WO2023143194A1

WO2023143194A1 - Ccr4 small molecule antagonist and use thereof

Info

Publication number: WO2023143194A1
Application number: PCT/CN2023/072403
Authority: WO
Inventors: 陈鑫德; 柳梦林; 宋云鹏; 郝欣
Original assignee: 瑞石生物医药有限公司
Priority date: 2022-01-25
Filing date: 2023-01-16
Publication date: 2023-08-03
Also published as: CN118475581A; TW202340197A

Abstract

The present invention relates to a CCR4 small molecule antagonist and the use thereof. Specifically, the present invention relates to a compound of formula (I) or isotope labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, and the use thereof in the preparation of a drug for treating or preventing CCR4-mediated diseases or disorders.

Description

A kind of CCR4 small molecule antagonist and its use

technical field

The invention belongs to the field of medicine, and in particular relates to a CCR4 small molecule antagonist and its application.

Background technique

CCR4 (C-C chemokine receptor type 4) belongs to G protein-coupled receptors and is a member of the chemokine receptor family. It is widely expressed on the surface of immune cells, especially Th2 cells and Treg cells. The main endogenous ligands of CCR4 include CCL22 (also known as macrophage-derived chemokine, MDC) and CCL17 (also known as thymus activation-regulated chemokine, TARC). The combination of CCR4 and endogenous ligand can activate the coupled G protein, and then a cascade of cell activation effects occurs. Through a series of information transmission, chemotactic target cells migrate to a specific location and exert biological effects.

Studies have confirmed that CCR4 is closely related to the occurrence and development of immune-related diseases such as atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus and rheumatoid arthritis. At the same time, CCR4 plays a regulatory role in the tumor microenvironment, inducing tumor immune escape and promoting tumor cell metastasis. Therefore, CCR4 has become an important drug target for the treatment of immune-related diseases and tumor immunotherapy, and the development of CCR4 small molecule antagonists will provide new options for the treatment of the above diseases.

So far, Mogamulizumab, a CCR4 monoclonal antibody, has been approved for marketing for the treatment of relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma, but no CCR4 small molecule antagonist has been approved for marketing. WO2018/022992 involves FLX475, which is currently the fastest-growing small-molecule antagonist of CCR4 in clinical practice. RPT193 is another small-molecule antagonist of CCR4 in clinical research. In addition, most small-molecule antagonists of CCR4 are in the stage of biological activity testing. It can be seen that the development of small molecule antagonists of CCR4 has a good application prospect.

Contents of the invention

The purpose of the present invention is to provide a new type of CCR4 small molecule antagonist, this type of compound has good activity in inhibiting CCR4, and exhibits excellent effects and functions.

In a first aspect, the present invention provides a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salts, or their prodrugs, or their metabolites,

in,

X ¹ and X ² are each independently selected from C or N;

X ³ , X ⁴ and X ⁵ are each independently selected from CR ^b or N;

Each R ¹ is independently selected from H, halogen, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₄ cycloalkyl or cyano;

R ² is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₄ cycloalkyl;

R ³ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₄ cycloalkyl;

^R4 is selected from

Y is selected from _CH2 or O;

R ^a is selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl or cyano, wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclic , 5-6 membered heteroaryl or phenyl are each independently optionally selected from one or more groups selected from halogen, hydroxyl, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy replaced by

Each R ^b is independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl or cyano, wherein the C ₁ -C ₃ alk radical, C ₁ -C ₃ alkoxy or C ₃ -C ₆ cycloalkyl each independently optionally selected from halogen, hydroxy, amino, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ One or more groups of alkoxy are substituted;

Each R ^c is independently selected from H, halogen, C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl, wherein each of the C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl is independently optionally substituted by one or more groups selected from halogen, hydroxyl, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

Each R ^d is independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl or cyano, wherein the C ₁ -C ₃ alk radical, C ₁ -C ₃ alkoxy or C ₃ -C ₆ cycloalkyl each independently optionally selected from halogen, hydroxy, amino, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ One or more groups of alkoxy are substituted;

each Re ^is independently -LR ^f ;

Each R ^f is independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered Heterocyclyl, R ^g C(O)NH-, R ^g NHC(O)-, R ^g OC(O)NH-, R ^g S(O) ₂ NH-, R ^g NHS(O) ₂ -, R g ^g S(O) ₂ -, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amino, -(CH ₂ ) _n -cyano, -(CH ₂ ) _n -carboxy or 2-oxa- Spiro[3,3]heptyl, wherein the C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amino, -(CH ₂ ) _n -cyano or -(CH ₂ ) _n -carboxyl are each independently optionally selected from halogen, hydroxyl, amino, cyano , C ₁ -C ₃ alkyl or one or more groups of C ₁ -C ₃ alkoxy;

Each R ^g is independently selected from C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or 3-6 membered heterocyclyl;

Each L is independently selected from a chemical bond, a 4-7 membered heterocyclic group, a C ₁ -C ₃ alkylene group or a C ₃ -C ₆ cycloalkylene group, wherein the 4-7 membered heterocyclic group, C ₁ -C ₃ alkylene or C ₃ -C ₆ cycloalkylene are each independently optionally selected Substituted by one or more groups from halogen, hydroxyl, amino, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

Z ¹ is any integer from 0 to 3;

Z ² is any integer from 0 to 3;

Z ³ is any integer from 0 to 4;

Z ⁴ is any integer from 0 to 2; and

Each n is independently any integer from 0 to 3.

In some embodiments of the present invention, in the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite,

One of ^X1 and ^X2 is N, the other is C,

At least one of X ³ , X ⁴ and X ⁵ is N.

selected from

In some embodiments of the present invention, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite is a compound of formula (II) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical acceptable salts, or prodrugs thereof, or metabolites thereof,

Wherein, R ¹ -R ³ , X ¹ -X ⁵ , Y, R ^a , R ^c , R ^d , R ^e , Z ¹ , Z ² , Z ³ and Z ⁴ are as defined in formula (I);

In particular,

selected from and / or

selected from R ^c , R ^d , ^Re , Z ² and Z ³ are as defined in formula (I);

More particularly, it is formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula ( II-7) or formula (II-8) compound or its isotope labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrugs, or its metabolites,

Wherein, R ¹ -R ³ , R ^a , R ^d , R ^e , Z ¹ and Z ³ are as defined in formula (I).

In some embodiments of the present invention, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite is a compound of formula (III) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical acceptable salts, or prodrugs thereof, or metabolites thereof,

Wherein, R ¹ -R ³ , R ^a , R ^e and Z ¹ are as defined in formula (I).

In some embodiments of the present invention, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite is a compound of formula (IV) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical acceptable salts, or prodrugs thereof, or metabolites thereof,

Wherein, R ¹ -R ³ , R ^a , R ^e and Z ¹ are as defined in formula (I).

In some embodiments of the present invention, in the formula (I), (II), (III), (IV) compound or its isotope labeled compound, or its optical isomer, geometric isomer, tautomer or Isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof,

each Re ^is independently -LR ^f ;

Each R ^f is independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₃ -C ₆ cycloalkyl, 4-7 membered hetero Cyclo, R ^g C(O)NH-, R ^g NHC(O)-, R ^g OC(O)NH-, R ^g S(O) ₂ NH-, R ^g NHS(O) ₂ -, R ^g S(O) ₂ -, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amino, -(CH ₂ ) _n -cyano, -(CH ₂ ) _n -carboxy or 2-oxa-spiro [3,3] Heptyl, wherein the C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amino, -(CH ₂ ) _n -cyano or -(CH ₂ ) _n -carboxyl are each independently optionally selected from hydroxyl or C ₁ -C ₃ alkyl Substituted by one or more groups; preferably each R ^f is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl , hydroxyl, carboxyl, methoxy, oxetanyl, azetidinyl, 1,1-dioxothietanyl, morpholinyl, pyrrolidinyl, piperidinyl, tetra Hydropyranyl, acetamido, methanesulfonyl, CH ₃ S(O) ₂ NH- or 2-oxa-spiro[3,3]heptyl;

R ^g is selected from C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl or 3-4 membered heterocyclic group, preferably selected from methyl, ethyl, cyclopropyl, cyclobutanyl or oxa cyclobutanyl;

each n is independently any integer from 0 to 3, and

L is selected from the group consisting of chemical bond, methylene optionally substituted by methyl or ethyl, ethylene, propylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, azepine Cyclobutane, pyrrolidinylene or piperidinylene;

In particular,

Each Re ^is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,

Each R ¹ is independently selected from H, halogen, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₁ -C ₃ alkoxy, preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or methanesulfonyl; and/or

R ^is selected from H or C ₁ -C ₃ alkyl, preferably from H or methyl; and/or

R ³ is selected from H or C ₁ -C ₃ alkyl, preferably from H or methyl.

Each R ^a is independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₄ cycloalkyl or cyano, wherein The C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or C ₃ -C ₄ cycloalkyl are each independently optionally replaced by halogen, hydroxyl, cyano, C ₁ -C ₃ alkyl or C ₁ - _C3alkoxy substitution, R ^is preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, Methoxy, ethoxy, hydroxymethyl, 1,1-dimethylhydroxymethyl, cyano, or methoxymethylene; and/or

Each R ^b is independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl or cyano, wherein the C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl Each is independently optionally substituted by halogen, hydroxyl, amino, cyano or C ₁ -C ₃ alkyl, R ^b is preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl group, difluoromethyl, trifluoromethyl, trifluoroethyl or cyano; and/or

Each R ^c is independently selected from H, halogen or C ₁ -C ₃ alkyl, preferably selected from H, fluorine, chlorine, methyl or ethyl; and/or

Each R ^d is independently selected from H, halogen, C ₁ -C ₃ alkyl or cyano, preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or cyano .

Z ¹ is 2; and/or

^Z2 is 0 or 1; and/or

^Z3 is 0 or 1; and/or

Z ⁴ is 1; and/or

Each n is independently 0 or 1.

Typical compounds of formula (I), (II), (III), (IV) of the present invention or their isotope-labeled compounds, or their optical isomers, geometric isomers, tautomers or isomer mixtures, Or its pharmaceutically acceptable salt, or its prodrug, or its metabolites include but not limited to:

For the sake of brevity, the "compound of formula (I), (II), (III), (IV)" or "compound of the present invention" described hereinafter may also cover formula (I), (II), (III), (IV) Any isotope-labeled compound of the compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its Metabolites.

The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can have an R configuration or an S configuration, and the various isomers thus constituted are optical isomers. Construct. Optical isomers include all diastereoisomers, enantiomers, mesoforms, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatographic columns or by chiral synthesis.

The term "geometric isomer" means that when a double bond exists in the compound, the compound may exist as a cis-isomer, a trans-isomer, an E-isomer and a Z-isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

The term "tautomer" refers to isomers that result from the rapid movement of an atom in a molecule between two positions. Those skilled in the art can understand that tautomers can transform into each other, and may reach an equilibrium state and coexist in a certain state.

Unless otherwise specified, references herein to "compounds of formula (I)" or "compounds of the present invention" also encompass isotopically labeled compounds in which any atom in the compound is replaced by its isotopic atom. The present invention includes all pharmaceutically acceptable isotope-labeled compounds of compounds of formula (I) in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number as atoms normally found in nature. replace.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H(D) and ³ H(T), isotopes of carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, isotopes of chlorine, such as ³⁶ Cl, isotopes of fluorine such as ¹⁸ F, isotopes of iodine such as ¹²³ I and ¹²⁵ I, isotopes of nitrogen such as ¹³ N and ¹⁵ N, isotopes of oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, and of sulfur Isotopes such ^as35S .

Isotope-labeled compounds of formula (I), (II), (III), (IV) can generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotope-labeled reagent instead of a previously used non-labeled reagent The preparation was carried out as described in the Examples and Preparations appended hereto.

Formula (I), (II), (III), (IV) compound can exist in the form of pharmaceutically acceptable salt, for example, the acid addition of formula (I), (II), (III), (IV) compound Salt formation and/or base addition salts. As used herein, unless otherwise indicated, "pharmaceutically acceptable salt" includes acid addition salts or base addition salts that may occur in compounds of formula (I), (II), (III), (IV).

The pharmaceutically acceptable salts of the compound of formula (I), (II), (III), (IV) include its acid plus Salt and base addition salt. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate , camphorsulfonate, citrate, cyclamate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, six Fluorophosphate, 2-(4-Hydroxybenzyl)benzoate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, 2-Isethionate, Lactate , malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotine, nitrate, orotate , Oxalate, Cetate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Pyroglutamate, Gluconate, Stearate, Salicylate, Tannin, Tartrate , tosylate and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Half-salts of acids and bases, such as the hemisulfate and hemicalcium salts, may also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds of formula (I), (II), (III), (IV) are included within the scope of the present invention whether they exist in solvated or unsolvated form.

Certain compounds of the present invention may exist in different crystalline or amorphous forms, and no matter in which form they exist, the compounds of formula (I), (II), (III) and (IV) are included within the scope of the present invention.

To avoid ambiguity, definitions of terms used herein are given below. Unless otherwise specified, the meanings of the terms used herein are as follows.

The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to a human. Preferably, the term refers to the use in mammals, preferably humans, certified by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA), etc.

"Prodrug" refers to a derivative that is converted into the compound of the present invention by reacting with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc. catalyzed by enzymes.

"Metabolite" refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.

The term "hydroxyl" refers to -OH; the term "amino" refers to _-NH2 ; the term "nitro" refers to _-NO2 ; and the term "cyano" refers to -CN; the term "carboxy" refers to -COOH.

The term "acyl" refers to -C(=O)-; the term "amido" refers to -C(=O) _-NH2 ; the term "sulfonyl" refers to -S(=O) _2- ; and the term ""Sulfonamido" means -S(=O) ₂ _-NH2 .

As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3, even more effectively 1 or 2) hydrogen atoms in a group are independently replaced by the corresponding number of substituents are substituted.

When used herein, the term "independently" means that when the number of substituents is more than one, the These substituents may be the same or different.

As used herein, the term "optional" or "optionally" means that the event it describes can or cannot occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, an alkyl group has 1-8, or 1-6, or 1-3 carbon atoms. For example, the term "C _1-8 alkyl" refers to a straight-chain or branched chain radical having 1-8 carbon atoms, and the term "C _1-6 alkyl" refers to a straight-chain or branched chain having 1-6 carbon atoms. A branched chain radical, the term "C _1-3 alkyl" refers to a straight chain or branched chain radical having 1 to 3 carbon atoms. The term "C _1-8 alkyl" includes within its definition the terms "C _1-6 alkyl", "C ₁ -C ₃ alkyl" and "C ₁ -C ₄ alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, iso Pentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3- Dimethylbutyl, hexyl, etc. Alkyl groups may optionally be substituted with one or more (eg, 1 to 5, preferably 1 to 3, even more effectively 1 or 2) suitable substituents.

As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom) . For example, the term "C _1- C ₆ haloalkyl" refers to a C _1- C ₆ alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group has one or more halogen substituents replaced by halogen atoms). As another example, the term "C _1- C ₄ haloalkyl" refers to a C _1- C ₄ alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen of the alkyl group atoms are all replaced by halogen atoms); the term "C _1- C ₃ haloalkyl" refers to a C _1- C ₃ alkyl group (up to perhaloalkyl, i.e., alkyl each hydrogen atom of the group is replaced by a halogen atom); and the term "C _1- C ₂ haloalkyl" refers to a C _1- C ₂ alkyl group having one or more halogen substituents (i.e., methyl or ethyl) (up to perhaloalkyl, ie, each hydrogen atom of the alkyl group is replaced by a halogen atom). As yet another example, the term "C haloalkyl" refers to a methyl group having 1, 2 or 3 halo substituents _. Examples of haloalkyl groups include: _CF3 , _C2F5 , _CHF2 , _CH2F _, _CH2CF3 _, _CH2Cl , and the like.

As used herein, the term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above. The alkylene group is preferably an alkylene group having 1-6 carbon atoms (i.e. C _1- C ₆ alkylene group), more preferably an alkylene group having 1-3 carbon atoms (i.e. C _1- C ₃ alkylene group alkyl). Examples of _alkylene groups include, but are not limited to _-CH2- , -CH( _CH3 ₎ -, -C( _CH3 ) _2- , _-CH2CH2- , -CH( _CH2CH3 )-, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, etc.

As used herein, the term "n-membered cycloalkyl" refers to an all-carbocyclic ring system having n carbon atoms. The term "C ₃ -C ₆ cycloalkyl" refers to a fully carbocyclic ring system having 3-6 carbon atoms, and "C ₃ -C ₄ cycloalkyl" refers to a fully carbocyclic ring system having 3-4 carbon atoms . Examples of C ₃ -C ₆ cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl. In addition, cycloalkyl groups may be optionally substituted with one or more suitable substituents.

The term "cycloalkylene" refers to a divalent cycloalkyl group, wherein cycloalkyl is as defined above.

As used herein, the term "n-membered heterocyclyl" refers to a heterocycloalkyl group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms selected from O, S, S(O) ₂ and N. For example, 4-7 membered heterocyclic groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, Piperidine, morpholine, piperazine, oxepane, thiepane, azepane, 1,1-dioxothietane. In addition, heterocyclyl may be optionally substituted with one or more suitable substituents.

The term "heterocyclylene" refers to a divalent heterocyclyl group, wherein heterocyclyl is as defined above.

As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (n-m) heteroatoms forming an aromatic ring selected from O, S and N. For example, 5-6 membered heteroaryl groups include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine. In addition, heteroaryl groups may be optionally substituted with one or more suitable substituents.

Herein, the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent enumeration of all integers within the range one by one, and the range is only used as a simplified representation. For example: "1-4 substituents" means 1, 2, 3 or 4 substituents; "3-8 ring atoms" means 3, 4, 5, 6, 7 or 8 ring atoms . Therefore, the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also cover any sub-range thereof, and each sub-range is also deemed to be disclosed herein.

The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds in the specific examples of the present invention, and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain the synthetic methods of other compounds.

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV) or its isotope-labeled compound, or its optical isomers, geometric isomers isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers can be organic or inorganic inert carrier materials, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, Mannitol, cellulose, cellulose derivatives, sodium saccharin, glucose, sucrose, magnesium carbonate, saline, glycerin, ethanol, etc. In addition, the pharmaceutical composition may also contain other pharmaceutical additives, such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like.

The dosage form of the pharmaceutical composition of the present invention may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc. The pharmaceutical composition of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various particle delivery systems.

In some embodiments, the dosage form of the pharmaceutical composition is selected from tablet, granule, powder, syrup, inhalation and injection.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (for example, sodium citrate or dicalcium phosphate), which may also include: (a) fillers or mixing agents (for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) Moisturizers (eg, glycerol); (d) disintegrants (eg, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solutions Blocking agents (e.g., paraffin); (f) absorption enhancers (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., cetyl alcohol and glyceryl monostearate); (h) adsorbents (eg, kaolin and bentonite) and (i) lubricants (eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

Formulations suitable for parenteral administration, such as injections, may include aqueous and nonaqueous isotonic sterile solutions suitable for injection, as well as aqueous and nonaqueous sterile suspensions. The parenteral formulations provided herein are optionally contained in unit-dose or multi-dose sealed containers, such as ampoules, and can be stored in freeze-dried (lyophilized) containers that require only the addition of a sterile liquid carrier (such as water for injection) immediately before use. ) conditions. Examples of suitable diluents for reconstitution of the pharmaceutical composition (eg, prior to injection) include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, Ringer's solution, saline, sterile water, Deionized water and combinations thereof.

Sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Inhalants may contain excipients such as lactose, or aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions as nasal drops or spray , or in gel form.

The content of the compound of the present invention in its pharmaceutical composition can be adjusted according to actual needs (such as dosage form, administration method, administration object, etc.), such as 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight , 10-80% by weight, etc.

Specifically, 0.01-10 g (eg, 0.05 g, 0.1 g, 0.5 g, 1 g or 5 g, etc.) of the compound of the present invention may be included in the pharmaceutical composition of the present invention.

In a third aspect, the present invention relates to compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof Use of a mixture of conformers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a medicament for treating or preventing a disease or condition mediated by CCR4 as a CCR4 antagonist. Compounds of formula (I), (II), (III), (IV) or their isotope-labeled compounds, or their optical isomers, geometric isomers, Tautomers or mixtures of isomers, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof may be used to treat or prevent diseases mediated by CCR4 in a subject in need thereof or illness.

The term "subject" as used herein refers to any human or non-human organism that could potentially benefit from treatment with a compound of formula (I), (II), (III), (IV). Exemplary subjects include humans or mammals of any age. Preferably, the subject is a human.

The term "treatment" as used herein includes treating a disease or condition in a mammal, especially a human and includes: (a) inhibiting an infection, disease or condition, i.e. arresting or delaying the development of an infection, disease or condition; (b) alleviating an infection, disease or condition; A disease or condition, ie causing regression of the disease or condition, and/or (c) cure of the infection, disease or condition.

As used herein, the term "prevention" includes prophylactic therapy in mammals, especially humans, aimed at reducing the likelihood of an infection, disease or condition occurring. Patients may be selected for prophylactic therapy based on an increased risk of infection or having a disease or condition compared to the general population as a factor. "Preventing" can include treating a subject who has not yet exhibited an infection or clinical condition, and preventing a second occurrence of the same or similar infection or clinical condition.

The inventors found that the compounds of the present invention can inhibit CCR4-mediated cell migration. Therefore, the compounds of the present invention can be used in the prevention or treatment of diseases or conditions mediated by CCR4.

In some embodiments, the disease or condition mediated by CCR4 may be selected from one or more of atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus and rheumatoid arthritis. Various immune-related diseases. In other embodiments, the disease or condition mediated by CCR4 may be cancer. The cancer is preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cell carcinoma, testicular cancer, Cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glia tumors, ependymomas, neuroblastomas, ganglioneuromas, medulloblastomas, pineal cell tumors, meningiomas, neurofibromas, schwannomas, and Wilms tumors.

In a fourth aspect, the present invention provides a method of treating or preventing a disease or condition mediated by CCR4, the method comprising administering to a subject in need a therapeutically effective amount of formula (I), (II), (III), (IV) compound or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its precursor drugs, or their metabolites.

In a fifth aspect, the present invention relates to compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof A mixture of conformers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein it is used for preventing or treating a disease or condition mediated by CCR4.

In some embodiments, the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, buccally, ocularly, via the lungs, via the respiratory tract, vaginally, rectally, intraperitoneally, intralesionally, Administer around the lesion and other routes.

A "therapeutically effective amount" refers to an amount of a compound of the present invention effective to treat or prevent a disease or condition mediated by CCR4 when administered alone or in combination.

The specific dosage administered will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician in determining the individual regimen and dosage level most suitable for a particular patient. For example, the daily dose of the compound of the invention may specifically be 0.001-150 mg/kg body weight (eg 0.1 mg/kg body weight, 1 mg/kg body weight, 10 mg/kg body weight or 100 mg/kg body weight etc.).

