TW202340197A - A small molecule antagonist of ccr4 and its use - Google Patents

Abstract

The invention relates to a small molecule antagonist of CCR4 and its use. Specifically, the present invention relates to a compound of formula (I) or an isotope-labeled compound thereof, or an optical isomer, geometric isomer, tautomer thereof or mixtures of isomers, or a pharmaceutically acceptable salt, or a precursor drug, or a metabolite thereof, and its use in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by CCR4.

Description

A CCR4 small molecule antagonist and its use

The present invention belongs to the field of medicine, and specifically relates to a CCR4 small molecule antagonist and its use.

CCR4 (C-C chemokine receptor type 4) is a G protein-coupled receptor and 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). CCR4 binds to endogenous ligands and activates the coupled G protein, which then causes a cascade cell activation effect. Through a series of information transmission, chemotactic target cells migrate to specific locations 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 evasion and promoting tumor cell metastasis. Therefore, CCR4 has become an important drug target for the treatment of immune-related diseases and tumor immunotherapy. The development of CCR4 small molecule antagonists will provide new options for the treatment of the above diseases.

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

The purpose of the present invention is to provide a new type of CCR4 small molecule antagonist. Such compounds have good activity in inhibiting CCR4 and exhibit excellent effects and effects.

In a first aspect, the 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 salt thereof , or its prodrug, or its metabolite,

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;

R ¹ is each 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 _4cycloalkyl 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;

、

或

； R ⁴ is selected from

,

or

;

Y is selected from CH ₂ 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 group, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl , 5-6 membered heteroaryl or phenyl, 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;

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 alkyl , C ₁ -C ₃ alkoxy or C ₃ -C ₆ cycloalkyl, each independently optionally selected from halogen, hydroxyl, amine, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ Substituted by one or more alkoxy groups;

Each R ^c is independently selected from H, halogen, C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl, wherein the C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl is each independently selected optionally substituted with 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 alkyl , C ₁ -C ₃ alkoxy or C ₃ -C ₆ cycloalkyl, each independently optionally selected from halogen, hydroxyl, amine, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ Substituted by one or more alkoxy groups;

Each R ^e 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 Member 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 S(O) ₂ -, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amine, -(CH ₂ ) _n -cyano, -(CH ₂ ) _n -carboxyl or 2-oxo Hetero-spiro[3,3]heptanyl, 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 -amine, -(CH ₂ ) _n -cyano or -(CH ₂ ) _n -carboxy are each independently selected from halogen, hydroxyl, and amino as needed. Substituted with one or more groups of , cyano, C ₁ -C ₃ alkyl or 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 chemical bond, 4-7 membered heterocyclylene, C ₁ -C ₃ (alkylene) or C ₃ -C ₆ (alkylene) cycloalkyl, wherein the 4- Each of the 7-membered (ethylene)heterocyclylene, C ₁ -C ₃ (ethylene)alkylene or C ₃ -C ₆ (ethylene)cycloalkyl group is independently selected from the group consisting of halogen, hydroxyl, amine, Substituted with one or more groups of 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, the compound of formula (I) or an isotopically labeled compound thereof, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite,

One of X ¹ and X ² is N, the other is C,

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

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

選自

、

、

、

Selected from

,

,

,

In some embodiments of the present invention, the compound of formula (I) or its isotopically 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 pharmaceutically acceptable salts, or prodrugs thereof, or metabolites thereof,

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

In particular,

選自

、

、

、

Selected from

,

,

,

、

或

；和/或

,

or

;and / or

選自

、

或

Selected from

,

or

；R^c、R^d、R^e、Z²和Z³如式(I)中所定義；

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

More specifically, it is formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula ( II-7) or the compound of formula (II-8) or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite,

Among them, R ¹ -R ³ , R ^a , R ^d , ^Re , 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 isotopically 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 pharmaceutically acceptable salts, or prodrugs thereof, or metabolites thereof,

Among them, R ¹ -R ³ , R ^a , Re and Z ¹ are as ^defined in formula (I).

In some embodiments of the present invention, the compound of formula (I) or its isotopically 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 pharmaceutically acceptable salts, or prodrugs thereof, or metabolites thereof,

Among them, R ¹ -R ³ , R ^a , Re and Z ¹ are as ^defined in formula (I).

In some embodiments of the present invention, compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof In a structural mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

Each R ^e is independently -LR ^f ;

R ^f is each 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 member 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 S(O) ₂ -, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amine, -(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, -( _CH2 ) _n -amine, -( _CH2 ) _n -cyano or -( _CH2 ) _n -carboxy are each independently selected from hydroxyl or _C1 - _C3 as appropriate Alkyl is substituted by one or more groups; preferably R ^f is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, Fluoromethyl, hydroxyl, carboxyl, methoxy, oxetanyl, azetidinyl, 1,1-bis-oxothietanyl, morpholinyl, pyrrolidinyl, piperidine base, tetrahydropyranyl, acetamide, methanesulfonyl, CH ₃ S(O) ₂ NH- or 2-oxa-spiro[3,3]heptyl;

^Rg is selected from C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl or 3-4 membered heterocyclyl, preferably selected from methyl, ethyl, cyclopropyl, cyclobutanyl or oxygen heterocyclobutanyl;

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

L is selected from chemical bonds, methylene, ethylidene, propylene, cyclopropylene, cyclobutylene optionally substituted by methyl or ethyl, (Extension)cyclopentyl, (Extension)cyclohexylene, (Extension)azetidinyl, (Extension)pyrrolidinyl or (Extension)piperidinylalkyl;

In particular,

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

,

In some embodiments of the present invention, compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof In a structural mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

R ¹ is each 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 is selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or methanesulfonyl; and/or

R ² is selected from H or C ₁ -C ₃ alkyl, preferably selected from H or methyl; and/or

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

In some embodiments of the present invention, compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof In a structural mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

R ^a is each 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 group, C ₁ -C ₃ alkoxy group or C ₃ -C ₄ cycloalkyl group is each independently optionally replaced by a halogen, a hydroxyl group, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ - C ₃ alkoxy substituted, R ^a 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

R ^b is each independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl or cyano, wherein each of the C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl 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, cyclo propyl, difluoromethyl, trifluoromethyl, trifluoroethyl or cyano; and/or

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

R ^d is each 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 base.

In some embodiments of the present invention, compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof In a structural mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof,

Z ¹ is 2; and/or

^Z2 is 0 or 1; and/or

Z ³ 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) or their isotope labeled compounds of the present invention, Or its optical isomers, geometric isomers, tautomers or isomer mixtures, or its pharmaceutically acceptable salts, or its prodrugs, or its metabolites including but not limited to:

For the sake of simplicity, the "compounds of formula (I), (II), (III), (IV)" or "compounds of the present invention" mentioned below can also cover formulas (I), (II), (III) , (IV) Any isotopically 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 exist in R configuration or S configuration, and the various isomers formed thereby are optical isomers. body. Optical isomers include all diastereoisomers, enantiomers, meso, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatography columns or by chiral synthesis.

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

The term "tautomer" refers to an isomer resulting from the rapid movement of an atom between two positions in a molecule. Those with ordinary knowledge in the technical field 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 include isotopically labeled compounds in which any atom in the compound is replaced by its isotope atom. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the compounds of formula (I) wherein one or more atoms are of the same atomic number but different atoms than those normally found in nature. mass or mass number of atoms.

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, and 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 sulfur Isotopes such as ^35S .

Isotopically labeled compounds of formulas (I), (II), (III) and (IV) can generally be prepared by conventional techniques known to those of ordinary skill in the art or by using appropriate isotopically labeled reagents instead of previously used ones. Non-labeled reagents are prepared in a manner similar to that described in the Examples and Preparations attached hereto.

The compounds of formula (I), (II), (III) and (IV) may exist in the form of pharmaceutically acceptable salts, for example, the acid addition of compounds of formula (I), (II), (III) and (IV) Salt-forming and/or base-addition salts. Unless otherwise indicated, "pharmaceutically acceptable salts" as used herein include acid addition salts or base addition salts that may occur in compounds of formula (I), (II), (III), (IV).

Pharmaceutically acceptable salts of compounds of formula (I), (II), (III) and (IV) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form nontoxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate Acid salt, citrate, cyclohexylamine sulfonate, ethylene disulfonate, formate, fumarate, glucose heptonate, gluconate, glucuronate, hexafluorophosphate , 2-(4-hydroxybenzyl)benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate, malate , maleate, malonate, methanesulfonate, methyl sulfate, naphthoate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate , hexadecanoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, Stearate, salicylate, tannin, tartrate, tosylate and trifluoroacetate. Suitable base addition salts are formed from bases that form nontoxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salt. Half-salts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts. 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 of ordinary skill in the art.

Certain compounds of the invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, compounds of formulas (I), (II), (III), and (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. No matter in which form they exist, compounds of formulas (I), (II), (III), and (IV) are included in the scope of the present invention.

To avoid ambiguity, the terms used in this article are defined below. Unless otherwise stated, the terms used herein have the following meanings.

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

"Prodrugs" refer to derivatives that are converted into compounds of the present invention by reacting with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, through oxidation, reduction, hydrolysis, etc., respectively catalyzed by enzymes.

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

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

The term "carboxyl" refers to -C(=O)-; the term "carboxyl" refers to -C(=O)-NH ₂ ; the term "sulfonyl" refers to -S(=O) ₂ -; And the term "sulfonamide" refers to -S(=O) ₂ -NH ₂ .

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 the group are independently substituted Replaced with corresponding number of substituents.

As used herein, the term "each independently" means that when there is more than one substituent, the substituents may be the same or different.

When used herein, the terms "optionally" or "optionally" mean that the event they describe may or may not occur. For example, a group that is "optionally substituted" means that the group may 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 of atoms having 1 to 8 carbon atoms, and the term "C _1-6 alkyl" refers to a straight-chain or branched radical having 1 to 6 carbon atoms. Branched chain radicals, the term "C _1-3 alkyl" refers to straight or branched chain radicals having 1 to 3 carbon atoms. The term "C _1-8 alkyl" includes in 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 , isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2, 3-dimethylbutyl, hexyl, etc. Alkyl groups are optionally 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 a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). replace). For example, the term "C _{1 -C 6} haloalkyl" refers to a C _{1 -C 6} alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen of the alkyl group atoms are 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 element of the alkyl group hydrogen atoms are replaced by halogen atoms); the term "C _1- C ₃ haloalkyl" refers to a C _1- C ₃ 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); 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, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As yet another example, the term "C ₁ haloalkyl" refers to a methyl group having 1, 2 or 3 halogen 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, where alkyl is as defined above. The (alkylene) group is preferably an (alkylene) group having 1 to 6 carbon atoms (i.e., C _1- C ₆ (alkylene) group), and more preferably an (alkylene) group having 1 to 3 carbon atoms. Alkylene (i.e. C _1- C ₃ (alkylene) alkyl). Examples of (alkylene) groups include, but are not limited to, -CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH(CH ₂ CH ₃ )- , -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 a fully carbocyclic ring system having n carbon atoms. The term "C ₃ -C ₆ cycloalkyl" refers to an all-carbocyclic ring system having 3 to 6 carbon atoms, and "C ₃ -C ₄ cycloalkyl" refers to an all-carbocyclic ring system having 3 to 4 carbon atoms. . Examples of C ₃ -C ₆ cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl. In addition, the cycloalkyl group may optionally be substituted with one or more appropriate 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 the group consisting of O, S, S (O) ₂ and N. For example, 4-7 membered heterocyclyl groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, Piperidine, morpholine, piperazine, oxepane, thiepane, azepane, 1,1-bisoxothiethane. In addition, the heterocyclyl group may optionally be substituted with one or more appropriate substituents.

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

In this article, the numerical range related to the number of substituents, the number of carbon atoms, and the number of ring atoms represents an enumeration of all integers within the range, and the range is only used as a simplified expression. 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 numerical range related to the number of substituents, the number of carbon atoms, and the number of ring atoms also covers any subrange thereof, and each subrange is also deemed to be disclosed herein.

The compounds of the present invention may be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those with ordinary knowledge in the relevant technical field can refer to the synthesis routes of specific compounds in specific embodiments of the present invention, and appropriately adjust the reaction raw materials and reaction conditions to obtain synthesis methods for other compounds.

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV) or an isotope-labeled compound thereof, or an optical isomer or geometric isomer thereof. , mutual transformation isomers or isomer mixtures, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof, and pharmaceutically acceptable carriers.

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 oil, polyalkylene glycol , petroleum jelly, mannitol, cellulose, cellulose derivatives, saccharin sodium, 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, etc.

