1,3-cyclohexanediamine derivatives as mrgprx2 inhibitors, preparation method therefor and pharmaceutical use thereof

Abstract

The present invention relates to a method for preparing 1,3-cyclohexanediamine derivatives as MrgprX2 inhibitors, and the use of the series of compounds and a pharmaceutical composition containing the series of compounds in the preparation of drugs for treating allergic reactions. The definitions of the substituents in general formula (I) are the same as those in the description.

Description

A class of 1,3-cyclohexanediamine derivatives of MrgprX2 inhibitors, their preparation methods and their pharmaceutical applications Technical Field

[0001] This invention relates to a method for preparing a class of 1,3-cyclohexanediamine derivatives as MrgprX2 inhibitors, and the use of pharmaceutical compositions containing this series of compounds and pharmaceutical compositions containing this series of compounds in the preparation of medicaments for treating allergic reactions. Background Technology

[0002] Mas-related G-protein-coupled receptors (MRGPRs) are important receptors that cause itching and allergic reactions. Activation of the MrgprX2 subfamily can cause mast cells to degranulate in a manner independent of IgE antibodies, thereby causing diseases such as chronic urticaria, angioedema, pain, and chronic itching.

[0003] Dozens of FDA-approved drugs are known to cause pseudoallergic reactions, such as clomipramine and aminophenatropin. Knockout of the murine receptor (MrgprB2) corresponding to MrgprX2 can significantly alleviate drug-induced pseudoallergic or anaphylactic reactions, demonstrating that these drug-induced allergic reactions are mediated by MrgprB2 and MrgprX2. 1 Therefore, MrgprX2 inhibitors can be used as a treatment for allergic reactions caused by MrgprX2 activation induced by drugs or other endogenous secretagogues in the body.

[0004] Studies from multiple companies have demonstrated that small molecule inhibitors of MrgprX2 can effectively inhibit drug-induced MrgprX2 activation, such as WO202215285, WO2023192901, and WO2021092240. However, currently only one compound (EP-262) has entered Phase 1 clinical trials, and more small molecule inhibitors with better drug-like properties need to be developed for clinical trials.

[0005] References:

[0006] 1. McNeil et al. Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions. Nature 519, 237-241 (2015). Summary of the Invention

[0007] Through experimental research, the inventors discovered that the compound of formula (I) can effectively inhibit the activation of MrgprX2.

[0008] in:

[0009] Y is selected from N or CR a ;

[0010] R a Selected from H, CN, or halogens;

[0011] R 1 The radical is selected from H, halogen, CN, C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic group, C1-C3 alkoxy or 4-7 heterocyclic group, wherein the C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic group, C1-C3 alkoxy or 4-7 heterocyclic group may optionally be further surrounded by 1-4 R radicals. b Replaced;

[0012] R b Each is independently selected from OH, halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0013] n = 0 to 2;

[0014] A is selected from phenyl or 5- to 10-membered heteroaryl groups, wherein the phenyl or 5- to 10-membered heteroaryl group may optionally be surrounded by 1 to 3 R groups. c What it replaced.

[0015] R c Selected independently from halogen, CN, OR d C1-C3 alkyl, C3-C7 cycloalkyl, or 4-7 heterocyclic group, wherein the C1-C3 alkyl, C3-C7 cycloalkyl, or 4-7 heterocyclic group may optionally be further surrounded by 1-4 R groups. e Replaced;

[0016] R d The group is selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 heterocyclic alkyl, phenyl or 5-10 heteroaryl, wherein the C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic, phenyl or 5-10 heteroaryl may optionally be further surrounded by 1-4 R groups. e Replaced;

[0017] R eThe substituted group is selected from halogen, hydroxyl, cyano, C1-C3 alkyl, phenyl, 5-10 heteroaryl, C1-C3 alkoxy, C3-C7 cycloalkyloxy, 4-7 heterocyclic oxy, C3-C7 cycloalkyl or 4-7 heterocyclic, wherein the C1-C3 alkyl, phenyl, 5-10 heteroaryl, C1-C3 alkoxy, C3-C7 cycloalkyloxy, 4-7 heterocyclic oxy, C3-C7 cycloalkyl or 4-7 heterocyclic may optionally be further substituted with 1-3 halogen, hydroxyl or cyano groups;

[0018] A compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0019] Among them, Y and R 1 And A as described in general formula (I);

[0020] Preferably, a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of general formula (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0021] Among them, Y and R 1 And A as described in general formula (I).

[0022] Preferably, a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of general formula (IV) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0023] Among them, R 1 And A as defined in claim 1;

[0024] Typical compounds of this invention include, but are not limited to:

[0025] The aforementioned typical compounds include their stereoisomers, tautomers, or pharmaceutically usable salts.

[0026] This invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

[0027] Under alkaline conditions, compounds of general formula (IA) and halogenated compounds of general formula (IB) undergo the Buchwald reaction in the presence of a catalyst to give compounds of general formula (I), wherein:

[0028] Y, R 1 , n and A are as defined in general formula (I), and X is a halogen, preferably bromine, iodine and chlorine;

[0029] The reagents providing alkaline conditions include organic and inorganic bases. The organic bases include, but are not limited to, sodium tert-butoxide, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, bis(trimethylsilylaminolithium), potassium acetate, sodium tert-butoxide, sodium methoxide, or potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, sodium bicarbonate, and lithium hydroxide. Preferably, the organic base is sodium tert-butoxide, and the inorganic base is cesium carbonate.