The specific administration frequency can be determined by those skilled in the art, for example, once a day, once a day, once a day, once a day, once a day, once a day, once a day, once a day, twice a day, 1 day 3 times etc.

Those skilled in the art can understand that the definitions and preferences described in one aspect of the present invention are also applicable to other aspects. Those skilled in the art can understand that the embodiments of various aspects of the present invention can be combined in various ways without departing from the subject and idea of the present invention, and these combinations are also included in the scope of the present invention.

Description of drawings

Figure 1 shows the inhibitory effect of test compounds on FITC-induced ear swelling in an animal model.

Figure 2 shows the effect of test compounds on body weight in FITC-induced animal models.

Figure 3 shows the inhibitory effect of test compounds on OXA-induced ear swelling in animal models.

Detailed ways

The compounds of formula (I) of the present invention can be synthesized by various methods familiar to those skilled in the art of organic synthesis. Some exemplary synthetic methods of compounds of formula (I) are given in the following specific examples, and these methods are well known in the field of synthetic chemistry. Apparently, with reference to the exemplary schemes in this patent, those skilled in the art can easily design the synthetic routes of other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.

The present invention is further described below in conjunction with examples; but these examples do not limit the scope of the present invention. Unless otherwise stated, all reactants used in each example were obtained from commercial sources; the instruments and equipment used in the synthesis experiment and product analysis and detection were conventional instruments and equipment commonly used in organic synthesis.

Intermediate A: (R)-1-(2,4-dichlorophenyl)ethan-1-amine

At room temperature, dissolve S-mandelic acid (56.00g, 368.29mmol) in a mixed solvent of isopropanol (420mL) and ethanol (280mL), raise the temperature to 60°C, and slowly add compound A-1 (70.00g, 368.29 mmol), the reaction mixture was stirred at 60°C for 30 minutes, then at room temperature for 24 hours. A large amount of white solid precipitated, filtered, the filter cake was washed with acetone (105mL), dried in vacuo, and isopropanol (315mL) and ethanol (210mL) were added in a mixed solvent, stirred at 60°C for 30 minutes, cooled to room temperature, and stirred for 12 hours. A large amount of white solid was precipitated, filtered, the filter cake was washed with acetone (70 mL), and dried in vacuo to obtain compound A-2. Compound A-2 (45.00 g, 131.49 mmol) was dissolved in dichloromethane (400 mL) and 4 mol/L sodium hydroxide aqueous solution (120 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After static liquid separation, the organic phase was washed with water (300 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate A. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.71(d, J=8.8Hz, 1H), 7.48(d, J=2.4Hz, 1H), 7.41(dd, J=8.4, 2.0Hz, 1H) , 4.35-4.24 (m, 1H), 1.92 (s, 2H), 1.20 (d, J=6.4Hz, 3H).

Intermediate B: tert-butyl (R)-3-(piperidin-3-yl)azetidine-1-carboxylate

1) Synthesis of compound B-2

At room temperature, compound B-1 (25.00g, 158.95mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (25.00g, 88.31mmol) were dissolved in isopropanol (400mL), and added Nickel iodide (2.76g, 8.83mmol), (1R,2R)-2-aminocyclohexanol hydrochloride (1.34g, 8.83mmol) and sodium bis(trimethylsilyl)amide (176.60mL, 176.61mmol , 1mol/L tetrahydrofuran solution), the reaction mixture was stirred at 80°C for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, slowly poured into ice water (250 mL) to quench, and extracted with methyl tert-butyl ether (250 mL×4). The organic phases were combined, washed with saturated brine (150mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound B-2. MS-ESI: m/z 269.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.30 (d, J = 2.4Hz, 1H), 7.71 (dd, J = 8.0, 2.4Hz, 1H), 7.35 (d, J = 8.4Hz, 1H), 4.38 (t, J=8.8Hz, 2H), 3.96-3.88(m, 2H), 3.78-3.69(m, 1H), 1.47(s, 9H).

2) Synthesis of Compound B-3

At room temperature, compound B-2 (26.00g, 96.75mmol) and (S)-4-isopropyloxazolidin-2-one (24.99g, 193.50mmol) were dissolved in anhydrous toluene (400mL), followed by Add tris(dibenzylideneacetone)dipalladium (4.43g, 4.84mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (2.31g, 4.84mmol) and cesium carbonate (31.52 g, 96.75mmol), replaced with nitrogen, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with methyl tert-butyl ether (500 mL), the organic phase was washed with saturated brine (500 mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue After separation by silica gel column chromatography (petroleum ether/ethyl acetate=1/1), the resulting crude product was slurried with petroleum ether (200 mL), filtered, and the filter cake was washed with petroleum ether (30 mL) and concentrated under reduced pressure to obtain compound B -3. ¹ H NMR (400MHz, CD ₃ OD) δ8.29 (d, J = 2.0Hz, 1H), 8.11 (d, J = 8.8Hz, 1H), 7.88 (dd, J = 8.4, 2.4Hz, 1H), 4.92-4.85(m,1H),4.47-4.41(m,1H),4.40-4.33(m,3H),3.98-3.90(m,2H),3.89-3.81(m,1H),2.51-2.40(m , 1H), 1.47 (s, 9H), 0.94 (d, J=7.2Hz, 3H), 0.82 (d, J=6.8Hz, 3H).

3) Synthesis of Intermediate B

At room temperature, compound B-3 (10.00g, 27.67mmol) was dissolved in anhydrous acetic acid (200mL), under the protection of nitrogen, slowly added platinum dioxide (1.00g, 4.40mmol), hydrogen replacement, the reaction mixture in hydrogen (15Psi ) atmosphere at room temperature for 15 hours. The reaction solution was filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (ethyl acetate/methanol=0/1) to obtain a crude product. The crude product was dissolved in dichloromethane (50 mL), and 1 mol/L aqueous sodium hydroxide solution (80 mL) was added to adjust the pH to 13. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude intermediate B. At room temperature, the crude intermediate B was dissolved in methyl tert-butyl ether (1000 mL), and S-mandelic acid (13.61 g, 89.45 mmol) was added in portions under reflux, and the reaction mixture was stirred at room temperature for 16 hours. A large amount of white solid precipitated, filtered, and the filter cake was washed with methyl tert-butyl ether (400 mL), and dissolved in dichloromethane (500 mL) and 1 mol/L sodium hydroxide aqueous solution (800 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. At room temperature, the crude product was dissolved in methyl tert-butyl ether (500 mL), and S-mandelic acid (8.23 g, 54.09 mmol) was added in portions under reflux, and the reaction mixture was reacted at room temperature for 16 hours. A large amount of white solid precipitated out, and the reaction mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (300 mL), and dissolved in dichloromethane (500 mL) and 1 mol/L sodium hydroxide aqueous solution (800 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate B. ¹ H NMR (400MHz, CD ₃ OD) δ4.00-3.88(m, 2H), 3.70-3.60(m, 2H), 3.00-2.89(m, 2H), 2.50(td, J＝12.0, 2.8Hz, 1H),2.35-2.23(m,1H),2.15(dd,J＝12.0,10.4Hz,1H),1.85-1.75(m,1H),1.72-1.56(m,2H),1.55-1.45(m, 1H), 1.43(s, 9H), 1.07-0.93(m, 1H).

Intermediate C: (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol hydrochloride

1) Synthesis of Compound C-1

At room temperature, intermediate B (10.00g, 36.13mmol) and 2-iodoethanol (12.43g, 72.25mmol) were dissolved in acetonitrile (100mL), potassium carbonate (14.98g, 108.38mmol) was slowly added, and the reaction solution was stirred at 80°C 16 hours. After the reaction solution was cooled to room temperature, dichloromethane (200 mL) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (ethyl acetate/methanol=0/1) to obtain a crude product, which was then purified with two Chloromethane (150 mL) was dissolved, filtered, and the filtrate was concentrated under reduced pressure to obtain compound C-1. ¹ H NMR (400MHz, CD ₃ OD) δ4.01-3.85 (m, 2H), 3.70 (t, J = 6.0Hz, 2H), 3.67-3.57 (m, 2H), 3.10-2.94 (m, 2H) , 2.66 (t, J=6.0Hz, 2H), 2.37-2.16 (m, 2H), 1.95-1.52 (m, 5H), 1.39 (s, 9H), 0.98-0.81 (m, 1H).

2) Synthesis of Intermediate C

At room temperature, compound C-1 (3.00g, 9.49mmol) was dissolved in dioxane (25mL), and 4mol/L hydrochloric acid dioxane solution (25mL) was slowly added, and the reaction mixture was stirred at room temperature for 4 hours . The reaction is complete Afterwards, the reaction solution was concentrated under reduced pressure to obtain intermediate C. The crude product was directly used in the next reaction without further purification. MS-ESI: m/z 185.1 [M+H] ⁺ .

Intermediate D: (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl Ester hydrochloride

1) Synthesis of compound D-2

At room temperature, compound D-1 (5.00g, 35.17mmol) was dissolved in a mixture solvent of tetrahydrofuran (30mL) and water (30mL), then lithium hydroxide (4.43g, 105.52mmol) was added, and the reaction solution was stirred at 25°C 15 hours. Adjust the pH of the reaction solution to ~4 with 1mol/L hydrochloric acid aqueous solution, and extract with dichloromethane (50mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound D-2. The crude product was directly used in the next reaction without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.57 (s, 1H), 3.42-3.37 (m, 2H), 2.99-2.92 (m, 2H), 1.47 (s, 3H).

2) Synthesis of Compound D-3

At room temperature, intermediate B (3.00g, 12.48mmol), compound D-2 (1.76g, 13.73mmol) and sodium triacetoxyborohydride (3.95g, 18.72mmol) were dissolved in 1,2-dichloroethyl Acetic acid (0.70 mL, 12.48 mmol) was slowly added dropwise to the reaction solution at -5°C, and stirred at 20°C for 15 hours after the addition was complete. Compound D-2 (800mg, 6.24mmol) and sodium triacetoxyborohydride (1316mg, 6.24mmol) were added, the reaction solution was stirred at 20°C for 3 hours, and compound D-2 (800mg, 6.24mmol) and three Sodium acetoxyborohydride (1316 mg, 6.24 mmol). After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain compound D-3. ¹ H NMR (400MHz, CD ₃ OD) δ4.04-3.95(m,2H),3.77-3.67(m,2H),3.24-3.16(m,1H),2.77-2.68(m,2H),2.61- 2.53(m,1H),2.43-2.36(m,1H),2.29(t,J＝12.0Hz,1H),2.13-2.02(m,2H),1.96-1.81(m,4H),1.79-1.68( m, 1H), 1.43(s, 9H), 1.42-1.40(m, 1H), 1.39(s, 3H), 1.17-1.05(m, 1H).

3) Synthesis of Compound D-4

At room temperature, compound D-3 (2.60g, 7.38mmol) was dissolved in a mixed solvent of dichloromethane (30mL) and methanol (3mL), and trimethylsilyldiazomethane (14.70mL , 29.51 mmol), followed by stirring at 20°C for 2 hours. After completion of the reaction, acetic acid was slowly added dropwise to the reaction solution until the color of the reaction solution changed from yellow to colorless and no longer bubbled, diluted with water (30mL), extracted with dichloromethane (30mL), saturated aqueous sodium chloride ( 25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound D-4. ¹ H NMR (400MHz, CD ₃ OD) δ4.00-3.89(m,2H),3.70(s,3H),3.68-3.61(m,2H),2.87-2.79(m,1H),2.77-2.67( m,2H),2.60-2.51(m,2H),2.36-2.25(m,1H),1.89-1.80(m,2H),1.79-1.64(m,4H),1.61-1.49(m,1H), 1.43 (s, 9H), 1.39 (d, J=10.8Hz, 1H), 1.36 (s, 3H), 0.93-0.78 (m, 1H).

4) Synthesis of Intermediate D

At room temperature, compound D-4 (1.75g, 4.78mmol) was dissolved in 1,4-dioxane (30mL), and 4mol/L dioxane hydrochloride solution (6.00mL, 24.00mmol) was slowly added to react The solution was stirred at 20°C for 15 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate D. The crude product was directly used in the next reaction without further purification.

Intermediate E: Allyl (R)-3-(azetidin-3-yl)piperidine-1-carboxylate hydrochloride

1) Synthesis of intermediate E-1

Intermediate B (500mg, 2.08mmol) was dissolved in dichloromethane (10mL) at room temperature, sodium carbonate (330mg, 3.12mmol) and allyl chloroformate (376mg, 3.12mmol) were added, and the reaction mixture was stirred at 25°C 16 hours. Dilute with water (50 mL), extract with ethyl acetate (50 mL×3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) , to obtain compound E-1. ¹ H NMR (400MHz, CDCl ₃ ) δ6.01-5.89(m, 1H), 5.30(d, J=17.2Hz, 1H), 5.22(d, J=10.4Hz, 1H), 4.59(d, J= 5.2Hz, 2H), 4.02-3.91(m, 3H), 3.88-3.70(m, 1H), 3.65(dd, J=8.4, 5.6Hz, 1H), 2.98-2.85(m, 1H), 2.70-2.41 (m,1H),2.35-2.23(m,1H),1.85-1.75(m,1H),1.73-1.63(m,2H),1.62-1.57(m,1H),1.55-1.47(m,1H) ,1.44(s,9H),1.14-1.02(m,1H).

2) Synthesis of Intermediate E

Compound E-1 (650 mg, 2.00 mmol) was dissolved in dioxane hydrochloride solution (4 mL, 4 mol/L) at room temperature, and the reaction solution was stirred at 25° C. for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain intermediate E. The crude product was directly used in the next reaction without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ9.80(s, 1H), 9.56(s, 1H), 6.01-5.87(m, 1H), 5.29(dd, J=17.2, 1.2Hz, 1H), 5.23( dd,J＝10.0,0.8Hz,1H),4.63-4.52(m,2H),4.17-4.03(m,2H),3.95-3.85(m,2H),3.84-3.72(m,2H),3.08- 2.98(m,1H),2.86-2.73(m,1H),2.72-2.61(m,1H),1.96-1.83(m,1H),1.81-1.71(m,1H),1.70-1.60(m,1H ), 1.54-1.42(m,1H), 1.17-1.05(m,1H).

Intermediate F: Allyl (R)-3-(azetidin-3-yl)piperidine-1-carboxylate hydrochloride

1) Synthesis of Compound F-1

At room temperature, sequentially add compound C-1 (3.00 g, 9.49 mmol, 90% purity) and tert-butyldiphenylchlorosilane (3.70 mL, 14.24 mmol) into dichloromethane (20 mL) and N,N-dimethyl After stirring evenly, imidazole (2.59 g, 37.98 mmol) was added, and the reaction solution was stirred at 60° C. for 16 hours. The reaction solution was diluted with ethyl acetate (150 mL), washed with water (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound F-1. MS-ESI: m/z 523.3 [M+H] ⁺ .

2) Synthesis of Intermediate F

Under ice-cooling, compound F-1 (3200 mg, 5.20 mmol, 85% purity) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (3.00 mL) was slowly added, and the reaction solution was reacted at room temperature for 16 hours. The reaction solution was diluted with methanol (30 mL), and a basic resin was added to adjust the pH of the solution to ~8, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (ethyl acetate/methanol=0/1) to obtain Intermediate F. MS-ESI: m/z 423.2 [M+H] ⁺ .

Example 1: 2-(R)-3-(1-(4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrazolo[1,5-a] [1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (1)

1) Synthesis of compound 1-2

At room temperature, compound 1-1 (1.00g, 5.49mmol) was dissolved in phosphorus oxychloride (10.00mL), and N,N-dimethylaniline (0.33g, 2.76mmol) was slowly added dropwise. °C and stirred for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, the resulting residue was diluted with water (20 mL), extracted with toluene (30 mL×2), the organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain compound 1-2. ¹ H NMR (400MHz, CDCl ₃ ) δ8.16 (d, J=2.0Hz, 1H), 6.52 (d, J=2.0Hz, 1H), 2.62 (s, 3H).

2) Synthesis of compound 1-3

At room temperature, compound 1-2 (600mg, 2.99mmol), intermediate A (568mg, 2.99mmol) and N,N-diisopropylethylamine (773mg, 5.98mmol) were dissolved in acetonitrile (15mL), and the reaction The solution was stirred at 25°C for 2 hours. After the reaction was completed, dilute with water (20mL), extract with ethyl acetate (30mL×2), wash with saturated aqueous sodium chloride solution (30mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. (petroleum ether/ethyl acetate=3/1) to obtain compound 1-3. MS-ESI: m/z 354.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.91(d, J=2.4Hz, 1H), 7.42(d, J=2.0Hz, 1H), 7.35(d, J=8.4Hz, 1H), 7.25(dd ,J=8.4,2.0Hz,1H),6.89(d,J=7.6Hz,1H),6.23(d,J=2.0Hz,1H),5.76-5.64(m,1H),2.47(s,3H) , 1.68 (d, J=7.2Hz, 3H).

3) Synthesis of compound 1-4

At room temperature, compound 1-3 (100mg, 0.28mmol) was dissolved in dichloromethane (5mL), m-chloroperoxybenzoic acid (172mg, 0.85mmol, 85% purity) was added in batches, and the reaction solution was stirred at 25°C 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 1-4. MS-ESI: m/z 386.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.13(d, J＝2.0Hz, 1H), 7.44(d, J＝2.4Hz, 1H), 7.40(d, J＝8.4Hz, 1H), 7.37(d, J＝7.6Hz, 1H), 7.31-7.27(m, 1H), 6.70 (d, J = 2.4Hz, 1H), 5.86-5.76 (m, 1H), 3.23 (s, 3H), 1.77 (d, J = 7.2Hz, 3H).

4) Synthesis of Compound 1

At room temperature, compound 1-4 (80mg, 0.21mmol), N,N-diisopropylethylamine (80mg, 0.62mmol) and intermediate C (46mg, 0.21mmol) were dissolved in acetonitrile (10mL), and the reaction The solution was stirred at 50°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5 μm; mobile phase: water (10mM ammonium bicarbonate ), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 44-74%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 1. MS-ESI: m/z 490.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.80(d, J=2.0Hz, 1H), 7.49(d, J=8.4Hz, 1H), 7.47(d, J=2.0Hz, 1H), 7.30( dd, J＝8.4, 2.0Hz, 1H), 5.83(d, J＝2.4Hz, 1H), 5.67-5.58(m, 1H), 4.08(t, J＝8.8Hz, 1H), 4.03-3.92(m ,1H),3.82-3.73(m,1H),3.69(t,J=6.0Hz,2H),3.64-3.47(m,1H),2.99-2.81(m,2H),2.55(t,J=6.0 Hz,2H),2.44-2.31(m,1H),2.04(t,J＝12.0Hz,1H),1.79-1.66(m,4H),1.63-1.56(m,4H),0.97-0.80(m, 1H).

Example 2: 2-(R)-3-(1-(4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-7-methylpyrazol[1, 5-a][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (2)

1) Synthesis of compound 2-2

At room temperature, compound 2-1 (25.00g, 280.61mmol) was dissolved in 1,2-dichloroethane (125mL), and oxalyl chloride (33.20mL, 392.86mmol) was slowly added dropwise, and the reaction mixture was stirred at 60°C 6 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-2. The crude product was directly used in the next reaction without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.25 (q, J=7.2Hz, 2H), 1.27 (t, J=7.2Hz, 3H).

2) Synthesis of compound 2-3

At room temperature, 3-amino-5-methylpyrazole (2.50g, 25.74mmol) was dissolved in acetonitrile (25mL), compound 2-2 (8.08g, 38.61mmol, 55% purity) was added, and the reaction mixture was Stir for 4 hours. finished responding After completion, dilute with water (50mL), extract with ethyl acetate (60mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (petroleum ether/ethyl acetate Ester = 1/1) separation to obtain compound 2-3. MS-ESI: m/z 213.1 [M+H] ⁺ .

3) Synthesis of compound 2-4

Compound 2-3 (1.00 g, 4.43 mmol) and 20% sodium ethoxide ethanol solution (2.26 g, 6.64 mmol) were dissolved in ethanol (30 mL) at room temperature, and the reaction solution was stirred at 80° C. for 3 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, slowly added dropwise to 1 mol/L hydrochloric acid (100 mL) aqueous solution, filtered, and the filter cake was vacuum-dried to obtain compound 2-4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.78 (s, 1H), 11.45 (s, 1H), 5.65 (s, 1H), 2.19 (s, 3H).

4) Synthesis of compound 2-5

At room temperature, compound 2-4 (200mg, 1.20mmol) and N,N-diethylaniline (539mg, 3.61mmol) were slowly added to phosphorus oxychloride (2.20mL), and the reaction mixture was stirred at 100°C for 3 hours . After the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 2-5. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 203.0 [M+H] ⁺ .

5) Synthesis of compound 2-6

Compound 2-5 (244mg, 1.20mmol), Intermediate A (343mg, 1.77mmol) and pyridine (1.00mL, 12.04mmol) were dissolved in acetonitrile (4mL) at room temperature, and the reaction mixture was stirred at 50°C for 1 hour. After the reaction was completed, dilute with water (30mL), extract with ethyl acetate (50mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue was subjected to silica gel column chromatography (petroleum ether/acetic acid Ethyl ester=3/1) separation to obtain compound 2-6. MS-ESI: m/z 335.9 [M+H] ⁺ .

6) Synthesis of Compound 2

At room temperature, compound 2-6 (160 mg, 0.40 mmol, 90% purity), intermediate C (89 mg, 0.40 mmol) and cesium fluoride (123 mg, 0.81 mmol) were mixed in dimethyl sulfoxide (4 mL), and the reaction The mixture was stirred at 60°C for 4 hours. After the reaction is complete, dilute with water (20 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, wash with water (15 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Thin layer chromatography (pure methanol) separation, and then preparative high performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Unisil 3-100C18Ultra 150*50mm*3μm; mobile phase: water (0.5% formic acid), acetonitrile ; Gradient ratio: acetonitrile phase (0-7min, 11-41%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 2. MS-ESI: m/z 504.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.99(d, J=7.2Hz, 1H), 7.65(d, J=8.8Hz, 1H), 7.59(d, J=2.0Hz, 1H), 7.43 (dd,J=8.4,2.0Hz,1H),5.67(s,1H),5.64-5.53(m,1H),4.02-3.83(m,2H),3.82-3.55(m,4H),3.15-2.86 (m,2H),2.64-2.53(m,4H),2.42-2.35(m,1H),2.30(s,3H),1.88-1.58(m,4H),1.52(d,J＝7.2Hz,3H ), 1.06-0.90(m,1H).

Example 3: 2-((R)-3-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-7-(trifluoromethyl )pyrazol[1,5-a][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (3)

1) Synthesis of compound 3-2

Compound 3-1 (1.80 g, 11.91 mmol) and ethoxycarbonyl isothiocyanate (1.56 g, 11.91 mmol) were dissolved in ethyl acetate (20 mL) at room temperature, and the reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (10/1, 15 mL), filtered, and the filter cake was dried in vacuum to obtain compound 3-2. MS-ESI: m/z 283.1 [M+H] ⁺ .

