Novel substituted tetrahydroisoquinoline-6-carboxylic acid derivatives, methods for preparing the same, and therapeutic uses of the same

Abstract

Disclosed herein is a compound of formula (I): [Formula 1] TIFF2025529875000148.tif58170 or a pharmaceutically acceptable salt thereof, In the formula, 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-, where 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"=, where R" represents a (C1-C3) alkyl group or a halogen atom, for example, 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, the 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. Also disclosed are methods for preparing the compounds of formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and compounds of formula (I) for use as inhibitors and degraders of estrogen receptors, particularly in the treatment of ovulation failure, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation.

Description

[Technical Field]

[0001] Disclosed herein are novel substituted tetrahydroisoquinoline-6-carboxylic acid derivatives, methods for preparing the same, and therapeutic uses of the same, particularly as anti-cancer agents via selective antagonism and degradation of estrogen receptors. [Background technology]

[0002] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily, which are involved in the regulation of eukaryotic gene expression, cell proliferation, and target tissues. ERs exist in two forms, estrogen receptor α (ERα) and estrogen receptor β (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormones, ERs reside primarily in the cytosol of cells. Upon binding of the hormone estrogen, ERs translocate from the cytosol to the cell nucleus, form dimers, and then bind to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to regulate the transcription of target genes.

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

[0004] ERα is expressed in less than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The pathogenetic role of estrogen in breast cancer is well established, and modulation of ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, several strategies exist to inhibit the estrogen system in breast cancer, including: 1) blocking estrogen synthesis with aromatase inhibitors, which are used to treat patients with early-stage and advanced ERα-positive breast cancer; 2) antagonizing estrogen ligand binding to ERα with tamoxifen, which is used to treat patients with ERα-positive breast cancer in both premenopausal and postmenopausal settings; and 3) antagonizing and downregulating ERα levels with fulvestrant, which is used to treat breast cancer in patients whose disease has progressed despite endocrine therapy, such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have contributed significantly to reducing breast cancer incidence, approximately one-third of ERα-positive patients exhibit de novo resistance or develop resistance to existing therapies over time. Several mechanisms have been described to explain resistance to such hormone therapy, such as the hypersensitivity of ERα to low estrogen levels during aromatase inhibitor treatment, the switch in tamoxifen effect from antagonistic to agonistic effects during tamoxifen treatment, or the involvement of multiple growth factor receptor signaling pathways. Acquired mutations in ERα that occur after the initiation of hormone therapy may also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), confer the ability to bind DNA in the absence of ligand, conferring hormone independence in cells harboring such mutant receptors.

[0006] Most of the identified endocrine therapy resistance mechanisms rely on ERα-dependent activity. One novel strategy to combat such resistance is to block ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data have shown that a significant number of resistance pathways can be circumvented by the use of SERDs. Summary of the Invention [Problem to be solved by the invention]

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

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful as SERDs. [Means for solving the problem]

[0009] We have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0010] Disclosed herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, 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-, where R9 represents a fluorine atom or a (C1-C3) alkyl group; - [ka] represents a single or double bond; - p is 0 or 1; - X represents -CH=, -N=, or -CR"=, where R" represents a (C1-C3) alkyl group, or a halogen atom, such as a fluorine atom or a chlorine atom, a cyano group, or a (C1-C3) fluoroalkyl group, such as trifluoromethyl; 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 trifluoromethyl; - n is 0, 1, or 2; and - R6 represents a (C1-C6) alkyl group, which is optionally substituted with 1 to 4 substituents independently selected from 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; A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011] The compounds of formula (I) may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers.

[0012] The compounds of formula (I) may also exist in tautomeric forms.

[0013] The compounds of formula (I) can exist in the form of a base, an acid, a zwitterion, or an addition salt with an acid or a base. Accordingly, there is provided herein a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] The salts may be prepared using pharmaceutically acceptable acids or bases, although other acid or base salts useful, for example, for purifying or isolating compounds of formula (I) are also provided.

[0015] Among the suitable salts of the compounds of formula (I), mention may be made of the hydrochloride salt.

[0016] As used herein, the following terms have the following definitions, unless otherwise stated throughout the specification: halogen atoms: fluorine, chloride, bromine or iodine atoms, in particular fluorine and chlorine atoms; - alkyl group: unless otherwise stated, an aliphatic group based on a linear or branched saturated hydrocarbon containing 1 to 6 carbon atoms (hence "(C1-C6) alkyl"). Examples may include, but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups, and the like; - cycloalkyl group: saturated or partially unsaturated, unsubstituted or substituted monocyclic alkyl group containing 3 to 4 carbon atoms unless otherwise stated; - Fluoroalkyl group: an alkyl group as defined above, in which the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include -CH2F, -CHF2, -CH2CHF2, -CH2CH2F, and the like. When all hydrogen atoms belonging to the alkyl group are replaced with fluorine atoms, the fluoroalkyl group can be named a perfluoroalkyl group. Examples include a trifluoromethyl group or a trifluoroethyl group, and the like; - alkoxy group: -O-alkyl group, wherein the alkyl group is as defined above. Examples may include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, and the like; - Fluoroalkoxy group: -O-alkyl group, where the alkyl group is as defined above, and the alkyl group is substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced with a fluorine atom. Examples include -OCH2F, -OCHF2, -OCH2CH2F, and the like. When all hydrogen atoms belonging to the alkyl group are replaced with fluorine atoms, the fluoroalkoxy group can be named a perfluoroalkoxy group. Examples include trifluoromethoxy group and the like; - Zwitterion refers to an overall neutral molecule that has positive and negative charges and has acidic and basic groups.

[0017] In another embodiment, in the compounds of formula (I) as defined above, R1 and R2 are hydrogen atoms.

[0018] 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.

[0019] In another embodiment, in the compounds of formula (I) as defined above, R3' and R3" both represent a hydrogen atom.

[0020] In another embodiment, in the compounds of formula (I) as defined above, R4 represents a hydrogen atom.

[0021] In another embodiment, in the compounds of formula (I) as defined above, R5 and R5' both represent a hydrogen atom.