[0030] Catalysts include, but are not limited to, palladium / carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, or tris(dibenzylideneacetone)palladium; preferred catalysts are palladium acetate and tris(dibenzylideneacetone)palladium.

[0031] Ligands include, but are not limited to, 2-biscyclohexylphosphine-2,6'-dimethoxybiphenyl, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-11'-biphenyl, 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl, and (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene] Ethyl di-tert-butylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; preferably, the ligands are 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-11'-biphenyl and (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine.

[0032] The above reaction is preferably carried out in a solvent, which includes, but is not limited to: methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, acetone, diethyl ether, N,N-dimethylformamide, and mixtures thereof; the preferred solvents are 1,4-dioxane and ethylene glycol dimethyl ether.

[0033] This invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

[0034] Under alkaline conditions, compounds of general formula (IA) and halogenated compounds of general formula (IB) undergo a Ullmann reaction in the presence of a catalyst to give compounds of general formula (I), wherein:

[0035] Y, R 1 , n and A are as defined in general formula (I), and X is a halogen, preferably bromine, iodine and chlorine;

[0036] The reagents providing alkaline conditions include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, potassium acetate, sodium tert-butoxide, sodium methoxide, or potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, sodium bicarbonate, and lithium hydroxide. Preferably, the organic base is sodium tert-butoxide, and the inorganic base is cesium carbonate.

[0037] The catalysts include, but are not limited to, copper powder, cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, copper acetylacetonate, copper acetate, copper thiophene-2-carboxylate, triphenylphosphine cuprous bromide, bis-(1,5-cyclooctadiene)nickel, ethylene glycol dimethyl ether nickel bromide, and bis(triphenylphosphine)dibromide nickel; the preferred catalyst is cuprous iodide.

[0038] Ligands include, but are not limited to, ethylenediamine, N,N-dimethylethylenediamine, dibenzyl oxalate, N,N-dimethylglycine, proline, o-phenanthroline, diphenylphosphine oxide, 2-(pyridyl)oxazoline, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide, and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide; preferred ligands are N,N-dimethylethylenediamine and N,N-dimethylglycine.

[0039] The above reaction is preferably carried out in a solvent, which includes, but is not limited to: toluene, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, acetone, diethyl ether, N,N-dimethylformamide, and mixtures thereof; the preferred solvent is 1,4-dioxane.

[0040] This invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

[0041] Under alkaline conditions, compounds of general formula (IA) and halogenated compounds of general formula (IB) are directly converted to compounds of general formula (I) by heating in solution, wherein:

[0042] Y, R 1 , n and A are as defined in general formula (I).

[0043] The reagents providing alkaline conditions include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, bis(trimethylsilylaminolithium), potassium acetate, sodium tert-butoxide, sodium methoxide, or potassium tert-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, sodium bicarbonate, and lithium hydroxide. Preferably, the organic base is N,N-diisopropylethylamine, and the inorganic base is potassium carbonate.

[0044] The above reaction is preferably carried out in a solvent, which includes, but is not limited to: toluene, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, acetone, diethyl ether, N,N-dimethylformamide and mixtures thereof; the preferred solvents are N,N-dimethylformamide and dimethyl sulfoxide.

[0045] The present invention provides a pharmaceutical composition comprising an effective dose of a compound of formulas (I) to (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

[0046] The present invention provides the use of compounds of general formulas (I) to (IV) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for MrgprX2 inhibitors.

[0047] The present invention provides the use of compounds of general formulas (I) to (IV) or their stereoisomers, tautomers or pharmaceutically usable salts or pharmaceutical compositions thereof in the preparation of medicaments for treating allergy-related diseases, wherein the allergy-related diseases are preferably urticaria, atopic dermatitis, Crohn's disease, etc.

[0048] Detailed description of the invention

[0049] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0050] "alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms of a saturated straight-chain or branched monovalent hydrocarbon group, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be optionally substituted or unsubstituted.

[0051] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted.

[0052] The terms “heterocyclic group” and “heterocycle” are used interchangeably in this application. Both refer to a non-aromatic heterocyclic group comprising 3-12 saturated or partially unsaturated monocyclic, bicyclic, or tricyclic rings, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, or sulfur. Preferably, it has a 5- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of “heterocyclic group” include, but are not limited to, morpholino, oxobutyryl, thiomorpholino, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidinyl, 2-oxo-piperidinyl, pyrrolyl, 2-oxo-pyrrolyl, piperazine-2-one, 8-oxa-3-aza-bicyclic [3.2.1]octyl, and piperazine. The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted.

[0053] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl groups are C6-C. 10Aryl, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted. The "aryl" group may be fused with a heteroaryl, heterocyclic, or cycloalkyl group, wherein the aryl ring is attached to the parent structure. Non-limiting embodiments include, but are not limited to:

[0054] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[a]dioxacyclopentenyl, benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazoleyl, benzisothiazolyl, benzo[a]oxazolyl, and benzisothiazolyl. Heteroaryl groups may be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting embodiments include, but are not limited to:

[0055] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0056] "Hydroxy" refers to the -OH group.