2) Synthesis of compound 3-3

Compound 3-2 (2.00 g, 6.82 mmol) was dissolved in 2 mol/L sodium hydroxide aqueous solution (20 mL) at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into 1 mol/L hydrochloric acid aqueous solution (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-3. MS-ESI: m/z 236.9 [M+H] ⁺ .

3) Synthesis of compound 3-4

Compound 3-3 (350 mg, 1.48 mmol) and iodomethane (210 mg, 1.48 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and the reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with saturated aqueous sodium chloride solution (15 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 3-4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.75 (s, 1H), 2.53 (s, 3H).

4) Synthesis of compound 3-5

At room temperature, compound 3-4 (0.25g, 0.10mmol), N,N-diethylaniline (0.45g, 3.00mmol) and phosphorus oxychloride (1.90mL, 19.98mmol) were dissolved in toluene (2mL) , the reaction mixture was stirred at 100°C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to obtain compound 3-5. The crude product was directly used in the next reaction without further purification. MS-ESI: m/z 268.9 [M+H] ⁺ .

5) Synthesis of compound 3-6

Compound 3-5 (268mg, 0.10mmol), Intermediate A (287mg, 1.48mmol) and pyridine (0.80mL, 9.99mmol) were dissolved in acetonitrile (10mL) at room temperature, and the reaction mixture was stirred at 50°C for 0.5 hours. Cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain compound 3-6. MS-ESI: m/z 422.0 [M+H] ⁺ .

6) Synthesis of compound 3-7

At room temperature, compound 3-6 (180mg, 0.43mmol) was dissolved in dichloromethane (10mL), m-chloroperoxybenzoic acid (260mg, 1.28mmol, 85% purity) was added in portions, and the reaction mixture was stirred at 20°C 3 hours. After the reaction was completed, the reaction solution was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 3-7. MS-ESI: m/z 453.9 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.48(d, J=2.0Hz, 1H), 7.42(d, J=8.4Hz, 1H), 7.37(d, J=7.6Hz, 1H), 7.31(dd , J=8.4, 2.0Hz, 1H), 6.92(s, 1H), 5.90-5.77(m, 1H), 3.26(s, 3H), 1.80(d, J=7.2Hz, 3H).

7) Synthesis of compound 3

Compound 3-7 (200mg, 0.44mmol) was dissolved in acetonitrile (8mL) at room temperature, Intermediate C (194mg, 0.88mmol) and N,N-diisopropylethylamine (227mg, 1.76mmol) were added, The reaction mixture was stirred at 50°C for 3 hours. After the reaction is completed, cool to room temperature, concentrate under reduced pressure, and the residue is subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5 μm; mobile phase: water (10mM carbonic acid ammonium hydrogen), acetonitrile; gradient ratio: acetonitrile phase (0-10min, 52-82%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 3. MS-ESI: m/z 558.0 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.54-7.45(m, 2H), 7.31(dd, J=8.8, 2.4Hz, 1H), 6.07(s, 1H), 5.70-5.57(m, 1H) ,4.20-3.91(m,2H),3.86-3.50(m,4H),3.00-2.83(m,2H),2.54(t,J=5.6Hz,2H),2.46-2.36(m,1H),2.04 (t, J=11.6Hz, 1H), 1.86-1.68(m, 4H), 1.65-1.53(m, 4H), 0.97-0.80(m, 1H).

Example 4: 2-((R)-3-(1-(7-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrazol[1 ,5-a][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (4)

1) Synthesis of compound 4-2

At room temperature, compound 4-1 (6.50g, 39.88mmol) and ethoxycarbonyl isothiocyanate (6.28g, 47.86mmol) were dissolved in ethyl acetate (50mL), replaced with nitrogen, and the reaction mixture was stirred at 80°C for 1 Hour. Cool to room temperature, filter, and vacuum-dry the filter cake to obtain compound 4-2. MS-ESI: m/z 292.9 [M+H] ⁺ .

2) Synthesis of compound 4-3

Compound 4-2 (17.00 g, 50.45 mmol, 92% purity) was dissolved in aqueous sodium hydroxide solution (50 mL, 2 mol/L) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into 1 mol/L hydrochloric acid aqueous solution (100 mL), filtered, and the filter cake was vacuum-dried to obtain compound 4-3. MS-ESI: m/z 246.9 [M+H] ⁺ .

3) Synthesis of compound 4-4

At room temperature, compound 4-3 (13.40g, 53.15mmol) and iodomethane (1.89g, 13.28mmol) were dissolved in N,N-dimethylformamide (150mL), and the reaction mixture was stirred at room temperature for 4 hours, and then Stir at 50°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Dilute with water (300 mL), extract with ethyl acetate (150 mL×3), wash with saturated aqueous sodium chloride solution (500 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 4-4. ¹ H NMR (400MHz,DMSO-d ₆ )δ13.08(brs,1H),6.53(s,1H),2.53(s,3H).

4) Synthesis of compound 4-5

At room temperature, compound 4-4 (1.50g, 5.75mmol), N,N-diethylaniline (2.57g, 17.23mmol) and phosphorus oxychloride (10.70mL, 114.90mmol) were dissolved in toluene (20mL) , the reaction mixture was stirred at 100°C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain compound 4-5. The crude product was directly used in the next reaction without further purification. MS-ESI: m/z 278.8 [M+H] ⁺ .

5) Synthesis of compound 4-6

At room temperature, compound 4-5 (1.60g, 5.74mmol), intermediate A (1.65g, 8.62mmol) and pyridine (4.60mL, 57.45mmol) were dissolved in acetonitrile (30mL), and the reaction mixture was stirred at 50°C for 0.5 Hour. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain compound 4-6. MS-ESI: m/z 431.9 [M+H] ⁺ .

6) Synthesis of compound 4-7

Dissolve Intermediate 4-6 (400mg, 0.92mmol) in 1-methyl-2-pyrrolidone (15mL) at room temperature, add cuprous chloride (457mg, 4.62mmol), replace with nitrogen, and heat to 150°C with microwave React for 16 hours. The reaction solution was cooled to room temperature, diluted with water (40mL) and ethyl acetate (80mL), filtered, the filter cake was washed with ethyl acetate (10mL×3), the filtrate was extracted with ethyl acetate (20mL×3), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to preparative high-performance liquid chromatography (hydrochloric acid/acetonitrile/water system, chromatographic column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: water (0.225% formic acid), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 70-100%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 4-7. MS-ESI: m/z 388.0 [M+H] ⁺ .

7) Synthesis of compound 4-8

Compound 4-7 (20 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL) at room temperature, m-chloroperoxybenzoic acid (31 mg, 0.15 mmol, 85% purity) was added, and the reaction mixture was stirred at 25°C for 1.5 hours. The reaction solution was filtered, and the filtrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 4-8. MS-ESI: m/z 419.8 [M+H] ⁺ .

8) Synthesis of Compound 4

At room temperature, compound 4-8 (12mg, 0.03mmol) and intermediate C (8mg, 0.03mmol) were dissolved in acetonitrile (2mL), diisopropylethylamine (37mg, 0.29mmol) was added, and the reaction mixture was heated at 50 °C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated by preparative thin-layer silica gel chromatography (ethyl acetate/methanol=1/1) to obtain compound 4. MS-ESI: m/z 524.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.50-7.45 (m, 2H), 7.31 (dd, J = 8.4, 2.0Hz, 1H), 5.78 (s, 1H), 5.64-5.57 (m, 1H) ,4.15-4.06(m,1H),4.05-3.94(m,1H),3.85-3.71(m,3H),3.19-3.03(m,2H),2.80-2.72(m,2H),2.48-2.37( m,1H),2.35-2.25(m,1H),2.07-1.96(m,1H),1.87-1.72(m,3H),1.70-1.62(m,1H),1.58(d,J＝6.8Hz, 3H), 1.35-1.27(m, 1H), 1.03-0.89(m, 1H).

Example 5: 4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(3-((R)-1-(2-hydroxyethyl)piper Pyridin-3-yl)azetidin-1-yl)pyrazol[1,5-a][1,3,5]triazine-7-carbonitrile (5)

1) Synthesis of Compound 5-1

At room temperature, Intermediate 4-6 (1.50g, 3.43mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.25g, 0.34mmol) and triethylamine (1.40mL, 10.28 mmol) was dissolved in methanol (20 mL), and the reaction mixture was stirred at 80° C. for 16 hours under an atmosphere of carbon monoxide (50 psi). The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 5-1. MS-ESI: m/z 412.0 [M+H] ⁺ .

2) Synthesis of compound 5-2

At room temperature, methanol (5 mL) was placed in a 100 mL three-neck flask, replaced with nitrogen, the temperature of the reaction solution was lowered to -65° C., and ammonia gas was introduced. At room temperature, compound 5-1 (400mg, 0.97mmol) was added, and the reaction mixture was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was slurried with a mixed solvent of petroleum ether and methyl tert-butyl ether (1/1, 20 mL), filtered, and the filter cake was vacuum-dried to obtain compound 5-2. MS-ESI: m/z 397.0 [M+H] ⁺ .

3) Synthesis of compound 5-3

Compound 5-2 (330 mg, 0.83 mmol), Burgess reagent (396 mg, 1.66 mmol) were dissolved in anhydrous dichloromethane (10 mL) at room temperature, and the reaction mixture was stirred at 20°C for 16 hours. Pour the reaction mixture into water (20mL), extract with dichloromethane (20mL×2), wash the organic phase with water (20mL) and saturated aqueous sodium chloride solution (20mL) successively, combine the organic phases, dry over anhydrous sodium sulfate, and filter , and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 5-3. ¹ H NMR (400MHz,DMSO-d ₆ )δ9.99(s,1H),7.63(d,J＝8.4Hz,1H),7.60(s,1H),7.43(d,J＝8.4Hz,1H) , 6.97 (s, 1H), 5.70-5.58 (m, 1H), 2.41 (s, 3H), 1.56 (d, J=6.8Hz, 3H).

4) Synthesis of Compound 5-4

Compound 5-3 (180 mg, 0.48 mmol), m-chloroperoxybenzoic acid (289 mg, 1.42 mmol, 85% purity) were dissolved in dichloromethane (3 mL) at room temperature, and the reaction mixture was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 5-4. MS-ESI: m/z 411.0 [M+H] ⁺ .

5) Synthesis of Compound 5

At room temperature, compound 5-4 (190mg, 0.38mmol, 83% purity), intermediate C (171mg, 0.77mmol), N,N-diisopropylethylamine (0.20mL, 1.15mmol) were dissolved in acetonitrile ( 5 mL), the reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5 μm; mobile phase: water (10mM ammonium bicarbonate ), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 52-82%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 5. MS-ESI: m/z 515.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.52-7.42(m, 2H), 7.28(dd, J=8.4, 2.0Hz, 1H), 6.18(s, 1H), 5.70-5.52(m, 1H) ,4.16-3.90(m,2H),3.85-3.45(m,4H),2.99-2.78(m,2H),2.60-2.48(m,2H),2.45-2.30(m,1H),2.01(t, J=10.8Hz, 1H), 1.87-1.65(m, 4H), 1.63-1.51(m, 4H), 0.96-0.76(m, 1H).

Example 6: 2-((R)-3-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-7-fluoropyrazol[1 ,5-a][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (6)

Compound 6 was prepared according to the synthesis method of Example 3. MS-ESI: m/z 508.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.55(s, 1H), 7.52-7.46(m, 2H), 7.33(dd, J=8.4, 2.0Hz, 1H), 5.67-5.58(m, 1H) ,5.45(d,J＝4.8Hz,1H),4.19-4.09(m,1H),4.08-3.93(m,1H),3.91-3.53(m,4H),3.43-3.35(m,1H),3.30 -3.22(m,1H),3.06-2.91(m,2H),2.67-2.53(m,1H),2.51-2.40(m,1H),2.39-2.23(m,1H),1.98-1.68(m, 4H), 1.59 (d, J=7.2Hz, 3H), 1.14-1.10 (m, 1H).

Example 7: 2-((R)-3-(1-(8-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrazol[1 ,5-a][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (7)

1) Synthesis of compound 7-1

Compound 1-3 (300mg, 0.80mmol) was dissolved in chloroform (6mL) at room temperature, then N-chlorosuccinimide (129mg, 0.97mmol) was added, and the reaction mixture was stirred at 50°C for 6 hours. Reaction liquid cooling After reaching room temperature, it was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 7-1. MS-ESI: m/z 389.9 [M+H] ⁺ .

2) Synthesis of Compound 7-2

At room temperature, compound 7-1 (250mg, 0.49mmol, 76% purity) was dissolved in dichloromethane (10mL), then m-chloroperoxybenzoic acid (298mg, 1.47mmol, 85% purity) was added, and the reaction solution was Stir at 20°C for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 7-2. MS-ESI: m/z 421.9 [M+H] ⁺ .

3) Synthesis of compound 7

At room temperature, compound 7-2 (170mg, 0.39mmol), intermediate C (131mg, 0.59mmol), N,N-diisopropylethylamine (203mg, 1.57mmol) were dissolved in acetonitrile (6mL) and dimethyl sulfoxide (2 mL), and the reaction solution was stirred at 30°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 50-80%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 7. MS-ESI: m/z 524.0 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.78(s, 1H), 7.52-7.46(m, 2H), 7.30(dd, J＝8.4, 2.0Hz, 1H), 5.68-5.57(m, 1H) ,4.28-3.74(m,4H),3.70(t,J＝6.0Hz,2H),3.01-2.85(m,2H),2.55(t,J＝6.0Hz,2H),2.45-2.33(m,1H ), 2.14-1.99 (m, 1H), 1.86-1.67 (m, 4H), 1.66-1.55 (m, 4H), 0.97-0.81 (m, 1H).

Example 8: 4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(3-((R)-1-(2-hydroxyethyl)piper Pyridin-3-yl)azetidin-1-yl)pyrazol[1,5-a][1,3,5]triazine-8-carbonitrile (8)

1) Synthesis of Compound 8-1

At room temperature, compound 1-3 (300mg, 0.85mmol) was dissolved in N,N-dimethylformamide (5mL), the ice bath was lowered to 0°C, and N-iodosuccinimide (191mg , 0.85mmol), the reaction mixture was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (50 mL) for dilution, and extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 8-1. MS-ESI: m/z 480.0 [M+H] ⁺ .

2) Synthesis of Compound 8-2

At room temperature, compound 8-1 (300 mg, 0.62 mmol) was added to 1-methyl-2-pyrrolidone (2 mL), followed by cuprous cyanide (277 mg, 3.09 mmol), replaced by nitrogen, and reacted at 140°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (30 mL) for dilution, extracted with ethyl acetate (20 mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/2), and the crude product was dissolved in methyl tert-butyl ether (30 mL), washed with saturated brine (10 mL×4), and the organic phase was washed with Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 8-2. MS-ESI: m/z 379.3 [M+H] ⁺ .

3) Synthesis of Compound 8-3

At room temperature, compound 8-2 (45mg, 0.08mmol, 70% purity) was dissolved in dichloromethane (5mL), m-chloroperoxybenzoic acid (34mg, 0.17mmol, 85% purity) was added, and the reaction mixture was heated at 25 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to obtain compound 8-3. MS-ESI: m/z 411.2 [M+H] ⁺ .

4) Synthesis of Compound 8

At room temperature, compound 8-3 (40 mg, 0.08 mmol, 85% purity) and intermediate C (37 mg, 0.17 mmol) were dissolved in 1,2-dichloroethane (5 mL), and N,N-diiso Propylethylamine (53mg, 0.41mmol), the reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 8. MS-ESI: m/z 515.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.08(s, 1H), 7.51-7.43(m, 2H), 7.31(dd, J＝8.4, 2.0Hz, 1H), 5.68-5.58(m, 1H) ,4.28-4.15(m,1H),4.04-3.78(m,4H),3.66-3.53(m,1H),3.52-3.40(m,1H),3.24-3.16(m,2H),2.95-2.80( m,1H),2.78-2.55(m,1H),2.54-2.43(m,1H),2.06-1.93(m,2H),1.92-1.71(m,2H),1.59(d,J＝6.8Hz, 3H), 1.33-1.30(m, 1H), 1.21-1.07(m, 1H).

Example 9: (1R,3r)-3-((R)-3-(1-(5-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[ 1,2,4]triazol[1,5-a]pyridin-7-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (9)

1) Synthesis of compound 9-2

At room temperature, compound 9-1 (8.00g, 35.26mmol), (2,4-dimethoxyphenyl) methylamine (8.84g, 52.89mmol) and cesium fluoride (10.71g, 70.52mmol) were added into dimethyl In base sulfoxide (50mL), the reaction solution was Stir at 100°C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (80 mL×2), the organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain compound 9-2. MS-ESI: m/z 357.0 [M+H] ⁺ .

2) Synthesis of compound 9-3

At room temperature, compound 9-2 (1.80 g, 4.58 mmol, 91% purity) was added into dichloromethane (10 mL), trifluoroacetic acid (10.00 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, slurried with methyl tert-butyl ether and petroleum ether (1/1, 100 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-3. MS-ESI: m/z 207.0 [M+H] ⁺ .

3) Synthesis of Compound 9-4

At room temperature, sequentially add compound 9-3 (1.50g, 3.73mmol, 80% purity) and ethoxycarbonyl isothiocyanate (0.98g, 7.47mmol) into dioxane (15mL), and the reaction solution was Stir for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether and petroleum ether (1/1, 50 mL), filtered, and dried to obtain compound 9-4. MS-ESI: m/z 337.9 [M+H] ⁺ .

4) Synthesis of compound 9-5

At room temperature, compound 9-4 (1.10g, 3.09mmol, 95% purity), N,N-diisopropylethylamine (1.50mL, 9.26mmol) and hydroxylamine hydrochloride (0.64g, 9.26mmol) were added to In methanol (10 mL) and ethanol (10 mL), the reaction mixture was reacted at 60° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was slurried with water (40 mL), filtered, and dried to obtain compound 9-5. MS-ESI: m/z 246.9 [M+H] ⁺ .

5) Synthesis of compound 9-6

At room temperature, compound 9-5 (0.80 g, 2.55 mmol, 79% purity) and tert-butyl nitrite (0.79 g, 7.66 mmol) were sequentially added into tetrahydrofuran (10 mL), and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to obtain compound 9-6. MS-ESI: m/z 232.0 [M+H] ⁺ .

6) Synthesis of compound 9-7

At room temperature, compound 9-6 (300mg, 1.29mmol) and intermediate A (442mg, 2.32mmol) were added to dimethyl sulfoxide (10mL), followed by cesium fluoride (294mg, 1.94mmol), and the reaction solution was Stir at 100°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (40 mL×2), combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to obtain compound 9-7. MS-ESI: m/z 384.9 [M+H] ⁺ .

7) Synthesis of compound 9-8

At room temperature, compound 9-7 (150mg, 0.33mmol, 85% purity), intermediate D (110mg, 0.36mmol) and potassium tert-butoxide (111mg, 0.99mmol), 2,2-bis(diphenylphosphine Base)-1,1-binaphthalene (41.13mg, 0.066mmol) was dissolved in tert-butanol (5mL) and ethylene glycol dimethyl ether (5mL), replaced with nitrogen, and then added tris(dibenzylideneacetone) di Palladium (30mg, 0.03mmol), the reaction mixture was stirred at 100°C for 16 hours. The reaction solution Cool to room temperature and concentrate under reduced pressure to obtain compound 9-8. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 571.2 [M+H] ⁺ .

8) Synthesis of Compound 9

Compound 9-8 (189 mg, 0.33 mmol) was added to water (5 mL) and methanol (5 mL) at room temperature, lithium hydroxide monohydrate (69 mg, 1.65 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL) for dilution, washed with ethyl acetate (20 mL×2), the organic phase was discarded, the aqueous phase was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (formic acid/acetonitrile/water system, Chromatographic column: Waters Xbridge C18 150*25mm*5μm; mobile phase: water (0.0225% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-10min, 37-67%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 9. MS-ESI: m/z 557.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.06(s, 1H), 7.52(d, J=2.0Hz, 1H), 7.49(d, J=8.4Hz, 1H), 7.30(dd, J=8.4 ,2.0Hz,1H),5.76(d,J=1.2Hz,1H),5.13-5.06(m,1H),4.76(d,J=1.2Hz,1H),3.97(t,J=8.0Hz,1H ),3.86(t,J=7.6Hz,1H),3.72-3.64(m,1H),3.59-3.53(m,1H),3.48(t,J=8.4Hz,1H),3.38-3.33(m, 1H),3.28-3.20(m,1H),2.81-2.69(m,2H),2.59-2.43(m,2H),2.28(t,J＝12.0Hz,1H),2.12-1.99(m,2H) , 1.98-1.82 (m, 3H), 1.78-1.67 (m, 1H), 1.64 (d, J=6.8Hz, 3H), 1.38 (s, 3H), 1.15-1.06 (m, 1H).

Example 10: (1R,3r)-3-((R)-3-(1-(2-chloro-5-(((R)-1-(2,4-dichlorophenyl)ethyl) Amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane Alkane-1-carboxylic acid (10)

1) Synthesis of compound 10-2

At room temperature, compound 10-1 (15.00g, 66.11mmol), (2,4-dimethoxyphenyl) methylamine (16.58g, 99.17mmol) and cesium fluoride (20.00g, 132.23mmol) were added into dimethyl sulfoxide (100 mL), the reaction mixture was stirred at 100°C for 16 hours. The reaction solution was diluted with water (100mL), extracted with ethyl acetate (100mL×3) The organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain compound 10-2. MS-ESI: m/z 357.1 [M+H] ⁺ .

2) Synthesis of compound 10-3

At room temperature, compound 10-2 (4.50 g, 12.58 mmol) was added into dichloromethane (20 mL), trifluoroacetic acid (20.00 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, slurried with methyl tert-butyl ether and petroleum ether (1/1, 100 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain compound 10-3. MS-ESI: m/z 206.8 [M+H] ⁺ .

3) Synthesis of Compound 10-4

At room temperature, compound 10-3 (3.42 g, 10.64 mmol) and ethoxycarbonyl isothiocyanate (2.79 g, 21.28 mmol) were sequentially added to dioxane (40 mL), and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, the crude product was slurried with methyl tert-butyl ether and petroleum ether (1/1, 50 mL), filtered, and the solid was dried to obtain compound 10-4. MS-ESI: m/z 337.9 [M+H] ⁺ .

4) Synthesis of Compound 10-5

At room temperature, compound 10-4 (3.50g, 10.34mmol), N,N-diisopropylethylamine (5.10mL, 31.01mmol) and hydroxylamine hydrochloride (2.15g, 31.01mmol) were added to methanol (30mL) in sequence and ethanol (30 mL), the reaction mixture was reacted at 60° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was slurried with water (50 mL), filtered, and the solid was dried to obtain compound 10-5. MS-ESI: m/z 246.9 [M+H] ⁺ .

