CN118406037B

CN118406037B - A triazole derivative and its preparation method and use

Info

Publication number: CN118406037B
Application number: CN202410825407.1A
Authority: CN
Inventors: 李清; 徐燕军; 代林君; 张裔; 庄鑫雨; 徐青锐
Original assignee: Sichuan Normal University
Current assignee: Sichuan Normal University
Priority date: 2024-06-25
Filing date: 2024-06-25
Publication date: 2025-02-25
Anticipated expiration: 2044-06-25
Also published as: CN118406037A

Abstract

本发明提供了一种三氮唑类衍生物及其制备方法和用途，属于化学医药领域。该类衍生物是式I所示的化合物及其药学上可接受的盐。本发明三氮唑类衍生物可作为FXIa小分子抑制剂，可以有效提高化合物的抗凝血作用。此外，本发明化合物可用于有效治疗和/或预防心脑血管疾病及血栓症状。式1。The present invention provides a triazole derivative and a preparation method and use thereof, belonging to the field of chemical medicine. The derivative is a compound shown in formula I and a pharmaceutically acceptable salt thereof. The triazole derivative of the present invention can be used as a small molecule inhibitor of FXIa, and can effectively improve the anticoagulant effect of the compound. In addition, the compound of the present invention can be used to effectively treat and/or prevent cardiovascular and cerebrovascular diseases and thrombotic symptoms. Formula 1.

Description

Triazole derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of chemical medicines, and particularly relates to a triazole derivative, a preparation method and application thereof.

Background

Cerebral stroke (commonly known as "stroke") is an acute cerebrovascular disease that is damaged by blockage of cerebral vessels (i.e., ischemic stroke) or rupture (i.e., hemorrhagic stroke). On one hand, the disease can cause heavy economic burden, and on the other hand, the morbidity, disability rate, recurrence rate and death rate are extremely high, thereby seriously threatening the physical and mental health of the national people in China. In the diseased population, up to 83% of patients suffer from ischemic stroke, and the annual recurrence rate can be up to 17.7%. According to researches, the general aged people are easy to suffer from diseases, but in recent years, the aged people are gradually younger, wherein people with irregular diet, lack of exercise, bad preference such as smoking alcoholism or diseases such as three highs and heart diseases are more easy to induce cerebral apoplexy. At present, anticoagulant drugs and antiplatelet drugs are mainly used for treating thrombotic diseases clinically, but they cannot distinguish pathological coagulation from physiological coagulation, and serious bleeding complications (bleeding) are caused when thrombus is treated, so that effective and satisfactory treatment methods for thrombotic diseases still need to be further studied and researched.

Factor XI (FXI) acts as a protease that plays a major role in the intrinsic coagulation pathway, and becomes factor XIa (FXIa) after activation, which acts primarily on the amplification stage of the coagulation cascade. In animal experiments, mice targeted for knockout of FXI gene were found to survive and have completely normal hemostatic function, while exhibiting prolonged activation of part of the thromboplastin time (ACTIVATED PARTIAL throm-boplastin time, aPTT) and normal prothrombin time (prothrom-bin time, PT). Patients with congenital FXI deficiency (hemophilia c) do not show symptoms in adulthood and do not spontaneously bleed, only a fraction of which may have a mild or moderate bleeding tendency after trauma or surgery. FXIa is therefore a new target with lower risk of potential bleeding.

FXIa is a novel target of anticoagulants, and published patent applications with small-molecule inhibitors of FXIa are CN105164112, WO2016015593, WO2017005725, WO2018041122, WO2019175043 and WO2021057818. Among these, the main clinical studies entered are JNJ-70033093 (BMS-986177, possen pharmaceutical) and BAY-2433334 (Bayer), and ONO-5450598 (field pharmaceutical) and SHR2285 (Hengrui pharmaceutical) at clinical stage I. The data previously disclosed indicate that they have a certain clinical effect. However, poor selectivity and poor activity are major drawbacks of these FXIa inhibitors, and no small molecule FXIa inhibitors have been marketed to date. There is therefore still a need to investigate novel FXIa inhibitors.

Plasma Kallikrein (PK) is associated with improved vascular permeability or other chronic inflammatory diseases. C1-INH is an endogenous PKa inhibitor, and a SERPING1 gene mutation in hereditary angioedema causes a lack of function. But the normal population will also suffer from hereditary angioedema, mainly due to uncontrolled Plasma Kallikrein (PK) activity and Bradykinin (BK) production leading to angioedema. Furthermore, plasma Kallikrein (PK) activates other factor XII first in the enhancement loop, thus expanding the initiation of the coagulation cascade, which in turn leads to an increase in endothelial permeability. Their activation can affect the regulation of the renin-angiotensin system and fibrinolysis. Thus PK activation is an important link between clotting and inflammatory processes.

Currently developed inhibitors of FXIa are mostly dual-target inhibitors of FXIa and PKa. FXIa inhibitors Asundexian, such as developed by bayer corporation, are only 6.7 times selective for PKa and therefore need to be developed with high selectivity for PKa. Furthermore, pharmacokinetic studies indicate that Asundexian is metabolized primarily to aniline and α -substituted butyric acid. While the subsequent conversion of aniline to the N-acetyl product is the primary metabolic pathway, oxidative bioconversion of aniline may also occur. Oxidative metabolism of aniline/anilino groups is a well-established structural alert, associated with mutagenicity, direct toxicity, methemoglobinemia and immunosensitive toxicity. In the carcinogen list published by the world health organization international cancer research institute in 2017, aromatic amines were in the 3-class carcinogen list. Aniline toxicity is the main reason for drug withdrawal and discontinuation of clinical trials in the later stages of drug development, and 1/3 of the drugs containing aromatic amines are currently withdrawn. The aromatic amine structure of Asundexian is thus a potentially toxic substance.Asundexian

Therefore, the development of anticoagulant drugs with low toxicity, reduced bleeding risk, high selectivity to FXIa and PKa double targets and excellent therapeutic effect becomes a technical problem to be solved in the field.

Disclosure of Invention

The invention aims to provide a triazole derivative, a preparation method and application thereof.

The technical proposal is that the compound and the pharmaceutically acceptable salt thereof are characterized in that the structure is shown as the formula I

I

Wherein the method comprises the steps of

R ₁ represents H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl;

R ₂ represents a substituted or unsubstituted aryl group, a substituted or unsubstituted unsaturated heterocyclic group;

X represents C-OCH ₃ or N

R ₃ represents 4-chlorotriazole or 4-trifluoromethyl triazo.

The compound and the pharmaceutically acceptable salt thereof are characterized in that,

The alkyl is C1-C20 straight chain or branched chain saturated aliphatic, C3-C20 cycloalkyl or C5-C20 spirocycloalkyl, the substituent of the aryl is C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, nitro, cyano, hydroxyl, carboxyl or amino, the unsaturated heterocyclic group comprises a part of unsaturated heterocyclic group and aromatic heterocyclic group, and the heteroatom of the heterocyclic group is selected from nitrogen, oxygen or sulfur.

The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, or 2, 2-diethylhexyl;

The cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanedienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl;

The spirocycloalkyl is single spirocycloalkyl, double spirocycloalkyl or multiple spirocycloalkyl;

The aryl is substituted phenyl or naphthyl.

A compound and its pharmaceutically acceptable salt have the structure shown in formula I

I

Wherein the method comprises the steps of

R ₁ represents H, ethyl or benzyl,

R ₂ represents a benzene ring, benzoate, benzoic acid or N-containing heterocycle,

X represents C-OCH ₃ or N,

R ₃ represents 4-chlorotriazole or 4-trifluoromethyl triazo.

Further, the compound is one of the following compounds: The invention also provides a preparation method of the compound, which comprises the following steps:

The compound of formula AI-A and the compound of formula AI-B are subject to click chemistry reaction under CuOAc catalysis to obtain the target compound AI

Wherein,

R ₁、X、R₂ is as defined above.

The invention also provides application of the compound and pharmaceutically acceptable salts thereof in preparing a coagulation factor FXIa inhibitor and/or a plasma bradykinin kinase PKA inhibitor.

The term "alkyl" refers to a saturated aliphatic group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any useful point of attachment, preferably one or more of the following independently selected from C ₁~C₈ alkoxy, halogen, hydroxy, amino, carboxy, nitro.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituted group, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cycloalkyl groups being preferred, and polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (called a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a completely common electron-withdrawing system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl.

The term "aryl" refers to all-carbon monocyclic or fused-polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. The aryl group may be substituted or unsubstituted, i.e., may be substituted with 0 to 4 substituents such as deuterium, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen, nitro, cyano, hydroxy, carboxyl, amino, etc. Aryl groups include spiro, fused and bridged aryl groups.

The term "unsaturated heterocyclyl" is an unsaturated cycloalkyl group containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, including partially unsaturated heterocyclyl groups as well as aromatic heterocyclyl groups.

The invention also provides application of the compound and pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating XIa-mediated diseases and cardiovascular and cerebrovascular diseases;

preferably, the disease is a thromboembolic disease;

more preferably, the disease is myocardial infarction, angina pectoris, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.

The invention also provides a medicine, which is a preparation prepared by taking the compound and pharmaceutically acceptable salt thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

The invention also provides a pharmaceutical composition comprising the aforementioned compound and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.

Another aspect of the invention relates to a method for preventing and/or treating factor XIa mediated diseases, comprising administering to a patient a therapeutically effective dose of a compound of the foregoing, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or a mixture thereof, or a pharmaceutical composition comprising the same.

Another aspect of the present invention relates to a method of treatment for preventing and/or treating cardiovascular and cerebrovascular diseases, comprising administering to a patient a therapeutically effective amount of a compound of the foregoing, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a pharmaceutical composition comprising the same, wherein said cardiovascular and cerebrovascular diseases are selected from myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortic coronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.

Another aspect of the invention relates to a medicament for inhibiting factor XIa, PKA, comprising a compound as described above, or a salt, stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug, or mixture thereof, or a pharmaceutical composition comprising the same.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or melts. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

The aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

Dispersible powders and granules suitable for use in preparing an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the DELTEC CADD-PLUS. TM.5400 type.

The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present invention are administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors including, but not limited to, the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc., and, in addition, the optimal mode of treatment such as the mode of treatment, the daily amount of the foregoing compound, or the type of pharmaceutically acceptable salt can be identified in accordance with conventional treatment protocols.