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 colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops agents, nose drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, 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 ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various particulate drug delivery systems.

In some embodiments, the dosage form of the pharmaceutical composition is selected from tablets, granules, powders, syrups, inhalants and injections.

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 admixtures (for example, starch , lactose, sucrose, glucose, mannitol and silicic acid); (b) binders (e.g. carboxymethylcellulose, alginate, coagulant gum, polyvinylpyrrolidone, sucrose and gum arabic); (c) humectants (e.g., glycerol); (d) disintegrants (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solution retardants (e.g., paraffin); (f) absorption enhancers (e.g., quaternary ammonium compounds); (g) wetting agents (e.g., hexadecan alkanols and glyceryl monostearate); (h) adsorbents (e.g., kaolin and bentonite) and (i) lubricants (e.g., 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 non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions. The parenteral preparations provided herein are optionally contained in unit-dose or multi-dose sealed containers (e.g., ampoules) and can be stored in freeze-dried (lyophilized) containers requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately before use. conditions. Examples of suitable diluents for reconstituting pharmaceutical compositions (e.g., prior to injection) include bacteriostatic water for injection, 5% aqueous dextrose solution, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water. Ionized water and combinations thereof.

Sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane. Inhalers may contain excipients such as lactose, or aqueous solutions such as polyethylene oxide-9-lauryl ether, glycolate and deoxycholate, or oily solutions as nasal drops or sprays , or administered 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.), for example, 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight. , 10-80% by weight, etc.

Specifically, the pharmaceutical composition of the present invention may specifically include 0.01-10 g (eg 0.05g, 0.1g, 0.5g, 1g or 5g, etc.) of the compound 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 The use of the mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a medicament as a CCR4 antagonist for the treatment or prevention of a disease or disorder mediated by CCR4. Compounds of formula (I), (II), (III), (IV) or their isotopically labeled compounds, or their optical isomers, geometric isomers, tautomers or isomer mixtures, or their pharmaceutically acceptable The accepted salts, or prodrugs thereof, or metabolites thereof may be used to treat or prevent diseases or conditions mediated by CCR4 in a subject in need thereof.

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 the treatment of a disease or condition in a mammal, especially a human, and includes: (a) inhibiting the infection, disease or condition, that is, containing or delaying the development of the infection, disease or condition; (b) alleviating the infection, disease or condition; Disease or condition, i.e. cause resolution of the disease or condition, and/or (c) cure of the infection, disease or condition.

The term "prevention" as used herein includes prophylactic therapy in mammals, especially humans, aimed at reducing the likelihood of occurrence of infection, disease or disorder. Patients may be selected for preventive therapy based on an increased risk of infection or disease or condition compared with the general population. "Prevention" may include treating subjects who have not yet developed 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 to prevent or treat diseases or disorders mediated by CCR4. disease.

In some embodiments, the CCR4-mediated disease or disorder may be selected from one or more of atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, and rheumatoid arthritis. related diseases. In other embodiments, the CCR4-mediated disease or disorder may be cancer. The cancer is preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cell cancer, testicular cancer, cervical cancer 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 neuroepithelialoma, glioma, Ependymomas, neuroblastomas, ganglioneuromas, medulloblastomas, pineal cell tumors, meningiomas, neurofibromas, schwannomas, and Wilms' tumors.

In a fourth aspect, the invention provides a method of treating or preventing a disease or disorder mediated by CCR4, the method comprising administering to a subject in need thereof a therapeutically effective amount of formula (I), (II), (III) ), (IV) the compound or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its 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 The mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, is used to prevent or treat diseases or conditions mediated by CCR4.

In some embodiments, the compounds of the invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, bucally, ocularly, transpulmonary, transrespiratory, transvaginally, transrectally, intraperitoneally, intralesionally , and around the lesion.

"Therapeutically effective amount" means that a compound of the invention when administered alone or in combination is effective in treating or An amount that prevents a disease or disorder mediated by CCR4.

The specific dose administered will depend on the route of administration, severity of the disease, age and weight of the patient, and other factors generally considered by the attending physician in determining the individual regimen and dosage level most appropriate 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 application frequency can be determined by those with ordinary knowledge in the technical field, for example, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 2 days. times, 3 times a day, etc.

Those of ordinary skill in the art will understand that the definitions and preferred terms described in one aspect of the invention are equally applicable to other aspects. Those with ordinary skill in the art will understand that the embodiments of various aspects of the present invention can be combined in various ways without departing from the subject matter and idea of the present invention, and these combinations are also included in the scope of the present invention.

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

Figure 2 shows the effects 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.

The compounds of formula (I) of the present invention can be synthesized by a variety of methods familiar to those with ordinary knowledge in the field of organic synthesis. The following specific examples provide some exemplary synthesis methods for compounds of formula (I). methods, which are well known in the field of synthetic chemistry. Obviously, with reference to the exemplary schemes in this patent, those with ordinary knowledge in the art can easily design synthetic routes for other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.

The present invention will be further described below with reference to examples; however, 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 experiments and product analysis and detection are conventional instruments and equipment commonly used in organic synthesis.

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

At room temperature, S -mandelic acid (56.00g, 368.29mmol) was dissolved in a mixed solvent of isopropyl alcohol (420mL) and ethanol (280mL), the temperature was raised to 60°C, and compound A-1 (70.00g, 70.00g, 368.29 mmol), the reaction mixture was stirred at 60°C for 30 minutes and then at room temperature for 24 hours. A large amount of white solid precipitated and was filtered. The filter cake was washed with acetone (105 mL). After vacuum drying, it was added to a mixed solvent of isopropyl alcohol (315 mL) and ethanol (210 mL), stirred at 60°C for 30 minutes, cooled to room temperature, and stirred for 12 hours. A large amount of white solid precipitated and was filtered. The filter cake was washed with acetone (70 mL) and dried under vacuum to obtain compound A-2 . Compound A-2 (45.00g, 131.49mmol) was dissolved in dichloromethane (400mL) and 4mol/L sodium hydroxide aqueous solution (120mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The liquids were separated at rest, and 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 )δ 7.71 (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: ( R )-3-(piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester

1) Synthesis of compound B-2

Compound B-1 (25.00g, 158.95mmol) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (25.00g, 88.31mmol) were dissolved in isopropanol (400mL) at room temperature. , add nickel iodide (2.76g, 8.83mmol), (1 R , 2 R )-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). Combine the organic phases, wash with saturated brine (150mL B-2 . MS-ESI: m/z 269.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.30 (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

Compound B-2 (26.00g, 96.75mmol) and ( S )-4-isopropyloxazolidin-2-one (24.99g, 193.50mmol) were dissolved in anhydrous toluene (400mL) at room temperature, and then Add tris(dibenzylideneacetone)dipalladium (4.43g, 4.84mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (2.31g, 4.84mmol) and cesium carbonate (31.52 g, 96.75 mmol), nitrogen replacement, 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 (500mL), the organic phase was washed with saturated brine (500mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue The material was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1). The crude product was beaten with petroleum ether (200mL) and filtered. The filter cake was washed with petroleum ether (30mL) and concentrated under reduced pressure to obtain Compound B-3 .

¹ H NMR (400MHz, CD ₃ OD) δ 8.29 (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

Compound B-3 (10.00g, 27.67mmol) was dissolved in anhydrous acetic acid (200mL) at room temperature. Under nitrogen protection, platinum dioxide (1.00g, 4.40mmol) was slowly added and replaced with hydrogen. The reaction mixture was heated 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 crude product. The crude product was dissolved in dichloromethane (50 mL), and 1 mol/L sodium hydroxide aqueous 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 crude intermediate B. Dissolve the crude product of Intermediate B in methyl tert-butyl ether (1000 mL) at room temperature, add S -mandelic acid (13.61g, 89.45mmol) in batches under reflux, and stir the reaction mixture at room temperature for 16 hours. A large amount of white solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (400 mL) and then 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 crude product. Dissolve the crude product in methyl tert-butyl ether (500 mL) at room temperature, add S -mandelic acid (8.23g, 54.09mmol) in batches under reflux, and react the reaction mixture at room temperature for 16 hours. A large amount of white solid precipitated, and the reaction mixture was filtered. The filter cake was washed with methyl tert-butyl ether (300 mL) and then 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)δ 4.00-3.88(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 at 80°C. Stir for 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 the crude product, which was then Dissolve in dichloromethane (150 mL), filter, and concentrate the filtrate under reduced pressure to obtain compound C-1 .

¹ H NMR(400MHz, CD ₃ OD)δ 4.01-3.85(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

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

Intermediate D: (1 R ,3 r )-3-(( R )-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1- Methyl formate hydrochloride

1) Synthesis of compound D-2

Compound D-1 (5.00g, 35.17mmol) was dissolved in a mixture solvent of tetrahydrofuran (30mL) and water (30mL) at room temperature, and then lithium hydroxide (4.43g, 105.52mmol) was added. The reaction solution was heated at 25°C. Stir for 15 hours. Adjust the pH of the reaction solution to ~4 with 1 mol/L hydrochloric acid aqueous solution, and extract with dichloromethane (50 mL × 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 used directly in the next reaction without purification. ¹ H NMR (400MHz, 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 triacetyloxyborohydride (3.95g, 18.72mmol) were dissolved in 1,2-bis Ethyl chloride (150 mL), acetic acid (0.70 mL, 12.48 mmol) was slowly added dropwise to the reaction solution at -5°C. After the dropwise addition was completed, the reaction solution was stirred at 20°C for 15 hours. Add compound D-2 (800mg, 6.24mmol) and sodium triacetyloxyborohydride (1316mg, 6.24mmol). The reaction solution is stirred at 20°C for 3 hours. Add compound D-2 (800mg, 6.24mmol) and Sodium triacetylborohydride (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)δ 4.04-3.95(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

Compound D-3 (2.60g, 7.38mmol) was dissolved in a mixed solvent of dichloromethane (30mL) and methanol (3mL) at room temperature, and trimethylsilyldiazomethane (14.70) was slowly added at 0°C. mL, 29.51 mmol), and then stirred at 20°C for 2 hours. After the reaction is completed, acetic acid is slowly added dropwise to the reaction solution until the color of the reaction solution changes from yellow to colorless and no longer bubbles. Add water (30 mL) to dilute, extract with dichloromethane (30 mL), and saturated sodium chloride aqueous solution (25 mL). Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound D-4 .

¹ H NMR(400MHz, CD ₃ OD)δ 4.00-3.89(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

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

Intermediate E: ( R )-3-(azetidin-3-yl)piperidine-1-carboxylic acid allyl ester hydrochloride

1) Synthesis of intermediate E-1

At room temperature, intermediate B (500mg, 2.08mmol) was dissolved in dichloromethane (10mL), sodium carbonate (330mg, 3.12mmol) and allyl chloroformate (376mg, 3.12mmol) were added, and the reaction mixture was heated at 25°C. Stir for 16 hours. Dilute with water (50 mL), extract with ethyl acetate (50 mL , compound E-1 was obtained.

¹ H NMR(400MHz, CDCl ₃ )δ 6.01-5.89(m,1H),5.30(d, J =17.2Hz,1H),5.22(d, J =10.4Hz,1H),4.59(d, J =5.2 Hz,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 is completed, concentrate under reduced pressure to obtain intermediate E. The crude product was used directly in the next reaction without purification.

¹ H NMR (400MHz, CDCl ₃ ) δ 9.80 (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: ( R )-3-(azetidin-3-yl)piperidine-1-carboxylic acid allyl ester hydrochloride

1) Synthesis of compound F-1

At room temperature, compound C-1 (3.00g, 9.49mmol, 90% purity) and tert-butyldiphenylsilyl chloride (3.70mL, 14.24mmol) were added to dichloromethane (20mL) and N , N - To dimethylformamide (20 mL), stir evenly, add imidazole (2.59 g, 37.98 mmol), and stir the reaction solution 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, 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 F-1 . MS-ESI: m/z 523.3[M+H] ⁺ .

2) Synthesis of intermediate F

Under ice bath, 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 allowed to react at room temperature for 16 hours. The reaction solution was diluted with methanol (30 mL), alkaline 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), N , N -dimethylaniline (0.33g, 2.76mmol) was slowly added dropwise, and the reaction solution was Stir at 110°C for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with toluene (30 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL), and anhydrous sodium sulfate. Dry, filter and concentrate under reduced pressure to obtain compound 1-2 . ¹ H NMR (400MHz, CDCl ₃ ) δ 8.16 (d, J =2.0Hz, 1H), 6.52 (d, J =2.0Hz, 1H), 2.62 (s, 3H).

