R7, R8, n, and X are defined as described above is subjected to a coupling step with one of compounds of formula 1G under coupling reaction conditions: 1G wherein R1, R2, R4, R5, R5’ and p are as defined above, for obtaining a compound of formula 1D: ( )p wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above, said step being optionally preceded by a step of obtaining compound 1F, wherein a compound of formula 1B: wherein R3’, R3’’, R6, and R8 are defined as described above is subjected to a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example DCE, with compound of formula 1E: wherein X, R7 and n are as defined above. Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1B: wherein R3’, R3’’, R6 and R8 are defined as described above is subjected to a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example dichloroethane (DCE), with compound of formula 1C: wherein R1, R2, R4, R5, R5’, R7, , n, p, X and Y are as defined above, for obtaining a compound of formula 1D: ( )p are defined as Herein is also provided a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1M:

, n, p, X and Y are defined as described above is subjected to a treatment in the presence of a base such as potassium carbonate (K2CO3) in DMF as a solvent with a compound of formula 1N: wherein R1, R2, R4, R5 and R5’ are as defined above, and W is Cl, Br or I or OSO ₂ R with R = CH ₃ , PhMe, CF ₃ or CF ₂ CF ₂ CF ₂ CF ₃ , for obtaining a compound of formula 1D: ( )p 1D wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above. Herein are also provided the intermediate compounds selected from compounds of formula 1J, or any of its pharmaceutically acceptable salt, ( )p wherein are defined above. In another aspect, herein is also provided a process for the preparation of a compound of formula (I), comprising a deprotection step of a compound of formula 1J as defined above, optionally followed by a purification step. Said purification steps may for example consist in an acidification step, for example with an aqueous solution of hydrochloric acid. The ¹ H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz. The liquid chromatography/mass spectra (LC/MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210-400 nm and flash Acquity UPLC CSH C181.7 µm, dimension 2.1x30 mm, mobile phase H ₂ O + 0.1% HCO ₂ H / CH ₃ CN + 0.1% HCO ₂ H. The following tables 1a and 1b comprises respectively specific compounds of formula (I) (name and structure) in accordance with the present disclosure as well their characterization ( ¹ H NMR and liquid chromatography/mass). Table 1a: (the first column “Ex” corresponds to the compound and example number) Structure Name Structure Name Structure Name Table 1b: P i NMR MAS Pre aration NMR MAS Pre aration NMR MAS The examples which follow describe the preparation of some compounds of formula (I) described herein. The numbers of the compounds exemplified below match those given in the Tables 1a and 1b above. All reactions are performed under inert atmosphere, unless otherwise stated. In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds. Examples Intermediates: Intermediate 1: (R)-3-(2-((2,2-Difluoropropyl)amino)propyl)phenol To a solution of commercially available 3-[(2R)-2-aminopropyl]phenol (1 g, 6.61 mmol) and DIPEA (3.47 ml, 19.84 mmol) in DMF (7 ml) was added 2,2-difluoropropyl trifluoromethanesulfonate (1.75 g, 7.27 mmol). The solution was stirred at 65 °C for 18 h. After cooling down to RT, water (10 ml) was added and the aqueous layer was extracted with DCM (3x10 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 1.45 g (96%) of (R)-3-(2- ((2,2-difluoropropyl)amino)propyl)phenol. LC/MS (m/z, MH+): 230 Intermediate 2: (R)-3-(2-((2,2,2-Trifluoroethyl)amino)propyl)phenol Intermediate 2 was prepared following a similar procedure to that of Intermediate 1 from 3- [(2R)-2-aminopropyl]phenol and 2,2,2-trifluoroethyltrifluoromethane sulfonate to give 4 g (66%) of (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol. LC/MS (m/z, MH+): 234 Intermediate 3: (S)-2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)amino)benzaldehyde Step 1: Tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate A suspension of tert-butyl N-[(3S)-pyrrolidin-3-yl] carbamate (5 g, 26.04 mmol), 1-fluoro- 3-iodopropane (5.38 g, 28.64 mmol) and K2CO3 (10.36 g, 74.21 mmol) in MeCN (100 ml) was stirred for 18 h at 50 °C. After cooling down to RT, the suspension was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was solubilized in EtOAc then successively washed with water and a saturated aqueous solution of NaCl, then dried over MgSO4, filtered and concentrated under reduced pressure to give 6.03 g (94 %) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate. LC/MS (m/z, MH+): 247 Step 2: (S)-2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino )benzaldehyde A mixture of 4-bromo-2,6-difluorobenzaldehyde (1.83 g, 8.12 mmol, 1 eq), Cs2CO3 (5.32 g, 16.24 mmol), palladium diacetate (0.038 g, 0.081 mmol), BINAP (0.101 g, 0.16 mmol), and tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (2 g, 8.12 mmol) in toluene (100 ml) was stirred for 96 h at 80 °C. After cooling down to RT, the reaction mixture was filtered through celite. Water (50 ml) was added to the filtrate then the organic layer was separated, and the aqueous phase was extracted again with EtOAc (2x20ml). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 30/70 to 00/100 to give 760 mg (24%) of (S)-2,6-difluoro-4-((1-(3- fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde as a yellow oil. LC/MS (m/z, MH+): 387 Intermediate 4: 1-(3-Fluoropropyl)azetidin-3-amine Step 1: Tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate A suspension of tert-butyl N-(azetidin-3-yl) carbamate hydrochloride (5 g, 23.5 mmol), 1- fluoro-3-iodopropane (4.86 g, 25.8 mmol) and K2CO3 (8.19 g, 58.7 mmol) in THF (100 ml) and water (0.21 ml, 11.7 mmol) was stirred at 70 °C for 5 hours. The crude mixture was cooled to RT, poured into water (100 ml) and extracted with EtOAc (200 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 5.37 g (98 %) of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate as a white powder. LC/MS (m/z, MH+): 233 Step 2: 1-(3-Fluoropropyl)azetidin-3-amine TFA (4.34 ml, 48.6 mmol) was added dropwise to a solution of tert-butyl (1-(3- fluoropropyl)azetidin-3-yl)carbamate (1 g, 4.305 mmol) in DCM (10 ml). The reaction mixture was stirred at RT for 16 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in MeOH (10 ml) and Amberlyst A26 (4 g) was added, and the mixture was stirred at RT for 64 hours. The reaction mixture was filtered to remove Amberlyst A26 and washed with MeOH, then concentrated under reduced pressure to give 0.5 g (88%) of 1-(3-fluoropropyl)azetidin-3-amine. LC/MS (m/z, MH+): 133 Intermediate 5: Tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3- yl)carbamate Intermediate 5 was prepared following a similar procedure to that of Step 2 of Intermediate 3 from tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate (Step 1 of Intermediate 4) and 4-bromo-2,6-difluorobenzaldehyde to give 2.95 g (92%) of tert-butyl (3,5-difluoro-4- formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate as an orange oil. LC/MS (m/z, MH+): 373 Intermediate 6: (S)-2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)b enzaldehyde To a solution of 2,6-difluoro-4-hydroxybenzaldehyde (0.88 g, 5.44 mmol) in dry THF (20 ml) were added (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) (1 g, 6.79 mmol), PPh ₃ (2.88 g, 10.9 mmol) and TMAD (1.87 g, 10.87 mmol). The reaction mixture was stirred at RT for 48 h. Water (50 ml) and EtOAc (100 ml) were added, then the aqueous layer was separated and extracted again with EtOAc (50 ml). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 to give 660 mg (36%) of (S)-2,6-difluoro-4-((1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde. LC/MS (m/z, MH+): 288 Intermediate 7: (S)-2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)b enzaldehyde Intermediate 7 was prepared following a similar procedure to that of Intermediate 6 from 5- hydroxypyridine-2-carbaldehyde and (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) to give 1.7 g (33%) of (S)-5-((1-(3-fluoropropyl)pyrrolidin- 3-yl)oxy)picolinaldehyde. LC/MS (m/z, MH+): 253 Intermediate 8: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzald ehyde Step 1: Tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate A mixture of 4-bromo-3,5-difluorophenol (2.09 g, 10 mmol), Cs ₂ CO ₃ (6.52 g, 20 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (2.25 mL, 12 mmol) in DMF (17 ml) was heated at 100 °C for 3h. After cooling down to RT, the reaction mixture was filtered, the solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The residual oil was diluted in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue obtained was washed with heptane and the precipitate was filtered to give 2.52 g (69%) of tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate as a white powder. LC/MS (m/z, MH+): 364 Step 2: 3-(4-Bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid Step 2 of Intermediate 8 was was prepared following a similar procedure to that of Step 2 of Intermediate 4 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1- carboxylate to give 2 g (crude) of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2- trifluoroacetic acid used as such in the next step. LC/MS (m/z, MH+): 264 Step 3: 3-(4-Bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid (2 g, crude), 1-iodo-3-fluoropropane (0.56 mL, 5.49 mmol), DIPEA (4.78 mL, 27.5 mmol) in DMF (20 ml) was stirred at RT for 16h. The crude mixture was poured into water and extracted with EtOAc. The organic phase was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting oil was dissolved in heptane and concentrated under reduced pressure to give 1.69 g (95%) of 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3- fluoropropyl)azetidine as a brown-yellow oil. LC/MS (m/z, MH+): 324 Step 4: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzald ehyde A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine (1.5 g, 4.63 mmol) in THF (46 ml) was cooled to -78°C. Then, n-BuLi 1.6M in hexane (3.05 ml, 4.86 mmol) was dropwise added to the crude mixture and stirred at this temperature for 30 minutes. Then, DMF (0.72 ml, 9.26 mmol) was dropwise added to the crude mixture at - 78°C and stirred at this temperature for 3 hours. The crude mixture was quenched with water at RT and stirred for 15 minutes. Then, the aqueous phase was extracted with EtOAc (50 ml), dried