The invention has the beneficial effects that in order to avoid the formation of amide bonds, a series of compounds taking 1,2, 3-triazole as a framework are synthesized by adopting click reaction, so that the amide bonds which are easy to break during the metabolism of the medicine are replaced, and the toxicity problem is solved. Surprisingly, some of the compounds exhibit excellent anticoagulant activity and selectivity. Specifically, the invention designs a small molecule inhibitor with a brand new structure, which solves the problem that aromatic amine with potential toxic effect is generated due to unstable amide bond fracture in asundexian metabolic process by introducing a triazole skeleton, and meanwhile, part of the compounds have higher selectivity, excellent anticoagulation activity and better drug generation property, and can be used for effectively treating and/or preventing cardiovascular and cerebrovascular diseases and thrombosis symptoms. It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.

Detailed Description

The raw materials and equipment used in the embodiment of the invention are all known products and are obtained by purchasing commercial products. Melting point was measured by RY-1 type melting point apparatus of Tianjin analytical instrument, 1H-NMR and 13C-NMR were measured by Bruker AM-600MHz,Varian 400MHz type nuclear magnetic resonance apparatus, TMS was used as internal standard, and MS was measured by thermo LC/MS type mass spectrometer. The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea on a tobacco stage as carrier. The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere. An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume. The hydrogen atmosphere means that the reactor flask is connected to a balloon of hydrogen gas of about L volume. The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times. The reaction temperature is room temperature and is 20-30 ℃ without special description in the embodiment. The monitoring of the reaction progress in the examples adopts Thin Layer Chromatography (TLC), the developing agent used in the reaction, the system of the eluent used in the column chromatography used for purifying the compound and the developing agent system of the thin layer chromatography comprise A methylene dichloride/methanol system, B normal hexane/ethyl acetate system, C petroleum riddle/ethyl acetate system, D acetone, E methylene dichloride/acetone system, F ethyl acetate/methylene dichloride system, G ethyl acetate/methylene dichloride/normal hexane, H ethyl acetate/methylene dichloride/acetone, I petroleum ether/ethyl acetate/methylene dichloride, and the volume ratio of the solvent can be adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can also be added for adjustment. The preparation method of the compound comprises the following steps: The first step of reaction is that nucleophilic substitution reaction is carried out on the compound of the formula AI-1 and the compound of the formula AI-2 to obtain the compound of the formula AI-A;

The second step of reaction is that the compound of formula AI-A and the compound of formula AI-B are subjected to click chemistry reaction under the catalysis of CuOAc to obtain the target compound AI

Reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylaminide, potassium acetate, sodium t-butoxide, or potassium t-butoxide, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide.

Conditions that provide acidity include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.

The above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, water or N, N-dimethylformamide.

General work-up procedure a (concentration under reduced pressure to remove solvent, extraction with water, ethyl acetate 3 times, combined organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtration off, spin-drying).

Example 1, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- ((1-phenyl-1H-1, 2, 4-triazol-4-yl) methyl) pyridin-2 (1H) -one (I-1)

4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one (I-1)

Step a preparation of azido-2-bromo-4-chlorobenzene (1 b)

Dissolving 2-bromo-4-chloroaniline (1 a) (20 g,96.87 mmol) in acetonitrile (150 mL), cooling to 0deg.C, slowly dropwise adding isoamyl nitrite (20.55 mL,145.3 mmol) and azido trimethylsilane (20.12 mL,63.55 mmol) in sequence, stirring at 0deg.C for 5 min, heating to room temperature, stirring for about 4h, TLC monitoring that the raw materials are completely reacted, removing most of acetonitrile by spinning, extracting with ethyl acetate and water, mixing the organic phases, washing with saturated saline solution, drying, concentrating, drying without spinning, pumping with oil to obtain brown solid 1b (25.89 g).¹H NMR (600 MHz, CDCl₃) δ 7.56, (d, J = 2.3 Hz, 1H), 7.32 (dd, J = 8.6, 2.3 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H).

Step b preparation of 1- (2-bromo-4-chlorophenyl) -4- (trimethylsilyl) -1H-1,2, 3-triazole (1 c)

1-(2-Bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (1c)

Dissolving compound 1b (25.89 g, 107.54 mmol) in toluene (250 mL), adding ethynyl trimethylsilane (32.34 g,46.53 mL,322.63 mmol) dropwise at room temperature, refluxing at 110deg.C overnight, after TLC monitoring 1b reaction is complete, spinning toluene away in a water bath at 65deg.C, adding water, extracting with ethyl acetate, combining ethyl acetate phases, drying, concentrating to obtain compound 1c (33.04 g,92.91%).¹H NMR (600 MHz, CDCl₃) δ 7.82 (s, 1H), 7.69, (d, J = 2.0 Hz, 1H), 7.43-7.39 (m, 2H), 0.32 (s, 9H). step C: preparation 1- (2-Bromo-4-chlorophenyl) -4-chloro-1H-1,2,3-triazole (1 d) 1- (2-Bromo-4-chlorophenyl) -4-chloro-1H-1,2,3-triazole (1 d)Compound 1C (30.04 g,90.84 mmol), NCS (145.56 g,1090 mmol) and KF (31.67 g,545.05 mmol) were weighed into a bottle, dissolved in acetonitrile, refluxed for 40H at 90 ℃, after completion of the TLC monitoring reaction, filtered, dried by spinning, extracted with ethyl acetate and water, the organic phases were combined, concentrated and the crude product was purified by column chromatography to give compound 1d (18.33 g,68.88%).¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.78, (d, J = 1.3 Hz, 1H), 7.50, (d, J = 1.3 Hz, 2H). step d, preparation of 4- (5-Chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2,5-dimethoxypyridine (1 e) 4- (5-Chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2,5-dimethoxypyridine (1 e)1D (18.33 g,62.57 mmol), 2, 5-Dimethoxypyridine-4-boronic acid (13.74 g,75.09 mmol), K ₃PO₄ (33.2 g,156.43 mmol) were dissolved in a degassed 1, 4-dioxane (160 mL): water (40 mL) =4:1 mixture, under argon protection, pdCl ₂(dppf)•CH₂Cl₂ (2.55 g,3.12 mmol) was added under argon protection, the reaction was refluxed for 12H at 90 ℃, after completion of the TLC monitoring, the 1, 4-dioxane was spun off, water was added, extracted with ethyl acetate, the organic phases were combined, dried, concentrated, and purified by column chromatography to compound 1e (15.37 g,69.95%).¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.76 (d, J = 1.3 Hz, 2H), 7.75 – 7.74 (m, 1H), 7.69 – 7.68 (m, 1H), 6.78 (s, 1H), 3.81 (s, 3H), 3.44 (s, 3H). step e:4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridine-2 (1H) -one (1 f) preparation 4- (5-Chloro-2- (4-chloro-1H-2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (1 f)1E (15.37 g,43.77 mmol) and pyridine hydrobromide (70.03 g,437.66 mmol) are dissolved in DMF (60 mL), stirred for 5H in an oil bath at 110 ℃, after TLC monitoring the reaction to completion, the reaction is cooled to room temperature, poured into a little ice water, a white solid is separated out, filtered and dried to obtain a compound 1f(13.59 g,92%).¹H NMR (400 MHz, DMSO-d₆) δ 11.20 (s, 1H), 8.60 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 6.96 (s, 1H), 6.33 (s, 1H), 3.27 (s, 3H)., step f, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (prop-2-yn-1-yl) pyridin-2 (1H) -one (1 g), preparation 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (1g)Preparation of 1g (1.45 g,43.66%).¹H NMR (400 MHz, Chloroform-d) δ 7.61 – 7.55 (m, 2H), 7.51 (s, 1H), 7.44 (d, J = 1.9 Hz, 1H), 6.99 (s, 1H), 6.58 (s, 1H), 4.76 (s, 2H), 3.36 (s, 3H), 2.51 (t, J = 2.6 Hz, 1H). step j 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- ((1-phenyl-1H-1, 2, 4-triazol-4-yl) methyl) pyridin-2 (1H) -one (I-1) by dissolving 1f (3 g,8.9 mmol) K ₂CO₃ (3.07 g,22.24 mmol) in DMF (18 mL), adding 3-bromopropylene (0.92 mL,10.68 mmol), stirring at RT to react 6H, adding a large amount of water, extracting multiple times with a small amount of ethyl acetate, combining the organic phases, drying, concentrating, purifying the crude product by column chromatography 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one (I-1)1G of the compound and azidobenzene (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-70/1) to obtain compound I-1 (71 mg, white solid, yield) ：53.89%).HPLC purity: 99.63%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.65 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.80 – 7.71 (m, 2H), 7.69 (s, 1H), 7.63 – 7.55 (m, 2H), 7.52 – 7.46 (m, 1H), 7.44 (s, 1H), 6.46 (s, 1H), 5.23 (s, 2H), 3.30 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 158.96, 144.35, 142.61, 139.98, 136.96, 135.07, 134.10, 133.94, 132.70, 131.25, 130.44, 130.35, 129.21, 127.62, 124.19, 122.33, 121.44, 120.55, 119.69, 56.60, 44.01. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₁₈Cl₂N₇O₂ ⁺ 494.0894, found 494.0903.

Example 2, methyl 2- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) benzoate (I-2)Methyl 2-(4-((4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoate (I-2)1G of the compound and methyl 2-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (140/1-70/1) to obtain compound I-2 (173.6 mg, white solid, yield) ：73.7%).HPLC purity: 99.11%.¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.36 (s, 1H), 7.94 – 7.89 (m, 1H), 7.82 – 7.76 (m, 1H), 7.76 – 7.72 (m, 1H), 7.72 – 7.67 (m, 2H), 7.66 – 7.61 (m, 2H), 7.36 (s, 1H), 6.46 (s, 1H), 5.21 (s, 2H), 3.54 (s, 3H), 3.28 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.09, 159.22, 143.06, 142.92, 140.34, 135.44, 135.22, 134.11, 133.94, 133.58, 132.46, 131.21, 131.00, 130.71, 130.61, 127.56, 127.50, 126.69, 125.80, 124.02, 121.10, 119.37, 56.53, 52.84, 43.81. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₅H₂₀Cl₂N₇O₄ ⁺ 552.0948, found 552.0950.