2) Synthesis of compounds 1-3

Compound 1-2 (600mg, 2.99mmol), intermediate A (568mg, 2.99mmol) and N , N -diisopropylethylamine (773mg, 5.98mmol) were dissolved in acetonitrile (15mL) at room temperature. The reaction solution was stirred at 25°C for 2 hours. After the reaction is completed, add water (20 mL) to dilute, extract with ethyl acetate (30 mL × 2), wash with saturated aqueous sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is passed through a silica gel column. Separate by chromatography (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 ) δ 7.91 (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 compounds 1-4

Dissolve compound 1-3 (100 mg, 0.28 mmol) in dichloromethane (5 mL) at room temperature, add m-chloroperoxybenzoic acid (172 mg, 0.85 mmol, 85% purity) in batches, and the reaction solution is at 25°C. Stir for 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 ) δ 8.13 (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

Compound 1-4 (80 mg, 0.21 mmol), N , N -diisopropylethylamine (80 mg, 0.62 mmol) and intermediate C (46 mg, 0.21 mmol) were dissolved in acetonitrile (10 mL) at room temperature. The reaction solution was stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography column: Waters Xbridge 150*25mm*5μm; mobile phase: water (10mM hydrogen carbonate) Ammonium), 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)δ 7.80(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 =6.0Hz ,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-methylpyrazolo[ 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), oxalyl chloride (33.20mL, 392.86mmol) was slowly added dropwise, and the reaction mixture was heated at 60 °C and stirred for 6 hours. After the reaction is completed, filter, and the filtrate is concentrated under reduced pressure to obtain compound 2-2 . The crude product was used directly in the next reaction without 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

Dissolve 3-amino-5-methylpyrazole (2.50g, 25.74mmol) in acetonitrile (25mL) at room temperature, add compound 2-2 (8.08g, 38.61mmol, 55% purity), and the reaction mixture Stir at room temperature for 4 hours. After the reaction was completed, add water (50 mL) to dilute, extract with ethyl acetate (60 mL Ethyl ester = 1/1) was separated to obtain compound 2-3 . MS-ESI: m/z 213.1[M+H] ⁺ .

3) Synthesis of compound 2-4

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

4) Synthesis of compounds 2-5

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

5) Synthesis of compounds 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, add water (30 mL) to dilute, extract with ethyl acetate (50 mL Ethyl ester = 3/1) was separated to obtain compound 2-6 . MS-ESI: m/z 335.9[M+H] ⁺ .

6) Synthesis of compound 2

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) at room temperature. The reaction mixture was stirred at 60°C for 4 hours. After the reaction is completed, add water (20 mL) to dilute, 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. Separated by layer chromatography (pure methanol), and then separated by preparative grade high performance liquid chromatography (formic acid/acetonitrile/water system, chromatography column: Unisil 3-100 C18 Ultra 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 ) δ 8.99 (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 yl)pyrazolo[1,5- a ][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-ol ( 3)

1) Synthesis of compound 3-2

Compound 3-1 (1.80g, 11.91mmol) and ethoxycarbonyl isothiocyanate (1.56g, 11.91mmol) were dissolved in ethyl acetate (20mL) 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 under vacuum to obtain compound 3-2 . MS-ESI: m/z 283.1[M+H] ⁺ .

2) Synthesis of compound 3-3

Compound 3-2 (2.00g, 6.82mmol) was dissolved in 2mol/L sodium hydroxide aqueous solution (20mL) 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 methyl iodide (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 sodium chloride aqueous 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 (400MHz, DMSO- d ₆ ) δ 6.75 (s, 1H), 2.53 (s, 3H).

4) Synthesis of compound 3-5

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) at room temperature. , 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 used directly in the next reaction without purification. MS-ESI: m/z 268.9[M+H] ⁺ .

5) Synthesis of compounds 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. . Cool to room temperature and concentrate under reduced pressure. The resulting residue is 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 compounds 3-7

Compound 3-6 (180 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and m-chloroperoxybenzoic acid (260 mg, 1.28 mmol, 85% purity) was added in portions. The reaction mixture was heated at 20°C. Stir for 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 ) δ 7.48 (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 (200 mg, 0.44 mmol) was dissolved in acetonitrile (8 mL) at room temperature, and intermediate C (194 mg, 0.88 mmol) and N , N -diisopropylethylamine (227 mg, 1.76 mmol) 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 grade high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography column: Waters Xbridge C18 150*25mm*5μm; mobile phase: water ( 10mM ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase (0-10min, 52-82%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 3 . MS-ESI: m/z 558.0[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.54-7.45 (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)pyrazolo [1,5- a ][1,3,5]triazin-2-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (4)

1) Synthesis of compound 4-2

Compound 4-1 (6.50g, 39.88mmol) and ethoxycarbonyl isothiocyanate (6.28g, 47.86mmol) were dissolved in ethyl acetate (50mL) at room temperature, replaced with nitrogen, and the reaction mixture was stirred at 80°C. 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 (17.00g, 50.45mmol, 92% purity) was dissolved in aqueous sodium hydroxide solution (50mL, 2mol/L) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is completed, the reaction mixture is poured into 1 mol/L hydrochloric acid aqueous solution (100 mL), filtered, and the filter cake is vacuum dried to obtain compound 4-3 . MS-ESI: m/z 246.9[M+H] ⁺ .

3) Synthesis of compound 4-4

Compound 4-3 (13.40g, 53.15mmol) and methyl iodide (1.89g, 13.28mmol) were dissolved in N , N -dimethylformamide (150mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. , and then stirred 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 ) δ 13.08 (brs, 1H), 6.53 (s, 1H), 2.53 (s, 3H).

4) Synthesis of compound 4-5

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) at room temperature. , the reaction mixture was stirred at 100°C for 2 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and concentrated under reduced pressure to obtain compound 4-5 . The crude product was used directly in the next reaction without purification. MS-ESI: m/z 278.8[M+H] ⁺ .

5) Synthesis of compounds 4-6

Compound 4-5 (1.60g, 5.74mmol), intermediate A (1.65g, 8.62mmol) and pyridine (4.60mL, 57.45mmol) were dissolved in acetonitrile (30mL) at room temperature, and the reaction mixture was stirred at 50°C. 0.5 hours. After the reaction was completed, 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 = 20/1) to obtain compound 4-6 . MS-ESI: m/z 431.9[M+H] ⁺ .

6) Synthesis of compounds 4-7

Dissolve intermediate 4-6 (400mg, 0.92mmol) in 1-methyl-2-pyrrolidone (15mL) at room temperature, add copper chloride (457mg, 4.62mmol), replace with nitrogen, and heat with microwave to 150 ℃ reaction 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), and anhydrous sodium sulfate was added. Dry, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to preparative-grade high-performance liquid chromatography (hydrochloric acid/acetonitrile/water system, chromatography column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% formic acid), Acetonitrile; gradient ratio: acetonitrile phase (0-10min, 70-100%); flow rate: 25mL/min; column temperature: room temperature) was separated to obtain compound 4-7 . MS-ESI: m/z 388.0[M+H] ⁺ .

7) Synthesis of compounds 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 liquid 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

Compound 4-8 (12 mg, 0.03 mmol) and intermediate C (8 mg, 0.03 mmol) were dissolved in acetonitrile (2 mL) at room temperature, diisopropylethylamine (37 mg, 0.29 mmol) was added, and the reaction mixture was React at 50°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated by silica gel preparative thin-layer 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) δ 7.50-7.45 (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) Piperidin-3-yl) azetidin-1-yl) pyrazolo[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(diphenylphosphorus)ferrocene palladium 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 a carbon monoxide (50 psi) atmosphere. 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 = 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-necked flask, replaced with nitrogen, lowered the temperature of the reaction solution to -65°C, and introduced amine gas. At room temperature, compound 5-1 (400 mg, 0.97 mmol) 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 dried under vacuum 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) and 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 (20 mL), extract with dichloromethane (20 mL × 2), wash the organic phase with water (20 mL) and saturated sodium chloride aqueous solution (20 mL) in sequence, combine the organic phases, dry over anhydrous sodium sulfate, and filter. 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 ) δ 9.99 (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) and m-chloroperbenzoic 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 resulting 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

Dissolve compound 5-4 (190 mg, 0.38 mmol, 83% purity), intermediate C (171 mg, 0.77 mmol), and N , N -diisopropylethylamine (0.20 mL, 1.15 mmol) in acetonitrile at room temperature. (5 mL), the reaction mixture was stirred at 50 °C for 2 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was subjected to preparative grade high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography column: Waters Xbridge 150*25mm*5μm; mobile phase: water (10mM carbonic acid Ammonium hydrogen), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 52-82%); flow rate: 25mL/min; column temperature: room temperature) was separated to obtain compound 5 . MS-ESI: m/z 515.2[M+H] ⁺ .

¹ H NMR(400MHz, CD ₃ OD)δ 7.52-7.42(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-fluoropyrazolo [1,5- a ][1,3,5]triazin-2-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (6)

Compound 6 was prepared according to the synthetic method of Example 3 . MS-ESI: m/z 508.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.55 (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)pyrazolo [1,5- a ][1,3,5]triazin-2-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (7)

1) Synthesis of compound 7-1

Compound 1-3 (300 mg, 0.80 mmol) was dissolved in chloroform (6 mL) at room temperature, then N -chlorosulfenimine (129 mg, 0.97 mmol) was added, and the reaction mixture was stirred at 50°C for 6 hours. The reaction solution 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 7-1 . MS-ESI: m/z 389.9[M+H] ⁺ .

2) Synthesis of compound 7-2

Compound 7-1 (250 mg, 0.49 mmol, 76% purity) was dissolved in dichloromethane (10 mL) at room temperature, and then m-chloroperoxybenzoic acid (298 mg, 1.47 mmol, 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 resulting 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

Compound 7-2 (170 mg, 0.39 mmol), intermediate C (131 mg, 0.59 mmol), N , N -diisopropylethylamine (203 mg, 1.57 mmol) were dissolved in acetonitrile (6 mL) and diisopropylethylamine (203 mg, 1.57 mmol) at room temperature. The reaction solution was stirred in methylsulfoxide (2 mL) at 30°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography 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) was separated to obtain compound 7 . MS-ESI: m/z 524.0[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.78 (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) Piperidin-3-yl) azetidin-1-yl) pyrazolo[1,5- a ][1,3,5]triazine-8-carbonitrile (8)

1) Synthesis of compound 8-1

Compound 1-3 (300 mg, 0.85 mmol) was dissolved in N , N -dimethylformamide (5 mL) at room temperature, cooled to 0°C in an ice bath, and then N -iodosuccinimide (5 mL) was added. 191 mg, 0.85 mmol), and 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), diluted, 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 copper cyanide (277 mg, 3.09 mmol), replaced with 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) and diluted, extracted with ethyl acetate (20 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 = 1/2), and the crude product was dissolved in methyl tert-butyl ether (30 mL), washed with saturated brine (10 mL × 4), and organically The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8-2 . MS-ESI: m/z 379.3[M+H] ⁺ .

3) Synthesis of compound 8-3

Compound 8-2 (45 mg, 0.08 mmol, 70% purity) was dissolved in dichloromethane (5 mL) at room temperature, m-chloroperoxybenzoic acid (34 mg, 0.17 mmol, 85% purity) was added, and the reaction mixture was Stir at 25°C for 2 hours. After the reaction is completed, the reaction solution is 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

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) at room temperature, and N , N -dichloroethane was added. Isopropylethylamine (53 mg, 0.41 mmol), 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) δ 8.08 (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: (1 R ,3 r )-3-(( R )-3-(1-(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 -1-Formic acid(9)

1) Synthesis of compound 9-2

At room temperature, compound 9-1 (8.00g, 35.26mmol), (2,4-dimethoxyphenyl)methanamine (8.84g, 52.89mmol) and cesium fluoride (10.71g, 70.52mmol) were added. The reaction solution was stirred in methylsulfoxide (50 mL) 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

Compound 9-2 (1.80 g, 4.58 mmol, 91% purity) was added to dichloromethane (10 mL) at room temperature, 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, beaten 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, compound 9-3 (1.50g, 3.73mmol, 80% purity) and ethoxycarbonyl isothiocyanate (0.98g, 7.47mmol) were added to dioxane (15mL) in sequence. Stir warm 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 the solid was 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 sequentially. The reaction mixture was added to methanol (10 mL) and ethanol (10 mL) and reacted at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was slurried with water (40 mL), filtered, and the solid was dried to obtain compound 9-5 . MS-ESI: m/z 246.9[M+H] ⁺ .