5) Synthesis of Compound 10-6

Under nitrogen protection at 0°C, tert-butyl nitrite (362mg, 3.52mmol) was slowly added dropwise to compound 10-5 (500mg, 1.76mmol, 87% purity) and copper chloride (283mg, 2.11mmol) in acetonitrile (5 mL) solution, the reaction mixture was stirred at 60°C for 1 hour. After the reaction was completed, water (50 mL) was added to the reaction mixture to dilute, and ethyl acetate (50 mL×3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 10-6. MS-ESI: m/z 265.9 [M+H] ⁺ .

6) Synthesis of compound 10-7

At room temperature, compound 10-6 (340 mg, 1.27 mmol) and intermediate A (363 mg, 1.91 mmol) were added to dimethyl sulfoxide (6 mL), followed by cesium fluoride (387 mg, 2.55 mmol), and the reaction solution was Stir at 100°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) , to obtain compound 10-7.

7) Synthesis of compound 10-8

Compound 10-7 (150mg, 0.30mmol, 85% purity), intermediate D (138mg, 0.45mmol) and cesium carbonate (296mg, 0.91mmol) were mixed in tert-amyl alcohol (3mL) at room temperature under the protection of nitrogen. Nitrogen replacement, adding methanesulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (49mg, 0.03mmol), the reaction mixture was stirred at 90°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=0/1) to obtain compound 10-8. The crude product was directly used in the next reaction without further purification. MS-ESI: m/z 605.2 [M+H] ⁺ .

8) Synthesis of Compound 10

At room temperature, compound 10-8 (330mg, 0.29mmol, 53% purity) and lithium hydroxide monohydrate (36mg, 0.87mmol) were dissolved in tetrahydrofuran (3mL) and water (3mL), and the reaction mixture was stirred at room temperature for 3 hours . After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: water (0.5% formic acid), Acetonitrile; gradient ratio: acetonitrile phase (0-10min, 30-60%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 10. MS-ESI: m/z 591.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.51(d, J=2.0Hz, 1H), 7.49(d, J=8.4Hz, 1H), 7.31(dd, J=8.4, 2.0Hz, 1H), 5.67(d,J=2.0Hz,1H),5.10-5.03(m,1H),4.94(d,J=2.0Hz,1H),3.98(t,J=7.6Hz,1H),3.87(t,J ＝8.4Hz,1H),3.72-3.64(m,1H),3.60-3.53(m,1H),3.52-3.41(m,1H),3.37-3.32(m,1H),3.25-3.18(m,1H ),2.78-2.68(m,2H),2.59-2.44(m,2H),2.32-2.21(m,1H),2.07-1.82(m,5H),1.77-1.65(m,1H),1.62(d , J=6.8Hz, 3H), 1.38(s, 3H), 1.17-1.02(m, 1H).

Example 11: (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrazole And[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (11)

1) Synthesis of Compound 11-2

At room temperature, compound 11-1 (600mg, 3.19mmol), intermediate A (619mg, 3.19mmol) and N,N-diisopropylethylamine (825mg, 6.38mmol) were dissolved in acetonitrile (10mL), and the reaction The mixture was stirred at 50°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 11-2. MS-ESI: m/z 341.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.97(d, J=7.6Hz, 1H), 8.18(d, J=2.4Hz, 1H), 8.65(d, J=2.0Hz, 1H), 8.62 (d,J=8.4Hz,1H),7.44(dd,J=8.4,2.0Hz,1H),6.45(d,J=2.4Hz,1H),5.74(s,1H),5.19-5.07(m, 1H), 1.62 (d, J=6.8Hz, 3H).

2) Synthesis of Compound 11

At room temperature, compound 11-2 (100mg, 0.29mmol), intermediate D (97mg, 0.32mmol), potassium tert-butoxide (98mg, 0.87mmol), (±)-2,2-bis(diphenylphosphino )-11-binaphthalene (36mg, 0.06mmol) plus into tert-butanol (3mL) and ethylene glycol dimethyl ether (5mL), nitrogen replacement, then tris(dibenzylideneacetone) dipalladium (26mg, 0.03mmol) was added to the reaction solution, and the reaction mixture was heated at 100 °C and stirred for 12 hours. The reaction solution was cooled to room temperature, poured into water (10 mL) for dilution, and washed with dichloromethane (20 mL×2). The organic phase was discarded, and the aqueous phase was subjected to preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex C18 75*30mm*3μm; mobile phase: water (10mM formic acid), acetonitrile; gradient ratio: acetonitrile phase ( 0-7min, 8-38%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 11. MS-ESI: m/z 557.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.83-7.79(m, 1H), 7.53-7.43(m, 2H), 7.32(dd, J=8.4, 2.0Hz, 1H), 5.99-5.93(m, 1H), 5.17-5.08(m, 1H), 4.71(s, 1H), 4.07(t, J=8.4Hz, 1H), 3.96(t, J=7.6Hz, 1H), 3.76(dd, J=8.4 ,5.6Hz,1H),3.71-3.63(m,1H),3.60-3.50(m,1H),3.39-3.33(m,1H),3.26-3.20(m,1H),2.81-2.67(m,2H ),2.62-2.47(m,2H),2.41-2.28(m,1H),2.10-1.97(m,3H),1.96-1.85(m,2H),1.77-1.67(m,1H),1.66-1.61 (m,3H), 1.38(s,3H), 1.15-1.04(m,1H).

Example 12: 2-(R)-3-(1-(5-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazole And[1,5-c]pyrimidin-7-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (12)

1) Synthesis of compound 12-2

At room temperature, sequentially dissolve compound 12-1 (3.50g, 18.23mmol), intermediate A (2.99g, 18.23mmol) and N,N-diisopropylethylamine (4.50mL, 27.34mmol) in isopropanol (500 mL), stirred at 100°C for 32 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (60 mL) and water (40 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate Ester = 2/1) separation to obtain compound 12-2. MS-ESI: m/z 317.1 [M+H] ⁺ .

2) Synthesis of compound 12-3

At room temperature, compound 12-2 (2.00g, 5.86mmol) was dissolved in dioxane (40mL), then ethoxycarbonyl isothiocyanate (1.54g, 11.71mmol) was added, and the reaction solution was stirred at 90°C 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 12-3. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 448.0 [M+H] ⁺ .

3) Synthesis of compound 12-4

At room temperature, compound 12-3 (2.63g, crude product) and N,N-diisopropylethylamine (2.90mL, 17.57mmol) were dissolved in a mixed solvent of methanol (20mL) and ethanol (20mL), and then separated Hydroxylamine hydrochloride (814mg, 11.71mmol) was added in batches, and the reaction solution was reacted at 45°C for 2 hours. After the reaction, the reaction liquid was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (60 mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=2/1) separation to obtain compound 12-4. MS-ESI: m/z 357.0 [M+H] ⁺ .

4) Synthesis of compound 12-5

At 0°C, compound 12-4 (1.00g, 2.71mmol) was dissolved in tetrahydrofuran (20mL), tert-butyl nitrite (0.84g, 8.14mmol) was slowly added dropwise, and the reaction solution was stirred at 0°C for 2 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =2/1) separation to obtain compound 12-5. MS-ESI: m/z 341.9 [M+H] ⁺ .

5) Synthesis of Compound 12

At room temperature, compound 12-5 (150mg, 0.44mmol), intermediate C (145mg, 0.59mmol) and cesium fluoride (133mg, 0.88mmol) were mixed in dimethylsulfoxide (3mL), and the reaction mixture was stirred at 60°C 16 hours. After the reaction is completed, filter, and the filtrate is subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Unisil 3-100C18Ultra 150*50mm*3μm; mobile phase: water (0.5% formic acid), acetonitrile; gradient Proportion: acetonitrile phase (0-7min, 10-40%); flow rate: 25mL/min; column temperature: room temperature) separation, and then separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 12. MS-ESI: m/z 490.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.51-7.46(m, 2H), 7.29(dd, J=8.4, 2.0Hz, 1H), 5.62-5.55(m, 1H) ,5.54(s,1H),4.00(t,J=8.4Hz,1H),3.93(t,J=8.4Hz,1H),3.74-3.66(m,3H),3.52-3.47(m,1H), 2.98-2.88(m,2H),2.58-2.53(m,2H),2.49-2.41(m,1H),2.10-2.01(m,1H),1.78-1.71(m,4H),1.61(d,J =7.2Hz, 4H), 0.95-0.85(m, 1H).

Example 13: (1R,3r)-3-((R)-3-(1-(2-chloro-5-(((R)-1-(2,4-dichlorophenyl)ethyl) Amino)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane Alkane-1-carboxylic acid (13)

1) Synthesis of compound 13-1

At 0°C, compound 12-4 (400mg, 1.12mmol) and copper chloride (180mg, 1.34mmol) were dissolved in acetonitrile (2mL), and tert-butyl nitrite (231mg, 2.24mmol) was slowly added dropwise, and the reaction mixture was Stir at 0°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 13-1. MS-ESI: m/z 375.9 [M+H] ⁺ .

2) Synthesis of compound 13-2

At room temperature, sequentially mix compound 13-1 (200mg, 0.53mmol), intermediate D (241mg, 0.80mmol) and cesium fluoride (161mg, 1.06mmol) in dimethyl sulfoxide (4mL), and the reaction mixture was Stir at 80°C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by preparative thin-layer chromatography on silica gel (ethyl acetate/methanol=5/1) to obtain compound 13-2. MS-ESI: m/z 606.0 [M+H] ⁺ .

3) Synthesis of compound 13

Compound 13-2 (170 mg, 0.28 mmol) and lithium hydroxide monohydrate (35 mg, 0.84 mmol) were dissolved in methanol (2 mL) and water (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: water (0.5% formic acid), Acetonitrile; gradient ratio: acetonitrile phase (0-10min, 19-49%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 13. MS-ESI: m/z 592.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.42(s, 1H), 7.51-7.46(m, 2H), 7.30(dd, J=8.4, 2.0Hz, 1H), 5.61-5.54(m, 1H) ,5.49(s,1H),4.06(t,J=8.4Hz,1H),3.96(t,J=8.4Hz,1H),3.78-3.69(m,1H),3.65-3.54(m,2H), 3.43-3.36(m,1H),3.28-3.21(m,1H),2.82-2.75(m,2H),2.67-2.57(m,1H),2.56-2.48(m,1H),2.42-2.31(m ,1H),2.13-1.98(m,3H),1.95-1.83(m,2H),1.80-1.68(m,1H),1.59(d,J=7.2Hz,3H),1.41(s,3H), 1.19-1.07(m,1H).

Example 14: 2-(R)-3-(1-(5-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-8-fluoro-[1,2, 4] Triazolo[1,5-c]pyrimidin-7-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (14)

1) Synthesis of compound 14-1

At room temperature, compound 12-4 (500mg, 1.40mmol) was dissolved in methanol (1.5mL) and acetonitrile (1.5mL), and then 1-fluoro-4-methyl-1,4-diazabicyclo[2.2 .2] Octane tetrafluoroborate (670mg, 2.10mmol), the reaction solution was stirred at 50°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated under reduced pressure. shrink. The resulting residue was separated by preparative thin-layer chromatography on silica gel (petroleum ether/ethyl acetate=1/1) to obtain compound 14-1. MS-ESI: m/z 375.1 [M+H] ⁺ .

2) Synthesis of compound 14-2

At room temperature, compound 14-1 (80mg, 0.16mmol, 77% purity) was dissolved in tetrahydrofuran (1mL), tert-butyl nitrite (51mg, 0.49mmol) was added under ice cooling, and the reaction solution was stirred at 0°C for 20 minutes . After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 14-2. MS-ESI: m/z 359.9 [M+H] ⁺ .

3) Synthesis of compound 14-3

At room temperature, compound 14-2 (59mg, 0.16mmol) and intermediate E (86mg, 0.33mmol) were dissolved in dimethylsulfoxide (2mL), cesium fluoride (75mg, 0.49mmol) was added, and the reaction mixture was heated at 80 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL) for dilution, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/2) to obtain compound 14-3. MS-ESI: m/z 548.2 [M+H] ⁺ .

4) Synthesis of compound 14-4

At room temperature, compound 14-3 (30mg, 0.06mmol) and tetrakistriphenylphosphine palladium (6mg, 0.01mmol) were mixed in dichloromethane (2mL), and phenylsilane (59mg, 0.55mmol) was added slowly, and the reaction mixture Stir at 25°C for 2 hours. After the reaction was completed, the obtained residue was separated by silica gel column chromatography (triethylamine/methanol=1/20) to obtain compound 14-4. MS-ESI: m/z 464.2 [M+H] ⁺ .

5) Synthesis of compound 14-5

At room temperature, compound 14-4 (10 mg, 0.02 mmol, 89% purity), acetic acid (12 mg, 0.19 mmol) and tert-butyldimethylsiloxane acetaldehyde (5 mg, 0.03 mmol) were dissolved in methanol (1 mL ), after stirring for 30 minutes, sodium cyanoborohydride (2mg, 0.04mmol) was added, and the reaction mixture was reacted at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 14-5. The crude product was directly used in the next reaction without further purification. MS-ESI: m/z 622.3 [M+H] ⁺ .

6) Synthesis of compound 14

Compound 14-5 (13 mg, 0.02 mmol, 84% purity) was dissolved in methanol (1 mL) at room temperature, trifluoroacetic acid (1.00 mL) was added, and the reaction solution was reacted at 30° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in methanol (1 mL), and aqueous ammonia was slowly added dropwise to pH ~ 8, then concentrated under reduced pressure. The resulting residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain Compound 14. MS-ESI: m/z 508.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.08(s, 1H), 7.49-7.43(m, 2H), 7.28(dd, J=8.4, 2.0Hz, 1H), 5.56-5.47(m, 1H) ,4.15-4.05(m,2H),3.88-3.82(m,1H),3.72(t,J＝6.0Hz,2H),3.65-3.58(m,1H),3.07-2.93(m,2H),2.64 (t,J=5.2Hz,2H),2.53-2.42(m,1H),2.23-2.12(m,1H),1.84-1.70(m,4H),1.68-1.61(m,1H),1.58(d , J=7.2Hz, 3H), 0.97-0.89(m, 1H).

Example 15: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazole And[1,5-a][1,3,5]triazin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (15)

1) Synthesis of compound 15-2

At room temperature, compound 15-1 (5.00g, 59.47mmol) was dissolved in N,N-dimethylformamide (50mL), and ethoxycarbonyl isothiocyanate (7.80g, 59.47mmol) was slowly added dropwise, The reaction solution was reacted at 25° C. for 15 hours. After the reaction was completed, the reaction solution was poured into water (500 mL), filtered, the filter cake was washed with water (100 mL), and dried in vacuo to obtain compound 15-2. ¹ H NMR (400MHz, DMSO-d ₆ )δ14.00(s,1H),12.15-11.68(m,1H),11.45(s,1H),8.54(s,1H),4.21(q,J=7.2 Hz, 2H), 1.25 (t, J = 7.2Hz, 3H).

2) Synthesis of compound 15-3

Compound 15-2 (5.00g, 23.23mmol) was dissolved in ethanol (80mL) at room temperature, aqueous sodium hydroxide solution (23.23mL, 2mol/L, 46.46mmol) was added, and the reaction mixture was stirred at 78°C for 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filter cake was dissolved by adding water (10mL), and the pH was adjusted to 6-7 with 1mol/L hydrochloric acid aqueous solution, and the mixture was passed through a reverse-phase column (acetonitrile/water system, chromatographic column: C18spherical20 -35μm 40g, mobile phase: water, acetonitrile; gradient ratio: acetonitrile phase (0-8min, 0-5%); flow rate: 35mL/min; column temperature: room temperature) separation to obtain compound 15-3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (brs, 1H), 7.92 (s, 1H).

3) Synthesis of compound 15-4

Compound 15-3 (3.40 g, 20.10 mmol) and iodomethane (2.85 g, 20.10 mmol) were dissolved in N,N-dimethylformamide (34 mL) at room temperature, and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 15-4. The crude product was directly used in the next reaction without purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 2.57 (s, 3H).

4) Synthesis of compound 15-5

At room temperature, compound 15-4 (1.00g, 5.46mmol) and N,N-diethylaniline (2.44g, 16.38mmol) were dissolved in phosphorus oxychloride (10.10mL, 109.17mmol), and the reaction mixture was heated at 100 °C and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain compound 15-5. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 201.9 [M+H] ⁺ .

5) Synthesis of compound 15-6

At room temperature, compound 15-5 (1.10g, 5.46mmol), intermediate A (1.56g, 8.19mmol) and pyridine (1.32mL, 16.38mmol) were dissolved in acetonitrile (11mL), and the reaction mixture was stirred at 50°C for 0.5 Hour. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 15-6. MS-ESI: m/z 355.0 [M+H] ⁺ .

6) Synthesis of Compound 15-7

Compound 15-6 (450 mg, 1.27 mmol) and m-chloroperoxybenzoic acid (819 mg, 3.80 mmol, 80% purity) were dissolved in dichloromethane (10 mL) at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 15-7. MS-ESI: m/z 387.0 [M+H] ⁺ .

7) Synthesis of Compound 15

Compound 15-7 (100 mg, 0.14 mmol, 54% purity), Intermediate C (46 mg, 0.21 mmol) and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were dissolved in acetonitrile (2 mL ), and the reaction solution was stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was separated by preparative thin-layer chromatography on silica gel (pure methanol), and then separated by preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Unisil 3-100C18Ultra 150* 50mm*3μm; mobile phase: water (0.5% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-7min, 10-40%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 15. MS-ESI: m/z 491.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.54(s, 1H), 8.05(s, 1H), 7.54-7.47(m, 2H), 7.34(dd, J＝8.4, 2.0Hz, 1H), 5.71 -5.61(m,1H),4.31-4.09(m,2H),4.05-3.58(m,5H),3.48-3.41(m,1H),3.14-3.04(m,2H),2.72(t,J= 11.6Hz, 1H), 2.55-2.40(m, 2H), 2.00-1.73(m, 4H), 1.62(d, J=6.8Hz, 3H), 1.18-1.05(m, 1H).

Example 16: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-[1,2 ,4] Triazolo[1,5-a][1,3,5]triazin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (16)

Compound 16 was prepared according to the synthesis method of Example 15. MS-ESI: m/z 505.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ9.27(s,1H),7.65-7.56(m,2H),7.41(dd,J＝8.0,2.0Hz,1H),5.61-5.46(m,1H ),4.38-4.28(m,1H),4.14-3.57(m,4H),3.54-3.42(m,2H),2.79-2.64(m,2H),2.41-2.33(m,3H),2.31(s ,3H),1.98-1.84(m,1H),1.72-1.53(m,4H),1.50(d,J＝6.8Hz,3H),1.46-1.33(m,1H),0.85-0.68(m,1H ).

Example 17: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)azetidin-3-yl)piperidin-1-yl)ethane -1-ol(17)

Compound 17 was prepared according to the synthesis method of Example 15. MS-ESI: m/z 559.5 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.52-7.46(m,2H),7.34-7.29(m,1H),5.71-5.57(m,1H),4.24-4.07(m,1H),4.02- 3.75(m,2H),3.74-3.54(m,3H),2.98-2.82(m,2H),2.59-2.50(m,2H),2.48-2.37(m,1H),2.12-1.99(m,1H ), 1.82-1.66 (m, 4H), 1.64-1.55 (m, 4H), 0.96-0.81 (m, 1H).

Example 18: 2-(R)-3-(1-(2-cyclopropyl-7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1, 2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)azetidin-3-yl)piperidin-1-yl)ethane-1- Alcohol(18)

Compound 18 was prepared according to the synthesis method of Example 15. MS-ESI: m/z 531.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.52-7.43(m,2H),7.35-7.28(m,1H),5.66-5.55(m,1H),4.21-4.09(m,1H),4.03- 3.73(m,4H),3.72-3.36(m,3H),3.24-3.08(m,2H),2.93-2.73(m,1H),2.67-2.42(m,2H),2.16-1.71(m,5H ), 1.59 (d, J=7.2Hz, 3H), 1.23-1.09 (m, 1H), 1.08-0.99 (m, 4H).

Example 19: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazole And[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (19)

1) Synthesis of Compound 19-1

At room temperature, compound 15-1 (5000mg, 59.47mmol) and diethyl malonate (11.43g, 71.36mmol) were dissolved in N,N-dimethylacetamide (50mL), and sodium hydrogen (4.76 g, 118.93 mmol, 60% purity), the reaction mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (200 mL) and shaken to dissolve, washed with ethyl acetate (50 mL×3), and the organic phase was discarded. The aqueous phase was slowly added dropwise with 2 mol/L dilute hydrochloric acid solution to pH~2, washed with ethyl acetate (50 mL×3), and the organic phase was discarded. The remaining aqueous phase was concentrated under reduced pressure to obtain compound 19-1. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 151.1 [MH] ^- .

2) Synthesis of compound 19-2

At room temperature, compound 19-1 (9.05g, 59.46mmol) was dissolved in phosphorus oxychloride (50.00mL), N,N-dimethylaniline (14.41g, 118.93mmol) was added, and the reaction mixture was stirred at 100°C 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (100 mL), washed with saturated brine (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 19-2. MS-ESI: m/z 189.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.28 (s, 1H).

3) Synthesis of compound 19-3

At room temperature, compound 19-2 (300mg, 1.59mmol) and intermediate A (302mg, 1.57mmol) were dissolved in dimethyl sulfoxide (10mL), cesium fluoride (362mg, 2.38mmol) was added, and the reaction mixture was Stir at 100°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (150 mL) for dilution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 19-3. MS-ESI: m/z 342.1 [M+H] ⁺ .

4) Synthesis of compound 19

At room temperature, compound 19-3 (200mg, 0.42mmol, 72% purity) and intermediate C (93mg, 0.42mmol) were dissolved in acetonitrile (10mL), and N,N-diisopropylethylamine (163mg, 1.26 mmol), and the reaction mixture was stirred at 80°C for 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain Compound 19. MS-ESI: m/z 490.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.08(s, 1H), 7.54(d, J=2.0Hz, 1H), 5.53(d, J=8.8Hz, 1H), 7.36(dd, J=8.4 ,2.0Hz,1H),5.18-5.11(m,1H),4.83(s,1H),4.20-3.95(m,2H),3.90-3.82(m,3H),3.78-3.67(m,1H), 3.46-3.36(m,2H),3.14-3.01(m,2H),2.79-2.64(m,1H),2.63-2.38(m,2H),2.15-2.01(m,1H),1.98-1.81(m , 3H), 1.67 (d, J=6.8Hz, 3H), 1.17-1.06 (m, 1H).

