Novel substituted tetrahydroisoquinoline-6-carboxylic acid derivatives, process for preparation thereof and therapeutic use thereof

Abstract

Disclosed herein are compounds of 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 methoxyl 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 (C1-C3) alkyl group; represents a single bond or a double bond; p is 0 or 1; x represents-CH =,-N = or-CR ''= wherein R'' represents a (C1-C3) alkyl or halogen atom, a cyano group, or a (C1-C3) fluoroalkyl group; r7 independently represents a (C1-C3) alkyl group, a halogen atom, a cyano group, or a (C1-C3) fluoroalkyl group; n is 0, 1 or 2; and R6 represents a (C1-C6) alkyl group, said alkyl group being optionally substituted; r8 represents a hydrogen atom, a (C1-C3) alkyl group, a-CH2F group, a-CHF2 group, a-CF3 group, or a (C3-C4) cycloalkyl group. Further disclosed are processes for preparing the same, pharmaceutical compositions comprising the same and the compounds of formula (I) for use as inhibitors and degrading agents of estrogen receptors, in particular for use in the treatment of ovulation dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation. # imgabs0 #

Description

[0001] Disclosed herein are novel substituted tetrahydroisoquinoline-6-carboxylic acid derivatives, methods for their preparation, and their therapeutic uses, particularly as anticancer agents via selective antagonism and degradation of estrogen receptors.

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

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

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

[0005] Although these endocrine therapies have made a great contribution to reducing the development of breast cancer, about more than one-third of ERα-positive patients show resistance to such existing therapies from the beginning or develop resistance over time. Several mechanisms have been described to explain resistance to such hormonal therapies. For example, the hypersensitivity of ERα to low estrogen levels during aromatase inhibitor treatment, the change of tamoxifen action from antagonism to agonism during tamoxifen treatment, or multiple growth factor receptor signaling pathways. ERα acquired mutations that occur after the initiation of hormone therapy may also lead to treatment failure and cancer progression. Certain mutations in ERα, especially those identified in the ligand binding domain (LBD), lead to the ability to bind to DNA in the absence of a ligand and enable cells carrying such mutant receptors to gain hormone independence.

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

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

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives that can be used as SERDs.

[0009] The inventors have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in cancer treatment.

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

[0011]

[0012] in:

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

[0014] - R3′ and R3″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group;

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

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

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

[0018] - represents a single or double bond;

[0019] -p is 0 or 1;

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

[0021] - R7 independently represents a (C1-C3)alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group;

[0022] -n is 0, 1, or 2; and

[0023] -R6 represents a (C1-C6) alkyl group, which is optionally substituted by 1 to 4 substituents independently selected from the group consisting of a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, a cyclopropyl group, an oxetanyl group, and an -OH group;

[0024] -R8 represents a hydrogen atom, a (C1-C3) alkyl group, a -CH2F group, a -CHF2 group, a -CF3 group, or a (C3-C4) cycloalkyl group.

[0025] The compounds of formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in the form of enantiomers.

[0026] The compounds of formula (I) may also exist in tautomeric forms.

[0027] The compound of formula (I) may exist in the form of a base, an acid, a zwitterion or an addition salt with an acid or a base. Accordingly, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0028] These salts may be prepared with pharmaceutically acceptable acids or bases, although salts of other acids or bases useful, for example, in the purification or isolation of compounds of formula (I) are also provided.

[0029] Among suitable salts of the compounds of formula (I), hydrochlorides may be cited.

[0030] As used herein, unless otherwise mentioned throughout this specification, the following terms have the following definitions:

[0031] - halogen atoms: fluorine, chlorine, bromine or iodine atoms, and in particular fluorine and chlorine atoms;

[0032] - Alkyl: a straight or branched saturated hydrocarbon aliphatic group, which, unless otherwise specified, contains from 1 to 6 carbon atoms (indicated as "(C1-C6) alkyl"). By way of example, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc. may be mentioned;

[0033] - Cycloalkyl: saturated or partially unsaturated and unsubstituted or substituted monocyclic alkyl which, unless otherwise specified, contains from 3 to 4 carbon atoms;

[0034] -Fluoroalkyl: an alkyl group as defined previously, wherein the alkyl group is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. By way of example, -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group may be named as a perfluoroalkyl group. By way of example, trifluoromethyl or trifluoroethyl, etc. may be mentioned;

[0035] - Alkoxy: -O-alkyl, wherein alkyl is as defined previously. By way of example, but not limited to, there may be mentioned: methoxy; ethoxy; propoxy; isopropoxy; linear butoxy, sec-butoxy or tert-butoxy; isobutoxy; pentyloxy or hexyloxy, etc.;

[0036] -Fluoroalkoxy: -O-alkyl, wherein alkyl is as defined previously and wherein alkyl is substituted by at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl is replaced by a fluorine atom. By way of example, -OCH2F, -OCHF2, -OCH2CH2F, etc. may be mentioned. When all hydrogen atoms belonging to the alkyl are replaced by fluorine atoms, the fluoroalkoxy may be named as perfluoroalkoxy. By way of example, trifluoromethoxy, etc. may be mentioned;

[0037] - Zwitterion means: a generally neutral molecule having both positive and negative charges and possessing both acidic and basic groups.

[0038] In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0039] 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.

[0040] In another embodiment, in the compounds of formula (I) as defined above, R3′ and R3″ both represent a hydrogen atom.

[0041] In another embodiment, in the compounds of formula (I) as defined above, R4 represents a hydrogen atom.

[0042] In another embodiment, in the compounds of formula (I) as defined above, R5 and R5' both represent a hydrogen atom.

[0043] 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.

[0044] In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH2-, -CH=, -O- or -NH-.

[0045] In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH2-. 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-.

[0046] In another embodiment, in the compounds of formula (I) as defined above, R7 is a halogen atom, and preferably a fluorine atom.

[0047] 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.

[0048] In another embodiment, in the compounds of formula (I) as defined above, R7 represents a fluorine atom and n is 1 or 2.

[0049] In another embodiment, in the compounds of formula (I) as defined above, R8 represents (C1-C6)alkyl, and preferably represents methyl.

[0050] 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.