5) Synthesis of compound 9-6

Compound 9-5 (0.80g, 2.55mmol, 79% purity) and tert-butyl nitrite (0.79g, 7.66mmol) were added to tetrahydrofuran (10mL) in sequence at room temperature, and the reaction was carried out 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 (300 mg, 1.29 mmol) and intermediate A (442 mg, 2.32 mmol) were added to dimethyl sulfoxide (10 mL), followed by cesium fluoride (294 mg, 1.94 mmol), 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), the organic phases were combined, 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 (150 mg, 0.33 mmol, 85% purity), intermediate D (110 mg, 0.36 mmol) and potassium tert-butoxide (111 mg, 0.99 mmol), 2,2-bis(diphenyl) Phosphino)-1,1-binaphthyl (41.13 mg, 0.066 mmol) was dissolved in tert-butyl alcohol (5 mL) and ethylene glycol dimethyl ether (5 mL), replaced with nitrogen, and then added tris(dibenzylidene) Acetone) dipalladium (30 mg, 0.03 mmol), and the reaction mixture was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain compound 9-8 . The crude product was used directly 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 slowly added, and the reaction mixture was stirred at room temperature for 16 hours. . The reaction solution was poured into water (30 mL) and diluted, washed with ethyl acetate (20 mL × 2), the organic phase was discarded, and the aqueous phase was concentrated under reduced pressure. The resulting residue was subjected to preparative-grade high performance liquid chromatography (formic acid/acetonitrile/water system, Chromatography column: Waters temperature: room temperature) to obtain compound 9 . MS-ESI: m/z 557.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.06 (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: (1 R ,3 r )-3-(( R )-3-(1-(2-chloro-5-((( R ))-1-(2,4-dichlorophenyl)ethyl) base)amino)-[1,2,4]triazolo[1,5- a ]pyridin-7-yl)azetidin-3-yl)piperidin-1-yl)-1-methyl cyclobutane-1-carboxylic acid (10)

1) Synthesis of compound 10-2

At room temperature, compound 10-1 (15.00g, 66.11mmol), (2,4-dimethoxyphenyl)methanamine (16.58g, 99.17mmol) and cesium fluoride (20.00g, 132.23mmol) were added. The reaction mixture was stirred in methylsulfoxide (100 mL) at 100°C for 16 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 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

Compound 10-2 (4.50 g, 12.58 mmol) was added to dichloromethane (20 mL) at room temperature, 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, beaten 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

Compound 10-3 (3.42g, 10.64mmol) and ethoxycarbonyl isothiocyanate (2.79g, 21.28mmol) were added to dioxane (40mL) in sequence at room temperature, and the mixture was stirred at room temperature 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 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 0°C and nitrogen protection, tert-butyl nitrite (362 mg, 3.52 mmol) was slowly added dropwise to the mixture of compound 10-5 (500 mg, 1.76 mmol, 87% purity) and copper chloride (283 mg, 2.11 mmol). The reaction mixture was stirred in acetonitrile (5 mL) at 60°C for 1 hour. After the reaction was completed, 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 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 dimethylsulfoxide (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). Combine the organic phases, wash with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1). , compound 10-7 was obtained.

7) Synthesis of compound 10-8

Under room temperature and nitrogen protection, compound 10-7 (150 mg, 0.30 mmol, 85% purity), intermediate D (138 mg, 0.45 mmol) and cesium carbonate (296 mg, 0.91 mmol) were mixed with third amyl alcohol (3 mL) Medium, replace with nitrogen, add methane sulfonic acid (4,5-bisdiphenylphosphine-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl ) palladium(II) (49 mg, 0.03 mmol), 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 obtained residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 0/1) to obtain compound 10-8 . The crude product was used directly in the next reaction without purification. MS-ESI: m/z 605.2[M+H] ⁺ .

8) Synthesis of compound 10

Compound 10-8 (330 mg, 0.29 mmol, 53% purity) and lithium hydroxide monohydrate (36 mg, 0.87 mmol) were dissolved in tetrahydrofuran (3 mL) and water (3 mL) at room temperature, and the reaction mixture was stirred at room temperature. 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatography column: Phenomenex luna C18 150*25mm*10μm; 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) δ 7.51 (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: (1 R ,3 r )-3-(( R )-3-(1-(7-((( R ))-1-(2,4-dichlorophenyl)ethyl)amino )Pyrazolo[1,5- a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (11)

1) Synthesis of compound 11-2

Compound 11-1 (600mg, 3.19mmol), intermediate A (619mg, 3.19mmol) and N , N -diisopropylethylamine (825mg, 6.38mmol) were dissolved in acetonitrile (10mL) at room temperature. The reaction 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 ) δ 8.97 (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(diphenyl) Phosphino)-11-binaphthyl (36 mg, 0.06 mmol) was added to tert-butanol (3 mL) and ethylene glycol dimethyl ether (5 mL), replaced with nitrogen, and then tris(dibenzylideneacetone) dipalladium (26 mg, 0.03 mmol) was added to the reaction solution, and the reaction mixture was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, poured into water (10 mL), diluted, and washed with dichloromethane (20 mL × 2). The organic phase was discarded, and the aqueous phase was subjected to preparative-grade high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatography 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) was separated to obtain compound 11 . MS-ESI: m/z 557.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.83-7.79(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]tri Azolo[1,5- c ]pyrimidin-7-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (12)

1) Synthesis of compound 12-2

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

2) Synthesis of compound 12-3

Compound 12-2 (2.00g, 5.86mmol) was dissolved in dioxane (40mL) at room temperature, 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 used directly in the next reaction without purification. MS-ESI: m/z 448.0[M+H] ⁺ .

3) Synthesis of compound 12-4

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) at room temperature, and then Hydroxylamine hydrochloride (814 mg, 11.71 mmol) was added in batches, and the reaction solution was reacted at 45°C for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), extracted with ethyl acetate (60 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 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

Compound 12-4 (1.00g, 2.71mmol) was dissolved in tetrahydrofuran (20mL) at 0°C, 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 (50 mL), extracted with ethyl acetate (50 mL =2/1) was separated to obtain compound 12-5 . MS-ESI: m/z 341.9[M+H] ⁺ .

5) Synthesis of compound 12

Compound 12-5 (150 mg, 0.44 mmol), intermediate C (145 mg, 0.59 mmol) and cesium fluoride (133 mg, 0.88 mmol) were mixed in dimethylsulfoxide (3 mL) at room temperature, and the reaction mixture was heated at 60°C. Stir for 16 hours. After the reaction is completed, filter, and the filtrate is subjected to preparative-grade high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography column: Unisil 3-100 C18 Ultra 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), 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) δ 8.03 (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: (1 R , 3 r )-3-(( R )-3-(1-(2-chloro-5-((( R ))-1-(2,4-dichlorophenyl)ethyl base)amino)-[1,2,4]triazolo[1,5- c ]pyrimidin-7-yl)azetidin-3-yl)piperidin-1-yl)-1-methyl cyclobutane-1-carboxylic acid (13)

1) Synthesis of compound 13-1

Dissolve compound 12-4 (400mg, 1.12mmol) and copper chloride (180mg, 1.34mmol) in acetonitrile (2mL) at 0°C, slowly add tert-butyl nitrite (231mg, 2.24mmol) dropwise, and react. The mixture was stirred at 0°C for 2 hours. After the reaction was completed, 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, compound 13-1 (200mg, 0.53mmol), intermediate D (241mg, 0.80mmol) and cesium fluoride (161mg, 1.06mmol) were mixed in dimethylsulfoxide (4mL) in sequence, 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 silica gel preparative thin layer chromatography (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 the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatography column: Phenomenex luna C18 150*25mm*10μm; 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) δ 8.42 (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) ethane-1-ol (14)

1) Synthesis of compound 14-1

Compound 12-4 (500 mg, 1.40 mmol) was dissolved in methanol (1.5 mL) and acetonitrile (1.5 mL) at room temperature, and then 1-fluoro-4-methyl-1,4-diazabicyclo[ 2.2.2] Octane tetrafluoroborate (670 mg, 2.10 mmol), 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. The obtained residue was separated by silica gel preparative thin layer chromatography (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

Compound 14-1 (80 mg, 0.16 mmol, 77% purity) was dissolved in tetrahydrofuran (1 mL) at room temperature, tert-butyl nitrite (51 mg, 0.49 mmol) was added under ice bath, and the reaction solution was stirred at 0°C. 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 (59 mg, 0.16 mmol) and intermediate E (86 mg, 0.33 mmol) were dissolved in dimethyl sulfoxide (2 mL), cesium fluoride (75 mg, 0.49 mmol) was added, and the reaction mixture was Stir at 80°C for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), diluted, 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 (30 mg, 0.06 mmol) and tetrakis triphenylphosphine palladium (6 mg, 0.01 mmol) were mixed in methylene chloride (2 mL), and phenylsilane (59 mg, 0.55 mmol) was slowly added to react. The mixture was stirred at 25°C for 2 hours. After the reaction is completed, the residue obtained is 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

Compound 14-4 (10 mg, 0.02 mmol, 89% purity), acetic acid (12 mg, 0.19 mmol) and tert-butyldimethylsiloxyacetaldehyde (5 mg, 0.03 mmol) were dissolved in methanol at room temperature. (1 mL), after stirring for 30 minutes, sodium cyanoborohydride (2 mg, 0.04 mmol) 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 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 obtained residue was dissolved in methanol (1 mL), aqueous ammonia was slowly added dropwise to pH ~ 8, and then concentrated under reduced pressure. The obtained 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) δ 8.08 (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]tri Azolo[1,5- a ][1,3,5]triazin-5-yl) azetidin-3-yl) piperidin-1-yl) ethane-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 is completed, the reaction solution is poured into water (500 mL), filtered, and the filter cake is washed with water (100 mL) and dried under vacuum to obtain compound 15-2 .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 14.00 (s, 1H), 12.15-11.68 (m, 1H), 11.45 (s, 1H), 8.54 (s, 1H), 4.21 (q, J =7.2Hz ,2H),1.25(t, J =7.2Hz,3H).

2) Synthesis of compound 15-3

40g，流動相：水，乙腈；梯度配比：乙腈相(0-8min,0-5%)；流速：35mL/min；管柱溫度：室溫)分離，得到化合物15-3。¹H NMR(400MHz,DMSO-d ₆)δ 11.53(brs,1H),7.92(s,1H)。 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 the reaction is completed, cool the reaction solution to room temperature, filter, add water (10 mL) to the filter cake to dissolve, adjust the pH to 6~7 with 1 mol/L hydrochloric acid aqueous solution, and pass the mixture through a reversed-phase column (acetonitrile/water system, chromatography tube Column: C18 spherical 20-35μm 100

40g, mobile phase: water, acetonitrile; gradient ratio: acetonitrile phase (0-8min, 0-5%); flow rate: 35mL/min; column temperature: room temperature) to obtain compound 15-3 . ¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53 (brs, 1H), 7.92 (s, 1H).

3) Synthesis of compound 15-4

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

4) Synthesis of compound 15-5

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

5) Synthesis of compound 15-6

Compound 15-5 (1.10g, 5.46mmol), intermediate A (1.56g, 8.19mmol) and pyridine (1.32mL, 16.38mmol) were dissolved in acetonitrile (11mL) at room temperature, and the reaction mixture was stirred at 50°C. 0.5 hours. 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

At room temperature, 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 and concentrated under reduced pressure. The resulting residue was separated by silica gel preparative thin layer chromatography (pure methanol), and then by preparative high performance liquid chromatography (formic acid/acetonitrile/water system, chromatography column: Unisil 3-100 C18 Ultra 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) Isolation gave compound 15 . MS-ESI: m/z 491.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.54 (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 =11.6 Hz,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)ethane-1- Alcohol(16)

Compound 16 was prepared according to the synthetic method of Example 15 . MS-ESI: m/z 505.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.27 (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)ethyl Alkan-1-ol(17)

Compound 17 was prepared according to the synthetic method of Example 15 . MS-ESI: m/z 559.5[M+H] ⁺ .

¹ H NMR(400MHz, CD ₃ OD)δ 7.52-7.46(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 synthetic method of Example 15 . MS-ESI: m/z 531.1[M+H] ⁺ .