Example 3, 3- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-4-yl) benzoic acid methyl ester (I-3)Methyl-(4-((4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoate (I-3)1G of the compound and methyl 3-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-80/1) to obtain compound I-3 (162 mg, white solid, yield) ：68.77%).HPLC purity: 99.71%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.68 (s, 1H), 8.42 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.80 – 7.72 (m, 3H), 7.69 (d, J = 2.2 Hz, 1H), 7.43 (s, 1H), 6.46 (s, 1H), 5.23 (s, 2H), 3.91 (s, 3H), 3.30 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.73, 158.96, 144.58, 142.60, 139.96, 137.21, 135.07, 134.12, 133.92, 132.69, 131.74, 131.26, 131.07, 130.45, 129.58, 127.63, 125.06, 124.20, 122.64, 121.48, 120.75, 119.68, 56.60, 53.06, 43.99. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₅H₂₀Cl₂N₇O₄ ⁺ 552.0948, found 552.0954.

Example 4, methyl 4- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-4-yl) benzoate (I-4)Methyl 4-(4-((4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoate (I-4)1G of the compound and methyl 4-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, and purifying with dichloromethane and methanol (140:1-70:1) as eluent to obtain compound I-4 (157.8 mg, off-white solid, yield) ：76.56%).HPLC purity: 99.43%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.70 (s, 1H), 8.16 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.6 Hz, 2H), 7.81 – 7.72 (m, 2H), 7.69 (d, J = 2.2 Hz, 1H), 7.44 (s, 1H), 6.46 (s, 1H), 5.23 (s, 2H), 3.89 (s, 3H), 3.29 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.79, 158.94, 144.74, 142.64, 140.13, 139.97, 135.06, 134.11, 133.91, 132.70, 131.44, 131.26, 130.45, 129.88, 127.63, 124.21, 122.53, 121.45, 120.40, 119.69, 56.59, 52.90, 44.01. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₅H₂₀Cl₂N₇O₄ ⁺ 552.0948, found 552.0959.

Example 5, 2- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (I-5)2-(4-((4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-5)The synthesis method is the same as that of I-2, I-2 is dissolved by a mixed solvent of THF (MeOH: H ₂ O=4:1:1), lithium hydroxide monohydrate (5 equiv) is added, stirring is carried out for 3.5H under ice bath, after TLC monitoring reaction is finished, the solvent is screwed off, a small amount of water is added, the pH is regulated to 2-3 by 4N HCl under ice bath, solid precipitation exists, and suction filtration is carried out to obtain the compound I-5 (80 mg, white solid and yield) ：74.62%).HPLC purity: 99.14%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.31 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.65 – 7.60 (m, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 6.47 (s, 1H), 5.20 (s, 2H), 3.26 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.99, 159.37, 143.00, 142.76, 140.51, 135.32, 135.29, 134.23, 133.87, 133.05, 132.30, 131.16, 130.90, 130.67, 128.84, 127.46, 126.78, 125.77, 123.94, 121.03, 119.27, 56.52, 43.85. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₄H₁₈Cl₂N₇O₄ ⁺ 538.0792, found 538.0800.

Example 6, 3- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (I-6)3-(4-((4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-6)The synthesis method is the same as that of I-3, I-3 is dissolved by a mixed solvent of THF (MeOH: H ₂ O=4:1:1), lithium hydroxide monohydrate (5 equiv) is added, stirring is carried out for 3.5H under ice bath, after TLC monitoring reaction is finished, the solvent is screwed off, a small amount of water is added, the pH is regulated to 2-3 by 4N HCl under ice bath, solid precipitation exists, and suction filtration is carried out to obtain the compound I-6 (87 mg, white solid and yield) ：79.7%).HPLC purity: 99.66%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.78 – 7.66 (m, 3H), 7.62 (d, J = 2.0 Hz, 1H), 7.38 (s, 1H), 6.46 (s, 1H), 5.22 (s, 2H), 3.27 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.79, 159.33, 144.24, 143.01, 140.49, 136.96, 135.26, 134.18, 133.88, 132.77, 132.34, 131.12, 131.04, 130.65, 129.94, 127.46, 124.85, 123.96, 122.62, 121.11, 120.97, 119.51, 56.54, 44.18. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₄H₁₈Cl₂N₇O₄ ⁺ 538.0792, found 538.0796.

Example 7, 4- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (I-7)4-(4-((4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-7)The synthesis method is the same as that of I-4, I-4 is dissolved by a mixed solvent of THF (MeOH: H ₂ O=4:1:1), lithium hydroxide monohydrate (5 equiv) is added, stirring is carried out for 3.5H under ice bath, after TLC monitoring reaction is finished, the solvent is screwed off, a small amount of water is added, the pH is regulated to 2-3 by 4N HCl under ice bath, solid precipitation exists, and suction filtration is carried out, thus obtaining the compound I-7 (107 mg, white solid and yield) ：79.84%). HPLC purity: 98.57%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.53 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.75 – 7.64 (m, 2H), 7.61 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 6.46 (s, 1H), 5.21 (s, 2H), 3.27 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.86, 158.96, 144.69, 142.64, 139.99, 139.83, 135.07, 134.11, 133.93, 132.69, 131.53, 131.26, 131.22, 130.45, 127.63, 124.21, 122.49, 121.44, 120.27, 119.68, 56.59, 44.01. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₄H₁₈Cl₂N₇O₄ ⁺ 538.0792, found 538.0801.

Example 8, 1- ((1- (1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-ylmethyl) -4- (5-chloro-2- (4-chloro-1H-1, 2, 4-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (I-8)1-((1-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (I-8)The compound 1g was weighed into a bottle with 4-azido-1H-pyrazole (1.5 equiv), dissolved in methanol, added with CuOAc (0.2 equiv), and stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (140/1-30/1) to obtain compound I-8 (39 mg, white solid, yield) ：37.77%).HPLC purity: 99.85%.¹H NMR (400 MHz, DMSO-d₆) δ 13.35 (s, 1H), 8.69 (s, 1H), 8.45 – 8.35 (m, 2H), 8.02 (s, 1H), 7.79 – 7.72 (m, 2H), 7.69 (s, 1H), 7.42 (s, 1H), 6.45 (s, 1H), 5.18 (s, 2H), 3.29 (s, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 158.93, 143.57, 142.62, 139.96, 135.08, 134.09, 133.93, 132.69, 131.73, 131.27, 130.45, 127.62, 124.20, 123.34, 122.11, 121.69, 121.38, 119.66, 56.58, 44.04. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₀H₁₆Cl₂N₉O₂ ⁺484.0799, found 484.0801.

Example 9, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- ((1- (1-methyl-1H-pyrazol-4-yl) -1H-1,2, 4-triazol-4-ylmethyl) pyridin-2 (1H) -one (I-9)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-((1-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one (I-9)1G of the compound and 4-azido-1-methyl-1H-pyrazole (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-40/1) to obtain compound I-9 (46 mg, white solid, yield) ：43.29%).HPLC purity: 99.88%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.38 (s, 2H), 7.96 (s, 1H), 7.81 – 7.72 (m, 2H), 7.69 (s, 1H), 7.42 (s, 1H), 6.45 (s, 1H), 5.18 (s, 2H), 3.90 (s, 3H), 3.29 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 158.91, 143.60, 142.61, 139.94, 135.07, 134.09, 133.92, 132.71, 131.34, 131.27, 130.44, 127.63, 124.31, 124.20, 123.20, 121.66, 121.39, 119.68, 56.59, 44.03. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₁H₁₈Cl₂N₉O₂ ⁺ 498.0955, found 498.0961.

Example 10, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- ((1- (2-methylpyridin-3-yl) -1H-1,2, 4-triazol-4-yl) methyl) pyridin-2 (1H) -one (I-10)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-((1-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one (I-10)1G of the compound and 3-azido-2-methylpyridine (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, and removing the solvent of dichloromethane and methanol (100/1-40/1) to obtain compound I-10 (34 mg, white solid, yield) ：22%).HPLC purity 97.89%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.70 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 7.43 (s, 1H), 6.46 (s, 1H), 5.24 (s, 2H), 3.29 (s, 3H), 2.35 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 158.94, 153.52, 150.63, 143.63, 142.58, 139.95, 135.08, 134.33, 134.11, 133.89, 132.92, 132.72, 131.26, 130.45, 127.66, 126.04, 124.21, 122.68, 121.42, 119.63, 56.59, 43.83, 21.31. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₁₉Cl₂N₈O₂ ⁺ 509.1003, found 509.1009.

Example 11, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- ((1- (6-chloro-2-methylpyridin-3-yl) -1H-1, 2-triazol-4-yl) methyl) -5-methoxypyridin-2 (1H) -one (I-11)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-1-((1-(6-chloro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-methoxypyridin-2(1H)-one (I-11)1G of the compound and 3-azido-6-chloro-2-methylpyridine (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-40/1) to obtain compound I-11 (80 mg, white solid, yield) ：46%).HPLC purity 95.20%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.48 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.80 – 7.72 (m, 2H), 7.69 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 6.46 (s, 1H), 5.24 (s, 2H), 3.29 (s, 3H), 2.34 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 158.96, 154.68, 150.24, 143.71, 142.63, 139.96, 137.79, 135.08, 134.10, 133.91, 132.70, 132.35, 131.26, 130.45, 127.65, 126.23, 124.20, 123.14, 121.39, 119.62, 56.58, 43.85, 21.10. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₁₈Cl₃N₈O₂ ⁺ 543.0613, found 543.0620.

Example 12, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- ((1- (6-methoxy-2-methylpyridin-3-yl) -1H-1,2, 4-triazol-4-yl) methyl) pyridin-2 (1H) -one (I-12)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-((1-(6-methoxy-2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one (I-12)1G of the compound and 3-azido-6-methoxy-2-methylpyridine (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-50/1) to obtain compound I-12 (80 mg, white solid, yield) ：50.59%).HPLC purity 97.99%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.35 (s, 1H), 7.81 – 7.72 (m, 3H), 7.69 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.46 (s, 1H), 5.23 (s, 2H), 3.91 (s, 3H), 3.29 (s, 3H), 2.23 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 163.48, 158.95, 151.73, 143.44, 142.58, 139.95, 137.71, 135.09, 134.10, 133.91, 132.71, 131.25, 130.44, 127.64, 126.94, 126.23, 124.19, 121.40, 119.61, 109.00, 56.58, 54.17, 43.86, 20.88. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₄H₂₁Cl₂N₈O₃ ⁺ 539.1108, found 539.1118.