[0057] "Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0058] "Optional" means that the event it describes can but does not have to happen. For example, "AR" 1 Choose one or more R c The statement that "replaces" contains AR 1 The group can be one or more R c Replace or not by R c The situation of substitution.

[0059] Unless otherwise specified, “substitution” or “substituted” in this specification means that a group may be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O.

[0060] The definition and conventional use of stereochemistry in this invention are generally referenced in the following literature:

[0061] SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Diastereomers can be separated into individual diastereomers based on their physicochemical differences by methods such as chromatography, crystallization, distillation, or sublimation. Enantiomers can be separated to convert a mixture of chiral isomers into a mixture of diastereomers by reacting with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acyl chloride), separating the diastereomers and converting individual diastereomers into their corresponding pure enantiomers. The intermediates and compounds of this invention can also exist in different tautomeric forms, and all such forms are included within the scope of this invention. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name the symbol for the plane polarization rotation of the compound; (-) or l indicates that the compound is levorotatory, and the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same order of atomic or atomic groups connected to each other, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are generally called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection in chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0062] "Tautomer" or "tautomer form" refers to isomers of structures with different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerizations of keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons. Unless otherwise indicated, the structural formulas described in this invention include all isomer forms (e.g., enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing an asymmetric center, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of this invention, or mixtures of their enantiomers, diastereomers, or geometric isomers, are within the scope of this invention.

[0063] "Pharmaceutical salts" refers to salts of the compounds of this invention that are safe and effective when used in humans or animals. Salts of the compounds can be obtained by adding sufficient amounts of base or acid in a pure solution or a suitable inert dissolution. Pharmaceutical base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, etc., and pharmaceutical acid addition salts include inorganic acid salts and organic acid salts, including hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, etc. (See Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).

[0064] Method for synthesizing the compounds of the present invention

[0065] The method of the present invention will be described below through specific embodiments to make the technical solution of the present invention easier to understand and master, but the present invention is not limited thereto. In the following embodiments... 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplyt, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0066] The mass spectrometry results were obtained using an LC / MS instrument, with ESI as the ionization method.

[0067] High-performance liquid chromatograph (HPLC) models: Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5μm); Mobile phase: A: ACN, B: Water (0.1% H3PO4); Flow rate: 1.0 mL / min; Gradient: 5% A for 1 min, increase to 20% A within 4 min, increase to 80% A within 8 min, 80% A for 2 min, back to 5% A within 0.1 min; Wavelength: 220 nm; Column oven: 35℃.

[0068] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in TLC are 0.2mm-0.3mm in diameter, and the plates used for TLC separation and purification are 0.4mm-0.5mm in diameter.

[0069] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0070] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Sinopharm Group, TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., Shaoyuan Technology (Shanghai) Co., Ltd., Beijing Leyan Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0071] CD3OD: Deuterated methanol

[0072] CDCl3: Deuterated chloroform

[0073] Pd2(dba)3: Tris(dibenzylacetone)dipalladium

[0074] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

[0075] Pd(OAc)2: Palladium acetate

[0076] XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene

[0077] XPhos: 2-Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl

[0078] BrettPhos:2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-11'-biphenyl

[0079] BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)

[0080] CyPFt-Bu:(R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine

[0081] DIEA: N,N-Diisopropylethylamine

[0082] DCM: Dichloromethane

[0083] DMF: N,N-Dimethylformamide

[0084] TLC: Thin-layer chromatography

[0085] HPLC: High Performance Liquid Chromatography

[0086] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0087] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0088] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0089] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, or the developing solvent system for TLC included: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: ethyl acetate and methanol. The volume ratio of the solvent varied depending on the polarity of the compound, and small amounts of acidic or basic reagents, such as acetic acid or triethylamine, could be added for adjustment.

[0090] intermediate synthesis

[0091] (1R,3S)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine int-1

[0092] Step 1: Compound int-1a (535.8 mg, 2.5 mmol) and tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (665.1 mg, 2.5 mmol) were added together to a 50 mL sealed tube equipped with a magnetic spool. After three N2 purgings, DIEA (1.7 mL, 10.0 mmol) was added to anhydrous dimethyl sulfoxide (10 mL). The mixture was then injected into the sealed tube using a syringe. The tube was sealed and placed in an oil bath preheated to 130 °C with stirring overnight. After the reaction was complete as shown by thin-layer chromatography (TLC), water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel column chromatography to obtain compound int-1b (970 mg, yield 87.5%). 1 H NMR(400MHz, CDCl3)δ:8.10(d,J=8.9Hz,1H),7.84(s,1H),7.61(dd,J=9.0,1.9Hz,1H),6.75(s,1H),3.76-3.55(m,2H),2.56-2.43(m ,1H),2.26-2.13(m,1H),2.12-2.03(m,1H),1.99-1.89(m,1H),1.63-1.48(m,2H),1.46(s,9H),1.38-1.25(m,2H),1.24-1.10(m,1H).