Example 20: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-methyl-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (20)

Example 20 was prepared referring to the synthesis method of Example 19. MS-ESI: m/z 504.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.53 (d, J = 2.4Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 7.34 (dd, J = 8.8, 2.4Hz, 1H), 5.14-5.06(m,1H),4.75(s,1H),4.08(t,J＝8.4Hz,1H),4.04-3.87(m,1H),3.82-3.56(m,4H),3.16-3.01( m,2H),2.71(t,J＝5.6Hz,2H),2.55-2.42(m,1H),2.40(s,3H),2.32-2.21(m,1H),2.01-1.75(m,5H) , 1.64 (d, J=7.2Hz, 3H), 1.01-0.88 (m, 1H).

Example 21: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (21)

Compound 21 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 558.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.54 (d, J = 2.0Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 7.34 (dd, J = 8.8, 2.0Hz, 1H), 5.17-5.09(m,1H),4.89(s,1H),4.16-3.96(m,2H),3.81(dd,J＝8.8,6.0Hz,1H),3.75-3.60(m,3H),2.97- 2.88(m,2H),2.54(t,J＝6.0Hz,2H),2.51-2.42(m,1H),2.08-2.00(m,1H),1.86-1.68(m,5H),1.65(d, J=6.8Hz, 3H), 1.62-1.52(m, 1H), 0.97-0.82(m, 1H).

Example 22: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(methoxymethyl) -[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (22)

Compound 22 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 534.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.53 (d, J = 2.0Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 7.34 (dd, J = 8.4, 2.0Hz, 1H), 5.17-5.07(m,1H),4.79(s,1H),4.55(s,2H),4.08(t,J＝8.4Hz,1H),4.04-3.91(m,1H),3.82-3.63(m, 4H),3.46(s,3H),3.04-2.91(m,2H),2.59(t,J＝6.0Hz,2H),2.52-2.39(m,1H),2.17-2.04(m,1H),1.85 -1.70(m,4H),1.67-1.58(m,4H),0.98-0.82(m,1H).

Example 23: 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-ethyl-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (23)

Compound 23 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 518.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.53 (d, J = 2.4Hz, 1H), 7.51 (t, J = 8.4Hz, 1H), 7.34 (dd, J = 8.4, 2.4Hz, 1H), 5.17-5.07(m,1H),4.76(s,1H),4.07(t,J＝8.8Hz,1H),4.02-3.86(m,1H),3.80-3.73(m,1H),3.73-3.53( m,3H),2.98-2.86(m,2H),2.76(q,J=7.6Hz,2H),2.53(t,J=6.0Hz,2H),2.50-2.41(m,1H),2.08-1.99 (m,1H),1.81-1.67(m,4H),1.64(d,J=6.8Hz,3H),1.62-1.53(m,1H),1.35(t,J=7.6Hz,3H),0.95- 0.83(m,1H).

Example 24: 2-(R)-3-(1-(2-cyclopropyl-7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1, 2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (24)

Compound 24 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 530.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.52(d, J=2.0Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.34(dd, J=8.4, 2.0Hz, 1H), 5.13-5.07(m,1H),4.74(s,1H),4.08(t,J＝8.4Hz,1H),4.04-3.94(m,1H),3.86-3.75(m,3H),3.74-3.64( m,1H),3.43-3.34(m,1H),3.04-2.97(m,2H),2.69-2.58(m,1H),2.57-2.45(m,1H),2.42-2.31(m,1H), 2.11-2.02(m,1H),2.01-1.95(m,1H),1.93-1.73(m,3H),1.64(d,J=6.8Hz,3H),1.39-1.21(m,1H),1.13- 1.04(m,1H),1.03-0.98(m,4H).

Example 25: N-(R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-(tetrahydro-2H-pyran-4-yl) Piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (25)

1) Synthesis of compound 25-1

At room temperature, compound 19-3 (7.30g, 21.31mmol) was dissolved in acetonitrile (80mL), then N,N-diisopropylethylamine (10.50mL, 63.92mmol) and intermediate E (6.67g, 25.57mmol), and the reaction solution was reacted at 60°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 25-1. MS-ESI: m/z 530.4 [M+H] ⁺ .

2) Synthesis of compound 25-2

Compound 25-1 (2.70g, 5.09mmol) was dissolved in dichloromethane (50mL) at room temperature, followed by the addition of phenylsilane (5.51g, 50.90mmol) and tetrakis(triphenylphosphine)palladium (590mg, 0.51mmol ), the reaction solution at room temperature Stir for 15 minutes. After the reaction was completed, the reaction solution was separated by silica gel column chromatography (methanol/triethylamine=5/1) to obtain compound 25-2. MS-ESI: m/z 446.1 [M+H] ⁺ .

3) Synthesis of compound 25

At room temperature, compound 25-2 (100mg, 0.22mmol), tetrahydropyran-4-one (67mg, 0.67mmol) and acetic acid (13mg, 0.22mmol) were dissolved in methanol (5mL), and the reaction mixture was heated at 25°C After stirring for 1 hour, sodium cyanoborohydride (42 mg, 0.67 mmol) was added to the reaction solution, and the reaction mixture was stirred at 25° C. for 12 hours. The reaction solution was poured into water (30 mL), extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to preparative high performance liquid chromatography ( Acetonitrile/ammonium bicarbonate system, chromatographic column: ACSWH-GX-A Waters Xbridge 150*25mm*5μm; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase (0-9min,60- 90%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 25. MS-ESI: m/z 530.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.52(d, J=2.0Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.33(dd, J=8.0 ,2.0Hz,1H),5.18-5.12(m,1H),4.80(s,1H),4.08(t,J＝8.4Hz,1H),3.98(dd,J＝11.2,3.6Hz,3H),3.77 (dd, J=8.8,6.0Hz,1H),3.72-3.51(m,1H),3.38(t,J=12.0Hz,2H),2.97-2.86(m,2H),2.57-2.41(m,2H ), 2.13(td, J=12.0, 2.8Hz, 1H), 1.87-1.68(m, 6H), 1.64(d, J=6.4Hz, 3H), 1.62-1.48(m, 3H), 0.95-0.82( m, 1H).

Example 26: 3-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazole And[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propan-1-ol (26)

At room temperature, compound 25-2 (100mg, 0.22mmol) was dissolved in acetonitrile (6mL), then 3-iodopropanol (83mg, 0.44mmol) and potassium carbonate (92mg, 0.67mmol) were added, and the reaction mixture was heated at 80°C Stir for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 35-65%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 26. MS-ESI: m/z 504.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.18-5.10(m,1H),4.81(s,1H),4.09(t,J=8.4Hz,1H),4.05-3.89(m,1H),3.78(dd,J= 8.4,5.6Hz,1H),3.74-3.55(m,3H),2.98-2.83(m,2H),2.53-2.41(m,3H),2.03-1.91(m,1H),1.82-1.70(m, 5H), 1.69-1.61(m, 4H), 1.61-1.49(m, 1H), 0.98-0.82(m, 1H).

Example 27: N-(2-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide (27)

1) Synthesis of compound 27-1

Compound 25-2 (200 mg, 0.45 mmol), tert-butyl (2-bromoethyl)carbamate (100 mg, 0.45 mmol) and potassium carbonate (186 mg, 1.34 mmol) were dissolved in acetonitrile (10 mL) at room temperature, The reaction mixture was stirred at 80°C for 2 hours. After the reaction was completed, it was diluted with water (30 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=0/1) to obtain compound 27-1. MS-ESI: m/z 589.2 [M+H] ⁺ .

2) Synthesis of compound 27-2

Compound 27-1 (300 mg, 0.43 mmol, 85% purity) was dissolved in dichloromethane (5 mL) at room temperature, then trifluoroacetic acid (1.00 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with water (30 mL), washed with ethyl acetate (30 mL×3), the aqueous phase was adjusted to pH~8 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 27-2. MS-ESI: m/z 489.3 [M+H] ⁺ .

3) Synthesis of Compound 27

Under ice-cooling, compound 27-2 (55 mg, 0.10 mmol, 89% purity), methanesulfonic anhydride (16 mg, 0.09 mmol) and triethylamine (30 mg, 0.30 mmol) were dissolved in dichloromethane (2 mL), The reaction mixture was stirred at 0°C for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5 μm; mobile phase: water (0.5% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase (0-9min, 45-75%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 27. MS-ESI: m/z 567.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ8.34(d, J=6.8Hz, 1H), 8.11(s, 1H), 7.65(d, J=2.0Hz, 1H), 7.63(d, J= 8.4Hz,1H),7.44(dd,J＝8.4,2.0Hz,1H),6.91-6.76(m,1H),5.06-4.96(m,1H),4.84(s,1H),3.99(t,J =8.8Hz,1H),3.95-3.86(m,1H),3.73-3.69(m,1H),3.64-3.56(m,1H),3.04(t,J=6.4Hz,2H),2.92(s, 3H), 2.79-2.70(m, 2H), 2.62-2.57(m, 1H), 2.38(t, J=6.8Hz, 2H), 1.96-1.87(m, 1H), 1.68-1.60(m, 3H) ,1.59-1.55(m,4H),1.49-1.36(m,1H),0.87-0.74(m,1H).

Example 28: N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-(2-(methylsulfonyl)ethyl) Piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (28)

1) Synthesis of compound 28-2

At room temperature, compound 28-1 (1.00g, 7.24mmol) was dissolved in pyridine (10mL), the system was cooled to 0°C, p-toluenesulfonyl chloride (1.69g, 8.86mmol) was added, and the reaction mixture was stirred at 25°C for 12 Hour. The reaction solution was quenched by pouring into water (20 mL), and extracted with ethyl acetate (30 mL). The organic phase was washed with 1 mol/L dilute hydrochloric acid (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane/methanol = 0/1) to obtain compound 28-2. The crude product was directly used in the next reaction without further purification.

2) Synthesis of compound 28

At room temperature, compound 28-2 (488mg, 1.75mmol) and compound 25-2 (300mg, 0.59mmol) were dissolved in acetonitrile (10mL), and N,N-diisopropylethylamine (227mg, 1.75mmol) was added , and the mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (20 mL) for dilution, and extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (ethyl acetate/methanol=0/1) to obtain compound 28. MS-ESI: m/z 552.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.52(d, J=2.0Hz, 1H), 7.49(d, J=8.4Hz, 1H), 7.32(dd, J=8.4 ,2.0Hz,1H),5.15-5.07(m,1H),4.79(s,1H),4.07(t,J=8.4Hz,1H),4.03-3.91(m,1H),3.78(dd,J= 8.4,6.0Hz,1H),3.74-3.56(m,1H),3.29-3.25(m,2H),3.03(s,3H),2.89-2.78(m,4H),2.55-2.41(m,1H) , 2.10-1.98 (m, 1H), 1.80-1.66 (m, 4H), 1.64 (d, J=7.2Hz, 3H), 1.61-1.47 (m, 1H), 0.97-0.83 (m, 1H).

Example 29: 5-(3-((R)-1-(2-oxaspiro[3.3]heptan-6-yl)piperidin-3-yl)azetidin-1-yl)- N-((R-1-(2,4-dichlorophenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (29)

Compound 25-2 (100mg, 0.22mmol) was dissolved in methanol (5mL) at room temperature, followed by the addition of 2-oxaspiro[3.3]heptane-6-one (74mg, 0.51mmol), sodium cyanoborohydride (41mg, 0.66mmol) and acetic acid (40mg, 0.66mmol), the reaction mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to preparative high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile; Gradient ratio: acetonitrile phase (0-10min, 46-76%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 29. MS-ESI: m/z 542.3[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.4Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.16-5.11(m,1H),4.81(s,1H),4.72(s,2H),4.59(s,2H),4.08(t,J＝8.4Hz,1H),4.04 -3.86(m,1H),3.82-3.75(m,1H),3.74-3.54(m,1H),2.88-2.72(m,2H),2.61-2.51(m,1H),2.50-2.37(m, 3H), 2.11-1.98(m, 2H), 1.83-1.68(m, 4H), 1.65(d, J=6.8Hz, 3H), 1.59-1.48(m, 1H), 1.42(t, J=10.4Hz ,1H), 0.97-0.81(m,1H).

Example 30: 3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4] Triazol[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)thietane-1,1-dioxide (30)

1) Synthesis of compound 30-2

Under ice-cooling, compound 30-1 (500mg, 4.09mmol), methanesulfonic anhydride (1.07g, 6.14mmol) and triethylamine (1.70mL, 12.28mmol) were dissolved in dichloromethane (10mL), and the reaction mixture Stir at room temperature for 1 hour to obtain compound 30-2, and the reaction solution was directly used in the next reaction.

2) Synthesis of compound 30

At room temperature, compound 25-2 (100mg, 0.22mmol), compound 30-2 (224mg, 1.12mmol, crude product, theoretical amount) and cesium carbonate (146mg, 0.45mmol) were dissolved in N,N-dimethylformamide (2 mL), the reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, add water (20 mL) to the reaction mixture to dilute, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated aqueous sodium chloride solution (30 mL×3), dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: water (0.5% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0 -10min, 18-48%)); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 30. MS-ESI: m/z 550.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.10(m,1H),4.81(s,1H),4.21-4.14(m,2H),4.12-3.94(m,4H),3.83-3.78(m,1H), 3.76-3.62(m,1H),3.23-3.13(m,1H),2.85-2.73(m,2H),2.60-2.47(m,1H),2.04-1.93(m,1H),1.81-1.72(m , 3H), 1.71-1.67(m, 1H), 1.65(d, J=6.8Hz, 3H), 1.62-1.53(m, 1H), 0.99-0.86(m, 1H).

Example 31 and Example 32: (1R,4r)-4-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl) Amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexyl alkan-1-ol and (1S,4s)-4-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexane-1-alcohol (31 and 32)

1) Synthesis of compound 31-2

Under ice-cooling, compound 31-1 (1000mg, 6.40mmol) was dissolved in tetrahydrofuran (15mL), replaced with nitrogen, and then a 3mol/L methylmagnesium bromide (2.50mL, 7.50mmol) ether solution was added, and the reaction solution was Stir at 0°C for 2 hours. After the reaction, the reaction solution was slowly poured into saturated ammonium chloride aqueous solution (50mL) to quench, extracted with ethyl acetate (50mL), washed with saturated brine (40mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure gave compound 31-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.97-3.86 (m, 4H), 1.94-1.81 (m, 2H), 1.73-1.52 (m, 6H), 1.27-1.23 (m, 3H).

2) Synthesis of compound 31-3

At room temperature, compound 31-2 (1.00g, 4.65mmol, 80% purity) was dissolved in tetrahydrofuran (15mL), then 1mol/L dilute hydrochloric acid (8.00mL, 8.00mmol) was added, and the reaction solution was stirred at 25°C for 16 hours . The reaction solution was extracted with ethyl acetate (50 mL), washed with saturated brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 31-3. ¹ H NMR (400MHz, CDCl ₃ ) δ2.75-2.66(m,2H),2.26-2.19(m,2H),1.99-1.93(m,2H),1.88-1.80(m,2H),1.35(s ,3H).

3) Synthesis of compound 31 and compound 32

At room temperature, compound 31-3 (209 mg, 1.30 mmol, 80% purity) was dissolved in 1,2-dichloroethane (10 mL), then compound 25-2 (300 mg, 0.65 mmol) and acetic acid (117 mg, 1.96mmol), the reaction mixture was stirred at 25°C for 2 hours, then sodium acetate borohydride (413mg, 1.96mmol) was added, and the reaction mixture was stirred at 50°C for 14 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (ethyl acetate/methanol=0/1), and then separated by preparative silica gel thin layer chromatography (pure methanol) to obtain compound 31-4. Then prepare supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250mm*50mm*10μm); mobile phase: hexane, ethanol (0.1% ammonia water); gradient ratio: ethanol phase 70%; flow rate: 100mL/min; Column temperature: room temperature) separation to obtain compound 31 and compound 32. (Compound 31 is the first eluting peak, compound 32 is the second eluting peak). Compound 31: MS-ESI: m/z 558.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.8Hz, 1H), 7.34(dd, J=8.8 ,2.4Hz,1H),5.17-5.09(m,1H),4.81(s,1H),4.09(t,J＝8.4Hz,1H),4.04-3.88(m,1H),3.81-3.73(m, 1H),3.72-3.54(m,1H),2.98-2.82(m,2H),2.52-2.42(m,1H),2.41-2.31(m,1H),2.30-2.21(m,1H),1.98- 1.90(m,1H),1.82-1.69(m,6H),1.67-1.62(m,4H),1.61-1.54(m,1H),1.46-1.26(m,4H),1.18(s,3H), 0.92-0.84 (m, 1H). Compound 32: MS-ESI: m/z 558.3 [M+1] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.4Hz, 1H), 7.51(d, J=8.8Hz, 1H), 7.34(dd, J=8.4, 2.0Hz, 1H),5.19-5.11(m,1H),4.81(s,1H),4.09(t,J＝8.4Hz,1H),4.05-3.92(m,1H),3.81-3.74(m,1H),3.72 -3.54(m,1H),2.97-2.82(m,2H),2.53-2.42(m,1H),2.39-2.30(m,1H),2.22-2.13(m,1H),1.91-1.80(m, 3H),1.79-1.68(m,5H),1.65(d,J＝10.8Hz,3H),1.53-1.41(m,3H),1.40-1.27(m,2H),1.22(s,3H),0.94 -0.84(m,1H).

Example 33: (1S,3s)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[ 1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1- Base (33) and Example 34: (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl )amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methyl ring Butan-1-ol(34)

At room temperature, compound 25-2 (200 mg, 0.44 mmol) was dissolved in methanol (6 mL), followed by addition of compound 33-1 (147 mg, 0.88 mmol, 60% purity), sodium cyanoborohydride (83 mg, 1.32 mmol) and acetic acid (79mg, 1.32mmol), the reaction mixture was stirred at 25°C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 33-2. Compound 33-2 (200mg, 90% purity) was subjected to normal phase liquid chromatography (column: DAICEL CHIRALPAK IC (250mm*50mm*10μm); mobile phase: hexane, ethanol (0.1% ammonia water); gradient ratio: ethanol Phase 70%; flow rate: 100mL/min; column temperature: room temperature) separation, and then separated by preparative thin-layer chromatography (pure methanol) to obtain compound 33 and compound 34. Compound 33: MS-ESI: m/z 530.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.06(s, 1H), 7.58-7.46(m, 2H), 7.34(dd, J=8.8, 2.4Hz, 1H), 5.17-5.11(m, 1H) ,4.59(s,1H),4.13(t,J＝8.4Hz,1H),4.08-3.93(m,1H),3.92-3.84(m,1H),3.83-3.64(m,2H),3.53-3.37 (m,2H),2.81-2.64(m,1H),2.62-2.30(m,6H),2.23-2.11(m,1H),2.02-1.82(m,3H),1.66(d,J＝6.8Hz ,3H), 1.40(s,3H), 1.24-1.09(m,1H). Compound 34: MS-ESI: m/z 530.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.52(d, J=1.6Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.33(dd, J=8.4 ,1.6Hz,1H),5.19-5.06(m,1H),4.80(s,1H),4.08(t,J＝8.4Hz,1H),4.03-3.88(m,1H),3.82-3.74(m, 1H),3.73-3.54(m,1H),2.90-2.74(m,2H),2.53-2.40(m,1H),2.38-2.28(m,1H),2.24-2.12(m,2H),2.00- 1.87(m,2H),1.83-1.68(m,4H),1.65(d,J＝6.8Hz,3H),1.60-1.51(m,1H),1.50-1.40(m,1H),1.30(s, 3H), 0.92-0.80 (m, 1H).

Example 35 and Example 36: N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-1-((1s,3S)-3 -Methoxycyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine and N - ((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-((1r,3R)-3-methoxycyclobutyl)piperidine -3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (35 and 36)

At room temperature, compound 25-2 (150mg, 0.34mmol) and 3-methoxycyclobutane-1-one (34mg, 0.34mmol) were dissolved in methanol (2mL), acetic acid (2mg, 0.03mmol) was added, and the reaction The solution was stirred at room temperature for 20 minutes, then sodium cyanoborohydride (32 mg, 0.50 mmol) was added, and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was separated by preparative thin-layer chromatography on silica gel (ethyl acetate/methanol=5/1) to obtain compound 35-1. Compound 35-1 (70mg, 0.13mmol) was resolved by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, ethanol (0.1% ammonia monohydrate); gradient Ratio: methanol phase 25%; flow rate: 55mL/min; column temperature: room temperature), compound 35 and compound 36 were obtained. (Compound 35 was the first eluting peak, compound 36 was the second eluting peak). Compound 35: MS-ESI: m/z 530.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.4Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.8 ,2.4Hz,1H),5.18-5.10(m,1H),4.82(s,1H),4.09(t,J＝8.8Hz,1H),4.04-3.95(m,1H),3.94-3.89(m, 1H), 3.78(dd, J＝8.0, 6.4Hz, 1H), 3.73-3.58(m, 1H), 3.24(s, 3H), 2.98-2.76(m, 3H), 2.54-2.41(m, 1H) ,2.24-2.01(m,4H),1.82-1.70(m,4H),1.65(d,J＝6.8Hz,3H),1.60-1.51(m,1H),1.46-1.39(m,1H),0.96 -0.81(m,1H). Compound 36: MS-ESI: m/z 530.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.18-5.11(m,1H),4.81(s,1H),4.09(t,J=8.8Hz,1H),4.05-3.90(m,1H),3.80(dd,J= 8.8,5.6Hz,1H),3.74-3.56(m,2H),3.24(s,3H),2.89-2.76(m,2H),2.54-2.41(m,3H),2.39-2.29(m,1H) ,1.84-1.69(m,6H),1.65(d,J=6.8Hz,3H),1.61-1.51(m,1H),1.46(t,J=10.8Hz,1H),0.96-0.81(m,1H ).

Example 37 and Example 38: N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-1-((1s,3S)-3 -(methylsulfonyl)cyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-7- Amine and N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-1-((1r,3R)-3-(methylsulfonyl )cyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (37 and 38)

1) Synthesis of Compound 37-2

Under ice bath, compound 37-1 (5.00 g, 28.37 mmol) was dissolved in methanol (20 mL), sodium borohydride (1.14 g, 30.14 mmol) was added in three batches, and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, it was quenched by adding water (20 mL), and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with water (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 37-2. ¹ H NMR (400MHz, CDCl ₃ )δ7.38-7.32(m,4H),7.31-7.27(m,1H),4.43(s,2H),3.91-3.86(m,1H),3.68-3.60(m ,1H), 2.78-2.67(m,2H), 1.98-1.90(m,2H).

2) Synthesis of compound 37-3

Under ice bath, compound 37-2 (4.50g, 25.25mmol), methanesulfonic anhydride (6.60g, 37.87mmol) and triethylamine (10.50mL, 75.75mmol) were dissolved in dichloromethane (50mL), and the reaction The mixture was stirred at room temperature for 4 hours. After the reaction was completed, it was diluted with dichloromethane (100 mL), and washed with water (50 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 37-3. ¹ H NMR (400MHz, CDCl ₃ )δ7.37-7.31(m,5H),4.69-4.61(m,1H),4.44(s,2H),3.78-3.71(m,1H),2.98(s,3H ), 2.89-2.79(m,2H), 2.40-2.28(m,2H).