¹ H NMR(400MHz, CD ₃ OD)δ 7.52-7.43(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]tri Azolo[1,5- a ]pyrimidin-5-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (19)

1) Synthesis of compound 19-1

Compound 15-1 (5000mg, 59.47mmol) and diethyl malonate (11.43g, 71.36mmol) were dissolved in N , N -dimethylacetamide (50mL) at room temperature, and sodium hydrogen was slowly added. (4.76g, 118.93mmol, 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), shaken to dissolve, washed with ethyl acetate (50 mL × 3), and the organic phase was discarded. Slowly add 2 mol/L dilute hydrochloric acid solution dropwise to the aqueous phase to pH ~ 2, wash with ethyl acetate (50 mL × 3), and discard the organic phase. The remaining aqueous phase was concentrated under reduced pressure to obtain compound 19-1 . The crude product was used directly in the next reaction without purification. MS-ESI: m/z 151.1[MH] ^- .

2) Synthesis of compound 19-2

Compound 19-1 (9.05g, 59.46mmol) was dissolved in phosphorus oxychloride (50.00mL) at room temperature, N , N -dimethylaniline (14.41g, 118.93mmol) was added, and the reaction mixture was heated at 100°C Stir for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained 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 (400MHz, CDCl ₃ ) δ 8.57 (s, 1H), 7.28 (s, 1H).

3) Synthesis of compound 19-3

At room temperature, compound 19-2 (300 mg, 1.59 mmol) and intermediate A (302 mg, 1.57 mmol) were dissolved in dimethylstyrene (10 mL), cesium fluoride (362 mg, 2.38 mmol) 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), diluted, 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

Compound 19-3 (200mg, 0.42mmol, 72% purity) and intermediate C (93mg, 0.42mmol) were dissolved in acetonitrile (10mL) at room temperature, and N , N -diisopropylethylamine (163mg ,1.26mmol), 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) δ 8.08 (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) ethane-1-ol (20)

Compound 20 was prepared according to the synthetic method of Example 19 . MS-ESI: m/z 504.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.53 (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 synthetic method of Example 19 . MS-ESI: m/z 558.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.54 (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 synthetic method of Example 19 . MS-ESI: m/z 534.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.53 (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) ethane-1-ol (23)

Compound 23 was prepared according to the synthetic method of Example 19 . MS-ESI: m/z 518.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.53 (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 synthetic method of Example 19 . MS-ESI: m/z 530.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.52 (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-2 H -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

Compound 19-3 (7.30g, 21.31mmol) was dissolved in acetonitrile (80mL) at room temperature, and then N , N -diisopropylethylamine (10.50mL, 63.92mmol) and intermediate E (6.67g) were added. ,25.57mmol), 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, and then phenylsilane (5.51g, 50.90mmol) and tetrakis(triphenylphosphine)palladium (590mg, 0.51 mmol), the reaction solution was stirred at room temperature for 15 minutes. After the reaction is completed, the reaction solution is 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

Compound 25-2 (100 mg, 0.22 mmol), tetrahydropyran-4-one (67 mg, 0.67 mmol) and acetic acid (13 mg, 0.22 mmol) were dissolved in methanol (5 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 1 hour, then 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 /Ammonium bicarbonate system, chromatography 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) δ 8.03 (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]tri Azolo[1,5- a ]pyrimidin-5-yl) azetidin-3-yl) piperidin-1-yl) propan-1-ol (26)

Compound 25-2 (100 mg, 0.22 mmol) was dissolved in acetonitrile (6 mL) at room temperature, and then 3-iodopropanol (83 mg, 0.44 mmol) and potassium carbonate (92 mg, 0.67 mmol) were added, and the reaction mixture was heated at 80 °C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography 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) was separated to obtain compound 26 . MS-ESI: m/z 504.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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, add water (30 mL) to dilute, and extract 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 is completed, add water (30 mL) to dilute, wash with ethyl acetate (30 mL × 3), adjust the aqueous phase to pH ~ 8 with saturated sodium bicarbonate aqueous solution, and extract 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 bath, dissolve compound 27-2 (55 mg, 0.10 mmol, 89% purity), methylsulfonic anhydride (16 mg, 0.09 mmol) and triethylamine (30 mg, 0.30 mmol) 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, chromatography column: Waters Xbridge 150*25mm*5μm; mobile phase: water (0.5% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile Phase (0-9min, 45-75%); flow rate: 25mL/min; column temperature: room temperature) was separated to obtain compound 27 . MS-ESI: m/z 567.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.34 (d, J =6.8Hz, 1H), 8.11 (s, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.63 (d, J = 8.4 Hz,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 heated at 25°C. Stir for 12 hours. The reaction solution was poured into water (20 mL) to quench, 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 obtained 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 purification.

2) Synthesis of compound 28

Compound 28-2 (488 mg, 1.75 mmol) and compound 25-2 (300 mg, 0.59 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and N , N -diisopropylethylamine (227 mg, 1.75 mmol) 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), diluted, 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) δ 8.03 (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 (100 mg, 0.22 mmol) was dissolved in methanol (5 mL) at room temperature, then 2-oxaspiro[3.3]heptan-6-one (74 mg, 0.51 mmol) was added, and cyanohydroboration was carried out. Sodium (41 mg, 0.66 mmol) and acetic acid (40 mg, 0.66 mmol), the reaction mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography 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) was separated to obtain compound 29 . MS-ESI: m/z 542.3[M+H] ⁺ .

¹ H NMR(400MHz, CD ₃ OD)δ 8.04(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 ]Triazolo[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 bath, dissolve compound 30-1 (500mg, 4.09mmol), methylsulfonic anhydride (1.07g, 6.14mmol) and triethylamine (1.70mL, 12.28mmol) in dichloromethane (10mL), and the reaction mixture Stir at room temperature for 1 hour to obtain compound 30-2 , and the reaction solution is directly used in the next reaction.

2) Synthesis of compound 30

Compound 25-2 (100 mg, 0.22 mmol), compound 30-2 (224 mg, 1.12 mmol, crude product, theoretical amount) and cesium carbonate (146 mg, 0.45 mmol) were dissolved in N , N -dimethylformate at room temperature. The reaction mixture was stirred in amide (2 mL) at room temperature for 8 h. After the reaction is completed, add water (20 mL) to the reaction mixture to dilute, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (30 mL × 3), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure. The obtained residue was subjected to preparative grade high performance liquid chromatography (formic acid/acetonitrile/water system, chromatography column: Phenomenex luna C18 150*25mm*10μm; 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) δ 8.04 (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: (1 R ,4 r )-4-(( R )-3-(1-(7-((( R ))-1-(2,4-dichlorophenyl)ethyl base)amino)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methyl cyclohexane-1-ol and (1 S ,4 s )-4-(( R )-3-(1-(7-((( R ))-1-(2,4-dichlorophenyl)ethyl) base)amino)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methyl Cyclohexan-1-ol (31 and 32)

1) Synthesis of compound 31-2

Under an ice bath, compound 31-1 (1000 mg, 6.40 mmol) was dissolved in tetrahydrofuran (15 mL), replaced with nitrogen, and then a diethyl ether solution of 3 mol/L methylmagnesium bromide (2.50 mL, 7.50 mmol) was added, and the reaction solution was Stir at 0°C for 2 hours. After the reaction, the reaction solution was slowly poured into a saturated aqueous solution of ammonium chloride (50 mL) to quench, extracted with ethyl acetate (50 mL), washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to Concentrate under pressure to obtain compound 31-2 . ¹ H NMR (400MHz, 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

Compound 31-2 (1.00g, 4.65mmol, 80% purity) was dissolved in tetrahydrofuran (15mL) at room temperature, 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 )δ 2.75-2.66(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

Compound 31-3 (209 mg, 1.30 mmol, 80% purity) was dissolved in 1,2-dichloroethane (10 mL) at room temperature, followed by addition of 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 resulting residue was separated by silica gel column chromatography (ethyl acetate/methanol = 0/1), and then separated by silica gel preparative thin layer chromatography (pure methanol) to obtain compound 31-4. . Then prepare supercritical fluid chromatography (chromatography column: DAICEL CHIRALPAK IC (250mm*50mm*10μm); mobile phase: hexane, ethanol (0.1% ammonia); gradient ratio: ethanol phase 70%; flow rate: 100mL/min ; Column temperature: room temperature) was separated to obtain compound 31 and compound 32 . (Compound 31 is the first eluted peak, and compound 32 is the second eluted peak). Compound 31 : MS-ESI: m/z 558.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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(400MHz, CD ₃ OD)δ 8.04(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: (1 S ,3 s )-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-yl (33) and Example 34: (1 R ,3 r )-3-(( R )-3-(1-(7-((( R ))-1-(2,4-dichloro phenyl)ethyl)amino)-[1,2,4]triazolo[1,5- a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl) -1-Methylcyclobutan-1-ol(34)

Compound 25-2 (200 mg, 0.44 mmol) was dissolved in methanol (6 mL) at room temperature, and then compound 33-1 (147 mg, 0.88 mmol, 60% purity), sodium cyanoborohydride (83 mg, 1.32 mmol) were added. ) and acetic acid (79 mg, 1.32 mmol), 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 analyzed by normal phase liquid chromatography (chromatography column: DAICEL CHIRALPAK IC (250mm*50mm*10μm); mobile phase: hexane, ethanol (0.1% ammonia); gradient ratio: Ethanol phase 70%; flow rate: 100 mL/min; column temperature: room temperature) was separated, 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) δ 8.06 (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) δ 8.04 (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-((1 s ,3 S ) -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-((1 r ,3 R )-3-methoxy ring Butyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5- a ]pyrimidin-7-amine (35 and 36)

At room temperature, compound 25-2 (150 mg, 0.34 mmol) and 3-methoxycyclobutan-1-one (34 mg, 0.34 mmol) were dissolved in methanol (2 mL), and acetic acid (2 mg, 0.03 mmol) was added. The reaction 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 silica gel preparative thin layer chromatography (ethyl acetate/methanol=5/1) to obtain compound 35-1 . Compound 35-1 (70mg, 0.13mmol) was resolved by supercritical fluid chromatography (chromatography column: DAICEL CHIRALCEL OJ (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, ethanol (0.1% amine monohydrate); gradient Proportion: methanol phase 25%; flow rate: 55mL/min; column temperature: room temperature) to obtain compound 35 and compound 36 . (Compound 35 is the first eluted peak, and compound 36 is the second eluted peak). Compound 35: MS-ESI: m/z 530.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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) δ 8.04 (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-((1 s ,3 S ) -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-((1 r ,3 R )-3- (methylsulfonyl)cyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5- a ]pyrimidine-7- Amines (37 and 38)

1) Synthesis of compound 37-2

Under ice bath, compound 37-1 (5.00g, 28.37mmol) was dissolved in methanol (20mL), sodium borohydride (1.14g, 30.14mmol) was added in three batches, and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction, and the reaction was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and 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 )δ 7.38-7.32(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, dissolve compound 37-2 (4.50g, 25.25mmol), methylsulfonic anhydride (6.60g, 37.87mmol) and triethylamine (10.50mL, 75.75mmol) in dichloromethane (50mL), and react The mixture was stirred at room temperature for 4 hours. After the reaction is completed, dilute with dichloromethane (100 mL) and wash 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 )δ 7.37-7.31(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

Compound 37-3 (6.20g, 24.19mmol) and sodium methylmercaptide (3.39g, 48.38mmol) were dissolved in N , N -dimethylformamide (65mL) at room temperature, and the reaction mixture was heated at room temperature. Stir for 16 hours. After the reaction was completed, add water (100 mL) to dilute, and extract 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 )δ 7.36-7.33(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

Compound 37-4 (1.00g, 4.80mmol) was dissolved in dichloromethane (10mL) at room temperature, then m-chloroperoxybenzoic acid (2.44g, 12.00mmol, 85% purity) was added, and the reaction mixture was dissolved at room temperature. Stir for 2 hours. The reaction liquid 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 )δ 7.38-7.31(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

Compound 37-5 (1.00g, 4.16mmol) was dissolved in methanol (20mL) at room temperature, and wet palladium on carbon (100mg, 0.94mmol, 10% purity) and wet palladium hydroxide (100mg, 0.71) were added under nitrogen protection. mmol), 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 celite, washed with methanol (20 mL×3), and the filtrate was concentrated under reduced pressure to obtain compound 37-6 .