[0093] Step 2: Compound int-1b (970 mg, 2.188 mmol) was added to a 100 mL single-necked flask equipped with a magnetic stir bar, followed by 16 mL of DCM and then 3.25 mL of trifluoroacetic acid (43.76 mmol). The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete (eluent: pure ethyl acetate). Saturated Na₂CO₃ solution was added to adjust the pH of the reaction solution to weakly alkaline. Dichloromethane and water were then added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound int-1 (670 mg, yield 89.2%). ESI-MS m / z 344.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ:8.36(d,J=2.2Hz,1H),7.90(d,J=9.0Hz,1H),7.67(d d,J=9.0,2.3Hz,1H),6.84(s,1H),3.82-3.67(m,1H),3.17-3.04(m,1H),2. 45-2.32(m,1H),2.12-2.07(m,J=12.2Hz,1H),2.06-2.01(m,J=6.1Hz,1H), 1.99-1.89(m,1H),1.63-1.51(m,1H),1.50-1.39(m,2H),1.35-1.22(m,1H).

[0094] Example 1

[0095] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-Methyl-1H-indolezol-3-yl)cyclohexane-1,3-diamine

[0096] Step 1: Compound 1a (198 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and methyl iodide (170.4 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 1b (160 mg, yield 75.5%). 1 H NMR (400MHz, CDCl3) δ: 7.61 (d, J = 8.2Hz, 1H), 7.47-7.41 (m, 1H), 7.36 (d, J = 8.5Hz, 1H), 7.24-7.17 (m, 1H), 4.05 (s, 3H).

[0097] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 1b (42.4 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), BINAP (24.9 mg, 0.04 mmol), and sodium tert-butoxide (38.4 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 1 (6 mg, yield 6.3%). ESI-MS m / z 474.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ: 8.36 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 9. 1,2.2Hz,2H),7.37-7.29(m,1H),7.24(d,J=8.5Hz,1H),6.95(ddd,J=7.7,6.9,0.7H z,1H),6.94(s,1H),3.87-3.75(m,1H),3.80(s,3H),2.73-2.64(m,1H),2.26-2.19( m,1H),2.18-2.10(m,1H),2.03-1.92(m,1H),1.73-1.60(m,1H),1.58-1.31(m,4H).

[0098] Example 2

[0099] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N3-(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine

[0100] Step 1: Compound 2a (197 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and methyl iodoform (170.4 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 2b (133 mg, yield 63.0%). 1H NMR (400MHz, CDCl3) δ: 8.17 (d, J = 6.0Hz, 1H), 8.07 (s, 1H), 7.27 (s, 1H), 4.09 (s, 3H).

[0101] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 2b (42.2 mg, 0.2 mmol), palladium acetate (4.5 mg, 0.02 mmol), CyPFt-Bu (22.2 mg, 0.04 mmol), and sodium tert-butoxide (38.4 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, ethylene glycol dimethyl ether (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 90 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 2 (36 mg, yield 38.0%). ESI-MS m / z 475.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:8.37(d,J=2.2Hz,1H),8.16(s,1H),7.90(d,J=9.0Hz,1H ),7.75(d,J=6.4Hz,1H),7.68(dd,J=9.0,2.2Hz,1H),6.97(s,1H),6.73(d,J=6 .3Hz,1H),4.23-4.12(m,1H),3.96(s,3H),3.92-3.82(m,1H),2.60-2.48(m,1H ),2.23-2.07(m,2H),1.77-1.60(m,1H),1.57-1.39(m,3H),1.35-1.30(m,1H).

[0102] Example 3

[0103] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-Isopropyl-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine

[0104] Step 1: Compound 3a (197 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and 2-iodopropane (204 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, N,N-dimethylformamide (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 3b (111 mg, yield 46.4%). 1 H NMR (400MHz, CDCl3) δ: 8.16 (s, 1H), 8.04 (d, J = 6.3Hz, 1H), 7.48 (d, J = 6.2Hz, 1H), 4.91-4.69 (m, 1H), 1.69 (d, J = 6.7Hz, 6H).

[0105] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 3b (47.8 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), XantPhos (23.1 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 3 (22 mg, yield 21.9%). ESI-MS m / z 503.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.00 (d, J = 9.0Hz, 1H), 7.97 (s, 1H), 7.77 (d, J = 6.4Hz, 1H), 7.7 2(d,J=1.8Hz,1H),7.62(dd,J=9.0,2.2Hz,1H),6.81(s,1H),6.68(d,J=6.4Hz,1H),5 .19-5.07(m,1H),4.81-4.63(m,2H),4.35-4.23(m,1H),3.86-3.73(m,1H),2.85-2.6 9(m,1H),2.35-2.18(m,2H),2.11-1.95(m,1H),1.77-1.58(m,2H),1.49-1.34(m,2H).

[0106] Example 4

[0107] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-Methyl-1H-pyrrolo[3,2-c]pyridin-4-yl)cyclohexane-1,3-diamine-4

[0108] Step 1: Compound 4a (196 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and methyl iodide (170.4 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 4b (140 mg, yield 66.7%). 1 H NMR (400MHz, CDCl3) δ: 8.09 (d, J = 5.8Hz, 1H), 7.22 (d, J = 5.8Hz, 1H), 7.14 (d, J = 3.2Hz, 1H), 6.59 (d, J = 3.2Hz, 1H), 3.82 (s, 3H).