3) Synthesis of compound 37-4

At room temperature, compound 37-3 (6.20g, 24.19mmol) and sodium thiomethoxide (3.39g, 48.38mmol) were dissolved in N,N-dimethylformamide (65mL), and the reaction mixture was stirred at room temperature for 16 hours . After the reaction was completed, it was diluted with water (100 mL), and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain compound 37-4. ¹ H NMR (400MHz, CDCl ₃ ) δ7.36-7.33(m, 4H), 7.32-7.27(m, 1H), 4.42(s, 2H), 4.38-4.30(m, 1H), 3.43-3.35(m ,1H), 2.47-2.39(m,2H), 2.29-2.22(m,2H), 2.06(s,3H).

4) Synthesis of compound 37-5

At room temperature, compound 37-4 (1.00g, 4.80mmol) was dissolved in dichloromethane (10mL), then m-chloroperoxybenzoic acid (2.44g, 12.00mmol, 85% purity) was added, and the reaction mixture was stirred at room temperature for 2 Hour. The reaction solution was filtered, and the filtrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain compound 37-5. ¹ H NMR (400MHz, CDCl ₃ )δ7.38-7.31(m,5H),4.45(s,2H),4.42-4.36(m,1H),3.74-3.62(m,1H),2.84(s,3H ), 2.82-2.74(m,2H), 2.51-2.42(m,2H).

5) Synthesis of compound 37-6

At room temperature, compound 37-5 (1.00g, 4.16mmol) was dissolved in methanol (20mL), and wet palladium on carbon (100mg, 0.94mmol, 10% purity) and wet palladium hydroxide (100mg, 0.71mmol) were added under nitrogen protection ), nitrogen replacement, hydrogen replacement, and the reaction solution was stirred at 30° C. for 16 hours under a hydrogen atmosphere (50 psi). After the reaction was completed, the reaction solution was filtered through diatomaceous earth, washed with methanol (20 mL×3), and the filtrate was concentrated under reduced pressure to obtain compound 37-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.73-4.61 (m, 1H), 3.75-3.63 (m, 1H), 2.90-2.80 (m, 5H), 2.47-2.36 (m, 2H).

6) Synthesis of compound 37-7

Compound 37-6 (510 mg, 3.40 mmol) was dissolved in dichloromethane (10 mL) at room temperature, Dess-Martin oxidant (4.32 g, 10.19 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (20 mL×2), and the filtrate was concentrated under reduced pressure. The obtained residue was slurried with ethyl acetate (10 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain compound 37-7. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.94-3.86 (m, 1H), 3.74-3.63 (m, 2H), 3.49-3.37 (m, 2H), 2.99 (s, 3H).

7) Synthesis of compound 37 and compound 38

At room temperature, compound 25-2 (200 mg, 0.45 mmol), compound 37-7 (266 mg, 0.90 mmol, 50% purity) and acetic acid (3 μL, 0.04 mmol) were dissolved in methanol (5 mL), and the reaction mixture was stirred at room temperature After 30 minutes, sodium cyanoborohydride (84 mg, 1.34 mmol) was added, and the reaction mixture was stirred at room temperature for 15.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 37-8. Compound 37-8 was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250mm×30mm*10μm); mobile phase: supercritical carbon dioxide, ethanol (0.1% ammonia monohydrate); gradient ratio: ethanol phase 40 %; flow rate: 70mL/min; column temperature: room temperature), compound 37 and compound 38 were obtained. (Compound 37 was the first eluting peak, compound 38 was the second eluting peak). Compound 37: MS-ESI: m/z 578.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.09(m,1H),4.81(s,1H),4.08(t,J＝8.4Hz,1H),4.04-3.88(m,1H),3.82-3.75(m, 1H),3.74-3.53(m,2H),2.86(s,3H),2.85-2.73(m,3H),2.54-2.37(m,3H),2.36-2.24(m,2H),1.88-1.80( m, 1H), 1.79-1.68 (m, 3H), 1.65 (d, J=6.8Hz, 3H), 1.61-1.48 (m, 2H), 0.96-0.82 (m, 1H). Compound 38: MS-ESI: m/z 578.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.10(m,1H),4.81(s,1H),4.09(t,J＝8.4Hz,1H),4.05-3.91(m,1H),3.82-3.76(m, 1H),3.75-3.55(m,2H),2.94-2.78(m,6H),2.54-2.40(m,3H),2.39-2.26(m,2H),1.97-1.87(m,1H),1.84- 1.69 (m, 3H), 1.65 (d, J=6.8Hz, 3H), 1.63-1.50 (m, 2H), 0.99-0.83 (m, 1H).

Example 39 and Example 40: (R)-1-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino) -[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol and (S)- 1-((R)-3- (1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidine-5 -yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol (39 and 40)

At room temperature, compound 25-2 (200mg, 0.44mmol) and 1-bromopropan-2-ol (92mg, 0.66mmol) were dissolved in acetonitrile (10mL), and diisopropylethylamine (172mg, 1.33mmol) was added , and the reaction solution was stirred at 80° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was separated by preparative thin-layer chromatography on silica gel (ethyl acetate/methanol=3/1) to obtain compound 39-1. Compound 39-1 (140mg, 0.28mmol) was resolved by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, ethanol (0.1% ammonia monohydrate); gradient Ratio: ethanol phase 25%; flow rate: 60mL/min; column temperature: room temperature), compound 39 and compound 40 were obtained. (Compound 39 was the first eluting peak, compound 40 was the second eluting peak). Compound 39: MS-ESI: m/z 504.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.10(m,1H),4.81(s,1H),4.10(t,J=8.0Hz,1H),4.07-3.92(m,2H),3.79(dd,J= 8.4,6.4Hz,1H),3.76-3.61(m,1H),3.12-2.96(m,2H),2.57-2.40(m,3H),2.37-2.23(m,1H),1.97-1.74(m, 4H), 1.69-1.60 (m, 4H), 1.16 (d, J=6.4Hz, 3H), 1.04-0.89 (m, 1H). Compound 40: MS-ESI: m/z 504.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.4Hz,1H),5.19-5.11(m,1H),4.81(s,1H),4.14-4.05(m,1H),4.01-3.87(m,2H),3.82-3.75(m,1H), 3.74-3.57(m,1H),3.00-2.81(m,2H),2.56-2.45(m,1H),2.41-2.26(m,2H),2.06-1.94(m,1H),1.85-1.69(m , 4H), 1.65 (d, J=6.8Hz, 3H), 1.63-1.50 (m, 1H), 1.14 (d, J=6.0Hz, 3H), 0.99-0.82 (m, 1H).

Example 41: 1-(((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4 ]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)methyl)cyclopropan-1-ol (41)

1) Synthesis of Compound 41-2

At room temperature, compound 41-1 (1.80g, 13.83mmol) was dissolved in N,N-dimethylformamide (30mL), the temperature was lowered to 0°C, and sodium hydrogen (830mg, 20.75mmol, 60% purity ), the reaction solution was stirred at 0°C for 20 minutes, p-methoxybenzyl chloride (2.38 g, 15.21 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction liquid to quench, and ethyl acetate (50 mL×2) was extracted. The organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (ethyl acetate/petroleum ether=5/1) to obtain compound 41-2. ¹ H NMR (400MHz, CDCl ₃ ) δ7.30(d, J=8.4Hz, 2H), 6.88(d, J=8.8Hz, 2H), 4.59(s, 2H), 4.24(q, J=6.8Hz ,2H), 3.80(s,3H), 1.35-1.33(m,2H), 1.32-1.26(m,3H), 1.25-1.20(m,2H).

2) Synthesis of Compound 41-3

Dissolve compound 41-2 (1.00g, 4.00mmol) in tetrahydrofuran (30mL) at room temperature, cool to 0°C, slowly add 2.5mol/L lithium aluminum hydride tetrahydrofuran solution (2.40mL, 6.00mmol) dropwise, and stir at 0°C 0.5 hours. After the reaction was completed, it was quenched by slowly adding saturated potassium sodium tartrate aqueous solution (50 mL) dropwise at 0° C., and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain compound 41-3. ¹ H NMR (400MHz, CDCl ₃ ) δ7.25(d, J=8.4Hz, 2H), 6.88(d, J=8.8Hz, 2H), 4.54(s, 2H), 3.81(s, 3H), 3.71 (s, 2H), 0.99-0.94 (m, 2H), 0.66-0.61 (m, 2H).

3) Synthesis of compound 41-4

At room temperature, compound 41-3 (150mg, 0.72mmol) and pyridine (342mg, 4.32mmol) were dissolved in dichloromethane (6mL), cooled to 0°C in an ice-water bath, and methanesulfonic anhydride (126mg, 0.72mmol) was added , and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with dichloromethane (50 mL), washed with water (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 41-4. The crude product was directly used in the next reaction without further purification. ¹ H NMR (400MHz, CDCl ₃ ) δ7.24(d, J=8.4Hz, 2H), 6.87(d, J=8.8Hz, 2H), 4.56(s, 2H), 4.40(s, 2H), 3.81 (s,3H), 3.07(s,3H), 1.11-1.06(m,2H), 0.83-0.78(m,2H).

4) Synthesis of Compound 41-5

At room temperature, compound 25-2 (130mg, 0.29mmol) and compound 41-4 (167mg, 0.58mmol) were dissolved in acetonitrile (5mL), then N,N-diisopropylethylamine (188mg, 1.46mmol ), and the reaction solution was stirred at 80° C. for 14 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was separated by silica gel preparative thin-layer chromatography (ethyl acetate/methanol=1/1) to obtain compound 41-5. MS-ESI: m/z 636.4 [M+H] ⁺ .

5) Synthesis of Compound 41

Compound 41-5 (50 mg, 0.05 mmol, 66% purity) was dissolved in dichloromethane (1 mL) at room temperature, then trifluoroacetic acid (1.00 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with a small amount of methanol, adjusted to pH ~ 9 with ammonia water, and the residue was separated by preparative silica gel thin-layer chromatography (pure methanol) to obtain compound 41. MS-ESI: m/z 516.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz 1H), 5.17-5.10(m, 1H), 4.81(s, 1H), 4.10(t, J＝8.4Hz, 1H), 4.05-3.93(m, 1H), 3.81(dd, J＝8.4, 6.0Hz 1H),3.74-3.61(m,1H),3.15-2.98(m,2H),2.59-2.43(m,3H),2.14-2.04(m,1H),1.85-1.68(m,4H),1.65( d, J=6.8Hz, 3H), 1.63-1.56(m, 1H), 0.96-0.87(m, 1H), 0.75-0.68(m, 2H), 0.54-0.46(m, 2H).

Example 42: N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-(oxetan-3-ylmethyl) )piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (42)

Compound 25-2 (150 mg, 0.34 mmol) was dissolved in acetonitrile (5 mL) at room temperature, and then 3-bromomethyloxetane (101 mg, 0.67 mmol) and potassium carbonate (139 mg, 1.01 mmol) were added, The reaction solution was stirred at 80°C for 14 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated by preparative thin-layer chromatography on silica gel (pure methanol) to obtain compound 42. MS-ESI: m/z 516.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz 1H),5.17-5.10(m,1H),4.82-4.77(m,3H),4.41(t,J＝6.0Hz,2H),4.08(t,J＝8.4Hz,1H),4.04- 3.90(m,1H),3.77(dd,J＝8.4,6.0Hz 1H),3.72-3.56(m,1H),3.29-3.26(m,1H),2.80-2.67(m,4H),2.53-2.41 (m,1H),2.02-1.91(m,1H),1.80-1.66(m,4H),1.65(d,J＝6.8Hz,3H),1.60-1.50(m,1H),0.94-0.83(m ,1H).

Example 43: 3-(((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4 ]triazol[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)methyl)thietane-1,1-dioxide ( 43)

1) Synthesis of compound 43-2

At room temperature, compound 43-1 (25.00 g, 211.63 mmol) and tetrahydropyrrole (30.10 g, 423.26 mmol) were dissolved in methyl tert-butyl ether (300 mL), then magnesium sulfate (6.00 g, 49.85 mmol) was added , and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, most of the solvent was concentrated under reduced pressure at low temperature. The remainder is reduced Pressure distillation (60°C-64°C, 0.03 Pa) gave compound 43-2. ¹ H NMR (400MHz, CDCl ₃ )δ4.68(s,1H),3.88(s,1H),3.60(s,1H),3.35(s,6H),3.19-3.09(m,4H),1.87- 1.78 (m, 4H).

2) Synthesis of compound 43-3

At room temperature, compound 43-2 (5.00g, 29.20mmol) and triethylamine (3.84g, 37.96mmol) were dissolved in methyl tert-butyl ether (25mL), cooled to 0°C, and then methylsulfonate was added dropwise Acyl chloride (4.10g, 35.80mmol) in methyl tert-butyl ether (25mL) solution, the internal temperature was controlled not to exceed 5°C, after the dropwise addition, the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (50ml) to quench, and extracted with dichloromethane (50ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40° C. to obtain compound 43-3. The crude product was directly used in the next reaction without purification. ¹ H NMR (400MHz, CDCl ₃ )δ4.45(s,1H),4.28-4.25(m,1H),4.24-4.21(m,1H),4.07-4.05(m,1H),4.04-4.01(m ,1H), 3.54(s,6H), 2.84-2.71(m,4H), 1.84-1.75(m,4H).

3) Synthesis of Compound 43-4

At room temperature, compound 43-3 (3.00g, 12.03mmol) was dissolved in dichloromethane (20mL), cooled to 0°C, and methyl trifluoromethanesulfonate (2.17g, 13.24mmol) was added to control the internal temperature. When the temperature exceeds 5°C, after the dropwise addition is completed, the reaction solution is reacted at room temperature for 14 hours. Then triethylamine (1.34 g, 13.24 mmol) was slowly added dropwise at 0° C. After the dropwise addition, the reaction solution was refluxed and stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and washed successively with water (20 mL), 1 mol/L aqueous hydrochloric acid (10 mL) and saturated aqueous sodium carbonate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 43-4. The crude product was directly used in the next reaction without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ6.76 (d, J = 1.2Hz, 1H), 5.16 (d, J = 0.8Hz, 1H), 4.46 (s, 2H), 3.38 (s, 6H).

4) Synthesis of compound 43-5

At room temperature, compound 43-4 (1.00g, 5.61mmol) was dissolved in ethanol (20mL), then wet palladium on carbon (0.20g, 10% purity) and palladium hydroxide on carbon (0.20g) were added, hydrogen replacement (50psi ), and the reaction solution was stirred at 50° C. for 14 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 43-5. The crude product was directly used in the next reaction without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.52 (d, J=6.4Hz, 1H), 4.15-4.01 (m, 4H), 3.41 (s, 6H), 2.84-1.76 (m, 1H).

5) Synthesis of Compound 43-6

Compound 43-5 (150 mg, 0.83 mmol) was dissolved in 1 mol/L hydrochloric acid aqueous solution (3 mL) at room temperature, and the reaction solution was stirred at 80° C. for 1 hour. After the reaction was completed, the reaction liquid was cooled to room temperature, poured into water (10 mL) for dilution, and extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 43-6. ¹ H NMR (400 MHz, CDCl ₃ ) δ9.82 (s, 1H), 4.47-4.36 (m, 2H), 4.35-4.24 (m, 2H), 3.43-3.29 (m, 1H).

6) Synthesis of compound 43

At room temperature, compound 43-6 (54.9mg, 0.41mmol), compound 25-2 (70mg, 0.14mmol) and acetic acid (8.19mg, 0.14mmol) were dissolved in methanol (10mL), and the reaction mixture was stirred at 25°C for 0.5 hours, then sodium cyanoborohydride (25.7mg, 0.41mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours hour. After the reaction was completed, the reaction solution was poured into water (30 mL) for dilution, and extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (dichloromethane/methanol=0/1) to obtain compound 43. MS-ESI: m/z 564.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.33(dd, J=8.4 ,2.0Hz,1H),5.18-5.07(m,1H),4.79(s,1H),4.24-4.12(m,2H),4.07(t,J＝8.8Hz,1H),4.04-3.90(m, 1H),3.86-3.73(m,3H),3.70-3.56(m,1H),2.84-2.72(m,3H),2.65-2.56(m,2H),2.55-2.43(m,1H),2.13- 1.98 (m, 1H), 1.80-1.67 (m, 4H), 1.64 (d, J=6.8Hz, 3H), 1.61-1.46 (m, 1H), 0.99-0.84 (m, 1H).

Example 44: N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-(2-(pyrrolidin-1-yl)ethyl) Base) piperidin-3-yl) azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (44)

At room temperature, compound 25-2 (100mg, 0.22mmol), 1-(2-chloroethyl)pyrrolidine (75mg, 0.44mmol) and N,N-diisopropylethylamine (229mg, 1.77mmol) were dissolved In acetonitrile (5 mL), the reaction mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was separated by silica gel preparative thin layer chromatography (pure methanol) to obtain compound 44. MS-ESI: m/z 543.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.50(d, J=8.4Hz, 1H), 7.33(dd, J=8.4 ,2.0Hz,1H),5.17-5.09(m,1H),4.80(s,1H),4.08(t,J=8.4Hz,1H),4.04-3.91(m,1H),3.77(dd,J= 8.8,6.0Hz,1H),3.74-3.57(m,1H),2.95-2.82(m,2H),2.74-2.66(m,2H),2.65-2.58(m,4H),2.57-2.51(m, 2H), 2.50-2.41(m, 1H), 2.05-1.96(m, 1H), 1.84-1.78(m, 4H), 1.77-1.67(m, 4H), 1.64(d, J＝6.8Hz, 3H) ,1.60-1.49(m,1H),0.99-0.82(m,1H).

Example 45: (1R,3r)-3-(4-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2, 4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-ol (45) and Example 46: (1S,3s)-3-(4-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-alcohol (46 )

1) Synthesis of compound 45-2

At room temperature, compound 45-1 (200mg, 0.83mmol), allyl chloroformate (120mg, 1.00mmol) and sodium carbonate (176mg, 1.66mmol) were mixed in dichloromethane (5mL), and the reaction mixture was stirred at room temperature for 16 Hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 45-2. ¹ H NMR (400MHz, CDCl ₃ )δ6.02-5.88(m,1H),5.34-5.26(m,1H),5.24-5.18(m,1H),4.59(d,J=5.6Hz,2H), 4.30-4.13(m,2H),3.96(t,J=8.4Hz,2H),3.64(dd,J=8.8,6.0Hz,2H),2.89-2.67(m,2H),2.31-2.17(m, 1H), 1.71-1.60 (m, 3H), 1.44 (s, 9H), 1.12-0.96 (m, 2H).

2) Synthesis of compound 45-3

Compound 45-2 (269 mg, 0.83 mmol) was dissolved in dioxane (3 mL) at room temperature, 4 mol/L dioxane hydrochloride solution (3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 45-3. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 225.2 [M+H] ⁺ .

3) Synthesis of compound 45-4

At room temperature, compound 19-3 (245 mg, 0.69 mmol), compound 45-3 (215 mg, 0.82 mmol) and N,N-diisopropylethylamine (0.30 mL, 2.06 mmol) were dissolved in acetonitrile (4 mL), The reaction mixture was stirred at 60°C for 16 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture to dilute, and ethyl acetate (30 mL×3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 45-4. MS-ESI: m/z 530.2 [M+H] ⁺ .

4) Synthesis of compound 45-5

At room temperature, compound 45-4 (375 mg, 0.71 mmol), tetrakis(triphenylphosphine) palladium (41 mg, 0.04 mmol) and phenylsilane (765 mg, 7.07 mmol) were mixed in dichloromethane (5 mL), and the reaction mixture Stir at room temperature for 3 hours. After the reaction was completed, the reaction solution was separated by silica gel column chromatography (triethylamine/methanol=10/1) to obtain compound 45-5. MS-ESI: m/z 446.2 [M+H] ⁺ .

5) Synthesis of compound 45 and compound 46

At room temperature, compound 45-5 (150 mg, 0.34 mmol), compound 33-1 (48 mg, 0.34 mmol, 70% purity) and acetic acid (2 mg, 0.03 mmol) were dissolved in methanol (3 mL), stirred at room temperature for 0.5 hours, Sodium cyanoborohydride (63 mg, 1.01 mmol) was then added and the reaction mixture was stirred at room temperature for a further 15.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 45-6. Compound 45-6 was resolved by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: methanol phase 40 %; flow rate: 70mL/min; column temperature: room temperature), compound 45 and compound 46 were obtained. Compound 45: MS-ESI: m/z 530.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.10(m,1H),4.81(s,1H),4.08(t,J＝8.4Hz,1H),4.04-3.93(m,1H),3.79-3.73(m, 1H),3.72-3.59(m,1H),2.96-2.86(m,3H),2.54-2.42(m,1H),2.18-2.11(m,2H),1.93-1.86(m,2H),1.84- 1.77(m,2H),1.75-1.69(m,2H),1.65(d,J＝6.8Hz,3H),1.56-1.51(m,1H),1.31(s,3H),1.21-1.15(m, 2H). Compound 46: MS-ESI: m/z 530.4 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.1Hz,1H),5.17-5.10(m,1H),4.81(s,1H),4.08(t,J＝8.4Hz,1H),4.04-3.89(m,1H),3.80-3.73(m, 1H),3.72-3.56(m,1H),2.95-2.88(m,2H),2.53-2.42(m,1H),2.40-2.29(m,1H),2.22-2.15(m,2H),1.98- 1.90(m,2H),1.88-1.79(m,2H),1.77-1.68(m,2H),1.65(d,J＝6.8Hz,3H),1.55-1.47(m,1H),1.29(s, 3H), 1.25-1.15 (m, 2H).

Example 47: (R)-2-(4-(1-(7-((1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (47)

1) Synthesis of compound 47-2

At room temperature, compound 19-3 (90 mg, 0.26 mmol), N,N-diisopropylethylamine (0.10 mL, 0.79 mmol) and compound 47-1 (65 mg, 0.27 mmol) were dissolved in acetonitrile (2 mL) , the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, add water (30mL) to the reaction liquid for dilution, extract with ethyl acetate (30mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. (petroleum ether/ethyl acetate=3/1) to obtain compound 47-2. MS-ESI: m/z 546.2 [M+H] ⁺ .

2) Synthesis of compound 47-3

Compound 47-2 (135 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (0.80 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, Compound 47-3 was obtained. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 446.1 [M+H] ⁺ .

3) Synthesis of Compound 47

Compound 47-3 (138mg, 0.25mmol), iodoethanol (127mg, 0.74mmol) and potassium carbonate (102mg, 0.74mmol) were mixed in acetonitrile (10mL) at room temperature, and the reaction mixture was stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was separated by silica gel column chromatography (pure methanol) to obtain compound 47. MS-ESI: m/z 490.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.54(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.09(m,1H),4.81(s,1H),4.09(t,J＝8.8Hz,1H),4.05-3.89(m,1H),3.80-3.74(m, 1H), 3.73-3.60(m, 3H), 3.15-3.05(m, 2H), 2.64(t, J=5.6Hz, 2H), 2.54-2.43(m, 1H), 2.29-2.16(m, 2H) , 1.78-1.70 (m, 2H), 1.65 (d, J=6.8Hz, 3H), 1.61-1.49 (m, 1H), 1.32-1.21 (m, 2H).