¹ H NMR (400MHz, 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 (400MHz, 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

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) at room temperature, and the reaction mixture was placed in the chamber. Stir at room temperature for 30 minutes, add sodium cyanoborohydride (84 mg, 1.34 mmol), and stir the reaction mixture at room temperature for 15.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the resulting residue is separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 37-8 . Compound 37-8 was then separated by supercritical fluid chromatography (chromatography column: DAICEL CHIRALPAK AS (250mm×30mm*10μm); mobile phase: supercritical carbon dioxide, ethanol (0.1% amine monohydrate); gradient ratio: ethanol phase 40%; flow rate: 70mL/min; column temperature: room temperature), compound 37 and compound 38 were obtained. (Compound 37 is the first eluted peak, and compound 38 is the second eluted peak). Compound 37 : MS-ESI: m/z 578.4[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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) δ 8.04 (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]triazole And[1,5- a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol (39 and 40)

Compound 25-2 (200 mg, 0.44 mmol) and 1-bromopropan-2-ol (92 mg, 0.66 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and diisopropylethylamine (172 mg, 1.33 mmol) was added. ), 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 silica gel preparative thin layer chromatography (ethyl acetate/methanol=3/1) to obtain compound 39-1 . Compound 39-1 (140mg, 0.28mmol) was resolved by supercritical fluid chromatography (chromatography column: DAICEL CHIRALCEL OJ (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, ethanol (0.1% amine monohydrate); gradient Proportion: ethanol phase 25%; flow rate: 60mL/min; column temperature: room temperature), compound 39 and compound 40 were obtained. (Compound 39 is the first eluted peak, and compound 40 is the second eluted peak). Compound 39 : MS-ESI: m/z 504.4[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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) δ 8.04 (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

Compound 41-1 (1.80g, 13.83mmol) was dissolved in N , N -dimethylformamide (30mL) at room temperature, 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 (2.38g, 15.21mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL × 2). 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 ) δ 7.30 (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, and slowly add 2.5mol/L lithium aluminum hydride tetrahydrofuran solution (2.40mL, 6.00mmol) dropwise at 0°C. Stir for 0.5 hours. After the reaction was completed, saturated potassium sodium tartrate aqueous solution (50 mL) was slowly added dropwise at 0°C to quench, and the mixture was 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 ) δ 7.25 (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

Compound 41-3 (150 mg, 0.72 mmol) and pyridine (342 mg, 4.32 mmol) were dissolved in dichloromethane (6 mL) at room temperature, cooled to 0°C in an ice-water bath, and methylsulfonic anhydride (126 mg, 0.72 mmol) was added. ), 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 used directly in the next reaction without purification.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.24 (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

Compound 25-2 (130 mg, 0.29 mmol) and compound 41-4 (167 mg, 0.58 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and then N , N -diisopropylethylamine (188 mg, 1.46 mmol), the reaction solution was stirred at 80°C for 14 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is 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 is completed, the reaction solution is concentrated under reduced pressure, diluted with a small amount of methanol, and adjusted to pH ~9 with ammonia water. The residue is separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 41 . MS-ESI: m/z 516.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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 silica gel preparative thin layer chromatography (pure methanol) to obtain compound 42 . MS-ESI: m/z 516.4[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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]Triazolo[1,5- a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)methyl)thietane-1,1-dioxide Object(43)

1) Synthesis of compound 43-2

Compound 43-1 (25.00g, 211.63mmol) and tetrahydropyrrole (30.10g, 423.26mmol) were dissolved in methyl tert-butyl ether (300mL) at room temperature, and then magnesium sulfate (6.00g, 49.85 mmol), the reaction solution was stirred at room temperature for 16 hours. After the reaction is completed, most of the solvent is concentrated under reduced pressure at low temperature. The residue was distilled under reduced pressure (60°C-64°C, 0.03 Pa) to obtain compound 43-2 .

¹ H NMR (400MHz, CDCl ₃ )δ 4.68(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), and the temperature was cooled to 0°C, and then formaldehyde was added dropwise. Prepare a solution of methyl tert-butyl ether (25 mL) of methyl sulfonyl chloride (4.10 g, 35.80 mmol) and control the internal temperature to not exceed 5°C. After the dropwise addition is completed, the reaction solution is stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (50 ml) to quench, and extracted with dichloromethane (50 ml × 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 used directly in the next reaction without purification.

¹ H NMR (400MHz, CDCl ₃ ) δ 4.45 (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

Dissolve compound 43-3 (3.00g, 12.03mmol) in dichloromethane (20mL) at room temperature, cool to 0°C, add methyl triflate (2.17g, 13.24mmol), and control the internal temperature. Not exceeding 5°C, after the dropwise addition is completed, the reaction solution reacts at room temperature for 14 hours. Then triethylamine (1.34g, 13.24mmol) was slowly added dropwise at 0°C. After the dropwise addition was completed, 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 with water (20 mL), 1 mol/L hydrochloric acid aqueous solution (10 mL) and saturated sodium carbonate aqueous solution (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 used directly in the next reaction without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.76 (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

Compound 43-4 (1.00g, 5.61mmol) was dissolved in ethanol (20mL) at room temperature, and then wet palladium on carbon (0.20g, 10% purity) and palladium hydroxide on carbon (0.20g) were added, followed by hydrogen replacement ( 50 psi), the reaction solution was stirred at 50°C for 14 hours. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated under reduced pressure to obtain compound 43-5 . The crude product was used directly 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 solution was cooled to room temperature, poured into water (10 mL), diluted, 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 (400MHz, CDCl ₃ ) δ 9.82 (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

Compound 43-6 (54.9 mg, 0.41 mmol), compound 25-2 (70 mg, 0.14 mmol) and acetic acid (8.19 mg, 0.14 mmol) were dissolved in methanol (10 mL) at room temperature, and the reaction mixture was stirred at 25°C. 0.5 h, then sodium cyanoborohydride (25.7 mg, 0.41 mmol) was added and the reaction mixture was stirred at 25°C for 12 h. After the reaction was completed, the reaction solution was poured into water (30 mL), diluted, 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) δ 8.03 (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) yl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5- a ]pyrimidin-7-amine (44)

Compound 25-2 (100 mg, 0.22 mmol), 1-(2-chloroethyl)pyrrolidine (75 mg, 0.44 mmol) and N , N -diisopropylethylamine (229 mg, 1.77 mmol) were mixed at room temperature. Dissolve in acetonitrile (5 mL) and stir the reaction mixture 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) δ 8.03 (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: (1 R , 3 r )-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-methylcyclobutan-1-ol (45) and Example 46: (1 S , 3 s )-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(46)

1) Synthesis of compound 45-2

Compound 45-1 (200 mg, 0.83 mmol), allyl chloroformate (120 mg, 1.00 mmol) and sodium carbonate (176 mg, 1.66 mmol) were mixed in dichloromethane (5 mL) at room temperature. The reaction mixture was kept at room temperature. Stir 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 = 2/1) to obtain compound 45-2 .

¹ H NMR (400MHz, CDCl ₃ )δ 6.02-5.88(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 used directly in the next reaction without purification. MS-ESI: m/z 225.2[M+H] ⁺ .

3) Synthesis of compound 45-4

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) at room temperature. , the reaction mixture was stirred at 60°C for 16 hours. After the reaction was completed, the reaction mixture 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 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 reacted The mixture was stirred at room temperature for 3 hours. After the reaction is completed, the reaction solution is 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

Dissolve 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) in methanol (3 mL) at room temperature, and stir for 0.5 at room temperature. hours, then sodium cyanoborohydride (63 mg, 1.01 mmol) was added, and the reaction mixture was continued to stir at room temperature for 15.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 45-6 . Compound 45-6 was separated by preparative supercritical fluid chromatography (chromatography column: DAICEL CHIRALPAK AD (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, methanol (0.1% amine 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) δ 8.03 (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) δ 8.03 (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) ethane-1-ol (47)

1) Synthesis of compound 47-2

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) at room temperature. , the reaction mixture was stirred at 80°C for 2 hours. After the reaction is completed, dilute the reaction solution with water (30 mL), extract with ethyl acetate (30 mL Separate by chromatography (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 the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 47-3 . The crude product was used directly in the next reaction without purification. MS-ESI: m/z 446.1[M+H] ⁺ .

3) Synthesis of compound 47

Compound 47-3 (138 mg, 0.25 mmol), iodoethanol (127 mg, 0.74 mmol) and potassium carbonate (102 mg, 0.74 mmol) were mixed in acetonitrile (10 mL) at room temperature, and the reaction mixture was stirred at 60°C for 2 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is 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) δ 8.04 (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 (40 mg, 0.09 mmol), 2-oxaspiro[3.3]heptan-6-one (12 mg, 0.11 mmol) and acetic acid (1 mg, 0.01 mmol) were dissolved in methanol (1 mL) at room temperature. medium, stir for 10 minutes, add sodium cyanoborohydride (17 mg, 0.27 mmol), and stir the reaction mixture at room temperature for 16 hours. After the reaction is completed, dilute the reaction mixture with water (20 mL), extract with ethyl acetate (30 mL (pure methanol) to obtain compound 48 . MS-ESI: m/z 542.3[M+H] ⁺ .

¹ H NMR(400MHz, CD ₃ OD)δ 8.04(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)

Compound 45-5 (100 mg, 0.22 mmol) and compound 49-1 (59 mg, 0.20 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and then N , N -diisopropylethylamine (87 mg, 0.67 mmol), 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 subjected to preparative grade high performance liquid chromatography (formic acid/acetonitrile/water system, chromatography column: Phenomenex Luna C18 150*25mm*10μm; 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) δ 8.05 (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 addition of acetic acid (11 mg, 0.18 mmol) and cyanohydroboration. Sodium (23 mg, 0.36 mmol), 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) δ 8.04 (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 =8.4 Hz,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

Compound 19-3 (200 mg, 0.58 mmol), compound 51-1 (168 mg, 0.70 mmol) and N , N -diisopropylethylamine (0.30 mL, 1.75 mmol) were dissolved in acetonitrile (3 mL) at room temperature. , 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 Ethyl ester = 3/1) was separated to obtain compound 51-2 .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.29 (d, J =7.6Hz, 1H), 8.13 (s, 1H), 7.67-7.62 (m, 2H), 7.44 (dd, J =8.4, 2.0Hz ,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 is completed, the reaction mixture is concentrated under reduced pressure to obtain compound 51-3 . The crude product was used directly in the next reaction without purification. MS-ESI: m/z 446.1[M+H] ⁺ .

3) Synthesis of compound 51-5

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) at room temperature, and the reaction mixture was stirred for 10 minutes, and then Sodium cyanoborohydride (94 mg, 1.50 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and 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 used directly 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, then trifluoroacetic acid (1.00 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is completed, the pH of the reaction mixture is adjusted to neutral with amine water, and the mixture is concentrated under reduced pressure. The resulting residue is subjected to preparative-grade high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography 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) separation, and then Silica gel preparative thin layer chromatography (ethyl acetate/methanol=0/1) separated to obtain compound 51 . MS-ESI: m/z 490.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.05 (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]undecan-3-yl)ethan-1-ol (52)

1) Synthesis of compound 52-2

Compound 19-3 (300 mg, 0.88 mmol) and compound 52-1 (223 mg, 0.88 mmol) were dissolved in acetonitrile (8 mL) at room temperature, and then N , N -diisopropylethylamine (339 mg, 2.63 mg) was added. mmol) and the reaction mixture was stirred at 80°C for 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 = 1/5) to obtain compound 52-2 . MS-ESI: m/z 560.0[M+H] ⁺ .

2) Synthesis of compound 52-3

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

3) Synthesis of compound 52

Compound 52-3 (180 mg, 0.34 mmol, 93% purity) was dissolved in acetonitrile (8 mL) at room temperature, and then 2-iodoethanol (116 mg, 0.67 mmol) and potassium carbonate (140 mg, 1.01 mmol) were added, and the reaction was carried out. The mixture was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative-grade high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography 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) was separated to obtain compound 52 . MS-ESI: m/z 504.3[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.05 (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) etan-1-ol (53 and 54)

1) Synthesis of compound 53-2

Compound 53-1 (500 mg, 3.30 mmol) was dissolved in toluene (6 mL) at room temperature, replaced with nitrogen, and a tetrahydrofuran solution of methylmagnesium bromide (3.30 mL, 9.90 mmol, 3 mol/L) was added, and the reaction mixture was Stir at 110°C for 18 hours. After the reaction solution is cooled to 0°C, dilute hydrochloric acid is slowly added dropwise to pH~2, the temperature is raised to reflux and stirred for 1 hour, and then cooled to room temperature. Slowly add sodium hydroxide to the reaction solution until pH~7, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate 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 )δ 7.51(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

Compound 53-2 (550 mg, 2.28 mmol, 70% purity) and sodium bicarbonate (575 mg, 6.85 mmol) were dissolved in ethanol (2 mL) at room temperature, and then hydroxylamine hydrochloride (317 mg, 4.57 mmol) was added to the reaction mixture. Stir at 25°C for 12 hours. The reaction solution was poured into water (30 mL), diluted, 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

Dissolve compound 53-3 (450 mg, 1.52 mmol, 62% purity) in tetrahydrofuran (10 mL) at room temperature, slowly drop into borane dimethyl sulfide solution (0.50 mL, 5.00 mmol, 10 mol/L), and react. The mixture was stirred 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 (200 mg, 0.84 mmol, 68% purity), compound 19-2 (158 mg, 0.84 mmol) and N , N -diisopropylethylamine (0.40 mL, 2.51 mmol) were dissolved in The reaction mixture was stirred in acetonitrile (5 mL) at 60°C for 4 hours. After the reaction is completed, add water (20 mL) 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. 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 used directly in the next reaction without purification. MS-ESI: m/z 322.0[M+H] ⁺ .