[0109] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 4b (42.0 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), XantPhos (23.1 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 4 (18 mg, yield 19.0%). ESI-MS m / z 474.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ: 7.98 (d, J = 9.0Hz, 1H), 7.74 (d, J = 1.7Hz, 1H), 7.70 (d, J = 6.3Hz, 1 H),7.60(dd,J=9.0,2.1Hz,1H),6.98(d,J=3.2Hz,1H),6.78(s,1H),6.65(d,J=6.3Hz,1H ),6.50(d,J=3.0Hz,1H),5.32(d,J=6.8Hz,1H),4.35-4.21(m,1H),3.81-3.76(m,1H),3 .75(s,3H),2.80-2.65(m,1H),2.32-2.16(m,2H),1.74-1.58(m,1H),1.58-1.31(m,4H).

[0110] Example 5

[0111] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-Methyl-1H-indazol-4-yl)cyclohexane-1,3-diamine 5

[0112] Step 1: Compound 5a (196 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and methyl iodide (170.4 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 5b (130 mg, yield 61.9%). 1 H NMR (400MHz, CDCl3) δ: 7.99 (d, J = 0.8Hz, 1H), 7.36-7.32 (m, 1H), 7.30 (dd, J = 7.3, 0.8Hz, 1H), 7.24 (dd, J = 8.2, 7.4Hz, 1H), 4.08 (s, 3H).

[0113] Step 2: 68.6 mg of compound int-1 (68.6 mg, 0.2 mmol), compound 5b (42.0 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), XantPhos (23.1 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added to a 10 mL sealed tube containing a magnetic magnet. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 5 (19 mg, yield 20.1%). ESI-MS m / z 474.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.00 (d, J = 9.0Hz, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.61 (dd,J=9.0,2.1Hz,1H),7.25(dd,J=8.2,7.7Hz,1H),6.77(d,J=9.4Hz,2H),6 .34(s,1H),5.32(s,1H),4.02(s,3H),3.80-3.69(m,2H),2.84-2.63(m,1H), 2.38-2.14(m,2H),2.11-1.94(m,1H),1.80-1.56(m,1H),1.53-1.34(m,2H).

[0114] Example 6

[0115] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(3-chloro-1-methyl-1H-indazol-4-yl)cyclohexane-1,3-diamine

[0116] Step 1: Compound 6a (196 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and methyl iodide (170.4 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 6b (130 mg, yield 61.9%). 1H NMR (400MHz, CDCl3) δ: 7.99 (d, J = 0.8Hz, 1H), 7.36-7.32 (m, 1H), 7.30 (dd, J = 7.3, 0.8Hz, 1H), 7.24 (dd, J = 8.2, 7.4Hz, 1H), 4.08 (s, 3H).

[0117] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 6b (42.0 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), XantPhos (23.1 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were weighed and added to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain the title compound 6 (19 mg, yield 20.1%). ESI-MS m / z 474.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.00 (d, J = 9.0Hz, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.61 (dd,J=9.0,2.1Hz,1H),7.25(dd,J=8.2,7.7Hz,1H),6.77(d,J=9.4Hz,2H),6 .34(s,1H),5.32(s,1H),4.02(s,3H),3.80-3.69(m,2H),2.84-2.63(m,1H), 2.38-2.14(m,2H),2.11-1.94(m,1H),1.80-1.56(m,1H),1.53-1.34(m,2H).

[0118] Example 7

[0119] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(5-fluoro-1-methyl-1H-indazol-4-yl)cyclohexane-1,3-diamine

[0120] Step 1: Compound 7a (196 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and methyl iodide (170.4 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 7b (130 mg, yield 61.9%). 1 H NMR (400MHz, CDCl3) δ: 7.99 (d, J = 0.8Hz, 1H), 7.36-7.32 (m, 1H), 7.30 (dd, J = 7.3, 0.8Hz, 1H), 7.24 (dd, J = 8.2, 7.4Hz, 1H), 4.08 (s, 3H).

[0121] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 7b (42.0 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), XantPhos (23.1 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain the title compound 7 (19 mg, yield 20.1%). ESI-MS m / z 474.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.00 (d, J = 9.0Hz, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.61 (dd,J=9.0,2.1Hz,1H),7.25(dd,J=8.2,7.7Hz,1H),6.77(d,J=9.4Hz,2H),6 .34(s,1H),5.32(s,1H),4.02(s,3H),3.80-3.69(m,2H),2.84-2.63(m,1H), 2.38-2.14(m,2H),2.11-1.94(m,1H),1.80-1.56(m,1H),1.53-1.34(m,2H).

[0122] Example 8

[0123] (1S,3R)-N 1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(6-chloro-1-methyl-1H-indazol-4-yl)cyclohexane-1,3-diamine

[0124] Step 1: Compound 8a (116 mg, 0.5 mmol), potassium carbonate (103.5 mg, 0.75 mmol), and methyl iodide (85.2 mg, 0.6 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 8b (81 mg, yield 65.9%). 1 H NMR (400MHz, CDCl3) δ: 7.95 (d, J = 0.8Hz, 1H), 7.36-7.35 (m, 1H), 7.31 (d, J = 1.4Hz, 1H), 4.04 (s, 3H).

[0125] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 8b (49.2 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), XantPhos (23.1 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 8 (21 mg, yield 20.7%). ESI-MS m / z 508.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.04(d,J=9.0Hz,1H),7.84(s,1H),7.69(s,1H),7.62(d,J=9.0Hz,1H),6.76(d,J=15.7Hz,2H),6.24(s,1H ),3.96(s,3H),3.84-3.74(m,1H),3.71-3.63(m,1H),2.79-2.63(m,1H),2.39-2.21(m,2H),2.12-1.97(m,1H),1.56-1.28(m,4H).