[0022] 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.

[0023] In another embodiment, in the compounds of formula (I) as defined above, Y represents -CH2-, -CH=, -O-, or -NH-.

[0024] In another embodiment, in a compound of formula (I) as defined above, Y represents -CH2-. In another embodiment, in a compound of formula (I) as defined above, Y represents -CH=. In another embodiment, in a compound of formula (I) as defined above, Y represents -O-. In another embodiment, in a compound of formula (I) as defined above, Y represents -NH-.

[0025] In another embodiment, in the compounds of formula (I) as defined above, R7 is a halogen atom, preferably a fluorine atom.

[0026] 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.

[0027] In another embodiment, in the compounds of formula (I) as defined above, R7 represents a fluorine atom and n is 1 or 2.

[0028] In another embodiment, in the compounds of formula (I) as defined above, R8 represents a (C1-C6) alkyl group, preferably a methyl group.

[0029] 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.

[0030] In another embodiment, in the compounds of formula (I) as defined above, X represents -N=.

[0031] 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.

[0032] In another embodiment, in the compounds of formula (I) as defined above, X represents -CR"=, wherein R" represents a hydrogen atom.

[0033] In another embodiment, in a compound of formula (I) as defined above, R6 represents a (C1-C6) alkyl group, said (C1-C6) alkyl group optionally substituted with 1 to 3 fluorine atoms, preferably said (C1-C6) alkyl group is substituted with 2 or 3 fluorine atoms.

[0034] In another embodiment, in the compounds of formula (I) as defined above, R6 represents a -CH2-CF3 group or a -CH2-CF2-CH3 group.

[0035] In another embodiment, in the compounds of formula (I) as defined above, [ka] represents a single bond. [ka] represents a double bond.

[0036] In another embodiment, in the compounds of formula (I) as defined above, p is equal to 1 when Y represents -CH2-, -O-, or -NH-.

[0037] In another embodiment, in the compounds of formula (I) as defined above, p is equal to 1.

[0038] Among the compounds of formula (I) described herein, mention may be made in particular of the following compounds or their pharmaceutically acceptable salts (especially their hydrochlorides): - (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).

[0039] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, particularly as an inhibitor and degrader of the estrogen receptor.

[0040] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular breast cancer.

[0041] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0042] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0043] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0044] 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 at least one pharmaceutically acceptable excipient.

[0045] The compounds of formula (I) may be prepared by the following methods.

[0046] Compounds of formula (I), and other related compounds having different substituents, are synthesized using techniques and materials described below or otherwise known to those skilled in the art. In addition, solvents, temperatures, and other reaction conditions shown below may be varied as deemed appropriate by those skilled in the art.

[0047] The following general methods for preparing compounds of formula (I), optionally modified by the use of appropriate reagents, and conditions for introducing the various moieties found in formula (I) are described below.

[0048] The following abbreviations and empirical formulas are used: MeCN acetonitrile NH4Cl Ammonium chloride BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) n-BuLi n-butyllithium CO Carbon monoxide CO2 Carbon dioxide Cs2CO3 Cesium Carbonate DCE Dichloroethane DCM dichloromethane SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMAP dimethylaminopyridine DMSO dimethyl sulfoxide EtOAc ethyl acetate HPLC High Performance Liquid Chromatography H2 Hydrogen HCl Hydrochloric acid IsoPrOH Isopropanol LG leaving group LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate Pd / C Palladium Carbon PtO2 platinum oxide K2CO3 Potassium Carbonate K3PO4 Potassium Phosphate NaHCO3 Sodium bicarbonate NaCl Sodium chloride NaOH Sodium hydroxide SFC Supercritical Fluid Chromatography tBuBrettPhos Dimethoxy-2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine tBuBrettPhos Pd G3 [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TMAD Tetramethylazodicarboxamide TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran PPh3 Triphenylphosphine RT room temperature

[0049] Scheme 1a Parts 1 and 2: Preparation of Compounds of Formula (I) - General Process Scheme 1a - Part 1: [ka] Scheme 1a - Part 2: [ka] Scheme 1a - Part 1 and Part 2 (wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X, Y, and [ka] is defined as described above), compound 1A can be converted to compound 1B in step 1 by treatment with compound R6-LG (wherein LG is a suitable leaving group, for example, a halogen atom (e.g., iodo, bromo, or chloro), or trifluoromethanesulfonate), in the presence of a suitable base (e.g., diisopropylethylamine (DIPEA)) in a suitable solvent (e.g., DMF).

[0050] Compound 1B can be converted to compound 1D in step 2 by treatment with compound 1C in a Pictet-Spengler cyclization reaction in the presence of an acid (e.g., TFA or acetic acid) in a suitable solvent (e.g., dichloroethane (DCE)) by heating the solvent to reflux.

[0051] Alternatively, compound 1D can be obtained in step 3 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 the solvent to reflux, followed by a coupling reaction between the resulting compound 1F and one of 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.

[0052] Compound 1D can be converted to compound 1H in step 5 by treatment with a triflation reagent (e.g., trifluoromethanesulfonic anhydride or 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide) in the presence of a base (e.g., triethylamine (TEA) or dimethylaminopyridine (DMAP)) in a solvent (e.g., DCM).

[0053] Compound 1H can be converted to compound 1J in step 6 by carbonylation with carbon monoxide (CO) in solution in MeOH in the presence of a palladium catalyst (e.g., palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl), complex with DCM).

[0054] Compound 1J can be converted to compound I in step 7 by treatment with aqueous sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product can provide the sodium or lithium salt of compound I. Acidification to pH 6-7 with aqueous HCl can provide the neutral form of compound I. Acidification to pH 1-2 with aqueous HCl can provide the hydrochloride salt of compound I. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can provide the formate or trifluoroacetate salt of compound I.

[0055] When Y=CH=, compound I can be reduced in step 8 by hydrogenation over a catalyst (e.g., PD / C, or platinum oxide (PtO)) under water (H) pressure to give the corresponding saturated compound I'.