Example 48: (R)-5-(3-(1-(2-oxaspiro[3.3]heptan-6-yl)piperidin-4-yl)azetidin-1-yl)- N-(1-(2,4-dichlorophenyl)ethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (48)

1) Synthesis of Compound 48

Compound 45-5 (40mg, 0.09mmol), 2-oxaspiro[3.3]heptan-6-one (12mg, 0.11mmol) and acetic acid (1mg, 0.01mmol) were dissolved in methanol (1mL) at room temperature , stirred for 10 minutes, sodium cyanoborohydride (17 mg, 0.27 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction is complete, add water (20 mL) to the reaction mixture to dilute, extract with ethyl acetate (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and prepare a thin layer of the residue on silica gel. Chromatography (pure methanol) yields compound 48. MS-ESI: m/z 542.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.52(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.08(m,1H),4.80(s,1H),4.72(s,2H),4.60(s,2H),4.09(t,J＝8.4Hz,1H),4.05 -3.90(m,1H),3.79-3.73(m,1H),3.72-3.60(m,1H),3.09-3.00(m,2H),2.88-2.77(m,1H),2.55-2.43(m, 3H), 2.19-2.12(m, 2H), 2.11-2.01(m, 2H), 1.84-1.74(m, 2H), 1.65(d, J=6.8Hz, 3H), 1.62-1.52(m, 1H) ,1.27-1.16(m,2H).

Example 49: (R)-N-(1-(2,4-dichlorophenyl)ethyl)-5-(3-(1-(3-(methylsulfonyl)propyl)piperidine- 4-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (49)

At room temperature, compound 45-5 (100mg, 0.22mmol) and compound 49-1 (59mg, 0.20mmol) were dissolved in acetonitrile (10mL), then N,N-diisopropylethylamine (87mg, 0.67mmol ), and the reaction solution was stirred at 80° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was subjected to preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex Luna C18 150*25mm*10 μm; mobile phase: water (0.1% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0 -10min, 20-40%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 49. MS-ESI: m/z 566.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.05(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.16-5.09(m,1H),4.81(s,1H),4.10(t,J=8.4Hz,1H),4.05-3.93(m,1H),3.78(dd,J= 8.4,6.0Hz,1H),3.73-3.62(m,1H),3.27-3.17(m,4H),2.99(s,3H),2.87-2.79(m,2H),2.56-2.39(m,3H) , 2.16-2.07 (m, 2H), 1.89-1.79 (m, 2H), 1.65 (d, J=6.8Hz, 4H), 1.38-1.23 (m, 2H).

Example 50: (R)-N-(1-(2,4-dichlorophenyl)ethyl)-5-(3-(1-(oxetan-3-yl)piperidine-4 -yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (50)

Compound 45-5 (80 mg, 0.18 mmol) and oxetanone (26 mg, 0.36 mmol) were dissolved in methanol (3 mL) at room temperature, followed by the addition of acetic acid (11 mg, 0.18 mmol) and sodium cyanoborohydride (23mg, 0.36mmol), the reaction solution was stirred at room temperature for 14 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 50. MS-ESI: m/z 502.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.53(d, J=2.0Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.17-5.09(m,1H),4.81(s,1H),4.68(t,J＝6.8Hz,2H),4.62-4.58(m,2H),4.09(t,J＝ 8.4Hz,1H),4.04-3.95(m,1H),3.80-3.73(m,1H),3.72-3.61(m,1H),3.53-3.44(m,1H),2.87-2.76(m,2H) ,2.56-2.43(m,1H),1.93-1.82(m,2H),1.79-1.69(m,2H),1.65(d,J＝6.8Hz,3H),1.59-1.45(m,1H),1.28 -1.17(m,2H).

Example 51: (R)-2-(3-(1-(7-((1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)piperidin-4-yl)azetidin-1-yl)ethan-1-ol (51)

1) Synthesis of compound 51-2

At room temperature, compound 19-3 (200mg, 0.58mmol), compound 51-1 (168mg, 0.70mmol) and N,N-diisopropylethylamine (0.30mL, 1.75mmol) were dissolved in acetonitrile (3mL) , the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/acetic acid Ethyl ester=3/1) separation to obtain compound 51-2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.29(d, J=7.6Hz, 1H), 8.13(s, 1H), 7.67-7.62(m, 2H), 7.44(dd, J=8.4, 2.0 Hz,1H),5.26(s,1H),5.14-5.03(m,1H),4.32-4.13(m,2H),3.91-3.74(m,2H),3.63-3.50(m,2H),2.92- 2.77(m,2H),2.24-2.11(m,1H),1.74-1.60(m,3H),1.58(d,J＝6.8Hz,3H),1.36(s,9H),0.99-0.72(m, 2H).

2) Synthesis of compound 51-3

Compound 51-2 (290 mg, 0.53 mmol) was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (1.60 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain compound 51-3. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 446.1 [M+H] ⁺ .

3) Synthesis of compound 51-5

At room temperature, compound 51-3 (280 mg, 0.50 mmol), compound 51-4 (105 mg, 0.60 mmol) and acetic acid (3 mg, 0.05 mmol) were dissolved in methanol (5 mL), and the reaction mixture was stirred for 10 minutes before adding Sodium cyanoborohydride (94mg, 1.50mmol), the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 51-5. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 604.3 [M+H] ⁺ .

4) Synthesis of compound 51

Compound 51-5 (290 mg, 0.40 mmol, 84% purity) was dissolved in dichloromethane (2.5 mL) at room temperature, and trifluoroacetic acid (1.00 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the pH of the reaction mixture was adjusted to neutral with ammonia water, concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography. (ammonia bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: water (0.5% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 25-55% ); flow rate: 25mL/min; column temperature: room temperature), and then separated by silica gel preparative thin-layer chromatography (ethyl acetate/methanol=0/1) to obtain compound 51. MS-ESI: m/z 490.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.05(s, 1H), 7.56-7.49(m, 2H), 7.34(dd, J=8.4, 2.0Hz, 1H), 5.20(s, 1H), 5.19 -5.13(m,1H),4.41-4.20(m,2H),3.58-3.47(m,4H),2.97(t,J＝7.6Hz,2H),2.94-2.80(m,2H),2.61(t ,J=6.0Hz,2H),2.28-2.13(m,1H),1.79-1.67(m,2H),1.65(d,J=6.8Hz,3H),1.63-1.57(m,1H),1.06- 0.93(m,1H),0.91-0.78(m,1H).

Example 52: (R)-2-(9-(7-((1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazolo[1,5 -a]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-ol (52)

1) Synthesis of compound 52-2

At room temperature, compound 19-3 (300mg, 0.88mmol) and compound 52-1 (223mg, 0.88mmol) were dissolved in acetonitrile (8mL), then N,N-diisopropylethylamine (339mg, 2.63mmol ), and the reaction mixture was stirred at 80°C for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/5) to obtain compound 52-2. MS-ESI: m/z 560.0 [M+H] ⁺ .

2) Synthesis of compound 52-3

At room temperature, compound 52-2 (300mg, 0.44mmol, 83% purity) was dissolved in dioxane (5mL), and after stirring evenly, 4mol/L dioxane hydrochloride solution (5.00mL) was slowly added, and the reaction The solution was stirred at 20°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 52-3. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 460.1 [M+H] ⁺ .

3) Synthesis of compound 52

At room temperature, compound 52-3 (180mg, 0.34mmol, 93% purity) was dissolved in acetonitrile (8mL), then 2-iodoethanol (116mg, 0.67mmol) and potassium carbonate (140mg, 1.01mmol) were added, and the reaction mixture Stir at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 36-66%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 52. MS-ESI: m/z 504.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.05(s, 1H), 7.54(d, J=2.4Hz, 1H), 7.51(d, J=8.4Hz, 1H), 7.34(dd, J=8.4 ,2.0Hz,1H),5.21(s,1H),5.19-5.13(m,1H),3.69(t,J＝6.4Hz,2H),3.65- 3.47(m, 4H), 2.61-2.46(m, 6H), 1.66(d, J=6.8Hz, 3H), 1.56(t, J=5.6Hz, 4H), 1.52-1.37(m, 4H).

Example 53 and Example 54: 2-((R)-3-(1-(7-(((R)-1-(2-chloro-4-methylphenyl)ethyl)amino)-[ 1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol and 2-(R) -3-(1-(7-((R)-1-(4-chloro-2-methylphenyl)ethyl)amino)-[1,2,4]triazolo[1,5-a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (53 and 54)

1) Synthesis of Compound 53-2

At room temperature, compound 53-1 (500mg, 3.30mmol) was dissolved in toluene (6mL), replaced with nitrogen, and a solution of methylmagnesium bromide in tetrahydrofuran (3.30mL, 9.90mmol, 3mol/L) was added, and the reaction mixture was heated at 110 °C and stirred for 18 hours. After the reaction solution was cooled to 0°C, dilute hydrochloric acid was slowly added dropwise to pH~2, the temperature was raised to reflux and stirred for 1 hour, and then cooled to room temperature. The reaction solution was slowly added sodium hydroxide to pH ~ 7, extracted with ethyl acetate (30 mL × 3), combined organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to obtain compound 53-2. MS-ESI: m/z 169.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.51(d, J=7.6Hz, 1H), 7.25(s, 1H), 7.15-7.11(m, 1H), 2.64(s, 3H), 2.37(s, 3H).

2) Synthesis of compound 53-3

At room temperature, compound 53-2 (550mg, 2.28mmol, 70% purity) and sodium bicarbonate (575mg, 6.85mmol) were dissolved in ethanol (2mL), then hydroxylamine hydrochloride (317mg, 4.57mmol) was added, and the reaction mixture was Stir at 25°C for 12 hours. The reaction solution was poured into water (30 mL) for dilution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 53-3. MS-ESI: m/z 184.1 [M+H] ⁺ .

3) Synthesis of Compound 53-4

At room temperature, compound 53-3 (450 mg, 1.52 mmol, 62% purity) was dissolved in tetrahydrofuran (10 mL), slowly added dropwise into borane dimethyl sulfide solution (0.50 mL, 5.00 mmol, 10 mol/L), and the reaction mixture Stir at 60°C for 16 hours. The reaction solution was cooled to 0°C, and methanol (10 mL) was slowly added dropwise until no obvious bubbles were generated. Stirring was continued at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 53-4. MS-ESI: m/z 153.0 [M-NH ₃ +H] ⁺ .

4) Synthesis of compound 53-5

At room temperature, compound 53-4 (200mg, 0.84mmol, 68% purity), compound 19-2 (158mg, 0.84mmol) and N,N-diisopropylethylamine (0.40mL, 2.51mmol) were dissolved in acetonitrile (5 mL), the reaction mixture was stirred at 60°C for 4 hours. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain compound 53-5. The crude product was directly used in the next reaction without further purification. MS-ESI: m/z 322.0 [M+H] ⁺ .

5) Synthesis of compound 53 and compound 54

At room temperature, compound 53-5 (110 mg, 0.27 mmol, 78% purity), intermediate C (89 mg, 0.40 mmol) and cesium fluoride (81 mg, 0.53 mmol) were dissolved in dimethyl sulfoxide (3 mL), and the reaction The mixture was stirred at 80°C for 16 hours. After completion of the reaction, filter, and the filtrate passes through a reversed-phase chromatographic column (acetonitrile/water system, chromatographic column: C18spherical 20-35 μm 40g, mobile phase: water (0.2% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 50-65%); flow rate: 40mL/min; column temperature: room temperature) separation to obtain compound 53-6. Then separated by supercritical fluid chromatography (chromatographic column: DAICEL CHIRALCEL OX (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: methanol phase 60%; flow rate: 80mL/min; column temperature: room temperature), to obtain compound 53 and compound 54. (Compound 53 was the first eluting peak, compound 54 was the second eluting peak). Compound 53: MS-ESI: m/z 470.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.04(s, 1H), 7.37(d, J=7.6Hz, 1H), 7.28(s, 1H), 7.13(d, J=7.6Hz, 1H), 5.15-5.08(m,1H),4.84(s,1H),4.08(t,J＝8.4Hz,1H),4.03-3.93(m,1H),3.80-3.75(m,1H),3.74-3.68( m,3H),3.05-2.95(m,2H),2.63(t,J＝5.6Hz,2H),2.51-2.43(m,1H),2.32(s,3H),2.20-2.12(m,1H) , 1.86-1.73 (m, 4H), 1.63 (d, J=6.8Hz, 3H), 1.62-1.56 (m, 1H), 0.96-0.88 (m, 1H). Compound 54: MS-ESI: m/z 470.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.05(s, 1H), 7.39(d, J=8.0Hz, 1H), 7.29(s, 1H), 7.14(d, J=8.0Hz, 1H), 5.17-5.10(m,1H),4.86(s,1H),4.10(t,J＝8.4Hz,1H),4.06-3.95(m,1H),3.83-3.78(m,1H),3.76-3.65( m,3H),3.06-2.94(m,2H),2.64(t,J＝6.0Hz,2H),2.54-2.45(m,1H),2.33(s,3H),2.20-2.11(m,1H) , 1.87-1.75 (m, 4H), 1.65 (d, J=6.8Hz, 3H), 1.64-1.57 (m, 1H), 0.97-0.90 (m, 1H).

Example 55: 2-(R)-3-(1-(7-((R)-1-(2,4-difluorophenyl)ethyl)amino)-[1,2,4]triazole And[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (55)

Compound 55 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 470.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.36(d, J=8.4Hz, 1H), 7.25(d, J=2.0Hz, 1H), 7.18(dd, J=8.4 ,2.0Hz,1H),4.97-4.93(m,1H),4.73(s,1H),4.12-4.04(m,1H),4.03-3.87(m,1H),3.82-3.74(m,1H), 3.73-3.60(m,3H),3.01-2.86(m,2H),2.56(t,J＝6.0Hz,2H),2.52-2.39(m,4H),2.13-2.01(m,1H),1.83- 1.69 (m, 4H), 1.67-1.53 (m, 4H), 0.96-0.85 (m, 1H).

Example 56: 2-(R)-3-(1-(7-((R)-1-(4-chloro-2-fluorophenyl)ethyl)amino)-[1,2,4]tri Azolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (56)

Compound 56 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 458.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.56-7.45(m, 1H), 7.08-6.93(m, 2H), 5.09-5.03(m, 1H), 4.97(s, 1H), 4.11(t, J=8.4Hz, 1H), 4.07-3.91(m, 1H), 3.84-3.78(m, 1H), 3.77-3.65(m, 3H), 3.04-2.91(m, 2H) ,2.59(t,J=6.0Hz,2H),2.53-2.45(m,1H),2.10(t,J=11.2Hz,1H),1.85-1.71(m,4H),1.70-1.57(m,4H ),0.96-0.86(m,1H).

Example 57: 2-(R)-3-(1-(7-((R)-1-(2-chloro-4-fluorophenyl)ethyl)amino)-[1,2,4]tri Azolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (57)

Compound 57 was prepared according to the synthesis method of Example 19. MS-ESI: m/z 474.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.03(s, 1H), 7.46(t, J＝8.4Hz, 1H), 7.26(dd, J＝10.4, 1.6Hz, 1H), 7.21(d, J =8.4Hz,1H),5.10-5.03(m,1H),4.95(s,1H),4.11(t,J=8.4Hz,1H),4.05-3.93(m,1H),3.80(dd,J= 8.4,6.0Hz,1H),3.74-3.63(m,3H),2.92(t,J=9.2Hz,1H),2.54(t,J=6.0Hz,2H),2.50-2.41(m,1H), 2.09-1.98 (m, 1H), 1.84-1.70 (m, 4H), 1.68 (d, J=6.8Hz, 3H), 1.63-1.53 (m, 1H), 0.94-0.85 (m, 1H).

Example 58: 2-(R)-2-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)morpholinyl)ethan-1-ol (58)

1) Synthesis of compound 58-2

At room temperature, compound 58-1 (3.00g, 16.20mmol) was dissolved in anhydrous methanol (30mL), under ice cooling, nitromethane (2.97g, 48.59mmol) and triethylamine (3.28g, 32.39mmol) were added ), and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain compound 58-2. ¹ H NMR (400MHz, CDCl ₃ ) δ4.52-4.45 (m, 1H), 4.39-4.32 (m, 2H), 4.00 (td, J=8.8, 1.6Hz, 2H), 3.93 (dd, J=8.8 , 5.2Hz, 1H), 3.74 (dd, J = 8.8, 5.6Hz, 1H), 3.32 (brs, 1H), 2.68-2.57 (m, 1H), 1.44 (s, 9H).

2) Synthesis of compound 58-3

At room temperature, compound 58-2 (3.60 g, 14.62 mmol) and platinum dioxide (664 mg, 2.92 mmol) were added into methanol (50 mL), and reacted at room temperature for 16 hours under hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 58-3. ¹ H NMR (400MHz, CDCl ₃ ) δ4.01-3.88 (m, 3H), 3.71 (dd, J=8.4, 5.6Hz, 1H), 3.65 (td, J=8.0, 3.2Hz, 1H), 2.82( dd, J=8.8, 3.6Hz, 1H), 2.57-2.38(m, 1H), 2.45(dd, J=12.8, 8.4Hz, 1H), 1.44(s, 9H).

3) Synthesis of compound 58-4

At room temperature, compound 58-3 (3.10g, 14.33mmol) and triethylamine (3.99mL, 28.67mmol) were dissolved in dichloromethane (50mL), and chloroacetyl chloride (1.78g, 15.77mmol) was slowly added dropwise, at room temperature React for 16 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 58-4. ¹ H NMR (400MHz, CDCl ₃ ) δ7.13-7.03 (m, 1H), 4.00 (s, 2H), 3.96 (td, J=12.8, 2.8Hz, 2H), 3.94-3.86 (m, 2H), 3.73 (dd, J = 8.8, 5.6 Hz, 1H), 3.50-3.41 (m, 1H), 3.26-3.17 (m, 1H), 3.64-2.52 (m, 1H), 1.44 (s, 9H).

4) Synthesis of intermediate 58-5

Compound 58-4 (3.10 g, 10.59 mmol) and potassium tert-butoxide (1.19 g, 10.59 mmol) were dissolved in tetrahydrofuran (20 mL) at room temperature, and the reaction solution was reacted at 60° C. for 2 hours. After completion of the reaction, the reaction liquid was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to obtain intermediate 58-5. ¹ H NMR (400MHz, CDCl ₃ ) δ6.57(s, 1H), 4.37-4.16(m, 2H), 3.98(td, J=8.4, 3.6Hz, 2H), 3.90(dd, J=8.8, 5.6 Hz,1H),3.87-3.81(m,1H),3.74(dd,J＝16.0,10.0Hz,1H),3.32-3.17(m,2H),3.69-2.60(m,1H),1.44(s, 9H).

5) Synthesis of Compound 58-6

At room temperature, sodium hydrogen (749mg, 18.73mmol, 60% purity) and N,N-dimethylformamide (30mL) were added sequentially, and intermediate 58-5 (3.20g, 12.49mmol) was added under nitrogen protection, and ice bath After reacting for 0.5 hours, benzyl-2-bromoethyl ether (4.03 g, 18.73 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated ammonium chloride aqueous solution (100 mL) was slowly added to the reaction liquid to quench, and extracted with ethyl acetate (80 mL×2). The organic phases were combined, washed with saturated brine (80 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate=0/1) to obtain compound 58-6. ¹ H NMR (400MHz, CDCl ₃ )δ7.39-7.34(m,2H),7.33-7.25(m,3H),4.51(s,2H),4.35-4.14(m,2H),3.96(td,J =8.4,2.0Hz,2H),3.88(dd,J=8.8,5.6Hz,1H),3.85-3.78(m,1H),3.73-3.67(m,3H),3.63-3.56(m,2H), 3.36-3.26 (m, 2H), 2.64-2.54 (m, 1H), 1.45 (s, 9H).

6) Synthesis of compound 58-8 and compound 58-9

At room temperature, compound 58-6 (2.60g, 6.66mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and borane dimethyl sulfide (3.30mL, 33.29mmol, 10mol/L) was added dropwise under ice cooling, and the reaction mixture was Stir at 50°C for 16 hours. The reaction solution was cooled to room temperature, methanol (10 mL) was slowly added dropwise to the reaction solution to quench borane until no bubbles emerged, and the reaction solution was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1), and distilled under reduced pressure to obtain the crude product. Glycerol (2 mL) and methanol (20 mL) were added, stirred overnight at room temperature, and concentrated under reduced pressure to obtain the residue After separation by silica gel column chromatography (petroleum ether/ethyl acetate=1/1), compound 58-7 was obtained. MS-ESI: m/z 377.1 [M+H] ⁺ . Compound 58-7 (1.67g) was resolved by supercritical fluid chromatography (chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient formulation Ratio: methanol phase 30%; flow rate: 60mL/min; column temperature: room temperature), to obtain compound 58-8 and compound 58-9. (Compound 58-8 was the first eluting peak, compound 58-9 was the second eluting peak).

7) Synthesis of compound 58-10

At room temperature, compound 58-9 (500mg, 1.33mmol) was dissolved in dichloromethane (10mL), replaced with nitrogen, the reaction solution was cooled to -78°C, and boron tribromide (3.33g, 13.28mmol) was slowly added dropwise, The reaction was stirred at -78°C for 30 minutes, then methanol (2 mL) was added, and the reaction mixture was stirred at -78°C for an additional 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain compound 58-10. The crude product was directly used in the next reaction without purification. MS-ESI: m/z 187.1 [M+H] ⁺ .

8) Synthesis of Compound 58

At room temperature, compound 21-3 (100mg, 0.17mmol, 71% purity) and compound 58-10 (46mg, 0.17mmol) were dissolved in dichloroethane (10mL), then diisopropylethylamine (112mg ,0.87mmol), the reaction solution was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5 μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 45-75%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 58. MS-ESI: m/z 560.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.54 (d, J = 2.0Hz, 1H), 7.51 (d, J = 8.8Hz, 1H), 7.35 (dd, J = 8.4, 1.6Hz, 1H), 5.18-5.09(m,1H),4.87-4.86(m,1H),4.09-3.97(m,2H),3.94-3.78(m,3H),3.73-3.61(m,4H),2.86-2.71(m ,3H),2.53(t,J=5.6Hz,2H),2.20(td,J=11.2,2.8Hz,1H),1.84(t,J=11.2Hz,1H),1.64(d,J=6.8Hz ,3H).

biological evaluation

The content of the present invention is further described and explained in conjunction with test examples below, but these test examples are not meant to limit the scope of the present invention.

Test Example 1: In Vitro CCR4 Calcium Flux Activity Detection Experiment

1.1. Experimental materials

1.2. Experimental steps

The in vitro CCR4 receptor cell functional assay was used to detect the activity of the compound to be tested by using a cell line stably expressing CCR4 and FLIPR assay. In the experiment, the initial concentration of the test compound was 10 μM, diluted 3 times, and a total of 10 concentrations were tested in duplicate wells.