Example 13, 5-bromo-3- (4- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) pyridine carbonitrile (I-13)5-Bromo-3-(4-((4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)picolinonitrile (I-13)1G of the compound was dissolved in a mixed solvent of 3-azido-5-bromopyridine nitrile (2 equiv) and t-BuOH: ACN: H ₂ O=2:1:1, followed by addition of CuSO ₄ (0.5 equiv) and sodium L-ascorbate (0.5 equiv) and stirring at room temperature for reaction 10H. After the completion of the reaction, TLC was followed by spin-drying, water addition, extraction with ethyl acetate, drying over anhydrous sodium sulfate, and concentration. The crude product is purified by column chromatography, eluting with methylene chloride and methanol (110/1-70/1) to give compound I-13 (138 mg, white solid, yield) ：78%).HPLC purity 98.22%. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 7.82 – 7.72 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.46 (s, 1H), 6.48 (s, 1H), 5.28 (s, 2H), 3.30 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 158.99, 152.55, 144.48, 142.77, 140.00, 136.65, 136.28, 135.09, 134.10, 133.96, 132.63, 131.28, 130.48, 127.66, 125.67, 125.51, 125.48, 124.19, 121.40, 119.64, 115.56, 56.59, 43.85. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₁₅BrCl₂N₉O₂ ⁺ 597.9904, found 597.9909.

Example 14, 6-chloro-3- (4- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) pyridine carbonitrile (I-14)6-Chloro-3-(4-((4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)picolinonitrile (I-14)1G of the compound was dissolved in a mixed solvent of 3-azido-6-chloropyridine nitrile (2 equiv) and t-BuOH: ACN: H ₂ O=2:1:1, followed by addition of CuSO ₄ (0.5 equiv) and sodium L-ascorbate (0.5 equiv) and stirring at room temperature for reaction 10H. After TLC monitoring the end of the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating the crude product, purifying by column chromatography, eluting with dichloromethane and methanol (110/1-70/1) to obtain compound I-14 (125 mg, white solid, yield) ：70.45%).HPLC purity 98.45%.¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.70 (s, 1H), 8.50 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.82 – 7.71 (m, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.47 (s, 1H), 6.47 (s, 1H), 5.28 (s, 2H), 3.30 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 158.98, 150.92, 144.49, 142.77, 140.00, 137.25, 136.09, 135.08, 134.10, 133.95, 132.65, 131.30, 130.47, 127.66, 126.60, 125.50, 124.19, 121.38, 119.66, 114.80, 56.58, 43.82. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₁₅Cl₃N₉O₂ ⁺ 554.0409, found 554.0416.

Example 15, 3- (4- ((4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) picolinic acid methyl ester (I-15)Methyl 3-(4-((4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2- oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)picolinate (I-15)1G of the compound and methyl 3-azidoquinolinate (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-70/1) to obtain compound I-15 (93 mg, white solid, yield) ：45.04%).HPLC purity: 98.98%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 – 8.80 (m, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.29 – 8.25 (m, 1H), 7.86 (dd, J = 8.0, 4.8 Hz, 1H), 7.81 – 7.72 (m, 2H), 7.70 (d, J= 2.2 Hz, 1H), 7.42 (s, 1H), 6.47 (s, 1H), 5.23 (s, 2H), 3.67 (s, 3H), 3.30 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.20, 158.94, 150.53, 144.65, 143.92, 142.66, 139.94, 135.08, 134.23, 134.10, 133.91, 132.71, 131.93, 131.30, 130.45, 127.67, 127.37, 125.49, 124.22, 121.38, 119.58, 56.58, 53.09, 43.75. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₄H₁₉Cl₂N₈O₄ ⁺ 553.0901, found 553.0909.

Example 16, 3- (4- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) methyl) -1H-1,2, 4-triazol-2-yl) picolinic acid (I-16)3-(4-((4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)picolinic acid (I-16)Synthesis method same as I-15 was dissolved in a mixed solvent of THF: meOH: H ₂ O=4:1:1, lithium hydroxide monohydrate (5 equiv) was added, stirred in an ice bath for 3.5H, after the completion of the TLC monitoring reaction, the solvent was removed by spinning, a small amount of water was added, the pH was adjusted to 2-3 with 4N HCl in an ice bath, and a solid was precipitated, and suction filtration was carried out to give I-16 (38 mg, white solid, yield ：64.98%).HPLC purity 97.77%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 – 8.76 (m, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.22 – 8.16 (m, 1H), 7.82 – 7.79 (m, 1H), 7.79 – 7.72 (m, 2H), 7.70 (d, J = 2.3 Hz, 1H), 7.39 (s, 1H), 6.47 (s, 1H), 5.23 (s, 2H), 3.29 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.30, 158.96, 150.32, 146.43, 143.74, 142.61, 139.93, 135.08, 134.31, 134.11, 133.93, 132.70, 131.39, 131.30, 130.46, 127.67, 126.71, 125.47, 124.21, 121.40, 119.52, 56.57, 43.70. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₁₇Cl₂N₈O₄+ 539.0744, found 539.0752.

Example 17, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (1- (1-phenyl-1H-1, 2, 4-triazol-4-yl) propyl) pyridin-2 (1H) -one (I-17)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl)pyridin-2(1H)-one (I-17) Step a preparation of 1-alkyne-3-methylsulfonyl pentyl ester (17 a) Pent-1-yn-3-yl methanesulfonate (17 a)Ethylethynyl methanol (5.23 mL,57.6 mmol) was dissolved with DCM, the reaction was cooled to 0℃under argon, et ₃ N (12.01 mL,86.4 mmol) was added dropwise to the reaction, and a solution of methanesulfonic anhydride (15.05 g,86.4 mmol) in DCM was added dropwise thereto, and the reaction was stirred overnight. The reaction solution was diluted with DCM, washed three times with water, dried and concentrated to give 17a (10.98 g) as a brown oil which was used directly in the next step . ¹H NMR (400 MHz, Chloroform-d) δ 5.12 (td, J = 6.4, 2.2 Hz, 1H), 3.13 (s, 3H), 2.70 (d, J = 2.2 Hz, 1H), 1.94 (qd, J = 7.3, 6.3 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H). preparation of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (pent-1-yn-3-yl) pyridin-2 (1H) -one (17 b) 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(pent-1-yn-3-yl)pyridin-2(1H)-one (17b)Dissolving 1f (1.2 g,3.56 mmol) with isopropanol (12 mL), adding tetramethylguanidine (1.37 mL,10.68 mmol), stirring at room temperature for 30min, protecting with argon, stirring at 40deg.C for 6H with oil bath, drying the solvent by TLC, adding water, extracting with ethyl acetate, drying, concentrating, purifying the crude product by column chromatography to obtain compound 17b (349 mg,24.28%).¹H NMR (400 MHz, CDCl₃) δ 7.63 – 7.54 (m, 3H), 7.48 (s, 1H), 7.04 (d, J = 4.7 Hz, 2H), 6.56 (s, 1H), 5.80 – 5.72 (m, 1H), 3.34 (s, 3H), 2.53 (d, J= 2.4 Hz, 1H), 1.93 – 1.80 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). step C, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (1- (1-phenyl-1H-1, 2, 4-triazol-4-yl) propyl) pyridin-2 (1H) -one (I-17) 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl)pyridin-2(1H)-one (I-17)Compound 17b and azidobenzene (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (140/1-100/1) to obtain compound I-17 (26 mg, white solid, yield) ：25.09%).HPLC purity: 99.59%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.62 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.81 – 7.74 (m, 2H), 7.74 – 7.70 (m, 1H), 7.64 – 7.56 (m, 2H), 7.51 – 7.47 (m, 1H), 7.07 (s, 1H), 6.47 (s, 1H), 6.16 (t, J = 7.9 Hz, 1H), 3.24 (s, 3H), 2.29 – 2.15 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 159.24, 147.34, 141.89, 140.47, 136.98, 135.10, 134.12, 133.90, 132.68, 131.08, 130.47, 130.37, 129.24, 127.59, 124.18, 122.32, 121.50, 120.55, 115.70, 56.74, 26.39, 10.74. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₅H₂₂C_l2N₇O₂ ⁺ 522.1207, found 522.1212.

Example 18, methyl 2- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoate (I-18)Methyl 2-(4-(1-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2oxopyridin-1(2H)-yl)propyl)-1H-1,2,3-triazol-1-yl)benzoate (I-18)Compound 17B and methyl 2-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-80/1) to obtain compound I-18 (60 mg, white solid, yield) ：22.53%).HPLC purity: 97.16%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 – 8.61 (m, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.87 – 7.77 (m, 2H), 7.76 – 7.66 (m, 4H), 7.02 (s, 1H), 6.49 (s, 1H), 6.20 (t, J = 8.1 Hz, 1H), 3.56 (s, 3H), 3.26 (s, 3H), 2.28 – 2.08 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.88, 159.13, 146.16, 141.86, 140.36, 135.74, 135.10, 134.13, 133.89, 133.58, 132.70, 131.19, 131.06, 130.66, 130.46, 127.63, 127.53, 126.95, 125.95, 124.20, 121.47, 115.36, 56.59, 52.81, 26.72, 10.83. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₇H₂₄Cl₂N₇O₄ ⁺ 580.1261, found 580.1271.

Example 19, methyl 3- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoate (I-19)Methyl 3-(4-(1-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propyl)-1H-1,2,3-triazol-1-yl)benzoate (I-19)Compound 17b was weighed into a bottle with methyl 3-azidobenzoate (1.5 equiv), dissolved in methanol, cuOAc (0.2 equiv) was added thereto, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (100/1-80/1) to obtain compound I-19 (143 mg, white solid, yield) ：61.11%).HPLC purity: 98.46%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.80 – 7.73 (m, 3H), 7.73 – 7.70 (m, 1H), 7.05 (s, 1H), 6.48 (s, 1H), 6.17 (t, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.24 (s, 3H), 2.31 – 2.16 (m, J = 7.1 Hz, 2H), 0.85 (t, J = 7.2 Hz, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 165.74, 159.24, 147.56, 141.87, 140.45, 137.26, 135.09, 134.14, 133.88, 132.70, 131.74, 131.07, 130.46, 129.58, 127.60, 125.03, 124.18, 122.67, 121.55, 120.73, 115.58, 56.77, 53.06, 26.31, 10.72. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₇H₂₄Cl₂N₇O₄ ⁺ 580.1261, found 580.1271.