over MgSO ₄ , filtered off and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of Heptane/EtOAc from 50/50 to 00/100 to give 0.38 g (30%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)oxy)benzaldehyde as a yellow liquid. LC/MS (m/z, MH+): 274 Intermediate 9: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)benzaldehyde Step 1: 3-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)az etidine, 2,2,2- trifluoroacetic acid TFA (2.89 mL, 38.96 mmol, 5 eq.) was dropwise added at RT to a solution of commercially available tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)az etidine-1- carboxylate (2.3 g, 7.79 mmol) in DCM (20 ml). The solution was stirred for 18 hours. The crude oil was concentrated under reduced pressure to give 2.67 g (crude) of 3-((4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid used as such in the next step. LC/MS (m/z, MH+): 196 Step 2: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)methylene)azetidine Step 2 of Intermediate 9 was prepared following a similar procedure to that of step 1 of Intermediate 3 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)az etidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane to give 1.05 g (60%) of 1-(3- fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)methylene)azetidine. LC/MS (m/z, MH+): 256 Step 3: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl )benzaldehyde A mixture of 4-bromo-2,6-difluorobenzaldehyde (324.82 mg, 1.47 mmol), K ₃ PO ₄ (936 mg, 4.409 mmol), palladium diacetate (16.5 mg, 0.073 mmol), SPhos (30.17 mg, 0.073 mmol) and 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)methylene) azetidine (750 mg, 2.94 mmol) in THF (1.57 ml) and water (0.16 ml) was heated at 40 °C for 18 h. After cooling to RT, the reaction mixture was diluted with EtOAc (10 ml) and water (5 ml). The aqueous layer was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 to give 243 mg (61%) of 2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde. LC/MS (m/z, MH+): 270 Intermediate 10: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)methylene)pyrrolidine, mixture of Z and E isomers Step 1: Tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)py rrolidine- 1-carboxylate, mixture of Z and E isomers To a solution of 2,2,6,6-tetramethylpiperidine (5.51 ml, 32.4 mmol) in 2- methyltetrahydrofuran (50 ml) at -78 °C was dropwise added n-BuLi 1.6 M in THF (20.2 ml, 32.4 mmol) (internal temperature maintained below -65 °C). The solution was stirred at -78°C for 30 minutes. Then at -78°C, a solution of 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2- dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (7.23 g, 27.0 mmol) in 2- methyltetrahydrofuran (50 ml) was dropwise added (internal temperature maintained below -65 °C). The reaction mixture was stirred at -78°C for 30 minutes. Then a solution of tert- butyl 3-oxopyrrolidine-1-carboxylate (5 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was dropwise added at -78°C (internal temperature maintained below -65 °C). The reaction was allowed to slowly warm to RT and stirred at this temperature for 18 h. The reaction mixture was cooled to 0 °C and slowly quenched with a 10% aqueous solution of NH4Cl (30 ml). The aqueous layer was separated and extracted again with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of gradient heptane/EtOAc from 90/10 to 70/30 to give 6.23 g (75%) of tert-butyl 3-((4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1- carboxylate, mixture of Z and E isomers as a colorless oil. LC/MS (m/z, MH+): 310

Step 2: 3-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)py rrolidine, hydrochloride, mixture of Z and E isomers To a solution of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)pyrrolidine-1-carboxylate, mixture of Z and E isomers (6.2 g, 20 mmol) in dioxane (20 ml) at RT was slowly added 4N HCl in dioxane (50 ml, 200 mmol). The solution was stirred at RT for 18 h then concentrated under reduced pressure to give 5.09 g (crude) of 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)py rrolidine, hydrochloride which was used as such in the next step. LC/MS (m/z, MH+): 210 Step 3: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2- yl)methylene)pyrrolidine, mixture of Z and E isomers Step 3 of Intermediate 10 was prepared following a similar procedure to that of step 1 of Intermediate 3 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)py rrolidine, hydrochloride, mixture of Z and E isomers and 1-fluoro-3-iodopropane to give 4.53 g (83%) of 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)methylene) pyrrolidine, mixture of Z and E isomers. LC/MS (m/z, MH+): 270 Intermediate 11: (1S,3R)-1-(4-Bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol A mixture of (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) (900 mg, 3.86 mmol), 4-bromo-2,6-difluorobenzaldehyde (853 mg, 3.86 mmol) and TFA (0.29 ml, 3.86 mmol) in DCE (25 ml) was stirred at 80 °C for 18h. After cooling to RT, DCM (25 ml) and a 10% aqueous solution of NaHCO3 (25 ml) were added. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 70/30 to 50/50 to give 1 g (83%) of (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol. LC/MS (m/z, MH+): 436 Intermediate 12: (1S,3R)-1-(4-Bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl )-3- methyl-1,2,3,4-tetrahydroisoquinolin-6-ol Intermediate 12 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol (Intermediate 1) and 4-bromo-2,6- difluorobenzaldehyde to give 950 mg (54%) of (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin- 6-ol. LC/MS (m/z, MH+): 397 Intermediate 13: (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroe thyl)- 1,2,3,4-tetrahydroisoquinolin-6-ol Intermediate 13 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and 5-bromopyridine- 2-carboxaldehyde to give 460 mg (89%) of (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol as a pale-yellow powder. LC/MS (m/z, MH+): 401 Examples Method A: Example 1: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tet rahydroisoquinoline-6- carboxylic acid Step 1: Tert-butyl (4-((1S,3R)-2-(2,2-difluoropropyl)-6-hydroxy-3-methyl-1,2,3, 4- tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)((S)-1-(3-flu oropropyl)pyrrolidin-3- yl)carbamate Step 1 of Example 1 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol (Intermediate 1) and (S)-2,6- difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzald ehyde (Intermediate 3) to give 836 mg (92%) of tert-butyl (4-((1S,3R)-2-(2,2-difluoropropyl)-6-hydroxy-3-methyl-1,2,3, 4- tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)((S)-1-(3-flu oropropyl)pyrrolidin-3- yl)carbamate. LC/MS (m/z, MH+): 596 Step 2: (1S,3R)-1-(4-((Tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3- yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methy l-1,2,3,4- tetrahydroisoquinolin-6-yl trifluoromethanesulfonate TEA (0.38 ml, 2.68 mmol) was added to the mixture of tert-butyl (4-((1S,3R)-2-(2,2- difluoropropyl)-6-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquin olin-1-yl)-3,5- difluorophenyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)carbam ate (800 mg, 1.34 mmol), N- phenyltrifluoromethanesulfonimide (574 mg, 1.61 mmol) and DMAP (16.5 mg, 0.13 mmol) in DCM (25 ml). Then, the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to give 1.6 g (crude) of (1S,3R)-1-(4-((tert- butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino) -2,6-difluorophenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate used as such in the next step. LC/MS (m/z, MH+): 730 Step 3: Methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3- yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methy l-1,2,3,4- tetrahydroisoquinoline-6-carboxylate In a stainless-steel bomb, a mixture of (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2 ,2-difluoropropyl)-3-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.6 g, 2.19 mmol), TEA (0.92 ml, 6.58 mmol) and [1,1`-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (0.38 g, 0.44 mmol) in MeOH (25 ml) was stirred at 100 °C under CO atmosphere (5 bars) for 18 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give 2.1 g (crude) of methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2 ,2-difluoropropyl)-3-methyl- 1,2,3,4-tetrahydroisoquinoline-6-carboxylate used as such in the next step. LC/MS (m/z, MH+): 640 Step 4: Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tet rahydroisoquinoline-6- carboxylate TFA (6 ml, 82 mmol) was dropwise added to a solution of methyl (1S,3R)-1-(4-((tert- butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino) -2,6-difluorophenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylate (2.1 g, 3.28 mmol) in DCM (50 ml). The reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure. Then DCM (50 ml) and a 10% aqueous solution of NaHCO3 (30 ml) were added. After decantation, the organic layer was dried over MgSO4, filtered and concentrated reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 95/05 to give 530 mg (30%) of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tet rahydroisoquinoline-6- carboxylate as a brown solid. LC/MS (m/z, MH+): 540 Step 5: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)amino)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid LiOH (2M in H ₂ O) (2.46 ml, 4.91 mmol) was added to a solution of methyl (1S,3R)-1-(2,6- difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phe nyl)-2-(2,2-difluoropropyl)-3- methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (530 mg, 0.98 mmol) in THF (0.8 ml) at RT. The reaction mixture was stirred at 60 °C for 18 h. After cooling to RT, EtOAc (10 ml) was added. After decantation, the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 to give 308 mg (60%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tet rahydroisoquinoline-6- carboxylic acid. Example 2: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-t etrahydroisoquinoline-6- carboxylic acid Step 1: Tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2-trifluo roethyl)- 1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)((S)-1-(3-fluoropr opyl)pyrrolidin-3- yl)carbamate Step 1 of Example 2 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and (S)-2,6- difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzald ehyde (Intermediate 3) to give 772 mg (86%) of tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)(( S)-1-(3- fluoropropyl)pyrrolidin-3-yl)carbamate. LC/MS (m/z, MH+): 600 Step 2: (1S,3R)-1-(4-((Tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3- yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroeth yl)-1,2,3,4- tetrahydroisoquinolin-6-yl trifluoromethanesulfonate Step 2 of Example 2 was prepared following a similar procedure to that of Step 2 of Example 1 from tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2-trifluo roethyl)- 1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)((S)-1-(3-fluoropr opyl)pyrrolidin-3- yl)carbamate to give 228 mg (94%) of (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-3-me thyl-2-(2,2,2-trifluoroethyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate. LC/MS (m/z, MH+): 734 Step 3: Methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3- yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroeth yl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylate Step 3 of Example 2 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3-yl)amino)- 2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3, 4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 287 mg (crude) of methyl (1S,3R)-1-(4-((tert- butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino) -2,6-difluorophenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylate used as such in the next step. LC/MS (m/z, MH+): 644 Step 4: Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-t etrahydroisoquinoline-6- carboxylate Step 4 of Example 2 was prepared following a similar procedure to that of Step 4 of Example 1 from methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)py rrolidin-3- yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroeth yl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylate to give 63 mg (30%) of methyl (1S,3R)-1-(2,6- difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phe nyl)-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate . LC/MS (m/z, MH+): 544 Step 5: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)amino)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino line-6-carboxylic acid Step 5 of Example 2 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-t etrahydroisoquinoline-6- carboxylate to give 31 mg (52%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2 -trifluoroethyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylic acid. Example 3: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) amino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid Step 1: Tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2-trifluo roethyl)- 1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)(1-(3-fluoropropyl )azetidin-3-yl)carbamate Step 1 of Example 3 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-y l)carbamate (Intermediate 5) to give 404 mg (69%) of tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)(1 -(3-fluoropropyl)azetidin-3- yl)carbamate as a pale-yellow powder. LC/MS (m/z, MH+): 586 Step 2: (1S,3R)-1-(4-((Tert-butoxycarbonyl)(1-(3-fluoropropyl)azetid in-3-yl)amino)-2,6- difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-te trahydroisoquinolin-6-yl trifluoromethanesulfonate Step 2 of Example 3 was prepared following a similar procedure to that of Step 2 of Example 1 from tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2-trifluo roethyl)- 1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)(1-(3-fluoropropyl )azetidin-3-yl)carbamate to give 620 mg (crude) of (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetid in-3- yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroeth yl)-1,2,3,4- tetrahydroisoquinolin-6-yl trifluoromethanesulfonate used as such in the next step. LC/MS (m/z, MH+): 720 Step 3: Methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetid in-3- yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroeth yl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylate Step 3 of Example 3 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetid in-3-yl)amino)-2,6- difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-te trahydroisoquinolin-6-yl trifluoromethanesulfonate to give 400 mg (crude) of methyl (1S,3R)-1-(4-((tert- butoxycarbonyl)(1-(3-fluoropropyl)azetidin-3-yl)amino)-2,6-d ifluorophenyl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carb oxylate used as such in the next step. LC/MS (m/z, MH+): 630 Step 4: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-t etrahydroisoquinoline-6- carboxylate Step 4 of Example 3 was prepared following a similar procedure to that of Step 4 of Example 1 from methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetid in-3-yl)amino)- 2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3, 4-tetrahydroisoquinoline-6- carboxylate to give 150 mg (47%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-t rifluoroethyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylate. LC/MS (m/z, MH+): 530 Step 5: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) amino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid Step 5 of Example 3 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) amino)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino line-6-carboxylate to give 35 mg (24%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) amino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid. Example 4: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tet rahydroisoquinoline-6- carboxylic acid Step 1: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-ol Step 1 of Example 