[0056] Alternatively, when Y=CH=, compound 1J' can be prepared in step 9 by hydrogenation of compound 1J with a catalyst (e.g., Pd / C or platinum oxide (PtO)) under hydrogen (H) pressure, followed by treatment of the resulting compound 1J' with an aqueous solution of NaOH or LiOH in MeOH or THF to give compound I'. Extraction of the product can give the sodium or lithium salt of compound I'. Acidification to pH 6-7 with an aqueous solution of HCl can give the neutral form of compound I'. Acidification to pH 1-2 with an aqueous solution of HCl can give the hydrochloride salt of compound I'. Purification using HPLC in the presence of formic acid or trifluoroacetic acid in the eluent can give the formate or trifluoroacetate salt of compound I'.

[0057] Scheme 1b: Alternative process for preparing intermediate 1D [ka] Scheme 1b (wherein R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, n, p, X, Y, and [ka] is defined as described above), compound 1F can be converted to compound 1L in step 1 by treatment in a coupling reaction with one of compounds 1G' under coupling reaction conditions. If necessary, the phenol group of compound 1F can be protected with a protecting group such as a pivaloyl group.

[0058] Alternatively, compound 1L can be obtained in step 2 by treatment of compound 1B with compound 1K in a Pictet-Spengler cyclization reaction in the presence of an acid (e.g., TFA or acetic acid) in a suitable solvent (e.g., DCE) by heating the solvent to reflux.

[0059] Compound 1L can be converted to compound 1M in step 3 by treatment with TFA or HCl.

[0060] Compound 1M can be converted to compound 1D in step 4 by treatment with compound 1N (wherein W is Cl, Br, or I, or OSO2R, and R = CH3, PhMe, CF3, or CF2CF2CF2CF3) in the presence of a base (e.g., potassium carbonate (K2CO3)) in DMF as a solvent.

[0061] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X, and Y are defined as illustrated) in the presence of a source of hydroxide ions (e.g., NaOH or LiOH in solution in methanol or THF) to a compound of formula (I), which is optionally preceded by a step of obtaining a compound of formula 1J, in which a compound of formula 1H: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X, and Y are defined as described above) is converted to a compound of formula 1J by carbonylation with carbon monoxide (CO) in solution in MeOH in the presence of a palladium catalyst; A method is also provided.

[0062] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1F: [ka] wherein R, R, R, R, R, n, and X are defined as described above, is reacted with a compound of formula 1G: [ka] wherein R1, R2, R4, R5, R5', and p are as defined above, to give a compound of formula 1D: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X, and Y are defined as described above), which step is optionally preceded by a step of obtaining compound 1F, in which a compound of formula 1B: [ka] wherein R, R, R, and R are defined as described above, with a compound of formula 1E: [ka] (wherein X, R7, and n are as defined above), subjected to a Pictet-Spengler cyclization reaction in the presence of an acid (e.g., TFA or acetic acid) in a suitable solvent (e.g., DCE), A method is also provided.

[0063] Also provided herein is a process for preparing a compound of formula (I) as defined above, comprising the step of reacting a compound of formula 1B: [ka] wherein R, R, R, and R are defined as described above, with a compound of formula 1C: [ka] (In the formula, R1, R2, R4, R5, R5', R7, [ka] , n, p, X, and Y are as defined above), to a Pictet-Spengler cyclization reaction in the presence of an acid (e.g., TFA or acetic acid) in a suitable solvent (e.g., dichloroethane (DCE)) to obtain a compound of formula 1D: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X, and Y are defined as described above), A method is also provided.

[0064] Also provided herein is a method for preparing a compound of formula (I) as defined above, comprising the step of preparing a compound of formula 1M: [ka] (In the formula, R3', R3", R6, R7, R8, [ka] , n, p, X, and Y are defined as described above) in the presence of a base (e.g., potassium carbonate (K2CO3)) in DMF as a solvent to give a compound of formula 1N: [ka] wherein R, R, R, R, R, and R' are as defined above, W is Cl, Br, or I, or OSOR, and R = CH, PhMe, CF, or CFCFCFCF, to form a compound of formula 1D: [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, [ka] , n, p, X, and Y are defined as described above), A method is also provided.

[0065] Also referred to herein is Formula 1J [ka] (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, n, p, [ka] , X, and Y are defined above), or any of the pharmaceutically acceptable salts thereof.

[0066] In another aspect, also provided herein is a process for preparing a compound of formula (I), comprising the step of deprotecting a compound of formula 1J as defined above, optionally followed by a purification step.

[0067] Said purification step may for example consist in an acidification step, for example with an aqueous solution of hydrochloric acid.

[0068] At 400 and 500 MHz 1 H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively, with chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0069] Liquid chromatography / mass spectra (LC / MS) were obtained on a UPLC Acquity Waters instrument, a Sedere light scattering detector, and an SQD Waters mass spectrometer using UV detection DAD 210-400 nm and a flash Acquity UPLC CSH C18 1.7 μm, dimensions 2.1 × 30 mm, mobile phase H2O + 0.1% HC02H / CH3CN + 0.1% HC02H.

[0070] Tables 1a and 1b below respectively list specific compounds (names and structures) of formula (I) according to the present disclosure, as well as their characterization ( 1 H HMR, and liquid chromatography / mass).