Example 20, methyl 4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoate (I-20)Methyl 4-(4-(1-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propyl)-1H-1,2,3-triazol-1-yl)benzoate (I-20)Compound 17b and methyl 4-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added, and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (160/1-80/1) to obtain compound I-20 (63 mg, white solid, yield) ：31.26%).HPLC purity: 99.12%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.62 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H), 7.80 – 7.73 (m, 2H), 7.72 (d, J = 2.2 Hz, 1H), 7.05 (s, 1H), 6.47 (s, 1H), 6.15 (t, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.24 (s, 3H), 2.33 – 2.16 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.79, 159.24, 147.71, 141.92, 140.48, 140.17, 135.09, 134.13, 133.88, 132.70, 131.46, 131.08, 130.47, 129.87, 127.61, 124.18, 122.55, 121.55, 120.39, 115.67, 56.77, 52.90, 26.24, 10.70. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₇H₂₄Cl₂N₇O₄ ⁺ 580.1261, found 580.1269.

Example 21, 2- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (I-21)2-(4-(1-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-21)The synthesis method is the same as that of I-18, I-18 is dissolved by using a mixed solvent of THF (MeOH: H ₂ O=4:1:1), lithium hydroxide monohydrate (5 equiv) is added, stirring is carried out for 3.5 hours under ice bath, after TLC monitoring reaction is finished, the solvent is screwed off, a small amount of water is added, the pH is regulated to 2-3 by using 4N HCl under ice bath, solid precipitation exists, and suction filtration is carried out, thus obtaining the compound I-21 (28 mg, white solid and yield ：57.39%).HPLC purity: 99.23%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 2H), 7.92 (d, J = 7.5 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.70 (s, 1H), 7.68 – 7.66 (m, 2H), 7.59 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.49 (s, 1H), 6.14 (t, J = 8.0 Hz, 1H), 3.21 (s, 3H), 2.24 – 2.04 (m, J = 7.5 Hz, 2H), 0.82 (t, J = 7.2 Hz, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 166.78, 159.53, 145.92, 142.18, 140.84, 135.56, 135.28, 134.14, 133.94, 133.15, 132.39, 130.99, 130.74, 130.65, 128.82, 127.49, 127.03, 125.93, 123.99, 121.12, 115.18, 56.57, 26.60, 10.61. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₆H₂₂Cl₂N₇O₄ ⁺ 566.1105, found 566.1113.

Example 22, 3- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin- (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (I-22)3-(4-(1-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-22)The synthesis method is the same as that of I-19, I-19 is dissolved by a mixed solvent of THF (MeOH: H ₂ O=4:1:1), lithium hydroxide monohydrate (5 equiv) is added, stirring is carried out for 3.5H under ice bath, after TLC monitoring reaction is finished, the solvent is screwed off, a small amount of water is added, the pH is regulated to 2-3 by 4N HCl under ice bath, solid precipitation exists, and suction filtration is carried out to obtain the compound I-22 (75 mg, white solid, yield ：69.87%).HPLC purity: 98.67%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.75 – 7.69 (m, 2H), 7.69 – 7.66 (m, 1H), 7.65 – 7.61 (m, 1H), 6.99 (s, 1H), 6.48 (s, 1H), 6.11 (t, J = 8.0 Hz, 1H), 3.18 (s, 3H), 2.28 – 2.08 (m, 2H), 0.80 (t, J = 7.1 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.80, 159.67, 147.41, 142.31, 140.96, 137.00, 135.31, 134.13, 133.90, 132.65, 132.32, 131.03, 130.92, 130.66, 129.92, 127.41, 124.84, 123.92, 122.54, 121.20, 120.97, 115.44, 56.68, 26.08, 10.55. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₆H₂₂Cl₂N₇O₄ ⁺ 566.1105, found 566.1107.

Example 23, 4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (I-23)4-(4-(1-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)propyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-23)The synthesis method is the same as that of I-20, dissolving I-20 with a mixed solvent of THF (MeOH: H ₂ O=4:1:1), adding lithium hydroxide monohydrate (5 equiv), stirring for 3.5H under ice bath, after TLC monitoring reaction, screwing off the solvent, adding a small amount of water, adjusting pH to 2-3 with 4N HCl under ice bath, precipitating solid, and suction filtering to obtain compound I-23 (30 mg, white solid, yield) ：61.49%).HPLC purity: 97.51%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.49 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.76 – 7.66 (m, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 6.49 (s, 1H), 6.12 (t, J = 8.0 Hz, 1H), 3.21 (s, 3H), 2.30 – 2.12 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.85, 159.56, 147.57, 142.27, 140.86, 139.86, 135.25, 134.08, 133.96, 132.43, 131.60, 130.97, 130.93, 130.63, 127.48, 123.99, 122.46, 121.27, 120.41, 115.65, 56.70, 26.11, 10.58. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₆H₂₂Cl₂N₇O₄ ⁺ 566.1105, found 566.1106.

Example 23a, (S) -4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (enantiomer 1)The separation was carried out using CHEMPARTNER SFC systems under conditions of column temperature of 35℃and chromatographic column of DAICEL CHIRALPAK AS (30X 250mm 5 μm), detection wavelength of 215. 215 nm, back pressure of 10. 10 MPa, mobile phase of scCO ₂/methanol=50/50, flow rate of 45. 45 mL/min.

Ee value ：99.28%; HPLC purity: 99.6%; ¹H NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.7 Hz, 2H), 7.82 – 7.63 (m, 3H), 7.03 (s, 1H), 6.46 (s, 1H), 6.24 – 6.08 (m, 1H), 3.22 (s, 3H), 2.32 – 2.10 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H).

Example 23b, (R) -4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) propyl) -1H-1,2, 4-triazol-2-yl) benzoic acid (enantiomer 2)The separation was carried out using CHEMPARTNER SFC systems under conditions of column temperature of 35℃and chromatographic column of DAICEL CHIRALPAK AS (30X 250mm 5 μm), detection wavelength of 215. 215 nm, back pressure of 10. 10 MPa, mobile phase of scCO ₂/methanol=50/50, flow rate of 45. 45 mL/min.

Ee value ：100%; HPLC purity：100%; ¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1H), 8.95 (s, 1H), 8.61 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 7.9 Hz, 2H), 7.81 – 7.64 (m, 3H), 7.03 (s, 1H), 6.45 (s, 1H), 6.22 – 6.04 (m, 1H), 3.22 (s, 3H), 2.33 – 2.08 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).

Example 24, 1- (1- (1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-ylpropyl) -4- (5-chloro-2- (4-chloro-1H-1, 2, 4-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (I-24)1-(1-(1-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)propyl)-4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (I-24)Compound 17b and 4-azido-1H-pyrazole (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added and the reaction was stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (80/1-30/1) to obtain compound I-24 (37 mg, white solid, yield) ：26.47%).HPLC purity 99.80%. ¹H NMR (600 MHz, DMSO-d₆) δ 13.36 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.81 – 7.73 (m, 2H), 7.72 (s, 1H), 7.07 (s, 1H), 6.46 (s, 1H), 6.17 – 6.05 (m, 1H), 3.24 (s, 3H), 2.29 – 2.12 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 159.20, 146.56, 141.88, 140.43, 135.10, 134.11, 133.90, 132.69, 131.80, 131.10, 130.46, 127.60, 124.19, 123.27, 122.19, 121.68, 121.48, 115.65, 56.71, 26.32, 10.76. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₂H₂₀C_l2N₉O₂ ⁺ 512.1112, found 512.1120.

Example 25, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (1- (1- (-1- (1-methyl-1H-pyrazol-4-yl) -1H-1,2, 4-triazol-4-ylpropyl) pyridin-2 (1H) -one (I-25)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(1-(1-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)propyl)pyridin-2(1H)-one (I-25)Compound 17b and 4-azido-1-methyl-1H-pyrazole (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added and the reaction stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (140/1-70/1) to obtain I-25 (33 mg, white solid, yield) ：25.28%). HPLC purity: 97.27%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 7.94 (s, 1H), 7.82 – 7.68 (m, 3H), 7.06 (s, 1H), 6.46 (s, 1H), 6.10 (t, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.24 (s, 3H), 2.28 – 2.12 (m, J = 7.2 Hz, 2H), 0.82 (t, J= 7.3 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 159.20, 146.60, 141.89, 140.44, 135.10, 134.11, 133.90, 132.69, 131.40, 131.09, 130.46, 127.60, 124.39, 124.18, 123.12, 121.65, 121.48, 115.59, 56.72, 26.31, 10.74. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₃H₂₂C_l2N₉O₂ ⁺ 526.1268, found 526.1275.

Example 26, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (1- (1- (2- (difluoromethyl) -1H-pyrazol-4-yl) -1H-1,2, 4-triazol-4-ylpropyl) -5-methoxypyridin-2 (1H) -one (I-26)4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-1-(1-(1-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)propyl)-5-methoxypyridin-2(1H)-one (I-26)Compound 17b and 4-azido-1- (difluoromethyl) -1H-pyrazole (1.5 equiv) were weighed into a bottle, dissolved in methanol, cuOAc (0.2 equiv) was added and the reaction stirred at room temperature overnight. After TLC monitoring the reaction, spin-drying, adding water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, purifying the crude product by column chromatography, eluting with dichloromethane and methanol (80/1-30/1) to obtain compound I-26 (61 mg, white solid, yield) ：39.77%).HPLC purity 95.21%. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 7.99 (d, J = 58.8 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.72 (d, J = 2.2 Hz, 1H), 7.04 (s, 1H), 6.48 (s, 1H), 6.12 (t, J = 8.0 Hz, 1H), 3.24 (s, 3H), 2.28 – 2.19 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 159.22, 146.92, 141.94, 140.46, 135.49, 135.10, 134.12, 133.89, 132.66, 131.08, 130.48, 127.61, 124.18, 123.83, 123.60, 122.21, 121.52, 115.62, 110.91 (t, J = 250.1 Hz), 56.72, 26.20, 10.72. HRMS(ESI) m/z: [M+H]⁺calcd for C₂₃H₂₀Cl₂F₂N₉O₂ ⁺ 562.1080, found 562.1087.