[0051] In another embodiment, in the compounds of formula (I) as defined above, X represents -N=.

[0052] 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.

[0053] In another embodiment, in the compounds of formula (I) as defined above, X represents -CR"=, wherein R" represents a hydrogen atom.

[0054] In another embodiment, in the compound of formula (I) as defined above, R6 represents (C1-C6) alkyl, said (C1-C6) alkyl is optionally substituted by 1 to 3 fluorine atoms, preferably said (C1-C6) alkyl is substituted by 2 or 3 fluorine atoms.

[0055] In another embodiment, in the compound of formula (I) as defined above, R6 represents a -CH2-CF3 group or a -CH2-CF2-CH3 group.

[0056] In another embodiment, in the compound of formula (I) as defined above, In another embodiment, Represents a double bond.

[0057] In another embodiment, in the compounds of formula (I) as defined above, when Y represents -CH2-, -O- or -NH-, p is equal to 1.

[0058] In another embodiment, in the compounds of formula (I) as defined above, p is equal to 1.

[0059] Among the compounds of formula (I) described herein, the following compounds or their pharmaceutically acceptable salts, in particular their hydrochlorides, may be mentioned in particular:

[0060] -(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)

[0061] -(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, (2)

[0062] -(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-carboxylic acid, (3)

[0063] -(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-carboxylic acid, (4)

[0064] -(1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, (5)

[0065] -(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, (6)

[0066] -(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, (7)

[0067] -(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)

[0068] -(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, (9)

[0069] -(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, (10)

[0070] -(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, a 50 / 50 mixture of diastereomers (11).

[0071] 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.

[0072] 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.

[0073] Another embodiment is a method for inhibiting and degrading estrogen receptors, which comprises administering a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof to a subject, especially a human, in need thereof.

[0074] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, which comprises administering to a subject, especially a human, in need thereof a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0075] Another embodiment is a method of treating cancer, which comprises administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0076] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, an effective dose of a compound selected from the above list or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0077] The compound of formula (I) can be prepared by the following method.

[0078] Compounds of formula (I) and other related compounds with different substituents are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0079] The following general methods for preparing compounds of formula (I) optionally modified by use of appropriate reagents and conditions for introducing the various moieties found in formula (I) are described below.

[0080] The following abbreviations and empirical formulas are used:

[0081] MeCN Acetonitrile

[0082] NH4Cl Ammonium chloride

[0083] BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

[0084] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride

[0085] n-BuLi n-butyllithium

[0086] CO Carbon monoxide

[0087] CO2 Carbon dioxide

[0088] Cs2CO3 Cesium carbonate

[0089] DCE Dichloroethane

[0090] DCM Dichloromethane

[0091] SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

[0092] DIPEA Diisopropylethylamine

[0093] DMF N,N-Dimethylformamide

[0094] DMAP dimethylaminopyridine

[0095] DMSO Dimethyl sulfoxide

[0096] EtOAc Ethyl acetate

[0097] HPLC High Performance Liquid Chromatography

[0098] H2 Hydrogen

[0099] HCl

[0100] IsoPrOH Isopropyl alcohol

[0101] LG Leaving Group

[0102] LiOH Lithium Hydroxide

[0103] MeOH Methanol

[0104] MgSO4 Magnesium sulfate

[0105] Pd / C Palladium / Carbon

[0106] PtO2 Platinum Oxide

[0107] K2CO3 Potassium carbonate

[0108] K3PO4 Potassium Phosphate

[0109] NaHCO3 Sodium bicarbonate

[0110] NaCl Sodium chloride

[0111] NaOH Sodium hydroxide

[0112] SFC Supercritical Fluid Chromatography

[0113] tBuBrettPhos Dimethoxy-2′,4′,6′-tri(1-methylethyl)[1,1′-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine

[0114] tBuBrettPhos Pd G3 [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II)

[0115]

[0116] Option 1a Parts 1 and 2 : Preparation of compounds of formula (I) - General method

[0117] Option 1a - Part 1 :

[0118]

[0119] Option 1a - Part 2 :

[0120]

[0121] According to Scheme 1a-Part 1 and Part 2, wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X, Y and As defined above, compound 1A can be converted to compound 1B in step 1 by treatment with compound R6-LG in the presence of a suitable base such as diisopropylethylamine (DIPEA) in a suitable solvent such as DMF, wherein LG is a suitable leaving group such as a halogen atom such as iodine, bromine or chlorine or a triflate.

[0122] Compound 1B can be converted to compound 1D in step 2 by treating 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 such as dichloroethane (DCE) by heating to solvent reflux.

[0123] Alternatively, compound 1D can be obtained by treating compound 1B with compound 1E in a Pictet-Spengler cyclization reaction in the presence of an acid (e.g., TFA or acetic acid) in a suitable solvent (e.g., DCE) by heating to solvent reflux in step 3, and then coupling the obtained compound 1F with one of the compounds 1G under coupling reaction conditions in step 4. If necessary, the phenol group of compound 1F can be protected with a protecting group such as a pivaloyl group.

[0124] Compound 1D can be converted to compound 1H in step 5 by treatment with a 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.

[0125] Compound 1H can be converted to compound 1J in step 6 by carbonylation with carbon monoxide (CO) in the presence of a palladium catalyst such as palladium acetate or a complex of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (Pd(dppf)Cl2) and DCM in solution in MeOH.

[0126] Compound 1J can be converted to Compound I in step 7 by treating with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. The product can be extracted to obtain the sodium or lithium salt of Compound I. Acidification with an aqueous solution of HCl to pH 6-7 can obtain the neutral form of Compound I. Acidification with an aqueous solution of HCl to pH 1-2 can obtain the hydrochloride salt of Compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can obtain the formate or trifluoroacetate salt of Compound I.

[0127] When Y═CH═, compound I can be reduced by hydrogenation in step 8 under hydrogen (H 2 ) pressure with a catalyst such as Pd / C or platinum oxide (PtO 2 ) to give the corresponding saturated compound I′.