[0071] [Table 1]

[0072] [Table 2]

[0073] [Table 3]

[0074] [Table 4]

[0075] [Table 5]

[0076] [Table 6]

[0077] The following examples illustrate the preparation of some of the compounds of formula (I) described herein. The number of compounds exemplified below corresponds to those shown in Tables 1a and 1b above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0078] In the following examples, where the source of a starting product is not specified, it is to be understood that said product is a known compound. [Example]

[0079] Intermediates: Intermediate 1: (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol [ka] 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 RT, water (10 mL) was added, and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 1.45 g (96%) of (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol. LC / MS (m / z, MH+): 230

[0080] Intermediate 2: (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol [ka] Intermediate 2 was prepared from 3-[(2R)-2-aminopropyl]phenol and 2,2,2-trifluoroethyl trifluoromethanesulfonate according to a similar procedure to Intermediate 1 to give (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol 4 g (66%). LC / MS(m / z, MH+): 234

[0081] Intermediate 3: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde [ka] Step 1: Tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate [ka] A suspension of tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (5 g, 26.04 mmol), 1-fluoro-3-iodopropane (5.38 g, 28.64 mmol), and K2CO3 (10.36 g, 74.21 mmol) in MeCN (100 ml) was stirred at 50 °C for 18 h. After cooling to RT, the suspension was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was solubilized with EtOAc, washed with water and a saturated aqueous solution of NaCl, then dried over MgSO4, filtered, and concentrated under reduced pressure to give 6.03 g (94%) of tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate. LC / MS(m / z, MH+): 247

[0082] Step 2: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde [ka] A mixture of 4-bromo-2,6-difluorobenzaldehyde (1.83 g, 8.12 mmol, 1 eq), CsCO (5.32 g, 16.24 mmol), palladium diacetate (0.038 g, 0.081 mmol), BINAP (0.101 g, 0.16 mmol), and tert-butyl (S)-(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate (2 g, 8.12 mmol) in toluene (100 ml) was stirred at 80 °C for 96 h. After cooling to RT, the reaction mixture was filtered through Celite. Water (50 ml) was added to the filtrate, then the organic layer was separated, and the aqueous phase was re-extracted with EtOAc (2 x 20 ml). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc 30 / 70 to 00 / 100 to afford 760 mg (24%) of (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde as a yellow oil. LC / MS(m / z, MH+): 387

[0083] Intermediate 4: 1-(3-fluoropropyl)azetidin-3-amine [ka] Step 1: Tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] A suspension of tert-butyl N-(azetidin-3-yl)carbamate hydrochloride (5 g, 23.5 mmol), 1-fluoro-3-iodopropane (4.86 g, 25.8 mmol), and K2CO3 (8.19 g, 58.7 mmol) in TFH (100 mL) and water (0.21 mL, 11.7 mmol) was stirred at 70 °C for 5 h. The crude mixture was cooled to RT, poured into water (100 mL), and extracted with EtOAc (200 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 5.37 g (98%) of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate as a white powder. LC / MS(m / z, MH+): 233

[0084] Step 2: 1-(3-fluoropropyl)azetidin-3-amine [ka] To a solution of tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate (1 g, 4.305 mmol) in DCM (10 ml) was added TFA (4.34 ml, 48.6 mmol) dropwise. The reaction mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (10 ml), Amberlyst A26 (4 g) was added, and the mixture was stirred for 64 h at RT. The reaction was filtered to remove Amberlyst A26, washed with MeOH, and then concentrated under reduced pressure to give 0.5 g (88%) of 1-(3-fluoropropyl)azetidin-3-amine. LC / MS(m / z, MH+): 133

[0085] Intermediate 5: Tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate [ka] Intermediate 5 was prepared from tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate (Step 1 of Intermediate 4) and 4-bromo-2,6-difluorobenzaldehyde according to a procedure similar to Step 2 of Intermediate 3 to afford 2.95 g (92%) of tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate as an orange oil. LC / MS(m / z, MH+): 373

[0086] Intermediate 6: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde [ka] To a solution of 2,6-difluoro-4-hydroxybenzaldehyde (0.88 g, 5.44 mmol) in dry THF (20 mL) was added (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) (1 g, 6.79 mmol), PPh3 (2.88 g, 10.9 mmol), and TMAD (1.87 g, 10.87 mmol). The reaction mixture was stirred at RT for 48 h. Water (50 mL) and EtOAc (100 mL) were added, and the aqueous layer was then separated and extracted again with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 80 / 20 to give (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde 660 mg (36%). LC / MS(m / z, MH+):288

[0087] Intermediate 7: (S)-2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)benzaldehyde [ka] Intermediate 7 was prepared from 5-hydroxypyridine-2-carbaldehyde and (R)-1-(3-fluoropropyl)pyrrolidin-3-ol (prepared according to WO2018091153) according to a similar procedure to Intermediate 6 to give (S)-5-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)picolinaldehyde 1.7 g (33%). LC / MS(m / z, MH+): 253

[0088] Intermediate 8: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde [ka] Step 1: Tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate [ka] A mixture of 4-bromo-3,5-difluorophenol (2.09 g, 10 mmol), CsCO (6.52 g, 20 mmol), and tert-butyl 3-iodoazetidine-1-carboxylate (2.25 mL, 12 mmol) in DMF (17 mL) was heated at 100° C. for 3 h. After cooling to RT, the reaction mixture was filtered, the solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The remaining oil was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude residue was washed with heptane, and the precipitate was filtered to give tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate 2.52 (69%) as a white powder. LC / MS(m / z, MH+): 364

[0089] Step 2: 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid [ka] Step 2 of intermediate 8 was prepared following a similar procedure as step 2 of intermediate 4 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1-carboxylate to afford 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid 2 g (crude), used directly in the next step. LC / MS(m / z, MH+):264

[0090] Step 3: 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine [ka] 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), and DIPEA (4.78 mL, 27.5 mmol) in DMF (20 ml) was stirred at RT for 16 hours. 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 tan oil. LC / MS(m / z, MH+): 324

[0091] Step 4: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde [ka] A mixture of 3-(4-bromo-3,5-difluoro-phenoxy)-1-(3-fluoropropyl)azetidine (1.5 g, 4.63 mmol) in THF (46 ml) was cooled to −78° C. Then, n-BuLi 1.6 M in hexane (3.05 ml, 4.86 mmol) was added dropwise to the crude mixture and stirred at this temperature for 30 minutes. Then, DMF (0.72 ml, 9.26 mmol) 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 RT and stirred for 15 minutes. The aqueous phase was then extracted with EtOAc (50 ml), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc 50 / 50 to 00 / 100 to give 0.38 g (30%) of 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde as a yellow liquid. LC / MS(m / z, MH+): 274

[0092] Intermediate 9: 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde [ka] Step 1: 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid [ka] 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) at RT was added TFA (2.89 mL, 38.96 mmol, 5 eq.) dropwise. The solution was stirred for 18 h. The crude oil was concentrated under reduced pressure to give 2.67 g (crude) of 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid, which was used directly in the next step. LC / MS(m / z, MH+): 196