[0126] Example 9

[0127] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-Methyl-1H-indazol-5-yl)cyclohexane-1,3-diamine

[0128] Step 1: Compound int-1 (68.6 mg, 0.2 mmol), compound 9a (42.0 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), BrettPhos (21.5 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 9 (26 mg, yield 27.5%). ESI-MS m / z 474.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:7.88(s,1H),7.80(d,J=9.1Hz,1H),7.39(d,J=2.5Hz,1H) ,7.32-7.26(m,3H),7.25(s,1H),6.73(s,1H),4.00(s,3H),3.79-3.68(m,1H),3 .61-3.51(m,1H),2.55-2.43(m,1H),2.21-2.07(m,2H),2.00-1.88(m,1H),1.69 -1.55(m,1H),1.50-1.40(m,1H),1.35(m,J=11.2,5.6Hz,1H),1.31-1.22(m,1H).

[0129] Example 10

[0130] N 2 -((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-N 4 N 4 -Dimethylpyrimidine-2,4-diamine 10

[0131] Step 1: Compound int-1 (68.6 mg, 0.2 mmol), compound 10a (40.2 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), CyPFt-Bu (22.2 mg, 0.04 mmol), and sodium tert-butoxide (38.4 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 10 (20 mg, yield 21.5%). ESI-MS m / z 465.2 [M+H] + . 1 H NMR(400MHz, CD3OD)δ:8.37(d,J=2.2Hz,1H),7.90(d,J=9.0Hz,1H),7.74-7.64(m,2H),6.87(s,1H),5.94(d,J=6.3Hz,1H),4.00-3.88( m,1H),3.83-3.73(m,1H),3.07(s,6H),2.58-2.42(m,1H),2.18-2.03(m,2H),1.98-1.89(m,1H),1.71-1.54(m,1H),1.53-1.31(m,3H).

[0132] Example 11

[0133] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(4-methoxypyrimidin-2-yl)cyclohexane-1,3-diamine

[0134] Step 1: Compound int-1 (68.6 mg, 0.2 mmol), compound 11a (47.2 mg, 0.2 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol), CyPFt-Bu (22.2 mg, 0.04 mmol), and sodium tert-butoxide (38.4 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, anhydrous 1,4-dioxane (3 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain the title compound 11 (24 mg, yield 26.6%). ESI-MS m / z 452.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ: 8.37 (d, J = 2.2Hz, 1H), 7.92 (dd, J = 11.4, 7.4Hz, 2H), 7.68 (dd, J = 9.0, 2.3Hz, 1H), 6.89 (s, 1H), 6.02 (d, J = 5.8Hz, 1H), 4.0 0-3.92(m,1H),3.89(s,3H),3.85-3.74(m,1H),2.56-2.41(m,1H),2.18 -2.04(m,2H),2.00-1.90(m,1H),1.70-1.56(m,1H),1.53-1.25(m,3H).

[0135] Example 12

[0136] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-Isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclohexane-1,3-diamine-12

[0137] Step 1: Compound 12a (198 mg, 1 mmol), potassium carbonate (207 mg, 1.5 mmol), and 2-iodopropane (204 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via a syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 12b (71 mg, yield 29.6%). 1H NMR (400MHz, CDCl3) δ: 9.02 (s, 1H), 8.15 (s, 1H), 5.21 (m, J = 6.7Hz, 1H), 1.59 (d, J = 6.7Hz, 6H).

[0138] Step 2: Compound int-1 (68.6 mg, 0.2 mmol), compound 12b (48.0 mg, 0.2 mmol), cuprous iodide (7.6 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three N2 displacements, N,N-dimethylethylenediamine (3.5 mg, 0.04 mmol) was added to anhydrous 1,4-dioxane (3 mL). The mixture was then injected into the sealed tube using a syringe. The tube was sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as shown by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 12 (15 mg, yield 14.9%). ESI-MS m / z 504.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.69 (s, 1H), 8.01 (d, J = 9.0Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 2.1Hz ,1H),7.62(dd,J=9.0,2.2Hz,1H),6.81(s,1H),5.45(d,J=6.1Hz,1H),5.18(d,J=7.2Hz,1 H),5.10-4.87(m,1H),4.23-4.05(m,2H),3.85-3.72(m,1H),2.80-2.63(m,1H),2.30-2.2 0(m,2H),2.04-1.98(m,1H),1.75-1.60(m,1H),1.54(d,J=6.7Hz,6H),1.45-1.29(m,4H).

[0139] Example 13

[0140] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(4-methylpyridin-2-yl)cyclohexane-1,3-diamine 13

[0141] Step 1: Compound int-1 (68.6 mg, 0.2 mmol), compound 13a (34.2 mg, 0.2 mmol), cuprous iodide (7.6 mg, 0.04 mmol), and cesium carbonate (130.3 mg, 0.4 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three N2 displacements, N,N-dimethylglycine (4.1 mg, 0.04 mmol) was added to anhydrous 1,4-dioxane (3 mL). The mixture was then injected into the sealed tube using a syringe. The tube was sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain the title compound 13 (25 mg, yield 28.8%). ESI-MS m / z 435.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.01 (d, J = 9.0Hz, 1H), 7.87 (d, J = 5.5Hz, 1H), 7.71 (d, J = 2.1Hz,1H),7.63(dd,J=9.0,2.2Hz,1H),6.75(s,1H),6.47(d,J=4.8Hz,1H),6.3 4(s,1H),5.29(d,J=7.9Hz,1H),3.88-3.63(m,2H),2.68-2.52(m,1H),2.29(s,3 H),2.24-2.13(m,2H),2.06-1.94(m,1H),1.68-1.54(m,1H),1.51-1.34(m,3H).