[0128] Alternatively, when Y=CH=, compound 1J' can be prepared in step 9 by hydrogenating compound 1J with a catalyst (e.g., Pd / C or platinum oxide (PtO2)) under hydrogen (H2) pressure, followed by treating the obtained compound 1J' with an aqueous solution of NaOH or LiOH in MeOH or THF to give compound I'. The product can be extracted to give a sodium salt or lithium salt of compound I'. Acidification with an aqueous solution of HCl to pH 6-7 can give a neutral form of compound I'. Acidification with an aqueous solution of HCl to pH 1-2 can give a hydrochloride salt of compound I'. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can give a formate or trifluoroacetate salt of compound I'.

[0129] Option 1b: Alternative method for preparing intermediate 1D

[0130]

[0131] According to Scheme 1b, wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X, Y and As defined above, compound 1F can be converted to compound 1L in step 1 by treating with one of compounds 1G' in a coupling reaction under coupling reaction conditions. If desired, the phenol group of compound 1F can be protected with a protecting group such as pivaloyl.

[0132] Alternatively, compound 1L can be obtained in step 2 by treating 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 such as DCE by heating to solvent reflux.

[0133] Compound 1L can be converted to compound 1M in step 3 by treatment with TFA or HCl.

[0134] Compound 1M can be converted to compound 1D by treatment with compound 1N (wherein W is Cl, Br or I or OSO2R, where R = CH3, PhMe, CF3 or CF2CF2CF2CF3) in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent in step 4.

[0135] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1J:

[0136]

[0137] Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and are converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step to obtain a compound of formula 1J, wherein a compound of formula 1H:

[0138]

[0139] Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above and are converted to compounds of formula 1J by carbonylation with carbon monoxide (CO) in MeOH solution in the presence of a palladium catalyst.

[0140] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1F:

[0141]

[0142] wherein R3′, R3″, R6, R7, R8, n, and X are as defined above, and a coupling step is performed with one of the compounds of formula 1G under coupling reaction conditions:

[0143]

[0144] wherein R1, R2, R4, R5, R5' and p are as defined above, to obtain the compound of formula 1D:

[0145]

[0146] Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above, and the step is optionally preceded by a step of obtaining compound 1F, wherein a compound of formula 1B:

[0147]

[0148] wherein R3′, R3″, R6, and R8 are as defined above, in the presence of an acid such as TFA or acetic acid, in a suitable solvent such as DCE, and undergoing a Pictet-Spengler cyclization reaction with a compound of formula 1E:

[0149]

[0150] wherein X, R7 and n are as defined above.

[0151] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1B:

[0152]

[0153] wherein R3′, R3″, R6 and R8 are as defined above, in the presence of an acid such as TFA or acetic acid, in a suitable solvent such as dichloroethane (DCE) and a compound of formula 1C undergoes a Pictet-Spengler cyclization reaction:

[0154]

[0155] Among them, R1, R2, R4, R5, R5', R7, n, p, X and Y are as defined above to obtain the compound of formula 1D:

[0156]

[0157] Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above.

[0158] Also provided herein is a process for preparing a compound of formula (I) as defined above, wherein a compound of formula 1M:

[0159]

[0160] Among them, R3', R3", R6, R7, R8, n, p, X and Y are as defined above and are treated with a compound of formula 1N in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent:

[0161]

[0162] wherein R1, R2, R4, R5 and R5' are as defined above, and W is Cl, Br or I or OSO2R, wherein R = CH3, PhMe, CF3 or CF2CF2CF2CF3, to obtain a compound of formula 1D:

[0163]

[0164] Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above.

[0165] Also provided herein is an intermediate compound selected from the compound of Formula 1J or any pharmaceutically acceptable salt thereof,

[0166]

[0167] Wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as defined above.

[0168] In another aspect, there is also provided herein a process for preparing a compound of formula (I), which comprises a deprotection step of a compound of formula 1J as defined above, optionally followed by a purification step.

[0169] The purification step may, for example, consist of an acidification step (for example with aqueous hydrochloric acid).

[0170] At 400 and 500MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, with chemical shifts (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0171] Liquid chromatography / mass spectrometry (LC / MS) was obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210-400 nm and fast Acquity UPLC CSH C18 1.7 μm, size 2.1x30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H.

[0172] Tables 1a and 1b below contain specific compounds (names and structures) of formula (I) according to the present disclosure and their characterizations ( 1 H NMR and LC / MS / MS).

[0173] Table 1a : (the first column "Example" corresponds to the compound and example number)

[0174]

[0175]

[0176]

[0177] Table 1b :

[0178]

[0179]

[0180]

[0181]

[0182] The following examples describe the preparation of some of the compounds of formula (I) described herein. The quantities of the compounds exemplified below match those given in Tables 1a and 1b above. Unless otherwise specified, all reactions were carried out under an inert atmosphere.

[0183] In the following examples, when the origin of the starting product is not specified, it is understood that the product is a known compound.

[0184] Examples

[0185] Intermediates:

[0186] Intermediate 1: (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol

[0187]

[0188] 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 to room temperature, 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%) (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol.

[0189] LC / MS(m / z,MH+):230

[0190] Intermediate 2: (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol

[0191]

[0192] Intermediate 2 was prepared from 3-[(2R)-2-aminopropyl]phenol and 2,2,2-trifluoroethyl trifluoromethanesulfonate following a similar procedure to Intermediate 1 to give 4 g (66%) of (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol.

[0193] LC / MS(m / z,MH+):234

[0194] Intermediate 3: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde

[0195]

[0196] Step 1: (S)-tert-butyl (1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate

[0197]

[0198] 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 KCO (10.36 g, 74.21 mmol) in MeCN (100 ml) was stirred at 50° C. for 18 h. After cooling to room temperature, the suspension was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc, then washed successively with water and a saturated aqueous solution of NaCl, then dried over MgSO, filtered and concentrated under reduced pressure to give 6.03 g (94%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate.