4 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and (S)-2,6- difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldeh yde (Intermediate 6) to give 500 mg (66%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tet rahydroisoquinolin-6-ol. LC/MS (m/z, MH+): 503 Step 2: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl trifluoromethanesulfonate To a solution of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tet rahydroisoquinolin-6-ol (300 mg, 0.6 mmol) in DCM (8 ml) cooled at -10 °C was dropwise added DMAP (220 mg, 1.8 mmol) then triflic anhydride (0.74 ml, 0.92 mmol). The reaction mixture was stirred at -5 °C for 2 hours. At -5 °C, the reaction mixture was quenched with water (5 ml), DCM (10 ml) and a 10 % aqueous solution of NH4Cl (5 ml). After decantation, the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 320 mg (crude) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)oxy)phenyl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate used as such in the next step. LC/MS (m/z, MH+): 635 Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tet rahydroisoquinoline-6- carboxylate Step 3 of Example 4 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl trifluoromethanesulfonate to give 34 mg (29%) of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)- 1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2, 2,2-trifluoroethyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylate. LC/MS (m/z, MH+): 545 Step 4: (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid Step 4 of Example 4 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin -3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tet rahydroisoquinoline-6- carboxylate to give 40 mg (34%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-t rifluoroethyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylic acid. Example 5: (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylic acid Step 1: (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol Step 1 of Example 5 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and (S)-5-((1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)picolinaldehyde (Intermediate 7) to give 200 mg (43%) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol. LC/MS (m/z, MH+): 468 Step 2: (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate Step 2 of Example 5 was prepared following a similar procedure to that of Step 2 of Example 4 from (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol and triflic anhydride to give 350 mg (crude) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl trifluoromethanesulfonate used as such in the next step. LC/MS (m/z, MH+): 600 Step 3: Methyl (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylate Step 3 of Example 5 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 205 mg (69%) of methyl (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin- 2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydrois oquinoline-6-carboxylate. LC/MS (m/z, MH+): 510 Step 4: (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylic acid Step 4 of Example 5 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylate to give 12 mg (6%) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyr idin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylic acid. Example 6: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylic acid Step 1: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino lin-6-ol Step 1 of Example 6 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and 2,6-difluoro- 4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde (Intermediate 9) to give 375 mg (96%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinolin-6- ol. LC/MS (m/z, MH+): 485 Step 2: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino lin-6-yl trifluoromethanesulfonate Step 2 of Example 6 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-ol to give 472 mg (crude) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl trifluoromethanesulfonate used as such in the next step. LC/MS (m/z, MH+): 617 Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylate Step 3 of Example 6 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl trifluoromethanesulfonate to give 51 mg (21%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2 ,2,2-trifluoroethyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylate. LC/MS (m/z, MH+): 527 Step 4: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino line-6-carboxylic acid Step 4 of Example 6 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylate to give 25 mg (51%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin- 3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1 ,2,3,4-tetrahydroisoquinoline- 6-carboxylic acid. Example 7: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline -6-carboxylic acid Step 1: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol Step 1 of Example 7 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol (Intermediate 1) and 2,6-difluoro- 4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) to give 431 mg (81%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol. LC/MS (m/z, MH+): 485 Step 2: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate Step 2 of Example 7 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol to give 509 mg (crude) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate used as such in the next step. LC/MS (m/z, MH+): 617 Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline -6-carboxylate Step 3 of Example 7 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 146 mg (34%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetra hydroisoquinoline-6- carboxylate. LC/MS (m/z, MH+): 527 Step 4: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino line-6-carboxylic acid Step 4 of Example 7 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl) oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline -6-carboxylate to give 43 mg (52%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yli dene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino line-6-carboxylic acid. Method B: Example 8: (1S,3R)-1-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylic acid Step 1: (1S,3R)-1-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol A mixture of (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroe thyl)-1,2,3,4- tetrahydroisoquinolin-6-ol (Intermediate 13) (300 mg, 0.75 mmol), Cs2CO3 (1.46 g, 4.42 mmol), 1-(3-fluoropropyl)azetidin-3-amine (Intermediate 4) (594 mg, 4.48 mmol), tBuBrettPhos (72 mg, 0.15 mmol) and tBuBrettPhos Pd G ₃ (64 mg, 0.074 mmol) in dry dioxane (30 ml) was heated at reflux for 24 hours. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 give 157 mg (46 %) of (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol as a sticky yellow powder. LC/MS (m/z, MH+): 453 Step 2: (1S,3R)-1-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate Step 2 of Example 8 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol to give 140 mg (98%) of (1S,3R)- 1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3 -methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate. LC/MS (m/z, MH+): 585 Step 3: Methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylate Step 3 of Example 8 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 117 mg (99%) of methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2- yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoq uinoline-6-carboxylate used as such in the next step. LC/MS (m/z, MH+): 495 Step 4: (1S,3R)-1-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carb oxylic acid Step 4 of Example 8 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylate to give 40 mg (34%) of (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin -2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carb oxylic acid. Method C: Example 9: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylic acid Step 1: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinolin-6- ol, mixture of Z and E A mixture of (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-tri fluoroethyl)- 1,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate 11) (600 mg, 1.38 mmol), 1-(3- fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)methylene)pyrrolidine, mixture of Z and E isomers (Intermediate 10) (740.46 mg, 2.75 mmol), K3PO4 (875.902 mg, 4.13 mmol, palladium acetate (11.38 mg, 0.069 mmol) and SPhos (28.23 mg, 0.069 mmol)) in THF (1.5 ml) and H2O (0.2 ml) was heated at 40°C for 5h. After cooling down to RT, MgSO4 was added, and the reaction mixture was filtered off. The filtrate was concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of heptane/EtOAc from 70/30 to 30/70 to give 728 mg (crude) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-y lidene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli n-6-ol as a mixture of Z and E isomers used as such in the following step. LC/MS (m/z, MH+): 499 Step 2: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinolin-6- yl trifluoromethanesulfonate, mixture of Z and E isomers Step 2 of Example 9 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-y lidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquino lin-6-ol, mixture of Z and E isomers to give 1.43 g (crude) of (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3- fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2- (2,2,2-trifluoroethyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate as a mixture of Z and E isomers used as such in the next step. LC/MS (m/z, MH+): 631 Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylate Step 3 of Example 9 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinolin-6- yl trifluoromethanesulfonate, mixture of Z and E isomers to give methyl (1S,3R)-1-(2,6- difluoro-4-(-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl) phenyl)-3-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as a mixture of Z and E isomers which was purified by preparative chiral SFC (Stationary phase: Chiralpak Daicel IG 100 x 4.6 mm, Mobile phase: CO ₂ / 15 % (isoPrOH + isopropylamine), to give 144 mg of methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3-ylidene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoli ne-6-carboxylate. LC/MS (m/z, MH+): 541 Step 4: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylic acid Step 4 of Example 9 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2 ,3,4-tetrahydroisoquinoline-6- carboxylate to give 51 mg (48%) of (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3- fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2- (2,2,2-trifluoroethyl)- 