A cell line stably expressing CCR4 (CCR4-HEK293) was cultured in DMEM medium supplemented with fetal bovine serum, G418 and penicillin-streptomycin. Configure 250mM FLIPR experimental buffer, 2×Fluo-4Direct ^TM loading buffer. Collect and resuspend CCR4-HEK293 cells to 1x10 ⁶ /mL, and add 20 μL of cell suspension to each reaction well of a 384-well cell culture microplate. Cells were cultured overnight. The next day, discard the supernatant from the cell reaction plate, and add 20 μL of assay buffer and 20 μL of Fluo-4Direct ^TM loading buffer. from Compound plate (pre-gradiently diluted in 384-well PP microplate) was added to the cell reaction plate with 10 μL of the dilution of the compound to be tested, incubated at 37°C in a 5% carbon dioxide environment for 50 minutes, and then incubated at room temperature for 10 minutes. The reaction plate was transferred to a FLIPR Tetra System (Molecular Devices). Add 10 μL of 6×EC ₈₀ recombinant human CCL22 dilution to the cell reaction plate and shake twice. Read the fluorescence value, use Graphpad software to analyze the data, and calculate the IC ₅₀ of the compound on the calcium flow inhibitory activity of CCR4 receptor cells.

1.3. Experimental results

The inhibitory activity of the disclosed compounds on CCR4 receptor cell calcium flow was determined by the above tests, and the measured IC ₅₀ values are shown in Table 1. The experimental results show that the test compound of the present invention has significant inhibitory activity on the calcium flow of CCR4 receptor cells.

Table 1: Inhibitory activity of test compounds on calcium flux

Note: Comparative Example 1 was prepared according to WO2018/02299; Comparative Example 2 was prepared according to Example 38 of WO2019/147862

Test Example 2: CCR4-mediated CCRF-CEM Cell Chemotaxis Inhibition Activity Test

2.1. Experimental materials

2.2. Experimental steps

Centrifuge the CCRF-CEM cells, remove the supernatant, resuspend in FBS, adjust the cell density to 2×10 ⁶ /mL, and divide the cells into 96-well cell plates, 99 μL per well. Prepare compound stock solutions with a concentration of 10 mM in test tubes using DMSO as a solvent, and then use DMSO as a solvent to serially dilute the samples as required. Transfer 1 μL of the compound to be tested to each well of the cells in the 96-well plate, and incubate for 0.5 hour at 37° C. in a 5% carbon dioxide incubator. Using DPBS as a solvent, prepare a hCCL22 solution with a concentration of 2.5 nM, take out the lower cell plate of ChemoTX, and dispense hCCL22 into the cell plate, 30 μL per well. Cover the lower plate with a ChemoTX microporous membrane, remove the cells from the incubator, transfer 50 μL of cells to the microporous membrane per well, cover the lid, and incubate for another 1.5 hours at 37°C in a 5% carbon dioxide incubator . Take out the cell plate, remove the microporous membrane, add 30 μL ATP binding agent CellTiter-Glo reagent to the cells in the lower plate, mix well with a row gun, transfer 30 μL per well to a white opaque 96-well plate, and incubate in the dark for 10 minutes , using the Envision multi-mode plate reader to read the luminescence (Luminescence) signal, using Graphpad software to fit the inhibitory rate of the compound on cell migration, and calculate the IC ₅₀ .

2.3. Experimental results

The inhibitory activity of the compounds of the present invention on CCR4-mediated chemotaxis of CCRF-CEM cells was determined by the above tests, and the measured IC ₅₀ values are shown in Table 2. The experimental results show that the test compounds of the present invention have significant inhibitory activity on CCRF-CEM cell chemotaxis, and the inhibitory activity of most compounds is obviously stronger than that of Comparative Example 1 and Comparative Example 2.

Table 2: Inhibitory activity of test compounds on chemotaxis of CCRF-CEM cells

Test Example 3: CCR4-mediated Th2 and Treg cell chemotaxis inhibitory activity test

3.1. Experimental materials

3.2. Experimental steps

The hTh2 (or hTreg) cells were centrifuged to remove the culture medium, resuspended in 100% fetal bovine serum, adjusted the cell density to 2×10 ⁶ /mL, and split the cells into 96-well cell plates, 99 μL per well. Prepare compound stock solutions with a concentration of 10 mM in test tubes using DMSO as a solvent, and then use DMSO as a solvent to serially dilute the samples as needed. Transfer 1 μL of the compound to be tested to each well of the cells in the 96-well plate, and incubate for 0.5 hour at 37° C. in a 5% carbon dioxide incubator. Using DPBS as a solvent, prepare a recombinant human CCL22 solution with a concentration of 2.5 nM, take out the lower cell plate of ChemoTX, and dispense recombinant human CCL22 into the cell plate, 30 μL per well. Cover the lower plate with a ChemoTX microporous membrane, take out the cells from the incubator, transfer 50 μL of cells per well to the microporous membrane, cover the lid, and store at 37°C in a fine atmosphere of 5% carbon dioxide. Incubate for another 1.5 hours in the incubator. Take out the cell plate, carefully remove the microporous membrane, add 30 μL ATP binding agent CellTiter-Glo reagent to the cells in the lower plate, mix well with a row gun, transfer 30 μL per well to a white opaque 96-well plate, and incubate in the dark for 10 minutes Finally, the luminescent signal was read with the Envision multi-mode plate reader, and the inhibition rate of the compound was obtained by fitting with Graphpad software.

3.3. Experimental results

The inhibitory activity of the compounds of the present invention on CCR4-mediated chemotaxis of Th2 and Treg cells was determined by the above tests, and the measured IC ₅₀ values are shown in Table 3. Experimental results show that the test compound of the present invention has significant inhibitory activity on both Th2 cell chemotaxis and Treg cell chemotaxis.

Table 3: Inhibitory activity of test compounds on Th2 and Treg cell chemotaxis

Test Example 4: Evaluation of the occupancy rate of the compound on the cell surface CCR4 receptor

4.1. Experimental materials

4.2. Experimental steps

The CCRF-CEM cells were centrifuged at 300 rcf to remove the medium, resuspended in 100% fetal calf serum, adjusted the cell density to 2×10 ⁶ /mL, and split the cells into 96-well cell plates, 99 μL per well. Prepare compound stock solutions with a concentration of 10 mM in test tubes using DMSO as a solvent, and then use DMSO as a solvent to serially dilute the samples as required. Two wells were set for each concentration of the compound, 1 μL of the compound to be tested was transferred to each well of the 96-well plate, and placed in a cell culture incubator with 5% carbon dioxide at 37° C. for 0.5 hours. by DPBS was used as the solvent, and hCCL22 solution with a concentration of 20 μM was prepared, and the 96-well plate was taken out of the cell culture incubator, and 1 μL of hCCL22 solution was added to one well of each concentration of the compound, and 1 μL of DPBS solution was added to the other well, and placed at 37 °C again. , and incubate for 0.5 hr in a 5% carbon dioxide incubator. Take out the cell plate, add 1 μL of PE-conjugated anti-human CD194 (CCR4) antibody to each cell well, and incubate in a refrigerator at 4°C in the dark for 0.5 hours. Remove the cell plate, centrifuge at 4°C and 300 rcf to remove the medium, add 200 μL of DPBS solution that was pre-cooled at 4°C to each well, resuspend the cells and centrifuge at 4°C and 300 rcf to remove the supernatant, add 200 μL of DPBS to wash again. After removing the supernatant by centrifugation, resuspend the cells with 100 μL of pre-cooled DPBS. The intensity of PE fluorescence signal in each well was detected by Cytek Aurora flow cytometer, and the curve of compound dose versus CCR4 occupancy was obtained by fitting with Graphpad software.

4.3. Experimental results

The occupancy rate of the compound of the present invention on the CCR4 receptor on the cell surface was determined by the above method, and the experimental results are shown in Table 4. The experimental results show that the test compound of the present invention can show a higher occupancy rate of CCR4 at a lower concentration, and under the premise of producing the same CCR4 occupancy rate, the required concentration of the test compound of the present invention is significantly lower than that of Comparative Example 1 and Comparative example 2.

Table 4: Evaluation of test compounds on cell surface CCR4 receptor occupancy

Test Example 5: Evaluation of Pharmacokinetic Properties in Mice

5.1. Experimental method

The test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Balb/c male mice were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg. The test compound was dissolved in 4% DMSO+96% (0.5% HPMC+0.1% TW-80) or 5% DMSO+40% PEG400+10% Solutol+45% water, vortexed and sonicated to prepare the corresponding concentration of clear The solution was filtered through a microporous membrane for later use. Balb/c male mice were selected, and the candidate compound solution was orally administered at a dose of 10 mg/kg or 50 mg/kg. Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated.

5.2. Experimental results

The experimental results are shown in Table 5. The experimental results show that the test compound of the present invention has better pharmacokinetic properties in mice.

Table 5: Pharmacokinetic properties of test compounds in mice

Test Example 6: Evaluation of Pharmacokinetic Properties in Rats

6.1. Experimental method

The test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Male SD rats were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg. The test compound was dissolved in 5% DMSO + 40% PEG400 + 10% Solutol + 45% water, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Male SD rats were selected, and the candidate compound solution was orally administered at a dose of 50 mg/kg. Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated.

6.2. Experimental results

The experimental results are shown in Table 6. The experimental results show that the test compound of the present invention has better pharmacokinetic properties in rats.

Table 6: Pharmacokinetic properties of test compounds in rats

Test Example 7: Evaluation of Pharmacokinetic Properties of Beagle Dogs

7.1. Experimental method

The test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Male Beagle dogs were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg. The test compound was dissolved in 5% DMSO + 40% PEG400 + 10% Solutol + 45% water, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Male Beagle dogs were selected, and the candidate compound solution was orally administered at a dose of 5 mg/kg. Collect whole blood at a certain time point, prepare plasma, analyze drug concentration by LC-MS/MS method, and calculate pharmacokinetics mechanical parameters.

7.2. Experimental results

The experimental results are shown in Table 7. The experimental results show that the test compound of the present invention has better in vivo pharmacokinetic properties in Beagle dogs.

Table 7: In vivo pharmacokinetic properties of test compounds in Beagle dogs

Test Example 8: Evaluation of the Inhibitory Activity of Compounds on the hERG Potassium Ion Channel

8.1. Experimental materials

8.2. Experimental steps

8.2.1. Cell culture and treatment

CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35 mm, placed in an incubator at 37°C and 5% CO ₂ , and subcultured at a ratio of 1:5 every 48 hours. The medium formula: 90% Ham's F12 culture Base, 10% fetal bovine serum, 100g/mL geneticin and 100g/mL hygromycin. Aspirate the cell culture medium, rinse with extracellular fluid once, add 0.25% trypsin-EDTA solution, and digest at room temperature for 3-5 minutes. Aspirate the digestion solution, resuspend the cells with extracellular solution, and transfer the cells to a laboratory dish for electrophysiological recording.

8.2.2. Electrophysiological recording process

In CHO cells stably expressing hERG potassium channels, hERG potassium channel currents were recorded by whole-cell voltage-clamp technique at room temperature. The resistance of the tip after perfusion with the inner solution of the electrode is about 2-5MΩ, and the glass microelectrode is inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp software through the computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz. After obtaining the whole-cell recording, the cell was clamped at -100mV, and the step voltage of the evoked hERG potassium current was given a 2s depolarization voltage from -100mV to +20mV, then repolarized to -50mV, and returned to - for 1s. 100mV. Give this voltage stimulation every 5s, and start the administration process after confirming that the hERG potassium current is stable (at least 1 minute), and give each test concentration of the compound at least 1 minute until the steady state of action. Data analysis and processing used pClamp 10, GraphPad and Excel software.

8.3. Experimental results

The experimental results are shown in Table 8. The experimental results showed that the test compounds had weak inhibitory activity on the hERG potassium ion channel, and the IC ₅₀ values of most test compounds were greater than 10 μM, showing a low risk of hERG potassium ion channel inhibition. The compound of Comparative Example 1 has strong inhibitory activity on the hERG potassium ion channel, with an IC ₅₀ value of 0.15 μM.

Table 8: Inhibitory activity of test compounds on hERG potassium ion channel

Test Example 9: Pharmacodynamic experiment of FITC-induced delayed-type hypersensitivity in mice in vivo

9.1. Experimental materials

9.2. Experimental steps

7-week-old BALB/c mice (Victoria Lihua) acclimatized for 1 week after arriving at the animal room. According to body weight, they were divided into model control group, positive control dexamethasone group and test compound group. On days 0 and 1, BALB/c mice were anesthetized with isoflurane, and their abdomens were shaved with 400 μL of 0.5% FITC (dissolved in 50% acetone + 50% dibutyl phthalate). sensitization. On days 6, 7, 8, and 9, 20 μL of 0.5% FITC was applied to the inner and outer sides of the left ear of the mice for modeling stimulation. Compound 19 and the compound of Comparative Example 1 were dissolved in the vehicle (5% DMSO+40% PEG400+10% Solutol+45% water), and the compound of Comparative Example 2 was dissolved in the vehicle (10% PEG400+90% water). Semethasone was dissolved in 0.5% MC. On day 5 and day 6, 7, 8, and 9, oral administration was performed 30 minutes before modeling stimulation, once a day. Before FITC stimulation on days 6, 7, 8, and 9 and 24 hours after the last stimulation, ear thickness measurements were performed on the left ear with a spiral micrometer. All animals were weighed once a day during the experiment. All experimental procedures have been reviewed by IACUC.

9.3. Experimental results

The experimental results are shown in Figure 1 and Figure 2. The experimental results showed that oral administration of Compound 19 could significantly inhibit ear swelling in this animal model. Moreover, at the same dose and the same route of administration, Compound 19 exhibited significantly better pharmacodynamic effects than those of Comparative Example 1 and Comparative Example 2.

Test Example 10: Pharmacodynamic experiment of OXA-induced mouse atopic dermatitis in vivo

10.1. Experimental materials

10.2. Experimental steps

7-week-old BALB/c mice (Shanghai Jihui) acclimatized for 1 week after arriving in the animal room. According to body weight, they were divided into model control group, positive control dexamethasone group and test compound group. On day 0, BALB/c mice were anesthetized with isoflurane, shaved their abdomen, and sensitized with 100 μL of 1.5% OXA (dissolved in 80% acetone + 20% olive oil). On day 7, 20 μL of 1.5% OXA was applied to the inner and outer sides of the left ear of the mice for modeling stimulation. Compound 19 and the compound of Comparative Example 1 were dissolved in the vehicle (5% DMSO+40% PEG400+10% Solutol+45% water), and the compound of Comparative Example 2 was dissolved in the vehicle (10% PEG400+90% water). Semethasone was dissolved in 0.5% MC. On the 6th and 7th day, continuous administration was performed orally, once a day. Ear thickness measurements were taken with a screw micrometer on the left ear on days 6 and 8 (24 hours after stimulation). All animals were weighed once a day during the experiment. All experimental procedures have been reviewed by IACUC.

10.3. Experimental results

The experimental results are shown in Figure 3. The experimental results showed that oral administration of Compound 19 could significantly inhibit ear swelling in this animal model. Moreover, at the same dose and the same route of administration, Compound 19 exhibited significantly better pharmacodynamic effects than those of Comparative Example 1 and Comparative Example 2.

Claims

The compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolites,

in,

X 1 and X 2 are each independently selected from C or N;

X 3 , X 4 and X 5 are each independently selected from CR b or N;

Each R 1 is independently selected from H, halogen, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl or cyano;

R 2 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 3 -C 4 cycloalkyl;

R 3 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 3 -C 4 cycloalkyl;

R4 is selected from

Y is selected from CH2 or O;

R a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl or cyano, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclic , 5-6 membered heteroaryl or phenyl are each independently optionally selected from one or more groups selected from halogen, hydroxyl, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy replaced by

Each R b is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl or cyano, wherein the C 1 -C 3 alk radical, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl each independently optionally selected from halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl or C 1 -C 3 One or more groups of alkoxy are substituted;

Each R c is independently selected from H, halogen, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, wherein each of the C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl is independently optionally substituted by one or more groups selected from halogen, hydroxyl, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy;

Each R d is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl or cyano, wherein the C 1 -C 3 alk radical, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl each independently optionally selected from halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl or C 1 -C 3 One or more groups of alkoxy are substituted;

each Re is independently -LR f ;

Each R f is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-7 membered Heterocyclyl, R g C(O)NH-, R g NHC(O)-, R g OC(O)NH-, R g S(O) 2 NH-, R g NHS(O) 2 -, R g g S(O) 2 -, -(CH 2 ) n -hydroxyl, -(CH 2 ) n -amino, -(CH 2 ) n -cyano, -(CH 2 ) n -carboxy or 2-oxa- Spiro[3,3]heptyl, wherein the C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, -(CH 2 ) n -hydroxyl, -(CH 2 ) n -amino, -(CH 2 ) n -cyano or -(CH 2 ) n -carboxyl are each independently optionally selected from halogen, hydroxyl, amino, cyano , C 1 -C 3 alkyl or one or more groups of C 1 -C 3 alkoxy;

Each R g is independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl;

Each L is independently selected from a chemical bond, a 4-7 membered heterocyclic group, a C 1 -C 3 alkylene group or a C 3 -C 6 cycloalkylene group, wherein the 4-7 membered heterocyclic group, C 1 -C 3 alkylene or C 3 -C 6 cycloalkylene are each independently optionally selected from halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy Substituted by one or more groups of the group;

Z 1 is any integer from 0 to 3;

Z 2 is any integer from 0 to 3;

Z 3 is any integer from 0 to 4;

Z 4 is any integer from 0 to 2; and

Each n is independently any integer from 0 to 3.
According to claim 1, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein,

One of X1 and X2 is N, the other is C,

At least one of X 3 , X 4 and X 5 is N.
According to claim 1 or 2, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein,
selected from
The compound of formula (I) or its isotope-labeled compound according to any one of claims 1-3, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable A salt, or a prodrug thereof, or a metabolite thereof, which is a compound of formula (II) or an isotope-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

Wherein, R 1 -R 3 , X 1 -X 5 , Y, R a , R c , R d , R e , Z 1 , Z 2 , Z 3 and Z 4 are as defined in claim 1;

In particular, among them,
selected from and / or
selected from Rc , Rd , Re , Z2 and Z3 are as defined in claim 1;

More particularly, it is formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula ( II-7) or formula (II-8) compound or its isotope labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrugs, or its metabolites,

Wherein, R 1 -R 3 , R a , R d , R e , Z 1 and Z 3 are as defined in claim 1.
The compound of formula (I) or its isotope-labeled compound according to any one of claims 1-3, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical An acceptable salt, or a prodrug thereof, or a metabolite thereof, which is a compound of formula (III) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer thereof body mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

Wherein, R 1 -R 3 , R a , R e and Z 1 are as defined in claim 1.
The compound of formula (I) or its isotope-labeled compound according to any one of claims 1-3, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical An acceptable salt, or a prodrug thereof, or a metabolite thereof, which is a compound of formula (IV) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer thereof body mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

Wherein, R 1 -R 3 , R a , R e and Z 1 are as defined in claim 1.
According to any one of claims 1-6, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein,

each Re is independently -LR f ;

Each R f is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-7 membered hetero Cyclo, R g C(O)NH-, R g NHC(O)-, R g OC(O)NH-, R g S(O) 2 NH-, R g NHS(O) 2 -, R g S(O) 2 -, -(CH 2 ) n -hydroxyl, -(CH 2 ) n -amino, -(CH 2 ) n -cyano, -(CH 2 ) n -carboxy or 2-oxa-spiro [3,3] Heptyl, wherein the C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, -(CH 2 ) n -hydroxyl, -(CH 2 ) n -amino, -(CH 2 ) n -cyano or -(CH 2 ) n -carboxyl are each independently optionally selected from hydroxyl or C 1 -C 3 alkyl Substituted by one or more groups; preferably each R f is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl , hydroxyl, carboxyl, methoxy, oxetanyl, azetidinyl, 1,1-dioxothietanyl, morpholinyl, pyrrolidinyl, piperidinyl, tetra Hydropyranyl, acetamido, methanesulfonyl, CH 3 S(O) 2 NH- or 2-oxa-spiro[3,3]heptyl;

R g is selected from C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl or 3-4 membered heterocyclic group, preferably selected from methyl, ethyl, Cyclopropyl, cyclobutanyl or oxetanyl;

each n is independently any integer from 0 to 3, and

L is selected from the group consisting of chemical bond, methylene optionally substituted by methyl or ethyl, ethylene, propylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, azepine Cyclobutane, pyrrolidinylene or piperidinylene;

In particular,

Each Re is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
The compound of formula (I) or its isotope-labeled compound according to any one of claims 1-7, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein,

Each R 1 is independently selected from H, halogen, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy, preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or methanesulfonyl; and/or

R is selected from H or C 1 -C 3 alkyl, preferably from H or methyl; and/or

R 3 is selected from H or C 1 -C 3 alkyl, preferably from H or methyl.
According to any one of claims 1-8, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein,

Each R a is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl or cyano, wherein The C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 3 -C 4 cycloalkyl are each independently optionally replaced by halogen, hydroxyl, cyano, C 1 -C 3 alkyl or C 1 - C3alkoxy substitution, R is preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, Methoxy, ethoxy, hydroxymethyl, 1,1-dimethylhydroxymethyl, cyano, or methoxymethylene; and/or

Each R b is independently selected from H, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl or cyano, wherein the C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl Each is independently optionally substituted by halogen, hydroxyl, amino, cyano or C 1 -C 3 alkyl, R b is preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl group, difluoromethyl, trifluoromethyl, trifluoroethyl or cyano; and/or

Each R c is independently selected from H, halogen or C 1 -C 3 alkyl, preferably selected from H, fluorine, chlorine, methyl or ethyl; and/or

Each R d is independently selected from H, halogen, C 1 -C 3 alkyl or cyano, preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or cyano .
According to any one of claims 1-9, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein,

Z 1 is 2; and/or

Z2 is 0 or 1; and/or

Z3 is 0 or 1; and/or

Z 4 is 1; and/or

Each n is independently 0 or 1.
According to any one of claims 1-10, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical An acceptable salt, or a prodrug thereof, or a metabolite thereof, selected from:
A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-11 or its isotope-labeled compound, or its optical isomers, geometric isomers, tautomers or A mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.
According to any one of claims 1-11, the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Use of an above-acceptable salt, or a prodrug thereof, or a metabolite thereof in the preparation of a medicament as a CCR4 antagonist, in particular, the medicament is used for treating or preventing a disease or condition mediated by CCR4.
The use according to claim 13, wherein the disease or disease mediated by CCR4 is selected from atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis One or more immune-related diseases in inflammation;

or,

The disease or condition mediated by CCR4 is cancer.