[0199] LC / MS(m / z,MH+):247

[0200] Step 2: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde

[0201]

[0202] A mixture of 4-bromo-2,6-difluorobenzaldehyde (1.83 g, 8.12 mmol, 1 eq), CsCO (5.32 g, 16.24 mmol), palladium acetate (0.038 g, 0.081 mmol), BINAP (0.101 g, 0.16 mmol), and (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (2 g, 8.12 mmol) in toluene (100 ml) was stirred at 80 ° C for 96 h. After cooling to room temperature, the reaction mixture was filtered through celite. Water (50 ml) was added to the filtrate, and the organic layer was then separated, and the aqueous phase was extracted again with EtOAc (2 x 20 ml). The combined organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluting with a gradient of heptane / EtOAc from 30 / 70 to 100 / 100) to give 760 mg (24%) of (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde as a yellow oil.

[0203] LC / MS(m / z,MH+):387

[0204] Intermediate 4: 1-(3-fluoropropyl)azetidine-3-amine

[0205]

[0206] Step 1: tert-Butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0207]

[0208] 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 KCO (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 room temperature, poured into water (100 ml) and extracted with EtOAc (200 ml). The organic layer was dried over MgSO, 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.

[0209] LC / MS(m / z,MH+):233

[0210] Step 2: 1-(3-Fluoropropyl)azetidine-3-amine

[0211]

[0212] To a solution of (1-(3-fluoropropyl)azetidine-3-yl)carbamic acid tert-butyl ester (1g, 4.305mmol) in DCM (10ml) was added TFA (4.34ml, 48.6mmol). The reaction mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in MeOH (10ml) and Amberlyst A26 (4g) was added, and the mixture was stirred at room temperature for 64 hours. The reaction mixture was filtered to remove Amberlyst A26, and washed with MeOH, then concentrated under reduced pressure to give 0.5g (88%) 1-(3-fluoropropyl)azetidine-3-amine.

[0213] LC / MS(m / z,MH+):133

[0214] Intermediate 5: tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate

[0215]

[0216] Intermediate 5 was prepared following a similar procedure to Intermediate 3, step 2 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.

[0217] LC / MS(m / z,MH+):373

[0218] Intermediate 6: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde

[0219]

[0220] To a solution of 2,6-difluoro-4-hydroxybenzaldehyde (0.88 g, 5.44 mmol) in anhydrous THF (20 ml), (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO 2018091153) (1 g, 6.79 mmol), PPh3 (2.88 g, 10.9 mmol) and TMAD (1.87 g, 10.87 mmol) were added. The reaction mixture was stirred at room temperature for 48 h. Water (50 ml) and EtOAc (100 ml) were added, and the aqueous layer was then separated and extracted again with EtOAc (50 ml). The combined organic layer was dried over MgSO4, 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.

[0221] LC / MS(m / z,MH+):288

[0222] Intermediate 7: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde

[0223]

[0224] Intermediate 7 was prepared following a similar procedure to Intermediate 6 from 5-hydroxypyridine-2-carbaldehyde and (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO 2018091153) to give 1.7 g (33%) of (S)-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)picolinaldehyde.

[0225] LC / MS(m / z,MH+):253

[0226] Intermediate 8: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde

[0227]

[0228] Step 1: tert-Butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate

[0229]

[0230] A mixture of 4-bromo-3,5-difluorophenol (2.09g, 10mmol), Cs2CO3 (6.52g, 20mmol) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (2.25mL, 12mmol) in DMF (17ml) was heated at 100°C for 3h. After cooling to room temperature, the reaction mixture was filtered, the solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The remaining 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 2.52g (69%) of 3- (3,5-difluoro-4-bromophenoxy) azetidine-1-carboxylic acid tert-butyl ester as a white powder.

[0231] LC / MS(m / z,MH+):364

[0232] Step 2: 3-(4-Bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid

[0233]

[0234] Intermediate 8, step 2 was prepared following a similar procedure to Intermediate 4, step 2 from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate to afford 2 g (crude) of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid which was used as such in the next step.

[0235] LC / MS(m / z,MH+):264

[0236] Step 3: 3-(4-Bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine

[0237]

[0238] 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 room temperature for 16 h. The crude mixture was poured into water and extracted with EtOAc. The organic phase was dried over MgSO4, 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 oil.

[0239] LC / MS(m / z,MH+):324

[0240] Step 4: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde

[0241]

[0242] A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine (1.5g, 4.63mmol) in THF (46ml) was cooled to -78 °C. Then, n-BuLi 1.6M (3.05ml, 4.86mmol) in hexane was added dropwise to the crude mixture and stirred at this temperature for 30 minutes. Then, DMF (0.72ml, 9.26mmol) was added dropwise to the crude mixture at -78 °C and stirred at this temperature for 3 hours. The crude mixture was quenched with water at room temperature and stirred for 15 minutes. Then, the aqueous phase was extracted with EtOAc (50ml), dried over MgSO4, 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 100 / 100) to give 0.38 g (30%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde as a yellow liquid.

[0243] LC / MS(m / z,MH+):274

[0244] Intermediate 9: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde

[0245]

[0246] Step 1: 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid

[0247]

[0248] At room temperature, TFA (2.89 mL, 38.96 mmol, 5 eq.) was added dropwise to a solution of commercially available tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine-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) 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid, which was used as is in the next step.

[0249] LC / MS(m / z,MH+):196

[0250] Step 2: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine

[0251]

[0252] Intermediate 9, step 2 was prepared following the analogous procedure to Intermediate 3, step 1 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 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-yl)methylene)azetidine.

[0253] LC / MS(m / z,MH+):256

[0254] Step 3: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde

[0255]

[0256] A mixture of 4-bromo-2,6-difluorobenzaldehyde (324.82 mg, 1.47 mmol), K3PO4 (936 mg, 4.409 mmol), palladium acetate (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-dioxaborolan-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 room temperature, 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 obtained residue 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.

[0257] LC / MS(m / z,MH+):270

[0258] Intermediate 10: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine (mixture of Z and E isomers)

[0259]

[0260] Step 1: tert-Butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate (mixture of Z and E isomers)

[0261]

[0262] To a solution of 2,2,6,6-tetramethylpiperidine (5.51 ml, 32.4 mmol) in 2-methyltetrahydrofuran (50 ml) was added n-BuLi 1.6 M (20.2 ml, 32.4 mmol) in THF at -78°C (the internal temperature was kept below -65°C). The solution was stirred at -78°C for 30 minutes. Then, a solution of 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolan (7.23 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise at -78°C (the internal temperature was kept below -65°C). The reaction mixture was stirred at -78°C for 30 minutes. Then at -78 ° C, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise (the internal temperature was kept below -65 ° C). The reaction was slowly warmed to room temperature 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 MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluting with a gradient of 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.