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid. 10: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydrois oquinoline-6- carboxylic acid Step 1: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinolin-6- ol, mixture of Z and E isomers Step 1 of Example 10 was prepared following a similar procedure to that of Step 1 of Example 9 from (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl )-3-methyl- 1,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate 12) and 1-(3-fluoropropyl)-3-((4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, mixture of Z and E isomers (Intermediate 10) to give 0.8 g (74%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difl uoropropyl)-3-methyl-1,2,3,4- tetrahydroisoquinolin-6-ol as a mixture of Z and E isomers, used as such in the next step. LC/MS (m/z, MH+): 495 Step 2: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, mixture of Z and E isomers Step 2 of Example 10 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinolin-6- ol, mixture of Z and E isomers to give 1.3 g (crude) of (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3- fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difl uoropropyl)-3-methyl-1,2,3,4- tetrahydroisoquinolin-6-yl trifluoromethanesulfonate as a mixture of Z and E isomers, used as such in the next step. LC/MS (m/z, MH+): 627 Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinoline-6- carboxylate Step 3 of Example 10 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, mixture of Z and E isomers to give methyl (1S,3R)-1-(2,6- difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)meth yl)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-ca rboxylate as a mixture of Z and E isomers which was separated by preparative chiral SFC (AD3100x4.6 mm, mobile phase: CO ₂ / 10% (iPrOH/isopropylamine, 3.5ml/min) to give 237 mg (15%) of methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3-ylidene)methyl)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline -6-carboxylate. LC/MS (m/z, MH+): 537 Step 4: (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinoline-6- carboxylic acid Step 4 of Example 10 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinoline-6- carboxylate to give 35 mg (15%) of (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3- fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difl uoropropyl)-3-methyl-1,2,3,4- tetrahydroisoquinoline-6-carboxylic acid. Method D: 11: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydrois oquinoline-6- carboxylic acid, 50/50 mixture of diastereomers Step 1: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-te trahydroisoquinoline-6- carboxylate, 50/50 mixture of diastereomers A mixture of methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin -3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3 ,4-tetrahydroisoquinoline-6- carboxylate (Step 3 of Example 10) (200 mg, 0.37 mmol) and PtO ₂ (12.7 mg, 0.056 mmol) in EtOAc (4 mL) was stirred under H ₂ atmosphere (1 bar) at rt for 18 h. The reaction mixture was filtered throught celite and the filtrate was evaporated under reduced pressure to give 150 mg (75%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-te trahydroisoquinoline-6- carboxylate, 50/50 mixture of diastereomers, used as such in the next step. LC/MS (m/z, MH+): 539 Step 2: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-y l)methyl)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline -6-carboxylic acid, 50/50 mixture of diastereomers Step 2 of Example 11 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-te trahydroisoquinoline-6- carboxylate, 50/50 mixture of diastereomers to give 44 mg (36%) of (1S,3R)-1-(2,6- difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl )-2-(2,2-difluoropropyl)-3- methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 50/50 mixture of diastereomers. 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 tables 1a and 1b. The measurements of the degradation activities were made using a breast cancer cell ERα 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 µL 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 2.5 µL at final concentrations ranging from 0.3-0.0000018 µM (in table 2), or 0.1 µM for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 µL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at RT and then washed twice with PBS. Then, 50 µL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at RT. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 µL anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) 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 anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 µM 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 ERα 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 IC ₅₀ ) in nM. The % of ERα 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 1 tested at 0.3 µM, 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 µM and with degradation levels greater than 50%. The compounds of formula (I) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors. 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. 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 α 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 (ERα 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.