5) Synthesis of Compound 53 and Compound 54

40g，流動相：水(0.2%甲酸)，乙腈；梯度配比：乙腈相(0-8min,50-65%)；流速：40mL/min；管柱溫度：室溫)分離，得到化合物53-6。再經超臨界流體色譜拆分(色譜管柱：DAICEL CHIRALCEL OX(250mm*30mm*10μm)；流動相：超臨界二氧化碳，甲醇(0.1%一水合胺)；梯度配比：甲醇相60%；流速：80mL/min；管柱溫度：室溫)，得到化合物53和化合物54。(化合物53為第一個沖提的峰，化合物54為第二個沖提的峰)。化合物53：MS-ESI：m/z 470.2[M+H]⁺。 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) at room temperature. The reaction mixture was stirred at 80°C for 16 hours. After the reaction is completed, filter and pass the filtrate through a reversed-phase chromatography column (acetonitrile/water system, chromatography column: C18 spherical 20-35μm 100

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) to obtain compound 53- 6 . Then separated by supercritical fluid chromatography (chromatography column: DAICEL CHIRALCEL OX (250mm*30mm*10μm); mobile phase: supercritical carbon dioxide, methanol (0.1% amine monohydrate); gradient ratio: methanol phase 60%; flow rate :80mL/min; column temperature: room temperature), compound 53 and compound 54 were obtained. (Compound 53 is the first eluted peak, and compound 54 is the second eluted peak). Compound 53 : MS-ESI: m/z 470.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.04 (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) δ 8.05 (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]tri Azolo[1,5- a ]pyrimidin-5-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (55)

Compound 55 was prepared according to the synthetic method of Example 19 . MS-ESI: m/z 470.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.03 (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] Triazolo[1,5- a ]pyrimidin-5-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (56)

Compound 56 was prepared according to the synthetic method of Example 19 . MS-ESI: m/z 458.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.03 (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] Triazolo[1,5- a ]pyrimidin-5-yl) azetidin-3-yl) piperidin-1-yl) ethane-1-ol (57)

Compound 57 was prepared according to the synthetic method of Example 19 . MS-ESI: m/z 474.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.03 (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)N-morpholinyl)ethane-1-ol (58)

1) Synthesis of compound 58-2

Compound 58-1 (3.00g, 16.20mmol) was dissolved in anhydrous methanol (30mL) at room temperature, and nitromethane (2.97g, 48.59mmol) and triethylamine (3.28g, 32.39mmol) were added under ice bath. ) and the reaction mixture was stirred at room temperature for 16 hours. 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 58-2 .

¹ H NMR (400MHz, CDCl ₃ ) δ 4.52-4.45 (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

Compound 58-2 (3.60g, 14.62mmol) and platinum dioxide (664mg, 2.92mmol) were added to methanol (50mL) at room temperature, and the reaction was carried out at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 58-3 .

¹ H NMR (400MHz, CDCl ₃ )δ 4.01-3.88(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. , react at room temperature 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 )δ 7.13-7.03(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 =8.8,5.6Hz,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 (3.10g, 10.59mmol) and potassium tert-butoxide (1.19g, 10.59mmol) were dissolved in tetrahydrofuran (20mL) at room temperature, and the reaction solution was reacted at 60°C for 2 hours. After the reaction was completed, the reaction solution 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 ) δ 6.57 (s, 1H), 4.37-4.16 (m, 2H), 3.98 (td, J =8.4, 3.6Hz, 2H), 3.90 (dd, J =8.8, 5.6Hz ,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 (749 mg, 18.73 mmol, 60% purity) and N , N -dimethylformamide (30 mL) were added in sequence, and intermediate 58-5 (3.20 g, 12.49 mmol) was added under nitrogen protection. The reaction was carried out in an ice bath for 0.5 hours, benzyl-2-bromoethyl ether (4.03g, 18.73mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction solution to quench, and the mixture was 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 )δ 7.39-7.34(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

Dissolve compound 58-6 (2.60g, 6.66mmol) in anhydrous tetrahydrofuran (50mL) at room temperature, add borane dimethyl sulfide (3.30mL, 33.29mmol, 10mol/L) dropwise in an ice bath, and the reaction mixture 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 the 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 a crude product. Add glycerin (2mL) and methanol (20mL), stir at room temperature overnight, and concentrate under reduced pressure to obtain The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 58-7 . MS-ESI: m/z 377.1[M+H] ⁺ . Compound 58-7 (1.67g) was resolved by supercritical fluid chromatography (chromatography column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: supercritical carbon dioxide, methanol (0.1% amine monohydrate); gradient Proportion: methanol phase 30%; flow rate: 60mL/min; column temperature: room temperature) to obtain compound 58-8 and compound 58-9 . (Compound 58-8 is the first eluted peak, and compound 58-9 is the second eluted peak).

7) Synthesis of compound 58-10

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

8) Synthesis of compound 58

Compound 21-3 (100 mg, 0.17 mmol, 71% purity) and compound 58-10 (46 mg, 0.17 mmol) were dissolved in dichloroethane (10 mL) at room temperature, followed by addition of diisopropylethylamine ( 112 mg, 0.87 mmol), 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 subjected to preparative grade high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatography column: Waters Xbridge 150*25mm*5μm; mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile Phase (0-8min, 45-75%); flow rate: 25mL/min; column temperature: room temperature) was separated to obtain compound 58 . MS-ESI: m/z 560.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.54 (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 following further describes and explains the content of the present invention in conjunction with test examples, 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

In vitro CCR4 receptor cell functional experiments detect the activity of test compounds by using cell lines stably expressing CCR4 and FLIPR experiments. In the experiment, the starting concentration of the test compound was 10 μM, diluted 3 times, a total of 10 concentrations, and tested in duplicate.

The cell line stably expressing CCR4 (CCR4-HEK293) was cultured in DMEM medium supplemented with fetal calf serum, G418 and penicillin-streptomycin. Configure 250mM FLIPR experiment buffer and 2×Fluo-4 Direct ^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 experimental buffer and 20 μL of Fluo-4 Direct ^TM loading buffer. Add 10 μL of the compound dilution to be tested from the compound plate (pre-gradient dilution in a 384-well PP microplate) to the cell reaction plate, incubate in a 37°C 5% carbon dioxide environment for 50 minutes, and then incubate at room temperature for 10 minutes. The reaction plate was transferred to the 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's inhibitory activity on calcium flow in CCR4 receptor cells.

1.3. Experimental results

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

Table 1: Inhibitory activity of test compounds on calcium flux

Test Example 2: CCR4-mediated CCRF-CEM cell chemotactic inhibitory 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 dispense the cells into a 96-well cell plate, 99 μL per well. Prepare a compound stock solution with a concentration of 10 mM in a test tube using DMSO as the solvent, and then use DMSO as the solvent to gradiently dilute the sample as needed. Transfer 1 μL of the test compound to each well of the cells in the 96-well plate, and incubate for 0.5 hours in a cell culture incubator at 37°C and 5% carbon dioxide. Use DPBS as the solvent to 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 ChemoTX microporous membrane, remove the cells from the incubator, transfer 50 μL of cells per well to the microporous membrane, cover the lid, and incubate for another 1.5 hours in a cell culture incubator at 37°C and 5% carbon dioxide. . Take out the cell plate, remove the microporous membrane, add 30 μL of ATP-binding reagent CellTiter-Glo reagent to the cells in the lower plate, mix with a volley gun, transfer 30 μL of each well to a white opaque 96-well plate, and incubate in the dark for 10 minutes. , use Envision multi-mode plate reader to read the luminescence signal, use Graphpad software to fit the compound's inhibitory rate 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 CCRF-CEM cell chemotaxis was measured by the above test, and the measured IC ₅₀ values are shown in Table 2. Experimental results show that the test compounds of the present invention have significant inhibitory activity on CCRF-CEM cell chemotaxis, and the inhibitory activities of most compounds are significantly stronger than those of Comparative Example 1 and Comparative Example 2.

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

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

3.1. Experimental materials

3.2. Experimental steps

Centrifuge hTh2 (or hTreg) cells to remove the culture medium, re-suspend them in 100% fetal calf serum, adjust the cell density to 2×10 ⁶ /mL, and dispense the cells into a 96-well cell plate, 99 μL per well. Prepare a compound stock solution with a concentration of 10 mM in a test tube using DMSO as the solvent, and then use DMSO as the solvent to gradiently dilute the sample as needed. Transfer 1 μL of the test compound to each well of the cells in the 96-well plate, and incubate for 0.5 hours in a cell culture incubator at 37°C and 5% carbon dioxide. Use DPBS as the solvent to prepare a recombinant human CCL22 solution with a concentration of 2.5 nM, take out the lower cell plate of ChemoTX, and dispense the recombinant human CCL22 into the cell plate, 30 μL per well. Cover the lower plate with ChemoTX microporous membrane, remove the cells from the incubator, transfer 50 μL of cells per well to the microporous membrane, cover the lid, and incubate for another 1.5 hours in a cell culture incubator at 37°C and 5% carbon dioxide. . Take out the cell plate, carefully remove the microporous membrane, add 30 μL of ATP-binding reagent CellTiter-Glo reagent to the cells in the lower plate, mix with a volley gun, then transfer 30 μL of each well to a white opaque 96-well plate, and incubate in the dark for 10 minutes. Finally, the luminescence signal was read with an Envision multi-mode plate reader, and the compound inhibition rate was obtained by fitting with Graphpad software.

3.3. Experimental results

The inhibitory activity of the compounds of the present invention on CCR4-mediated Th2 and Treg cell chemotaxis was measured by the above test, 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 compound’s occupancy rate of CCR4 receptor on cell surface

4.1. Experimental materials

4.2. Experimental steps

Centrifuge the CCRF-CEM cells at 300 rcf to remove the culture medium, re-suspend them in 100% fetal calf serum, adjust the cell density to 2×10 ⁶ /mL, and dispense the cells into a 96-well cell plate, with 99 μL per well. Prepare a compound stock solution with a concentration of 10 mM in a test tube using DMSO as the solvent, and then use DMSO as the solvent to gradiently dilute the sample as needed. Set up 2 wells for each concentration of the compound, transfer 1 μL of the compound to be tested into each well of the 96-well plate, and incubate in a cell culture incubator at 37°C and 5% carbon dioxide for 0.5 hours. Using DPBS as the solvent, prepare a hCCL22 solution with a concentration of 20 μM. Take out the 96-well plate from the cell culture incubator. Add 1 μL of hCCL22 solution to one well of each concentration of the compound, and add 1 μL of DPBS solution to the other well. Place it again at 37 Incubate in a cell culture incubator at ℃ and 5% carbon dioxide for 0.5 hours. Remove the cell plate, add 1 μL of PE-conjugated anti-human CD194 (CCR4) antibody to each cell well, and incubate in a 4°C refrigerator in the dark for 0.5 hours. Take out the cell plate, centrifuge at 4°C and 300rcf to remove the culture medium, add 200 μL of DPBS solution pre-cooled at 4°C to each well, resuspend the cells and centrifuge again at 4°C and 300rcf to remove the supernatant, add 200 μL of DPBS again and wash once. After centrifugation to remove the supernatant, resuspend the cells in 100 μL of pre-chilled DPBS. Use Cytek Aurora flow cytometer to detect the intensity of PE fluorescent signal in each well, and use Graphpad software to fit the curve of compound dose versus CCR4 occupancy rate.

4.3. Experimental results

The occupancy rate of the CCR4 receptor on the cell surface by the compounds of the present invention was measured by the above method. The experimental results are shown in Table 4. Experimental results show that the test compound of the present invention can show a higher occupancy rate of CCR4 at a lower concentration, and on 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 1 Comparative Example 2.

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

Test Example 5: Evaluation of pharmacokinetic properties in mice

5.1. Experimental methods

The test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and ultrasonicated to prepare a clear solution of corresponding concentration, and filtered with a microporous membrane for later 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 is 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 clarification of the corresponding concentration. Solution, filter with microporous membrane and set aside. Select Balb/c male mice were orally administered a solution of the candidate compound at a dose of 10 mg/kg or 50 mg/kg. Collect whole blood at a certain time point, prepare plasma, analyze drug concentration using LC-MS/MS method, and calculate pharmacokinetic parameters.