Example 27, 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (2-phenyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) ethyl) pyridin-2 (1H) -one (I-27)4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)ethyl)pyridin-2(1H)-one (I-27)Step a preparation of 1-phenyl-3-butyn-2-ol (27 a) 1-phenylbut-3-yn-2-ol (27 a)A reaction flask of 0.5 mol/L ethynylmagnesium bromide (79.9 mL,39.95 mmol) under argon atmosphere was set at 0℃and phenylacetaldehyde (3.7 mL,33.29 mmol) diluted with tetrahydrofuran (30 mL) was slowly added dropwise thereto, and the reaction was allowed to proceed to room temperature for 5 hours. The reaction was quenched by dropwise addition of saturated ammonium chloride solution (50 mL) at low temperature and treated with general work-up method A, and the crude product was purified by column chromatography (PE/EtOAc, v/v, 30/1) to give a yellow oil (2.64 g, yield ：54.2%）.¹H NMR (400 MHz, CDCl₃) δ 7.36 – 7.31 (m, 2H), 7.31 – 7.24 (m, 3H), 4.69 – 4.51 (m, 1H), 3.10 – 2.98 (m, 2H), 2.50 (d, J = 2.2 Hz, 1H), 1.84 (s, 1H). step b: preparation 1-phenylbut-3-yn-2-yl methanesulfonate (27 b) of 1-phenyl-3-butyn-2-ylmethylsulfonate (27 b)Intermediate 27a (2.63 g,17.99 mmol) was weighed out and dissolved in dichloromethane (30 mL), argon protected, placed at 0 ℃, and then triethylamine (3.75 mL,26.99 mmol) and dichloromethane diluted methanesulfonic anhydride (4.8 g,26.99 mmol) were added dropwise in sequence to react for 5 hours. Water quenching was used and worked up using general work-up procedure A to give crude brown oil (4.03 g, yield ：100%）.¹H NMR (400 MHz, CDCl₃) δ 7.37 – 7.31 (m, 2H), 7.31 – 7.27 (m, 3H), 5.36 – 5.27 (m, 1H), 3.20 (dd, J = 6.8, 2.7 Hz, 2H), 2.93 (s, 3H), 2.72 – 2.71 (m, 1H). step c: preparation Azidobenzene of azidobenzene (27 c)Aniline (0.5 g,5.37 mmol) was weighed and dissolved in acetonitrile (5 mL), placed at 0 ℃, and isoamyl nitrite (943.43 mg,8.05 mmol) and sodium trimethylsilylazide (927.83 mg,8.05 mmol) were added dropwise in sequence, and the mixture was allowed to react at room temperature for 4 hours. Work-up using general work-up procedure A gave a crude brown oil (626 mg, yield: 97.88%) which was used directly in the next step. Step d preparation of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (1-phenyl-3-butyn-2-yl) pyridin-2 (1H) -one (27 d) 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(1-phenylbut-3-yn-2-yl)pyridin-2(1H)-one（27d）Intermediate 1f (1 g,2.97 mmol) was weighed and dissolved in 10mL isopropanol/acetone solution (v/v, 4/1), then tetramethylguanidine (1.02 g,8.9 mmol) was added, stirred at room temperature for half an hour, then intermediate 27b (1.46 g,6.53 mmol) was added and heated to 40 ℃ under argon atmosphere for oil bath reaction for 5 hours. Purification of the crude product by column chromatography (PE/EtOAc, v/v, 6/1) using general work-up procedure A afforded preparation of yellow solid (0.26 g, yield ：18.84%）.¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 7.81 – 7.71 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.26 – 7.23 (m, 1H), 7.11 (d, J = 7.4 Hz, 2H), 6.92 (s, 1H), 6.42 (s, 1H), 5.93 – 5.86 (m, 1H), 3.64 (d, J = 2.5 Hz, 1H), 3.19 (s, 3H), 3.15 (d, J = 6.8 Hz, 2H). step e:4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (2-phenyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) ethyl) pyridin-2 (1H) -one (I-27) 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)ethyl)pyridin-2(1H)-one (I-27).Intermediate 27d (100 mg, 214.9. Mu. Mol) was weighed out and dissolved in methanol (2 mL), intermediate 27C (38.4 mg, 322.35. Mu. Mol) and cuprous acetate (5.27 mg, 42.98. Mu. Mol) were added and reacted under argon atmosphere at 30℃for 5 hours. Purification of the crude product by column chromatography (DCM/MeOH, v/v, 120/1-70/1) using general work-up procedure A gave a white solid (35 mg, yield ：27.87%）.HPLC purity: 97.17%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.60 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.80 – 7.69 (m, 2H), 7.67 – 7.57 (m, 3H), 7.54 – 7.46 (m, 1H), 7.34 – 7.26 (m, 2H), 7.23 (s, 1H), 7.22 – 7.12 (m, 3H), 6.54 – 6.44 (m, 1H), 6.37 (s, 1H), 3.64 – 3.48 (m, 2H), 3.28 (s, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 158.92, 146.98, 141.97, 140.19, 137.39, 136.97, 135.08, 134.14, 133.92, 132.65, 131.22, 130.45, 130.42, 129.57, 129.29, 128.86, 127.72, 127.05, 124.14, 124.07, 122.53, 121.51, 120.53, 56.83, 38.76. HRMS(ESI) m/z: [M+H]⁺calcd for C₃₀H₂₄Cl₂N₇O₂ ⁺ 584.1363, found 584.1373.

Example 28, 1- (1- (1- (1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-yl) -2-phenethyl) -4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (I-28)1-(1-(1-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-2-phenylethyl)-4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (I-28)Preparation of 4-azido-1H-pyrazole (28 a) 4-azido-1H-pyrazole (28 a)4-Aminopyrazole (1 g,12.03 mmol) was weighed and dissolved in 6 mol/L hydrochloric acid (10 mL), placed at 0℃and an aqueous solution of sodium nitrite (1.1 g,16.01 mmol) was slowly added dropwise (5 mL), stirred for half an hour, then an aqueous solution of sodium azide (1.11 g,17.09 mmol) (5 mL) was added dropwise, and the mixture was allowed to react at room temperature for 3 hours. Work up using general work-up procedure A gave a crude orange solid (1.04 g, yield: 79.14%) which was used directly in the next step. Step b preparation of 1- (1- (1- (1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-yl) -2-phenethyl) -4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (I-28) 1-(1-(1-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-2-phenylethyl)-4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (I-28)Preparation method is the same as I-27, intermediate 27c is replaced with intermediate 28a to give a white solid (yield ：26.63%）.HPLC purity: 99.73%; ¹H NMR (600 MHz, DMSO-d₆) δ 13.36 (s, 1H), 8.68 – 8.56 (m, 2H), 8.40 (s, 1H), 8.02 (s, 1H), 7.81 – 7.71 (m, 2H), 7.67 – 7.63 (m, 1H), 7.37 – 7.25 (m, 2H), 7.25 – 7.19 (m, 2H), 7.19 – 7.12 (m, 2H), 6.50 – 6.40 (m, 1H), 6.35 (s, 1H), 3.62 – 3.49 (m, 2H), 3.27 (s, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 158.88, 146.19, 141.95, 140.14, 137.41, 135.07, 134.11, 133.90, 132.65, 131.76, 131.22, 130.43, 129.55, 128.89, 128.82, 127.73, 127.02, 124.11, 123.39, 122.21, 121.67, 121.45, 56.80, 38.67. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₇H₂₂Cl₂N₉O₂ ⁺ 574.1268, found 574.1287.

Example 29, methyl 4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoate (I-29)Methyl 4-(4-(1-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy- 2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoate (I-29)Preparation of methyl 4-azidobenzoate (29 a) 4-azidobenzoate (29 a)Methyl 4-aminobenzoate (0.5 g,3.31 mmol) was weighed and dissolved in acetonitrile (5 mL), placed at 0 ℃, and then isoamyl nitrite (0.74 mL,4.96 mmol) and sodium trimethylsilylazide (0.69 mL,4.96 mmol) were added dropwise in sequence, and the mixture was allowed to react for 4 hours after the completion of the dropwise addition, and the reaction was allowed to stand at room temperature. Work up using general work-up procedure A gave a crude orange solid (0.58 g, yield: 98.21%) which was used directly in the next step. Step b 4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid methyl ester (I-29)Methyl 4-(4-(1-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2- oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoate (I-29) was prepared in the same manner as I-27, intermediate 27c was replaced with intermediate 29a to give a yellow solid (yield) ：53.23%）.HPLC purity: 95.51%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.58 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.80 – 7.67 (m, 2H), 7.62 (s, 1H), 7.33 – 7.23 (m, 2H), 7.22 – 7.09 (m, 4H), 6.52 – 6.40 (m, 1H), 6.35 (s, 1H), 3.88 (s, 3H), 3.63 – 3.47 (m, 2H), 3.26 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.79, 158.95, 147.36, 142.03, 140.21, 140.13, 137.30, 135.07, 134.13, 133.91, 132.63, 131.50, 131.20, 130.45, 129.92, 129.56, 128.87, 127.71, 127.07, 124.08, 122.73, 121.51, 120.36, 56.83, 52.90, 38.53. HRMS(ESI) m/z: [M+H]⁺ calcd for C₃₂H₂₆Cl₂N₇O₄ ⁺ 642.1418, found 642.1416.

EXAMPLE 30 4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (I-30)4-(4-(1-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-30)I-29 (147 mg, 228.79. Mu. Mol) was weighed out and dissolved in a 6 mL THF/MeOH/H ₂ O solution (v/v/v, 4/1/1), lithium hydroxide (27.39 mg,1.14 mmol) was added and reacted at room temperature for 3 hours. Concentrating under reduced pressure, adding 2mL distilled water, adjusting pH to about 3 with 2 mol/L HCl, separating out solid, filtering, and draining to obtain white solid (120 mg, yield) ：83.45%）.HPLC purity: 97.83%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.48 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 7.76 – 7.62 (m, 2H), 7.57 (d, J = 2.3 Hz, 1H), 7.31 – 7.23 (m, 2H), 7.23 – 7.08 (m, 4H), 6.54 – 6.39 (m, 1H), 6.36 (s, 1H), 3.63 – 3.44 (m, 2H), 3.23 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.88, 158.95, 147.30, 142.02, 140.23, 139.81, 137.29, 135.08, 134.11, 133.91, 132.62, 131.58, 131.31, 131.19, 130.46, 129.55, 128.86, 127.71, 127.07, 124.08, 122.70, 121.49, 120.25, 56.82, 38.61. HRMS(ESI) m/z: [M+H]⁺ calcd for C₃₁H₂₄Cl₂N₇O₄ ⁺ 628.1261, found 628.1255.

Example 30a, (S) -4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (enantiomer 1)The resolution was performed using CHEMPARTNER SFC systems, column temperature: 35 ℃, chromatographic column: DAICEL CHIRALPAK ℃ REGIS (30 x 250mm 10 μm), detection wavelength: 215 nm, backpressure: 10 MPa, mobile phase: scCO ₂/(methanol/acetonitrile, 0.1% 7M ammonia methanol) =50/50, flow rate: 45 mL/min.