[0093] Step 2: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine [ka] Intermediate 9, step 2, was prepared 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 following a procedure similar to Intermediate 3, step 1, to afford 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine 1.05 g (60%). LC / MS(m / z, MH+): 256

[0094] Step 3: 2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde [ka] A mixture of 4-bromo-2,6-difluorobenzaldehyde (324.82 mg, 1.47 mmol), KPO (936 mg, 4.409 mmol), palladium diacetate (16.5 mg, 0.073 mmol), SPhos (30.17 mg, 0.073 mmol), and 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-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 RT, the reaction mixture was diluted with EtOAc (10 mL) and water (5 mL). The aqueous layer was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 80 / 20 to give 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)benzaldehyde 243 mg (61%). LC / MS (m / z, MH+): 270

[0095] 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 [ka] 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 [ka] To a solution of 2,2,6,6-tetramethylpiperidine (5.51 ml, 32.4 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise at −78° C. 1.6 M n-BuLi in THF (20.2 ml, 32.4 mmol) (internal temperature maintained below −65° C.). The solution was stirred at −78° C. for 30 minutes. Then, at −78° C., a solution of 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (7.23 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was added dropwise (internal temperature maintained below −65° C.). The reaction mixture was stirred at −78° C. for 30 minutes. A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5 g, 27.0 mmol) in 2-methyltetrahydrofuran (50 ml) was then added dropwise at −78° C. (internal temperature maintained below −65° C.). The reaction was allowed to warm slowly to RT and stirred at this temperature for 18 h. The reaction mixture was cooled to 0° C. and slowly quenched with 10% aqueous NH4Cl (30 ml). The aqueous layer was separated and re-extracted with EtOAc (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient heptane / EtOAc 90 / 10 to 70 / 30 to afford 6.23 g (75%) of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, a mixture of Z and E isomers, as a colorless oil. LC / MS (m / z, MH+): 310

[0096] Step 2: 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, hydrochloride, mixture of Z and E isomers [ka] To a solution of tert-butyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate, a mixture of Z and E isomers (6.2 g, 20 mmol) in dioxane (20 mL) at RT was slowly added 4 N HCl in dioxane (50 mL, 200 mmol). The solution was stirred at RT 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 directly in the next step. LC / MS (m / z, MH+): 210

[0097] Step 3: 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, a mixture of Z and E isomers [ka] Intermediate 10, step 3, was prepared from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, hydrochloride, a mixture of Z and E isomers, and 1-fluoro-3-iodopropane following a procedure similar to Intermediate 3, step 1, to afford 4.53 g (83%) of 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, a mixture of Z and E isomers. LC / MS (m / z, MH+): 270

[0098] Intermediate 11: (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol [ka] 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 RT, DCM (25 mL) and a 10% aqueous solution of NaHCO (25 mL) were added. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc 70 / 30 to 50 / 50 to give (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol 1 g (83%). LC / MS(m / z, MH+): 436

[0099] Intermediate 12: (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol [ka] Intermediate 12 was prepared from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol (Intermediate 1) and 4-bromo-2,6-difluorobenzaldehyde according to a similar procedure to Intermediate 11 to give (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol 950 mg (54%). LC / MS(m / z, MH+): 397

[0100] Intermediate 13: (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol [ka] Intermediate 13 was prepared from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and 5-bromopyridine-2-carboxaldehyde according to a similar procedure to Intermediate 11 to afford 460 mg (89%) of (1S,3R)-1-(5-bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol as a pale yellow powder. LC / MS(m / z, MH+):401

[0101] Example Method A: Example 1: (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid [ka] 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 [ka] Step 1 of Example 1 was prepared 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) according to the same procedure as Intermediate 11 to afford 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. LC / MS(m / z, MH+):596

[0102] 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 [ka] 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) was added TEA (0.38 ml, 2.68 mmol). The reaction mixture was then stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to give 1.6 g (crude) of (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, which was used directly in the next step. LC / MS (m / z, MH+): 730

[0103] Step 3: Methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka]

[0104] In a stainless-steel bomb, a mixture of (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.6 g, 2.19 mmol), TEA (0.92 ml, 6.58 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (0.38 g, 0.44 mmol) in MeOH (25 ml) was stirred at 100° C. under a CO atmosphere (5 bar) for 18 hours. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give 2.1 g (crude) of methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate, which was used directly in the next step. LC / MS(m / z, MH+):640

[0105] Step 4: Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] To a solution of methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (2.1 g, 3.28 mmol) in DCM (50 ml) was added TFA (6 ml, 82 mmol) dropwise. The reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure. Then, DCM (50 ml) and a 10% aqueous solution of NaHCO3 (30 ml) were added. After decantation, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 95 / 05 to afford 530 mg (30%) of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as a brown solid. LC / MS(m / z, MH+): 540

[0106] 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 [ka] To a solution of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (530 mg, 0.98 mmol) in THF (0.8 ml) was added LiOH (2 M in HO) (2.46 ml, 4.91 mmol) at RT. The reaction mixture was stirred at 60° C. for 18 h. After cooling to RT, EtOAc (10 ml) was added. After decantation, the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 80 / 20 to afford 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.