[0263] LC / MS(m / z,MH+):310

[0264] Step 2: 3-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, hydrochloride (mixture of Z and E isomers)

[0265]

[0266] 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) was slowly added 4N HCl in dioxane (50 ml, 200 mmol) at room temperature. The solution was stirred at room temperature for 18 h and 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)pyrrolidine, hydrochloride, which was used as is in the next step.

[0267] LC / MS(m / z,MH+):210

[0268] Step 3: 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine (mixture of Z and E isomers)

[0269]

[0270] Intermediate 10, step 3 was prepared following a similar procedure to Intermediate 3, step 1 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, 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-dioxaborolan-2-yl)methylene)pyrrolidine (mixture of Z and E isomers).

[0271] LC / MS(m / z,MH+):270

[0272] Intermediate 11: (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

[0273]

[0274] 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 18 h. After cooling to room temperature, 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 obtained residue 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.

[0275] LC / MS(m / z,MH+):436

[0276] Intermediate 12: (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol

[0277]

[0278] Intermediate 12 was prepared following a similar procedure to 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.

[0279] LC / MS(m / z,MH+):397

[0280] Intermediate 13: (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

[0281]

[0282] Intermediate 13 was prepared following a similar procedure to Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and 5-bromopyridine-2-carbaldehyde 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 light yellow powder.

[0283] LC / MS(m / z,MH+):401

[0284] Examples

[0285] Method A:

[0286] 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-tetrahydroisoquinoline-6-carboxylic acid

[0287]

[0288] 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-fluoropropyl)pyrrolidin-3-yl)carbamate

[0289]

[0290] Example 1, Step 1 was prepared following a similar procedure to 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)benzaldehyde (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-fluoropropyl)pyrrolidin-3-yl)carbamate.

[0291] LC / MS(m / z,MH+):596

[0292] Step 2: (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

[0293]

[0294] TEA (0.38 ml, 2.68 mmol) was added to a mixture 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-fluoropropyl)pyrrolidin-3-yl)carbamate (800 mg, 1.34 mmol), N-phenyltrifluoromethanesulfonimide (574 mg, 1.61 mmol) and DMAP (16.5 mg, 0.13 mmol) in DCM (25 ml). The reaction mixture was then stirred at room temperature 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, which was used as such in the next step.

[0295] LC / MS(m / z,MH+):730

[0296] Step 3: (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-carboxylic acid methyl ester

[0297]

[0298] In a stainless steel reactor, 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 bar) for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give 2.1 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester, which was used as is in the next step.

[0299] LC / MS(m / z,MH+):640

[0300] Step 4: (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 methyl ester

[0301]

[0302] TFA (6 ml, 82 mmol) was added dropwise to a solution 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester (2.1 g, 3.28 mmol) in DCM (50 ml). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. DCM (50 ml) and a 10% aqueous solution of NaHCO3 (30 ml) were then added. After decantation, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluting with a gradient of DCM / MeOH from 100 / 00 to 95 / 05) to give 530 mg (30%) 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester as a brown solid.

[0303] LC / MS(m / z,MH+):540

[0304] 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-tetrahydroisoquinoline-6-carboxylic acid

[0305]

[0306] LiOH (2M in H2O) (2.46 ml, 4.91 mmol) was added to a solution 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester (530 mg, 0.98 mmol) in THF (0.8 ml) at room temperature. The reaction mixture was stirred at 60°C for 18 h. After cooling to room temperature, EtOAc (10 ml) was added. After decantation, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue 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-tetrahydroisoquinoline-6-carboxylic acid.

[0307] 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-tetrahydroisoquinoline-6-carboxylic acid

[0308]

[0309] Step 1: 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

[0310]

[0311] Example 2, Step 1 was prepared following a similar procedure to 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)benzaldehyde (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.

[0312] LC / MS(m / z,MH+):600

[0313] Step 2: (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-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate

[0314]

[0315] Step 2 of Example 2 was prepared according to a procedure similar to Step 2 of Example 1 from 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 to give 228 mg (94%) of (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-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate.

[0316] LC / MS(m / z,MH+):734

[0317] Step 3: (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-tetrahydroisoquinoline-6-carboxylic acid methyl ester

[0318]

[0319] Step 3 of Example 2 was prepared according to a procedure similar to Step 3 of Example 1 from (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-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 287 mg (crude) (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-tetrahydroisoquinoline-6-carboxylic acid methyl ester, which was used as is in the next step.

[0320] LC / MS(m / z,MH+):644

[0321] Step 4: (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 methyl ester

[0322]

[0323] Step 4 of Example 2 was prepared according to a procedure similar to Step 4 of Example 1 from (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-tetrahydroisoquinoline-6-carboxylic acid methyl ester to give 63 mg (30%) 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 methyl ester.

[0324] LC / MS(m / z,MH+):544

[0325] 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-tetrahydroisoquinoline-6-carboxylic acid

[0326]

[0327] Step 5 of Example 2 was prepared according to a procedure similar to Step 5 of Example 1 from (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 methyl ester 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.

[0328] 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-tetrahydroisoquinoline-6-carboxylic acid

[0329]

[0330] Step 1: 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

[0331]

[0332] Step 1 of Example 3 was prepared 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-yl)carbamate (Intermediate 5) following a similar procedure to Intermediate 11 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 light yellow powder.

[0333] LC / MS(m / z,MH+):586

[0334] Step 2: (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate

[0335]

[0336] Step 2 of Example 3 was prepared according to a procedure similar 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-trifluoroethyl)-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)azetidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, which was used as such in the next step.

[0337] LC / MS(m / z,MH+):720

[0338] Step 3: (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester

[0339]

[0340] Step 3 of Example 3 was prepared according to a procedure similar to that of Step 3 of Example 1 from (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 400 mg (crude) (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester, which was used as such in the next step.