Ee value ：100%; HPLC purity：100%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.81 – 7.54 (m, 2H), 7.50 (d, J = 2.3 Hz, 1H), 7.35 – 7.19 (m, 2H), 7.17 – 6.93 (m, 4H), 6.54 – 6.35 (m, 1H), 6.33 (s, 1H), 3.59 – 3.41 (m, 2H), 3.18 (s, 3H).

Example 30b, (R) -4- (4- (1- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (enantiomer 2)The resolution was performed using CHEMPARTNER SFC systems, column temperature: 35 ℃, chromatographic column: DAICEL CHIRALPAK ℃ REGIS (30 x 250mm 10 μm), detection wavelength: 215 nm, backpressure: 10 MPa, mobile phase: scCO ₂/(methanol/acetonitrile, 0.1% 7M ammonia methanol) =50/50, flow rate: 45 mL/min.

Ee value ：99.46%; HPLC purity：99.7%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.42 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.77 – 7.59 (m, 2H), 7.53 (d, J = 2.3 Hz, 1H), 7.33 – 7.20 (m, 2H), 7.18 – 6.99 (m, 4H), 6.51 – 6.40 (m, 1H), 6.33 (s, 1H), 3.62 – 3.40 (m, 2H), 3.20 (s, 3H).

EXAMPLE 31 6- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3- (1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) propyl) pyrimidin-4 (3H) -one (I-31) Step a preparation of 4-chloro-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline 31aThe compound 2-bromo-4-chloroaniline (30 g,140.3 mmol) was dissolved in toluene (200 mL), and pinacol ester of bisboric acid (40.6 g,159.8 mmol) and potassium acetate (37.1 g,377.8 mmol) were added in this order, and replaced with nitrogen 3 to 4 times. PdCl ₂(dppf)•CH₂Cl₂ (3.6 g,4.4 mmol) was added rapidly under nitrogen and warmed to 90℃and stirred for 12: 12 h. After the reaction solution was cooled to room temperature, the reaction solution was dried by spin-drying. Purification of the crude product by silica gel column chromatography gives the compound (24.7 g, yield ：67%）.¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 8.6, 2.6 Hz, 1H), 6.53 (d, J = 8.6 Hz, 1H), 4.75 (s, 2H), 1.33 (s, 12H). preparation of step b: 4-chloro-2- (6-methoxypyrimidin-4-yl) aniline 31bCompound 31a (24.7 g,97.3 mmol) was dissolved in a mixed solution of degassed 1, 4-dioxane (200 mL) and water (50 mL), then 4-chloro-6-methoxypyrimidine (14.1 g,97.3 mmol) and potassium acetate (23.9 g,243.4 mmol) were added, and replaced with nitrogen 3 to 4 times. PdCl ₂(dppf)•CH₂Cl₂ (2.4 g,2.9 mmol) was added rapidly under nitrogen, heated to 80 ℃, stirred for 12 h, tlc monitored complete consumption of compound 1a, the reaction cooled to room temperature, dried by spinning, then extracted with ethyl acetate and the organic phases combined. The organic phase was washed 3 times with a saturated saline solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated. Purification of the crude product by silica gel column chromatography gave Compound 31b as a white solid (14.7 g, yield ：64 %）.¹H NMR (400 MHz, CDCl₃) δ 8.78 (d, J = 1.1 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.7, 2.4 Hz, 1H), 6.99 (d, J = 1.1 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.35 (s, 2H), 4.02 (s, 3H). preparation of step c:4- (2-azido-5-chlorophenyl) -6-methoxypyrimidine (31 c)Compound 31b (10 g,42.4 mmol) was dissolved in 100 mL acetonitrile and the reaction cooled to 0℃and isoamyl nitrite (7.5 g,63.6 mmol) and azido trimethylsilane (8.3 g,63.6 mmol) were slowly added dropwise and the reaction was allowed to warm to room temperature for 10 hours. The solid was precipitated, and the solid was filtered and dried to give compound 31c (10.3 g, yield: 88%). Directly put into the next step without column chromatography purification. Step d preparation of 4- (5-chloro-2- (4- (trimethylsilyl) -1H-1,2, 3-triazol-1-yl) phenyl) -6-methoxypyrimidine (31 d)Compound 31C (10.3 g,39.5 mmol) and ethynyl trimethylsilane (7.0 g,71.1 mmol) were dissolved in 100 mL toluene solution and reacted at 110℃under reflux for 12 hours, and the organic solvent was removed by concentration under reduced pressure. Water was added, extracted with ethyl acetate and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography to give compound 31d (12 g, yield: 84%).

¹H NMR (600 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.5, 2.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 3.89 (s, 3H), 0.26 (s, 9H). Step e preparation of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-methoxypyrimidine (31 e)Compound 31d (10.7 g,29.6 mmol), NCS (29.1 g,217.7 mmol) and silica gel (29.7 g) were dissolved in 100 mL acetonitrile and reacted at 80℃for 6 hours. The organic solvent was removed by concentration under reduced pressure. The residue obtained is taken up in 100 mL of water, extracted with ethyl acetate and the organic phases are combined. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. Purification of the crude product gave 31e (5 g, yield ：52%）.¹H NMR (400 MHz, DMSO-d₆) δ 8.75 – 8.71 (m, 1H), 8.66 – 8.62 (m, 1H), 7.98 – 7.93 (m, 1H), 7.89 – 7.83 (m, 1H), 7.81 – 7.76 (m, 1H), 7.00 – 6.94 (m, 1H), 3.96 – 3.90 (m, 3H). step f: preparation of 6- (5-chloro-2-4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) pyrimidin-4 (3H) -one (31 f)To acetic acid (5 mL) of compound 31e (5 g,15.4 mmol) was slowly added dropwise 48% aqueous hydrobromic acid (16.5 mL,146.3 mmol). The temperature was raised to 80℃and the reaction was carried out for 2.5 hours. After the reaction solution was cooled, the reaction solution was rotary evaporated to dryness, then ethyl acetate was added, diluted with saturated sodium bicarbonate solution, and the organic phase was collected by layering, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude product 31f (4.6 g, yield: 97%) which was used without purification in the next step .1H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.02 (s, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.77 (dd, J = 8.5, 2.4 Hz, 1H), 7.71 – 7.68 (m, 1H), 6.17 (s, 1H)., step g, 6- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) benzene) -3- (pent-1-yn-3-yl) pyrimidin-4 (3H) -one (31 g) 6- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3- (pent-1-yn-3-yl) pyrimidin-4 (3H) -onePreparation method is the same as 17 b, 1f is replaced by 31f to obtain white solid (773 mg, yield 64%).¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.47 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.5, 2.2 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 6.49 (s, 1H), 5.40 (t, J = 7.1 Hz, 1H), 3.69 (s, 1H), 1.96 – 1.83 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). step H: preparation of 6- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3- (1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) propyl) pyrimidin-4 (3H) -one (I-31)

Preparation method as in I-17, substituting 17b for intermediate 31g gave a white solid (60 mg, yield 46%）.HPLC purity: 99.13%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.92 – 7.87 (m, 2H), 7.85 – 7.79 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.64 – 7.57 (m, 2H), 7.54 – 7.47 (m, 1H), 6.50 (s, 1H), 5.93 (t, J = 7.9 Hz, 1H), 2.36 – 2.19 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); ¹³C NMR (151 MHz, DMSO-d₆) δ 160.25, 158.15, 150.78, 146.54, 136.94, 135.52, 135.28, 134.20, 133.50, 131.15, 130.72, 130.38, 129.30, 128.92, 124.78, 122.63, 120.57, 114.41, 26.28, 10.74. HRMS(ESI) m/z: [M+H] ⁺ calcd for C₂₃H₁₉Cl₂N₈O⁺ 493.1053, found 493.1064.

Example 32, 3- (1- (1- (1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-yl) phenyl) -6- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) pyrimidin-4 (3H) -one (I-32)3-(1-(1-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)propyl)-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)-one (I-32)The preparation method is the same as that of I-31, and 27c is replaced by 28a. Obtained as a white solid (68 mg, yield 53%). HPLC purity: 97.43%;¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.85 – 7.79 (m, 1H), 7.75 (d, J= 8.6 Hz, 1H), 6.48 (s, 1H), 5.89 (t, J = 7.8 Hz, 1H), 2.32 – 2.18 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 160.23, 158.16, 150.79, 145.78, 135.52, 135.27, 134.20, 133.49, 131.81, 131.15, 130.73, 128.92, 124.78, 123.54, 122.25, 121.62, 114.39, 26.19, 10.76. HRMS(ESI) m/z: [M+H]⁺calcd for C₂₀H₁₇Cl₂N₁₀O⁺ 483.0958, found 483.0968.

Example 33, 6- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3- (1- (1- (1-methyl-1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-yl) propyl) pyrimidin-4 (3H) -one (I-33)6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-3-(1-(1-(1-methyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)propyl)pyrimidin-4(3H)-one (I-33)Preparation method same as I-31 substitution of 27c with 4-azido-1-methyl-1H-pyrazole to give white solid (69 mg, yield 52%). HPLC purity: 99.57%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.85 – 7.80 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 6.48 (s, 1H), 5.88 (t, J = 7.9 Hz, 1H), 3.90 (s, 3H), 2.35 – 2.15 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 160.23, 158.15, 150.79, 145.81, 135.52, 135.28, 134.20, 133.49, 131.41, 131.15, 130.73, 128.93, 124.78, 124.44, 123.40, 121.58, 114.39, 26.17, 10.74. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₁H₁₉Cl₂N₁₀O⁺ 497.1115, found 497.1126.