[0107] 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 [ka] 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 [ka] Step 1 of Example 2 was prepared 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) according to a procedure similar to that for Intermediate 11 to afford 772 mg (86%) of tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate. LC / MS (m / z, MH+): 600

[0108] 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 [ka] Step 2 of Example 2 was prepared 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 according to a procedure similar to Step 2 of Example 1 to yield 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. LC / MS(m / z, MH+):734

[0109] Step 3: Methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 3 of Example 2 was prepared 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 according to a procedure similar to Step 3 of Example 1 to afford 287 mg of methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (crude), used directly in the next step. LC / MS(m / z, MH+):644

[0110] Step 4: Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 4 of Example 2 was prepared from methyl (1S,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 4 of Example 1 to afford 63 mg (30%) of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate. LC / MS(m / z, MH+):544

[0111] 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 [ka] Step 5 of Example 2 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0112] 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 [ka] 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 [ka] 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) according to the same procedure as Intermediate 11 to afford 404 mg (69%) of tert-butyl (3,5-difluoro-4-((1S,3R)-6-hydroxy-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)(1-(3-fluoropropyl)azetidin-3-yl)carbamate as a pale yellow powder. LC / MS(m / z, MH+):586

[0113] 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 [ka] Step 2 of Example 3 was prepared 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 according to a procedure similar to Step 2 of Example 1 to yield 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 directly in the next step. LC / MS (m / z, MH+): 720

[0114] Step 3: Methyl (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-carboxylate [ka] Step 3 of Example 3 was prepared 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 according to a procedure similar to Step 3 of Example 1 to yield 400 mg of methyl (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-carboxylate (crude), used directly in the next step. LC / MS(m / z, MH+): 630

[0115] Step 4: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 4 of Example 3 was prepared from methyl (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-carboxylate according to a procedure similar to Step 4 of Example 1 to afford 150 mg (47%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate. LC / MS (m / z, MH+): 530

[0116] 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 [ka] Step 5 of Example 3 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0117] 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 [ka] 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 [ka] Step 1 of Example 4 was prepared 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) according to a procedure similar to Intermediate 11 to afford (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 500 mg (66%). LC / MS(m / z, MH+):503

[0118] 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 [ka] 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., DMAP (220 mg, 1.8 mmol) was added dropwise, followed by triflic anhydride (0.74 ml, 0.92 mmol). The reaction mixture was stirred at −5° C. for 2 hours. At −5° C., the reaction mixture was quenched with water (5 ml), DCM (10 ml), and 10% aqueous NH4Cl (5 ml). After decantation, the organic layer was dried over MgSO, 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 directly in the next step. LC / MS(m / z, MH+): 635

[0119] Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 3 of Example 4 was prepared 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 according to a procedure similar to Step 3 of Example 1 to afford methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate 34 mg (29%). LC / MS(m / z, MH+): 545

[0120] 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 [ka] Step 4 of Example 4 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0121] 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 [ka] 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 [ka] Step 1 of Example 5 was prepared 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) according to a procedure similar to Intermediate 11 to afford (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 200 mg (43%). LC / MS(m / z, MH+):468

[0122] 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 [ka] Step 2 of Example 5 was prepared 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 triflic anhydride according to a procedure similar to Step 2 of Example 4 to yield 350 mg 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 (crude), which was used directly in the next step. LC / MS (m / z, MH+): 600

[0123] Step 3: Methyl (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-carboxylate [ka] Step 3 of Example 5 was prepared 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 according to a procedure similar to Step 3 of Example 1 to afford 205 mg (69%) of methyl (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-carboxylate. LC / MS (m / z, MH+): 510

[0124] 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 [ka] Step 4 of Example 5 was prepared from methyl (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-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0125] 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 [ka] 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 [ka] Step 1 of Example 6 was prepared 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) according to the same procedure as Intermediate 11 to afford (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 375 mg (96%). LC / MS(m / z, MH+): 485

[0126] 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 [ka] Step 2 of Example 6 was prepared 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 according to a procedure similar to Step 2 of Example 1 to yield 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 directly in the next step. LC / MS(m / z, MH+):617

[0127] Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 3 of Example 6 was prepared 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 according to a procedure similar to Step 3 of Example 1 to provide methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate 51 mg (21%). LC / MS(m / z, MH+):527

[0128] 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 [ka] Step 4 of Example 6 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0129] 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 [ka] 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 [ka] Step 1 of Example 7 was prepared 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) according to a procedure similar to Intermediate 11 to afford (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 431 mg (81%). LC / MS(m / z, MH+): 485

[0130] 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 [ka] Step 2 of Example 7 was prepared 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 according to a procedure similar to Step 2 of Example 1 to yield 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 directly in the next step. LC / MS(m / z, MH+):617

[0131] Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 3 of Example 7 was prepared 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 according to a procedure similar to Step 3 of Example 1 to afford 146 mg (34%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate. LC / MS(m / z, MH+):527

[0132] 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 [ka] Step 4 of Example 7 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0133] Method B: Example 8: (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid [ka] 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 [ka] 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), CsCO (1.46 g, 4.42 mmol), 1-(3-fluoropropyl)azetidin-3-amine (Intermediate 4) (594 mg, 4.48 mmol), tBuBrettPhos (72 mg, 0.15 mmol), and tBuBrettPhos Pd G (64 mg, 0.074 mmol) in dry dioxane (30 mL) was heated to reflux for 24 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a gradient of DCM / MeOH 100 / 00 to 80 / 20 to afford 157 mg (46%) of (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol as a sticky yellow powder. LC / MS(m / z, MH+): 453

[0134] 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 [ka] Step 2 of Example 8 was prepared 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 according to a procedure similar to Step 2 of Example 1 to yield 140 mg (98%) of (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate. LC / MS(m / z, MH+): 585

[0135] Step 3: Methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] Step 3 of Example 8 was prepared 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 according to a procedure similar to Step 3 of Example 1 to yield 117 mg (99%) of methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate, which was used directly in the next step. LC / MS(m / z, MH+): 495

[0136] 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 [ka] Step 4 of Example 8 was prepared from methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to afford 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.