5.2. Experimental results

The experimental results are shown in Table 5. Experimental results show that the test compound of the present invention has good 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 methods

The test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and ultrasonicated to prepare a clear solution of corresponding concentration, and filtered with a microporous membrane for later 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 ultrasonicated to prepare a clear solution of corresponding concentration, and filtered with a microporous membrane for later use. Male SD rats were selected and the candidate compound solution was orally administered at a dose of 50 mg/kg. Collect whole blood at a certain time point, prepare plasma, and analyze drug concentration using LC-MS/MS method. degree, and calculate pharmacokinetic parameters.

6.2. Experimental results

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

Table 6: Pharmacokinetic properties of test compounds in rats

Test Example 7: Evaluation of Pharmacokinetic Properties in Beagle Dogs

7.1. Experimental methods

The test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and ultrasonicated to prepare a clear solution of corresponding concentration, and filtered with a microporous membrane for later 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 ultrasonicated to prepare a clear solution of corresponding concentration, and filtered with a microporous membrane for later 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 using LC-MS/MS method, and calculate pharmacokinetic parameters.

7.2. Experimental results

The experimental results are shown in Table 7. Experimental results show that the test compound of the present invention has good pharmacokinetic properties in beagle dogs.

Table 7: Pharmacokinetic properties of test compounds in beagle dogs

Test Example 8: Evaluation of the inhibitory activity of compounds on hERG potassium ion channels

8.1. Experimental materials

8.2. Experimental steps

8.2.1. Cell culture and processing

CHO cells stably expressing hERG are cultured in a 35mm diameter cell culture dish in an incubator at 37°C and 5% _CO2 . They are passaged every 48 hours at a ratio of 1:5. The medium formula is: 90% Ham's F12 medium. , 10% fetal bovine serum, 100g/mL geneticin and 100g/mL hygromycin. Aspirate the cell culture medium, rinse once with extracellular fluid, add 0.25% trypsin-EDTA solution, and digest at room temperature for 3-5 minutes. Aspirate the digestion solution, resuspend with extracellular fluid, and transfer the cells to a test dish for electrophysiological recording.

8.2.2. Electrophysiological recording process

In CHO cells stably expressing hERG potassium channels, hERG potassium channel currents were recorded at room temperature using whole-cell voltage clamp technology. The tip resistance after perfusion of the electrode liquid is about 2-5MΩ. The glass microelectrode can be connected to the patch clamp amplifier by inserting it into the amplifier probe. The clamping voltage and data recording are controlled and recorded by computer through pClamp software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz. exist After obtaining the whole-cell recording, the cells were clamped at -100mV, and the step voltage to induce hERG potassium current was given a 2s depolarization voltage from -100mV to +20mV, then repolarization to -50mV, and continued for 1s before returning to -100mV. . This voltage stimulation is given every 5 s. After confirming that the hERG potassium current is stable (at least 1 minute), the administration process begins. Each test concentration of the compound is administered for at least 1 minute until the effect is steady state. Data analysis and processing used pClamp 10, GraphPad and Excel software.

8.3. Experimental results

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

Table 8: Inhibitory activity of test compounds on hERG potassium channels

Test Example 9: Pharmacodynamic experiment on delayed-type hypersensitivity reaction in mice induced by FITC in vivo

9.1. Experimental materials

9.2. Experimental steps

7-week-old BALB/c mice (Vital Lever) were allowed to adapt for 1 week after arriving in the animal room. According to body weight, they were divided into model control, 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 mouse's left ear respectively for modeling stimulation. Compound 19 and the compound of Comparative Example 1 were dissolved in the solvent (5% DMSO+40% PEG400+10% Solutol+45% water), and the compound of Comparative Example 2 was dissolved in the solvent (10% PEG400+90% water). Dexamethasone was dissolved in 0.5% MC. Orally administer the drug 30 minutes before modeling stimulation on the 5th day and the 6th, 7th, 8th and 9th days, once a day. On days 6, 7, 8, and 9, before FITC stimulation and 24 hours after the last stimulation, the ear thickness of the left ear was measured using 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 Figures 1 and 2. Experimental results show that oral administration of compound 19 can significantly inhibit ear swelling in this animal model. Moreover, at the same dose and the same route of administration, Compound 19 showed significantly better efficacy than Comparative Example 1 and Comparative Example 2.

Test Example 10: Pharmacodynamic experiment on OXA-induced mouse specific dermatitis in vivo

10.1. Experimental materials

10.2. Experimental steps

7-week-old BALB/c mice (Shanghai Jihui) were adapted for 1 week after arriving in the animal room. According to body weight, they were divided into model control, positive control dexamethasone group and test compound group. On day 0, BALB/c mice were anesthetized with isoflurane, their abdomens were shaved, and they were sensitized with 100 μL of 1.5% OXA (dissolved in 80% acetone + 20% olive oil). On the 7th day, 20 μL of 1.5% OXA was applied to the inner and outer sides of the mouse's left ear respectively for modeling stimulation. Compound 19 and the compound of Comparative Example 1 were dissolved in the solvent (5% DMSO+40% PEG400+10% Solutol+45% water), and the compound of Comparative Example 2 was dissolved in the solvent (10% PEG400+90% water). Dexamethasone was dissolved in 0.5% MC. Oral administration was performed continuously on days 6 and 7, once a day. Ear thickness measurements were performed on the left ear using a spiral micrometer 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. Experimental results show that oral administration of compound 19 can significantly inhibit ear swelling in this animal model. Moreover, at the same dose and the same route of administration, Compound 19 showed significantly better efficacy than Comparative Example 1 and Comparative Example 2.

Claims (14)

A compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, 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; R ¹ is each 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 _4cycloalkyl 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; R ⁴ is selected from

,

or

; Y is selected from CH ₂ 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 group, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-7 membered heterocyclyl , 5-6 membered heteroaryl or phenyl are each independently selected from one or more groups selected from halogen, hydroxyl, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy. replaced; 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 alkyl , C ₁ -C ₃ alkoxy or C ₃ -C ₆ cycloalkyl, each independently optionally selected from halogen, hydroxyl, amine, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ Substituted by one or more alkoxy groups; Each R ^c is independently selected from H, halogen, C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl, wherein the C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl is each independently selected optionally substituted with 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 alkyl , C ₁ -C ₃ alkoxy or C ₃ -C ₆ cycloalkyl, each independently optionally selected from halogen, hydroxyl, amine, cyano, C ₁ -C ₃ alkyl or C ₁ -C ₃ Substituted by one or more alkoxy groups; Each R ^e 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 Member 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 S(O) ₂ -, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amine, -(CH ₂ ) _n -cyano, -(CH ₂ ) _n -carboxyl or 2-oxo Hetero-spiro[3,3]heptanyl, 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 -amine, -(CH ₂ ) _n -cyano or -(CH ₂ ) _n -carboxy are each independently selected from halogen, hydroxyl, and amino as needed. Substituted with one or more groups of , cyano, C ₁ -C ₃ alkyl or 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 chemical bond, 4-7 membered heterocyclylene, C ₁ -C ₃ (alkylene) or C ₃ -C ₆ (alkylene) cycloalkyl, wherein the 4- Each of the 7-membered (ethylene)heterocyclylene, C ₁ -C ₃ (ethylene)alkylene or C ₃ -C ₆ (ethylene)cycloalkyl group is independently selected from the group consisting of halogen, hydroxyl, amine, Substituted with one or more groups of 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. The compound of formula (I) as described in claim 1 or its isotopically 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 X ¹ and X ² is N, the other is C, At least one of X ³ , X ⁴ and X ⁵ is N. The compound of formula (I) as described in claim 1 or 2, or its isotopically 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 isotopically labeled compound as described in any one of claims 1 to 3, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, which are compounds of formula (II) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof , or its pharmaceutically acceptable Accepted salts, or prodrugs thereof, or metabolites thereof,

Among them, R ¹ -R ³ , X ¹ -X ⁵ , Y, R ^a , R ^c , R ^d , ^Re , Z ¹ , Z ² , Z ³ and Z ⁴ are as defined in request item 1; In particular, among

Selected from

,

,

,

,

or

;and / or

Selected from

,

or

;R ^c , R ^d , R ^e , Z ² and Z ³ are as defined in claim 1; More specifically, it is formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula ( II-7) or the compound of formula (II-8) or its isotope labeled compound, or its optical isomer, geometric isomer, Tautomers or mixtures of isomers, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof,

Where R ¹ -R ³ , R ^a , R ^d , ^Re , Z ¹ and Z ³ are as defined in claim 1. The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 3, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, which are compounds of formula (III) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof , or its pharmaceutically acceptable Accepted salts, or prodrugs thereof, or metabolites thereof,

Where R ¹ -R ³ , R ^a , ^Re and Z ¹ are as defined in claim 1. The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 3, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, which are compounds of formula (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomer mixtures thereof , or its pharmaceutically acceptable salt, or its prodrug, or its metabolite,

Where R ¹ -R ³ , R ^a , ^Re and Z ¹ are as defined in claim 1. The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 6, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein, Each R ^e is independently -LR ^f ; R ^f is each 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 member 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 S(O) ₂ -, -(CH ₂ ) _n -hydroxyl, -(CH ₂ ) _n -amine, -(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, -( _CH2 ) _n -amine, -( _CH2 ) _n -cyano or -( _CH2 ) _n -carboxy are each independently selected from hydroxyl or _C1 - _C3 as appropriate Alkyl is substituted by one or more groups; preferably R ^f is each independently selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, Fluoromethyl, hydroxyl, carboxyl, methoxy, oxetanyl, azetidinyl, 1,1-bis-oxothietanyl, morpholinyl, pyrrolidinyl, piperidine base, tetrahydropyranyl, acetamide, methanesulfonyl, CH ₃ S(O) ₂ NH- or 2-oxa-spiro[3,3]heptyl; ^Rg is selected from C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl or 3-4 membered heterocyclyl, preferably selected from methyl, ethyl, cyclopropyl, cyclobutanyl or oxygen heterocyclobutanyl; Each n is independently any integer from 0 to 3, and L is selected from the group consisting of chemical bonds, methylene, ethylidene, propylene, cyclopropylene, cyclobutylene optionally substituted by methyl or ethyl, (Ex)cyclopentyl, (Ex)cyclohexylene, (Ex)azetidinyl, (Ex)pyrrolidinyl or (Ex)piperidinyl alkyl; In particular, Each Re ^is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,

,

The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 7, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein, R ¹ is each 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 is selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or methanesulfonyl; and/or R ² is selected from H or C ₁ -C ₃ alkyl, preferably selected from H or methyl; and/or R ³ is selected from H or C ₁ -C ₃ alkyl, preferably from H or methyl. The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 8, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, wherein, R ^{a is} each 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 group, C ₁ -C ₃ alkoxy group or C ₃ -C ₄ cycloalkyl group is each independently optionally replaced by a halogen, a hydroxyl group, a cyano group, a C ₁ -C ₃ alkyl group or a C ₁ - C ₃ alkoxy substituted, R ^a 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 R ^b is each independently selected from H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl or cyano, wherein each of the C ₁ -C ₃ alkyl or C ₃ -C ₄ cycloalkyl 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, cyclo propyl, difluoromethyl, trifluoromethyl, trifluoroethyl or cyano; and/or R ^c is each independently selected from H, halogen or C ₁ -C ₃ alkyl, preferably selected from H, fluorine, chlorine, methyl or ethyl; and/or R ^d is each 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 base. The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 9, 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 Z ³ is 0 or 1; and/or Z ⁴ is 1; and/or Each n is independently 0 or 1. The compound of formula (I) or its isotopically labeled compound as described in any one of claims 1 to 10, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical Acceptable salts, or prodrugs thereof, or metabolites thereof, are selected from:

A pharmaceutical composition comprising the compound of formula (I) as described in any one of claims 1 to 11 or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier. A compound of formula (I) as described in any one of claims 1 to 11 or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or a pharmaceutical thereof The use of the above acceptable salts, or their prodrugs, or their metabolites in the preparation of medicaments as CCR4 antagonists, in particular, the medicaments are used to treat or prevent diseases or conditions mediated by CCR4. The use as described in claim 13, wherein the disease or condition mediated by CCR4 is selected from one of atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, and rheumatoid arthritis. or various immune-related diseases; or, The disease or condition mediated by CCR4 is cancer.