[0341] LC / MS(m / z,MH+):630

[0342] Step 4: (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-carboxylic acid methyl ester

[0343]

[0344] Step 4 of Example 3 was prepared according to a procedure similar to Step 4 of Example 1 from (1S,3R)-1-(4-((tert-butoxycarbonyl)(1-(3-fluoropropyl)azetidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester to give 150 mg (47%) 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester.

[0345] LC / MS(m / z,MH+):530

[0346] 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-tetrahydroisoquinoline-6-carboxylic acid

[0347]

[0348] Step 5 of Example 3 was prepared according to a similar procedure to Step 5 of Example 1 from (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-carboxylic acid methyl ester 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-tetrahydroisoquinoline-6-carboxylic acid.

[0349] 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-tetrahydroisoquinoline-6-carboxylic acid

[0350]

[0351] 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-tetrahydroisoquinolin-6-ol

[0352]

[0353] Step 1 of Example 4 was prepared following a similar procedure to 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)benzaldehyde (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-tetrahydroisoquinolin-6-ol.

[0354] LC / MS(m / z,MH+):503

[0355] 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-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate

[0356]

[0357] 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-tetrahydroisoquinolin-6-ol (300 mg, 0.6 mmol) in DCM (8 ml) cooled at -10°C was added DMAP (220 mg, 1.8 mmol) followed by trifluoromethanesulfonic anhydride (0.74 ml, 0.92 mmol). The reaction mixture was stirred at -5°C for 2 hours. The reaction mixture was quenched with water (5 ml), DCM (10 ml) and 10% aqueous solution of NH4Cl (5 ml) at -5°C. After decantation, the organic layer was dried over MgSO4, 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, which was used as is in the next step.

[0358] LC / MS(m / z,MH+):635

[0359] Step 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-carboxylic acid methyl ester

[0360]

[0361] Step 3 of Example 4 was prepared according to a procedure similar to 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-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 34 mg (29%) 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester.

[0362] LC / MS(m / z,MH+):545

[0363] 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-tetrahydroisoquinoline-6-carboxylic acid

[0364]

[0365] Step 4 of Example 4 was prepared according to the similar procedure as Step 5 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester 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-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid.

[0366] Example 5 :(1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

[0367]

[0368] Step 1: (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

[0369]

[0370] Step 1 of Example 5 was prepared following a similar procedure to 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)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol.

[0371] LC / MS(m / z,MH+):468

[0372] Step 2: (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate

[0373]

[0374] Step 2 of Example 5 was prepared according to a procedure similar to Step 2 of Example 4 from (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol and trifluoromethanesulfonic anhydride to give 350 mg (crude) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, which was used as such in the next step.

[0375] LC / MS(m / z,MH+):600

[0376] Step 3: (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester

[0377]

[0378] Step 3 of Example 5 was prepared according to a procedure similar to Step 3 of Example 1 from (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 205 mg (69%) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester.

[0379] LC / MS(m / z,MH+):510

[0380] Step 4: (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

[0381]

[0382] Step 4 of Example 5 was prepared according to a procedure similar to Step 5 of Example 1 from (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester to give 12 mg (6%) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid.

[0383] 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

[0384]

[0385] Step 1: (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

[0386]

[0387] Step 1 of Example 6 was prepared following a similar procedure to 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.

[0388] LC / MS(m / z,MH+):485

[0389] Step 2: (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-yl trifluoromethanesulfonate

[0390]

[0391] Step 2 of Example 6 was prepared according to a procedure similar to that of Step 2 of Example 1 from (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 to give 472 mg (crude) 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-yl trifluoromethanesulfonate, which was used as such in the next step.

[0392] LC / MS(m / z,MH+):617

[0393] Step 3: (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 methyl ester

[0394]

[0395] Step 3 of Example 6 was prepared according to a procedure similar to Step 3 of Example 1 from (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-yl trifluoromethanesulfonate to give 51 mg (21%) 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 methyl ester.

[0396] LC / MS(m / z,MH+):527

[0397] Step 4: (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

[0398]

[0399] Step 4 of Example 6 was prepared according to the similar procedure as Step 5 of Example 1 from (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 methyl ester 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.

[0400] 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

[0401]

[0402] 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

[0403]

[0404] Step 1 of Example 7 was prepared following a similar procedure to 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.

[0405] LC / MS(m / z,MH+):485

[0406] 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

[0407]

[0408] Step 2 of Example 7 was prepared according to a procedure similar 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, which was used as such in the next step.

[0409] LC / MS(m / z,MH+):617

[0410] Step 3: (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 methyl ester

[0411]

[0412] Step 3 of Example 7 was prepared according to a procedure similar to 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 (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 methyl ester.

[0413] LC / MS(m / z,MH+):527

[0414] Step 4: (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

[0415]

[0416] Step 4 of Example 7 was prepared according to the similar procedure as Step 5 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester to give 43 mg (52%) 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.

[0417] Method B:

[0418] 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-carboxylic acid

[0419]

[0420] 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

[0421]

[0422] A mixture of (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate 13) (300 mg, 0.75 mmol), Cs2CO3 (1.46 g, 4.42 mmol), 1-(3-fluoropropyl)azetidine-3-amine (Intermediate 4) (594 mg, 4.48 mmol), tBuBrettPhos (72 mg, 0.15 mmol) and tBuBrettPhosPd G3 (64 mg, 0.074 mmol) in anhydrous dioxane (30 ml) was heated under reflux for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (eluting with a gradient of DCM / MeOH from 100 / 00 to 80 / 20) to 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.

[0423] LC / MS(m / z,MH+):453

[0424] 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

[0425]

[0426] Step 2 of Example 8 was prepared according to the similar procedure as 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.

[0427] LC / MS(m / z,MH+):585

[0428] Step 3: (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 methyl ester

[0429]

[0430] Step 3 of Example 8 was prepared according to a procedure similar to 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 (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 methyl ester, which was used as such in the next step.

[0431] LC / MS(m / z,MH+):495

[0432] 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-carboxylic acid

[0433]

[0434] Step 4 of Example 8 was prepared according to the similar procedure as Step 5 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester 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-carboxylic acid.