[0137] Method C: Example 9: (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid [ka] 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 [ka] (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 A mixture of 2-dioxaborolan-2-yl)methylene)pyrrolidine, a mixture of Z and E isomers (Intermediate 10) (740.46 mg, 2.75 mmol), KPO (875.902 mg, 4.13 mmol), palladium acetate (11.38 mg, 0.069 mmol), and SPhos (28.23 mg, 0.069 mmol) was heated at 40° C. for 5 h. After cooling to RT, MgSO was added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography eluting with a gradient of heptane / EtOAc 70 / 30 to 30 / 70 to afford 728 mg (crude) of (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 as a mixture of Z and E isomers, which was used directly in the next step. LC / MS(m / z, MH+): 499

[0138] 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 [ka] Step 2 of Example 9 was prepared 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, following a procedure similar to Step 2 of Example 1 to afford 1.43 g (crude) of (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate as a mixture of Z and E isomers, which was used directly in the next step. LC / MS(m / z, MH+):631

[0139] Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] 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, a mixture of Z and E isomers, according to a procedure similar to Step 3 of Example 1 to give methyl (1S,3R)-1-(2,6-difluoro-4-(-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as a mixture of Z and E isomers, which was purified by preparative chiral SFC (stationary phase: Chiralpak Daicel IG Purification on a 100x4.6 mm column with a mobile phase of CO2 / 15% (isoPrOH + isopropylamine) gave 144 mg of methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate. LC / MS(m / z, MH+):541

[0140] 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 [ka] Step 4 of Example 9 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to provide (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 51 mg (48%).

[0141] 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 [ka] 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 [ka] Step 1 of Example 10 was prepared from (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate 12) and 1-(3-fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, a mixture of Z and E isomers (Intermediate 10), according to a procedure similar to Step 1 of Example 9 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-ol 0.8 g (74%) was obtained as a mixture of Z and E isomers and used directly in the next step. LC / MS(m / z, MH+): 495

[0142] 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 [ka] Step 2 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-ol, a mixture of Z and E isomers, following a procedure similar to Step 2 of Example 1 to afford 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 as a mixture of Z and E isomers, which was used directly in the next step. LC / MS(m / z, MH+): 627

[0143] Step 3: Methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate [ka] 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, a mixture of Z and E isomers, according to a procedure similar to Step 3 of Example 1 to give methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate as a mixture of Z and E isomers, which was purified by preparative chiral SFC (AD3 Separation on a 100 × 4.6 mm column with a mobile phase of CO2 / 10% (iPrOH / isopropylamine, 3.5 ml / min) gave 237 mg (15%) of methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate. LC / MS(m / z, MH+):537

[0144] 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 [ka] Step 4 of Example 10 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate according to a procedure similar to Step 5 of Example 1 to provide 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.

[0145] Method D: 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 [ka] Step 1: Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate, 50 / 50 mixture of diastereomers [ka] A mixture of methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (Step 3 of Example 10) (200 mg, 0.37 mmol) and PtO (12.7 mg, 0.056 mmol) in EtOAc (4 mL) was stirred under a H atmosphere (1 bar) for 18 h. The reaction mixture was filtered through Celite and the filtrate was evaporated under reduced pressure to give methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate, 150 mg (75%) of a 50 / 50 mixture of diastereomers, which was used directly in the next step. LC / MS(m / z, MH+):539

[0146] 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 [ka] Step 2 of Example 11 was prepared from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate, a 50 / 50 mixture of diastereomers, following a procedure similar to Step 5 of Example 1 to yield 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, a 50 / 50 mixture of diastereomers.

[0147] The compounds set out in Table 1 above were subjected to pharmacological testing to determine their disruptive effect on the estrogen receptor.

[0148] Test: Estrogen receptor degrading activity Said test involves measuring the in vitro degradation activity of the compounds of Tables 1a and 1b.

[0149] Measurement of degradation activity was performed using breast cancer cell ERα in a cell Western assay as described below.

[0150] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells per well in phenol red-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran-striped FBS. The following day, nine serial 1:5 dilutions of each compound were added to the cells in 2.5 μL at final concentrations ranging from 0.3 to 0.0000018 μM (Table 2), or fulvestrant (used as a positive control) at a final concentration of 0.1 μM. Four hours after compound addition, cells were fixed by adding 25 μL of formalin (5% formalin with 0.1% Triton) for 10 min at RT and then washed twice with PBS. Next, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 min at RT. The LI-COR blocking buffer was removed, and the cells were incubated overnight in a cold room with 50 μL of anti-ER rabbit monoclonal antibody (Thermo Scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% Tween-20. Wells treated with blocking buffer but without antibody served as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 μM final concentration). The cells were then washed three times with 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.

[0151] The degradative activity of the estrogen receptor in this test is expressed as the concentration (or IC ) required to degrade 50% of the estrogen receptor in nM. 50 ) is given by

[0152] The % reduction in ERα levels was defined as follows: % inhibition=100*(1-(sample-fulvestrant:DMSO-fulvestrant)).

[0153] Table 2 below shows the estrogen receptor degrading activity results for the compounds of Table 1 tested at 0.3 μM, demonstrating that the compounds have significant degrading activity against the estrogen receptor.

[0154] [Table 7]

[0155] Therefore, it is clear that the tested compounds have degradation activity on estrogen receptors with IC50 of less than 1 μM and degradation levels of more than 50%. Therefore, the compounds of formula (I) can be used to prepare drugs, in particular, drugs that are estrogen receptor degraders.

[0156] Accordingly, also provided herein is a medicament comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0157] There is also provided herein a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above for use as a pharmaceutical.

[0158] There is also provided herein a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular for use as an inhibitor and degrader of the estrogen receptor.

[0159] There is also provided herein a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia, or inflammation.

[0160] A particular embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of cancer.

[0161] In some embodiments, the cancer is a hormone-dependent cancer.

[0162] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0163] 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.

[0164] In another embodiment, the metastasis is a cerebral metastasis.

[0165] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0166] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0167] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6, mTOR, or PI3K inhibitors.

[0168] According to another aspect, provided herein is a method of treating the above-noted pathological conditions, 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 some embodiments of this method of treatment, the subject is a human.

[0169] 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 in treating any of the pathological conditions set out above, more particularly useful in treating cancer.

[0170] Also provided herein are pharmaceutical compositions comprising a compound of formula (I) as an active ingredient, the pharmaceutical composition also comprising an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0171] Said excipients are selected according to the desired pharmaceutical form and method of administration from the conventional excipients known to those skilled in the art.

[0172] The active ingredient of formula (I) above, or its base, acid, zwitterion or salt thereof, in unit dosage form, in admixture with conventional pharmaceutical excipients, may be administered to animals and humans for the treatment of the above disorders or diseases in oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration.