[0142] Example 14

[0143] (1S,3R)-N 1 -(6-chloro-2-(trifluoromethyl)quinolin-4-yl)-N 3 -(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)cyclohexane-1,3-diamine 14

[0144] Step 1: Compound 14a (197.0 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), and 1,1,1-trifluoro-2-iodoethane (252 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via a syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 14b (155 mg, yield 55.6%).1 H NMR (400MHz, CDCl3) δ: 8.26 (d, J = 6.0Hz, 1H), 8.17 (d, J = 0.7Hz, 1H), 7.34 (d, J = 6.0Hz, 1H), 4.97 (q, J = 8.3Hz, 2H).

[0145] Step 2: Compound int-1 (68.6 mg, 0.2 mmol) and compound 14b (55.8 mg, 0.2 mmol) were added together to a 10 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DIEA (0.13 mL, 0.8 mmol) was added to anhydrous dimethyl sulfoxide (3 mL). The mixture was then injected into the sealed tube using a syringe. The tube was sealed and placed in an oil bath preheated to 130 °C with stirring overnight. After the reaction was complete as shown by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain title compound 14 (20 mg, yield 18.5%). ESI-MS m / z 543.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:8.37(d,J=2.2Hz,1H),8.27(d,J=0.6Hz,1H),7.90(d,J=9.0H z,1H),7.81(d,J=6.3Hz,1H),7.68(dd,J=9.0,2.3Hz,1H),6.97(s,1H),6.81(d,J=6 .3Hz,1H),5.10(q,J=8.8Hz,2H),4.23-4.14(m,1H),3.94-3.80(m,1H),2.62-2.48( m,1H),2.23-2.08(m,2H),2.05-1.94(m,1H),1.76-1.62(m,1H),1.58-1.39(m,3H).

[0146] Example 15

[0147] 3-Chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)-3,4-dihydroquinoline-4-yl)amino)cyclohexyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide 15

[0148] Step 1: Compound 15a (160 mg, 1 mmol), potassium carbonate (207 mg, 1.5 mmol), and 1,1,1-trifluoro-2-iodoethane (252 mg, 1.2 mmol) were added together to a 25 mL sealed tube equipped with a magnetic spool. After three purgings with N2, DMF (8 mL) was added to the sealed tube via syringe. The tube was then sealed and placed in an oil bath preheated to 110 °C with stirring overnight. After the reaction was complete as indicated by TLC, water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 15b (162 mg, yield 66.9%).

[0149] Step 2: Compound 15b (162 mg, 0.67 mmol) and lithium hydroxide (80.3 mg, 3.35 mmol) were added together to a 50 mL single-necked flask equipped with a magnetic swivel. Methanol (6 mL) and water (2 mL) were mixed and added to the flask. The reaction system was placed in an oil bath preheated to 40 °C and stirred for 4 h. After the reaction was complete as shown by TLC, the methanol was evaporated to dryness. HCl (1 N) solution was added to adjust the pH of the reaction solution to weakly acidic. Water and ethyl acetate were added for extraction. The organic phase was evaporated to dryness and purified by silica gel plate to obtain compound 15c (140 mg, yield 91.7%). 1 H NMR (400MHz, CD3OD) δ: 7.92 (s, 1H), 5.01 (q, J = 8.6Hz, 2H).

[0150] Step 3: Take 15c (45.6 mg, 0.2 mmol) and add it to a 50 mL single-necked flask equipped with a magnetic stir bar. Dissolve it in tetrahydrofuran (12 mL). Then, add HATU (35.9 mg, 0.26 mmol), int-1 (68.6 mg, 0.2 mmol), and DIEA (0.07 mL, 0.4 mmol) to the stirred solution. Place the mixture in an oil bath preheated to 50 °C and stir overnight. After the reaction is complete as shown by TLC, extract with water and ethyl acetate. Dry the organic phase by rotary evaporation and purify with silica gel to give compound 15 (35 mg, yield 31.5%). ESI-MS m / z 554.1 [M+H] + . 1H NMR(400MHz,CD3OD)δ:8.37(d,J=2.2Hz,1H),8.20(s,1H),7.91(d,J=9.0Hz, 1H),7.69(dd,J=9.0,2.2Hz,1H),6.90(s,1H),4.95(dd,J=17.2,8.6Hz,2H), 4.12-3.98(m,1H),3.90-3.73(m,1H),2.49-2.33(m,1H),2.20-2.09(m,1H), 2.08-2.01(m,1H),1.99-1.91(m,1H),1.71-1.58(m,1H),1.57-1.33(m,3H).