[0435] Method C:

[0436] 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

[0437]

[0438] 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

[0439]

[0440] A mixture of (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-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-yl)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 5 h. After cooling to room temperature, MgSO was added and the reaction mixture was filtered off. The filtrate was concentrated under reduced pressure and the obtained residue was purified by flash chromatography (eluting with a gradient of heptane / EtOAc from 70 / 30 to 30 / 70) to give 728 mg (crude) (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 isomers), which was used as is in the next step.

[0441] LC / MS(m / z,MH+):499

[0442] 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)

[0443]

[0444] Step 2 of Example 9 was prepared according to a procedure similar to that of Step 2 of Example 1 from (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 (a 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 (a mixture of Z and E isomers), which was used as such in the next step.

[0445] LC / MS(m / z,MH+):631

[0446] Step 3: (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 methyl ester

[0447]

[0448] Step 3 of Example 9 was prepared 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 (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-carboxylic acid methyl ester (mixture of Z and E isomers), which was purified by preparative chiral SFC (stationary phase: Chiralpak Daicel IG 100x4.6mm, mobile phase: CO2 / 15% (isopropanol+isopropylamine) to give 144mg 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 methyl ester.

[0449] LC / MS(m / z,MH+):541

[0450] 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

[0451]

[0452] Step 4 of Example 9 was prepared according to a procedure similar to Step 5 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-tetrahydroisoquinoline-6-carboxylic acid methyl ester 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.

[0453] Example 10 :(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

[0454]

[0455] 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)

[0456]

[0457] Example 10, step 1: According to a procedure similar to that of Example 9, (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)pyrrolidone were prepared. Pyrrolidine (mixture of Z and E isomers) (Intermediate 10) was prepared 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-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol (mixture of Z and E isomers) which was used as such in the next step.

[0458] LC / MS(m / z,MH+):495

[0459] 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)

[0460]

[0461] Step 2 of Example 10 was prepared according to a procedure similar 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 (a 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-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (a mixture of Z and E isomers), which was used as such in the next step.

[0462] LC / MS(m / z,MH+):627

[0463] Step 3: (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 methyl ester

[0464]

[0465] Step 3 of Example 10 was prepared 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) according to a procedure similar to that of Step 3 of Example 1 to give (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 1,2,3,4-Tetrahydroisoquinoline-6-carboxylic acid methyl ester (mixture of Z and E isomers) was separated by preparative chiral SFC (AD3100x4.6mm, mobile phase: CO2 / 10% (iPrOH / isopropylamine, 3.5ml / min) to give 237mg (15%) (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 methyl ester.

[0466] LC / MS(m / z,MH+):537

[0467] 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

[0468]

[0469] Step 4 of Example 10 was prepared according to a procedure similar to Step 5 of Example 1 from (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 methyl ester 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-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid.

[0470] Method D:

[0471] Example 11:(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

[0472]

[0473] Step 1: (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 methyl ester, 50 / 50 mixture of diastereomers

[0474]

[0475] A mixture of (1S,3R)-methyl 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 PtO2 (12.7 mg, 0.056 mmol) in EtOAc (4 mL) was stirred under H2 atmosphere (1 bar) at room temperature for 18 h. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 150 mg (75%) of (1S,3R)-methyl 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-carboxylate, a 50 / 50 mixture of diastereomers, which was used as such in the next step.

[0476] LC / MS(m / z,MH+):539

[0477] Step 2: (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

[0478]

[0479] Step 2 of Example 11 was prepared following a procedure analogous to Step 5 of Example 1 from (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 methyl ester, 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.

[0480] The compounds according to Table 1 above were subjected to pharmacological testing for determining their degradation effect on estrogen receptors.

[0481] Test: Estrogen receptor degradation activity

[0482] The test involves measuring the in vitro degradation activity of the compounds of Tables 1a and 1b.

[0483] Degradation activity of ERα was measured using breast cancer cells in a cellular Western blot assay as described below.

[0484] MCF7 cells (ATCC) were seeded at 10,000 cells / 30 μL / well in (collagen-coated) 384-well microplates in phenol red-free MEMα medium (Invitrogen) containing 5% charcoal dextran-treated FBS. The next day, 9 serial 1:5 dilutions of each compound were added to the cells at 2.5 μL, with a final concentration range of 0.3-0.0000018 μM (Table 2), and a final concentration of 0.1 μM for Fulvestrant (used as a positive control). Four hours after compound addition, cells were fixed for 10 minutes at room temperature by adding 25 μL of formalin (final concentration: 5% formalin containing 0.1% triton) and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate at room temperature and left for 30 minutes. LI-COR blocking buffer was removed, and cells were incubated overnight in a cold room with 50 μL of anti-ER rabbit monoclonal antibody (Thermoscientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells treated with blocking buffer but without antibody were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated at 37°C for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and DNA dye Syto-64 (2 μM final concentration). The cells were then washed 3 times in PBS and scanned in an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0485] The degradation activity of estrogen receptor in this test is measured by the concentration that degrades 50% of estrogen receptor (or IC 50 ) is given in nM.

[0486] The % reduction in ERa levels was determined as follows: % inhibition = 100*(1 - (sample-fulvestrant:DMSO-fulvestrant)).

[0487] Table 2 below shows the estrogen receptor degradation activity results of the compounds of Table 1 tested at 0.3 μM, and demonstrates that the compounds have significant degradation activity on the estrogen receptor.

[0488] Table 2 :

[0489]

[0490] Therefore, it is obvious that the tested compounds have degradation activity on estrogen receptors, with IC50 less than 1 μM and degradation level greater than 50%. Therefore, the compounds of formula (I) can be used to prepare drugs, especially drugs as degraders of estrogen receptors.

[0491] Therefore, also provided herein is a medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0492] Also provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0493] Also provided herein are compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, particularly as inhibitors and degraders of estrogen receptors.

[0494] Also provided herein is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[0495] A particular aspect is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0496] In embodiments, the cancer is a hormone-dependent cancer.

[0497] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular the cancer is an estrogen receptor alpha dependent cancer.

[0498] In another embodiment, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer, and lung cancer, or metastases thereof.