[0173] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, it is possible to use the compounds of formula (I) in creams, gels, ointments or lotions.

[0174] As an example, a unit dosage form of a compound of formula (I) in tablet form may contain the following components: Compound of formula (I) 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Cornstarch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0175] There may be particular cases in which higher or lower dosages are appropriate. According to normal practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration, and the weight and response of said patient.

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, 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 is -CH ２ -, -CH=, -CR9=, -O-, or -NH-, where R9 is a fluorine atom or (C １ ~C ３ ) represents an alkyl group; － 【Chemistry 2】 represents a single or double bond; p is 0 or 1; X represents -CH=, -N=, or -CR"=, where R" is (C １ ~C ３ ) an alkyl group, or a halogen atom, such as a fluorine atom or a chlorine atom, a cyano group, or (C １ ~C ３ ) represents a fluoroalkyl group, such as trifluoromethyl; R7 is independently (C １ ~C ３ ) an alkyl group, such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or (C １ ~C ３ ) represents a fluoroalkyl group, for example, trifluoromethyl; n is 0, 1 or 2; and - R6 is (C １ ~C ６ ) alkyl group, and the alkyl group is １ ~C ３ ) an alkoxy group, (C １ ~C ３ ) optionally substituted with 1 to 4 substituents independently selected from fluoroalkoxy groups, cyclopropyl groups, oxetanyl groups, and —OH groups; R8 is a hydrogen atom, (C １ ~C ３ ) alkyl group, —CH ２ F group, -CHF ２ group, -CF ３ group, or (C ３ ~C ４ ) represents a cycloalkyl group, A compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

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

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

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

6. Y is -CH ２ 6. The compound of formula (I) according to any one of claims 1 to 5, wherein the compound represents -, -CH=, -O-, or -NH-, or a pharmaceutically acceptable salt thereof.

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

8. R8 is (C １ ~C ６ 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: 1) represents an alkyl group, preferably 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. R6 is (C １ ~C ６ ) alkyl group, and the (C １ ~C ６ ) alkyl group is optionally substituted with 1 to 3 fluorine atoms, and preferably １ ~C ６ 10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the alkyl group is substituted with 2 or 3 fluorine atoms.

11. R6 is -CH ２ -CF ３ group or —CH ２ -CF ２ -CH ３ 11. The compound of formula (I) according to any one of claims 1 to 10, wherein R represents a group, or a pharmaceutically acceptable salt thereof.

12. 【Chemical 3】 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein represents a single bond.

13. Y is -CH ２ Compounds of formula (I) or pharmaceutically acceptable salts thereof according to any one of claims 1 to 12, characterized in that p is equal to 1 when representing -, -O- or -NH-, in particular p is equal to 1.

14. The compound is the following compound: (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) 14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in particular the hydrochloride thereof, selected from:

15. A method for preparing a compound of formula (I) according to any one of claims 1 to 14, comprising the step of: 【Chemistry 4】 (In the formula, R1, R2, R3', R3", R4, R5, R5', R6, R7, R8, 【Chemistry 5】 , n, p, X and Y are as described in any one of claims 1 to 12), in the presence of a source of hydroxide ions such as NaOH or LiOH in a solution in methanol or THF, to a compound of formula (I), said step being optionally preceded by a step to obtain a compound of formula 1J, in which a compound of formula 1H: 【Chemistry 6】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 7】 , n, p, X and Y are as described in any one of claims 1 to 12) to a compound of formula 1J by carbonylation with carbon monoxide (CO) in solution in MeOH 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, comprising the step of: 【Chemistry 8】 wherein R3′, R3″, R6, R7, R8, n, and X are as described in any one of claims 1 to 13, is reacted under coupling reaction conditions to give a compound of formula 1G: 【Chemistry 9】 wherein R1, R2, R4, R5, R5' and p are as defined in any one of claims 1 to 13, to give a compound of formula 1D: 【Chemistry 10】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 11】 , n, p, X, and Y are as defined in any one of claims 1 to 13), said step being optionally preceded by a step of obtaining a compound of formula 1F, in which a compound of formula 1B: 【Chemistry 12】 wherein R3′, R3″, R6, and R8 are as described in any one of claims 1 to 13, with a compound of formula 1E: 【Chemistry 13】 wherein X, R7, and n are as defined above, are subjected to a Pictet-Spengler cyclization reaction in the presence of an acid such as TFA or acetic acid in a suitable solvent such as DCE.

17. A method for preparing a compound of formula (I) according to any one of claims 1 to 14, comprising the step of: 【Chemistry 14】 wherein R3′, R3″, R6, and R8 are as described in any one of claims 1 to 13, by reacting a compound of formula 1C: 【Chemistry 15】 (In the formula, R1, R2, R4, R5, R5', R7, 【Chemistry 16】 , n, p, X, and Y 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), to give a compound of formula 1D: 【Chemistry 17】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemistry 18】 , 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, comprising the step of: 【Chemistry 19】 (In the formula, R3', R3", R6, R7, R8, 【Chemistry 20】 , n, p, X, and Y are as described in any one of claims 1 to 13) in DMF as a solvent. ２ CO ３ ), in the presence of a base such as 【Chemical 21】 wherein R1, R2, R4, R5, and R5' are as defined in any one of claims 1 to 13, and W is Cl, Br, or I, or OSO ２ R, where R=CH ３ , PhMe, CF ３ , or CF ２ CF ２ CF ２ CF ３ ) to give a compound of formula 1D: 【Chemical 22】 (In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, 【Chemical 23】 , n, p, X and Y are as described in any one of claims 1 to 13.

19. Formula 1J 【Chemistry 24】 or a pharmaceutically acceptable salt thereof, In the formula, R1, R2, R3', R3'', R4, R5, R5', R6, R7, R8, n, p, 【Chemistry 25】 , X and Y are as described in any one of claims 1 to 13; A compound of formula 1J, or any of its pharmaceutically acceptable salts:

20. A drug comprising a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising 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. 15. 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 hyperplasia, or inflammation.

24. 24. The 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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