[0151] Biological evaluation

[0152] Test Example 1: The IC50 of the compound inhibiting G protein recruitment signaling in HEK293T cells transiently expressing the MrgprX2 receptor. 50 Measurement

[0153] The inhibitory effect of the compounds of the present invention on the recruitment signaling of Gαq protein in HEK293T cells by transiently transexpressed MRGPRX2 receptor in vitro was determined by the following method:

[0154] 1) Cell seeding: Take HEK293T cells in good logarithmic growth phase, and take 2 × 10⁶ cells. 6 Cells were cultured in a 10cm dish at 37°C and 5% CO2 for 12 hours.

[0155] 2) Cell transfection: Use a total of 3 μg of DNA, with a receptor to G protein plasmid mass ratio of 1:5. Add 5 times the mass of transfection reagent PEI, dissolve the DNA and PEI in Opti-MEM medium, and incubate at room temperature for 40 min. Drop the mixture into a prepared 10 cm dish and incubate at 37°C and 5% CO2 for 24 hours.

[0156] 3) Cell plating: Resuspend transfected cells in DMEM medium containing 1% dFBS and 1% PS, and evenly spread the cells from a 10cm disc into two 96-well plates. Incubate at 37°C and 5% CO2 for 6 hours.

[0157] 4) Drug administration: Dilute the compound with 1×HBSS containing 0.1% BSA: Place 6 μl of the compound at an initial concentration of 10 mM in a dilution plate, add 194 μl of the above buffer solution, and perform a tenfold serial dilution to achieve a final concentration of 10 mM added to the cells. -4 10 -5 10 -6 10 -7 10-8 10 -9 10 -10 10 -11 M. Add 30 μl of buffer containing the compound to each well of a 96-well plate and incubate at room temperature in the dark for 30 min. Then, add 5 μM Coelenterazine h dye to each well of a 96-well blank and incubate at room temperature in the dark for 5 min. Finally, add (R)-ZINC-3573 diluted with buffer to a final concentration of 3 μM and incubate at room temperature in the dark for 15 min.

[0158] 5) Detection: Use BERTHOLD Tristar3 to detect the values ​​of eYFP and RLUC, and use eYFP / RLUC as the final signal value.

[0159] 6) Calculation: The IC50 value was calculated using Graphpad Prism software based on the compound concentration and the corresponding signal value. Experimental results: See Table 1.

[0160] Table 1 shows the inhibitory IC50 values ​​of the compounds in this invention on Gαq protein recruitment signaling in HEK293T cells transiently expressing MrgprX2 receptor. 50 (nM)

[0161] Conclusion: The compounds of this invention have a significant inhibitory effect on the recruitment signal of Gαq protein in HEK293T cells that overexpress transiently transexpress the MrgprX2 receptor.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: Y is selected from N or CR a ; R a Selected from H, CN, or halogens; R 1 The radical is selected from H, halogen, CN, C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic group, C1-C3 alkoxy or 4-7 heterocyclic group, wherein the C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic group, C1-C3 alkoxy or 4-7 heterocyclic group may optionally be further surrounded by 1-4 R radicals. b Replaced; R b Each is independently selected from OH, halogen, C1-C3 alkyl, or C1-C3 alkoxy; n＝0～2； A is selected from phenyl or 5- to 10-membered heteroaryl groups, wherein the phenyl or 5- to 10-membered heteroaryl group may optionally be surrounded by 1 to 3 R groups. c What it replaced. R c Selected independently from halogen, CN, and OR d C1-C3 alkyl, C3-C7 cycloalkyl, or 4-7 heterocyclic group, wherein the C1-C3 alkyl, C3-C7 cycloalkyl, or 4-7 heterocyclic group may optionally be further surrounded by 1-4 R groups. e Replaced; R d The group is selected from H, C1-C3 alkyl, C3-7 cycloalkyl, or 4-C7 heterocyclic, phenyl, or 5-10 heteroaryl, wherein the C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic, phenyl, or 5-10 heteroaryl group may optionally be further surrounded by 1-4 R groups. e Replaced; R e The substituted group is selected from halogen, hydroxyl, cyano, C1-C3 alkyl, phenyl, 5-10 heteroaryl, C1-C3 alkoxy, C3-C7 cycloalkyloxy, 4-7 heterocyclic oxy, C3-C7 cycloalkyl or 4-7 heterocyclic, wherein the C1-C3 alkyl, phenyl, 5-10 heteroaryl, C1-C3 alkoxy, C3-C7 cycloalkyloxy, 4-7 heterocyclic oxy, C3-C7 cycloalkyl or 4-7 heterocyclic may optionally be further substituted with 1-3 halogen, hydroxyl or cyano groups.

2. A compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: Y, R 1 And A as defined in claim 1.

3. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein it is a compound of general formula (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in, Y, R 1 And A as defined in claim 1.

4. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is a compound of general formula (IV), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in, R 1 And A as defined in claim 1.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

6. A method for preparing a compound of general formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, the method comprising: Under alkaline conditions, compounds of general formula (IA) react with compounds of general formula (IB) to give compounds of general formula (I). in: X is a halogen; Y, R 1 The definitions of , n and A are as described in claim 1.

7. A pharmaceutical composition comprising an effective dose of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier, excipient or combination thereof.

8. The use of the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating allergic diseases, wherein the allergic diseases are urticaria, atopic dermatitis, or Crohn's disease.

9. A method for treating allergic diseases, characterized in that, This includes administering a therapeutically effective amount of the pharmaceutical composition as described in claim 7 to a patient in need.

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