[0499] In another embodiment, the metastasis is a brain metastasis.

[0500] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0501] In another embodiment, the cancer is resistant to anti-hormone therapy.

[0502] In further embodiments, the compounds of Formula (I) are used as single agents or in combination with other agents such as CDK4 / 6, mTOR or PI3K inhibitors.

[0503] According to another aspect, provided herein is a method of treating the above indicated pathological conditions, the method 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.

[0504] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of any of the above indicated pathological conditions, more particularly useful for the treatment of cancer.

[0505] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0506] The excipients are selected from the customary excipients known to those skilled in the art, depending on the desired pharmaceutical form and the method of administration.

[0507] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, external, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I) or its base, acid, zwitterion or salt thereof can be administered to animals and humans in a unit administration form, mixed with conventional pharmaceutical excipients, to treat the above disorders or diseases.

[0508] Suitable unit administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for inhalation, external application, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For external application, the compound of formula (I) can be used in creams, gels, ointments or lotions.

[0509] As an example, a unit administration form of a compound of formula (I) in the form of a tablet may comprise the following components:

[0510]

[0511] In special cases, higher or lower doses may be necessary. As a rule of thumb, the dose appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of the patient.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: - R1 and R2 independently represent a hydrogen atom or a deuterium atom; - R3′ and R3″ 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 (C1-C3) alkyl group; - represents a single or double bond; -p is 0 or 1; -X represents -CH=, -N= or -CR"=, wherein R" represents a (C1-C3)alkyl group or a halogen atom such as a fluorine or chlorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group; - R7 independently represents a (C1-C3)alkyl group such as a methyl group, a halogen atom such as a fluorine atom, a cyano group, or a (C1-C3)fluoroalkyl group such as a trifluoromethyl group; -n is 0, 1, or 2; and -R6 represents a (C1-C6) alkyl group, which is optionally substituted by 1 to 4 substituents independently selected from the group consisting of a fluorine atom, a (C1-C3) alkoxy group, a (C1-C3) fluoroalkoxy group, a cyclopropyl group, an oxetanyl group, and an -OH group; -R8 represents a hydrogen atom, a (C1-C3) alkyl group, a -CH2F group, a -CHF2 group, a -CF3 group, or a (C3-C4) cycloalkyl group.

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

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that R3' and R3" both represent a hydrogen atom.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that R4 represents a hydrogen atom.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that R5 and R5' both represent a hydrogen atom.

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

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that R7 represents a fluorine atom, and n is 1 or 2.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that R8 represents a (C1-C6) alkyl group, and preferably represents a methyl group.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that X represents -N= or -CR"=, wherein R" represents a halogen atom, preferably a fluorine atom.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that R6 represents a (C1-C6) alkyl group, the (C1-C6) alkyl group is optionally substituted by 1 to 3 fluorine atoms, preferably the (C1-C6) alkyl group is substituted by 2 or 3 fluorine atoms.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that R6 represents a -CH2-CF3 group or a -CH2-CF2-CH3 group.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized in that Indicates a single bond.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that When Y represents -CH2-, -O- or -NH-, p is equal to 1, and is particularly characterized in that p is equal to 1.

14. A compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, in particular a hydrochloride thereof, characterized in that The compound is selected from the following compounds: -(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-tetrahydroisoquinoline-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-carboxylic 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-carboxylic acid, (4) -(1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl -2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, (5) -(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, (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-carboxylic 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-tetrahydroisoquinoline-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-tetrahydroisoquinoline-6-carboxylic acid, (10) -(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, a 50 / 50 mixture of diastereomers (11).

15. A method for preparing a compound of formula (I) according to any one of claims 1 to 14, wherein the compound of formula 1J: Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 12, converted to a compound of formula (I) in the presence of a hydroxide ion source such as NaOH or LiOH in solution in methanol or THF, said step optionally being preceded by a step of obtaining a compound of formula 1J, wherein a compound of formula 1H: Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 12, and are converted into a compound of formula 1J by carbonylation with carbon monoxide (CO) in MeOH solution in the presence of a palladium catalyst.

16. A method for preparing a compound of formula (I) according to any one of claims 1 to 14, wherein the compound of formula 1F: wherein R3′, R3″, R6, R7, R8, n, and X are as described in any one of claims 1 to 13, and are coupled with one of the compounds of formula 1G under coupling reaction conditions: wherein R1, R2, R4, R5, R5' and p are as described in any one of claims 1 to 13, for obtaining a compound of formula 1D: Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 13, said step being optionally preceded by a step of obtaining a compound of formula 1F, wherein a compound of formula 1B: wherein R3′, R3″, R6, and R8 are as described in any one of claims 1 to 13, and undergo a Pictet-Spengler cyclization reaction with a compound of formula 1E in the presence of an acid such as TFA or acetic acid in a suitable solvent such as DCE: wherein X, R7 and n are as defined above.

17. A method for preparing a compound of formula (I) according to any one of claims 1 to 14, wherein the compound of formula 1B: wherein R3′, R3″, R6 and R8 are as described in any one of claims 1 to 13, in the presence of an acid such as TFA or acetic acid, in a suitable solvent such as dichloroethane (DCE), and a compound of formula 1C is subjected to a Pictet-Spengler cyclization reaction: Among them, R1, R2, R4, R5, R5', R7, n, p, X and Y are as described in any one of claims 1 to 13, for obtaining a compound of formula 1D: Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 13.

18. A method for preparing a compound of formula (I) according to any one of claims 1 to 14, wherein the compound of formula 1M: Among them, R3', R3", R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 13, treated with a compound of formula 1N in the presence of a base such as potassium carbonate (K2CO3) in DMF as solvent: wherein R1, R2, R4, R5 and R5' are as described in any one of claims 1 to 13, and W is Cl, Br or I or OSO2R, wherein R = CH3, PhMe, CF3 or CF2CF2CF2CF3, to obtain a compound of formula 1D: Among them, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 13.

19. A compound of formula 1J or any pharmaceutically acceptable salt thereof, Wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X and Y are as described in any one of claims 1 to 13.

20. A drug characterized in that The medicament comprises a compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

22. A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

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

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