EXAMPLE 34 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (2-phenyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) ethyl) pyridin-2 (1H) -one (II-1)4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)ethyl)pyridin-2(1H)-one(II-1)Step a-c same as I-27 step d preparation of N- (2-bromo-4-chlorophenyl) carboxamide (34 a)2-Bromo-4-chloroaniline (50 g,242.17 mmol) and sodium formate (8.23 g,121.08 mmol) were weighed into formic acid (44.58 g,968.68 mmol) and reacted under argon at 25℃for 23 hours. After the reaction, an appropriate amount of ethyl acetate was added, the organic layer was washed with water and saturated NaHCO ₃, dried, and concentrated to give 34a as a gray solid (44.5 g, yield ：78.37%）.1H NMR (400 MHz, CDCl₃) δ 8.49 (d, J = 1.7 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.9, 2.5 Hz, 1H). step e: preparation of 2-bromo-4-chloro-1-isocyanobenzene (34 b))Compound 34a (39 g,166.33 mmol) was weighed and dissolved in 450 mL tetrahydrofuran, triethylamine (100.99 g,997.97 mmol) was added at 0℃and then a mixed solution of POCl ₃ (51 g,332.66 mmol) dissolved in 200 mL dry tetrahydrofuran was added dropwise to the reaction system for 1 hour. After the completion of the reaction, the reaction solution was poured into ice water, and potassium carbonate was added thereto, followed by stirring for 5 minutes, extraction with methyl tertiary ether, drying over anhydrous sodium sulfate, suction filtration, and concentration to give 34b (36 g, yield: 100%) as a brown solid, which was directly used for the next reaction. Step f preparation of 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole (34 c)Compound 34b (27 g,124.73 mmol) was weighed into a toluene solution (490, mL) of 2-diaza-1, 1-trifluoroethane (0.5M), ag ₂CO₃ (6.88 g,24.95 mmol), 4A molecular sieve (14.72, g) and DMF (100, mL) were added and reacted in an oil bath at 40 ℃ for 16 hours. Preparation of 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (34 d) by chromatography on a column (PE/EtOAc, v/v, 100/1) to give 34c as a dark red oil (28.5 g, yield ：69.98%）.¹H NMR (400 MHz, CDCl₃) δ 8.26 – 8.24 (m, 1H), 7.83 – 7.80 (m, 1H), 7.54 – 7.51 (m, 2H)., step g:4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridineIntermediate 34C (21 g,64.32 mmol), 2, 5-dimethoxypyridine-4-boronic acid (14.12 g,77.18 mmol), K ₃PO₄ (27.84 g,160.8 mmol) were weighed out and dissolved in 200mL 1, 4-dioxane/H ₂ O solution (v/v, 4/1), and PdCl ₂（dppf）•CH₂Cl₂ (2.63 g,3.22 mmol) was added and reacted under reflux at 85℃for 12 hours under argon atmosphere. Purification of the crude product by column chromatography (PE/EtOAc, v/v, 20/1) according to general post-treatment method A afforded 34d (19.2 g, yield ：46.94%）.¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 7.82 (d, J = 1.8 Hz, 2H), 7.74 – 7.71 (m, 2H), 6.85 (s, 1H), 3.81 (s, 3H), 3.37 (s, 3H). step H preparation of 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (34 e)Intermediate 34d (16.82g,43.72 mmol) and pyridinium hydrobromide (69.95 g,437.17 mmol) were weighed out and dissolved in DMF (60 mL) and reacted at 110 ℃ under reflux for 4 hours. Using general work-up procedure B, off-white solid 34e (14.7 g, yield ：90.7%）.¹H NMR (600 MHz, DMSO-d₆) δ 9.18 (s, 1H), 7.80 (d, J = 1.9 Hz, 2H), 7.72 (s, 1H), 6.94 (s, 1H), 6.41 (s, 1H), 3.21 (s, 3H). step i:4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (1-phenyl-3-butyn-2-yl) pyridin-2 (1H) -one was obtained （34f）4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(1-phenylbut-3-yn-2-yl)pyridin-2(1H)-one（34f）The preparation method is the same as that of intermediate 27d, and intermediate 1f is replaced by intermediate 34e to obtain intermediate (yield ：15.3%）.¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H), 7.82 (d, J = 1.2 Hz, 2H), 7.74 – 7.71 (m, 1H), 7.33 – 7.27 (m, 2H), 7.27 – 7.18 (m, 1H), 7.11 (d, J = 6.1 Hz, 2H), 6.92 (s, 1H), 6.48 (s, 1H), 5.91 – 5.85 (m, 1H), 3.61 (d, J = 2.4 Hz, 1H), 3.15 (s, 3H), 3.14 (d, J = 6.8 Hz, 2H). step j:4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-1- (2-phenyl-1- (1-phenyl-1H-1, 2, 3-triazol-4-yl) ethyl) pyridin-2 (1H) -one (II-1)4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)ethyl)pyridin-2(1H)-one (II-1)

The preparation method is the same as I-27, and intermediate 27d is replaced by intermediate 34f to obtain white solid (yield ：27.33%）.HPLC purity: 100%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.89 (s, 1H), 7.93 – 7.85 (m, 2H), 7.84 – 7.76 (m, 2H), 7.71 – 7.67 (m, 1H), 7.65 – 7.56 (m, 2H), 7.54 – 7.46 (m, 1H), 7.31 – 7.23 (m, 2H), 7.22 – 7.11 (m, 4H), 6.54 – 6.45 (m, 1H), 6.43 (s, 1H), 3.64 – 3.47 (m, 2H), 3.22 (s, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 158.95, 146.96, 141.73, 139.98, 137.38, 137.09 (q, J = 38.8 Hz), 137.00, 135.54, 133.74, 133.08, 131.28, 130.58, 130.44, 129.57, 129.33, 128.89, 128.03, 127.66, 127.07, 122.53, 122.06, 121.91, 120.53, 56.57, 38.73. HRMS(ESI) m/z: [M+H]⁺ calcd for C₃₁H₂₄ClF₃N₇O₂ ⁺ 618.1627, found 618.1662.

Example 35, 1- (1- (1- (1H-pyrazol-4-yl) -1H-1,2, 3-triazol-4-yl) -2-phenethyl) -4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (II-2)1-(1-(1-(1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)-2-phenylethyl)-4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (II-2)The preparation method is the same as II-1, and intermediate 27c is replaced by intermediate 28a to obtain white solid (yield ：28.75%）.HPLC purity: 97.13%; ¹H NMR (400 MHz, DMSO-d₆) δ 13.34 (s, 1H), 9.17 (s, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.84 – 7.75 (m, 2H), 7.68 (s, 1H), 7.31 – 7.23 (m, 2H), 7.22 – 7.07 (m, 4H), 6.48 – 6.36 (m, 2H), 3.60 – 3.45 (m, 2H), 3.22 (s, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 158.90, 146.17, 141.70, 139.91, 137.41, 137.06 (q, J = 38.7 Hz), 135.51, 133.72, 133.06, 133.00, 131.74, 131.28, 130.55, 129.54, 128.84, 128.03, 127.66, 127.02, 123.37, 122.15, 121.85, 121.69, 56.54, 38.62. HRMS(ESI) m/z: [M+H]⁺ calcd for C₂₈H₂₂ClF₃N₉O₂ ⁺ 608.1532, found 608.1573.

Example 36, methyl 4- (4- (1- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoate (II-3)Methyl 4-(4-(1-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoate (II-3)Preparation method As in II-1, intermediate 27c was replaced with intermediate 29a to give a yellow solid (yield ：65.3%）.HPLC purity: 99.8%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 9.04 (s, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.80 (s, 2H), 7.68 (s, 1H), 7.32 – 7.23 (m, 2H), 7.22 – 7.11 (m, 4H), 6.56 – 6.44 (m, 1H), 6.43 (s, 1H), 3.89 (s, 3H), 3.67 – 3.44 (m, 2H), 3.22 (s, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 165.81, 158.94, 147.34, 141.74, 140.15, 139.97, 137.29, 137.05 (q, J = 38.5 Hz), 135.51, 133.72, 133.03, 131.52, 131.26, 130.56, 129.94, 129.54, 128.88, 128.02, 127.64, 127.07, 122.72, 121.92, 120.34, 56.56, 52.94, 38.52. HRMS(ESI) m/z: [M+H]⁺ calcd for C₃₃H₂₆ClF₃N₇O₄ ⁺ 676.1681, found 676.1718.

Example 37, 4- (4- (1- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (II-4)4-(4-(1-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (II-4)The preparation method is the same as I-30, and I-29 is replaced by II-3 to obtain white solid (yield ：91.2%）.HPLC purity: 100%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.91 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.80 – 7.66 (m, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.20 – 7.06 (m, 4H), 6.53 – 6.44 (m, 1H), 6.42 (s, 1H), 3.62 – 3.44 (m, 2H), 3.18 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.87, 158.94, 147.31, 141.75, 139.99, 139.90, 137.31, 137.06 (q, J = 38.7 Hz), 135.52, 133.73, 133.05, 131.62, 131.27, 131.19, 130.57, 129.55, 128.88, 128.03, 127.65, 127.07, 122.70, 121.91, 120.24, 56.58, 38.55. HRMS(ESI) m/z: [M+H]⁺ calcd for C₃₂H₂₄ClF₃N₇O₄ ⁺ 662.1525, found 662.1528.

Example 37a, 4- (4- (1- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (enantiomer 1)

The resolution was performed using CHEMPARTNER SFC systems, column temperature: 35 ℃, chromatographic column: DAICEL CHIRALPAK ℃ REGIS (30 x 250mm 10 μm), detection wavelength: 215 nm, backpressure: 10 MPa, mobile phase: scCO ₂/(methanol/acetonitrile, 0.1% 7M ammonia methanol) =50/50, flow rate: 45 mL/min.

Ee value ：100%; HPLC purity：100%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.78 (s, 1H), 8.08 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.75 – 7.60 (m, 2H), 7.56 (d, J = 2.3 Hz, 1H), 7.31 – 7.18 (m, 2H), 7.16 – 7.01 (m, 4H), 6.53 – 6.42 (m, 1H), 6.40 (s, 1H), 3.64 – 3.38 (m, 2H), 3.13 (s, 3H).

Example 37b, 4- (4- (1- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2-phenethyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (enantiomer 2)

Ee value ：99.1%; HPLC purity：99.6%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.76 (s, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H), 7.78 – 7.59 (m, 2H), 7.54 (d, J = 2.3 Hz, 1H), 7.31 – 7.18 (m, 2H), 7.16 – 6.96 (m, 4H), 6.56 – 6.43 (m, 1H), 6.40 (s, 1H), 3.60 – 3.39 (m, 2H), 3.12 (s, 3H).

Comparative example 1

4- (2- (4- (5-Chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyramide) -2-fluorobenzamide (asundexian)

4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-fluorobenzamide

The synthesis adopts a asundexian similar method reported in the literature, and the target compound (114 mg, white solid) is obtained by purifying the crude product by silica gel column chromatography ,73%).HPLC purity: 99.03%.¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.11 (s, 1H), 7.86 – 7.78 (m, 2H), 7.76 (d, J = 2.0 Hz, 1H), 7.70 – 7.59 (m, 2H), 7.52 (d, J = 10.2 Hz, 2H), 7.35 (dd, J = 8.5, 1.9 Hz, 1H), 7.11 (s, 1H), 6.52 (s, 1H), 5.51 (t, J = 8.2 Hz, 1H), 3.24 (s, 3H), 2.15 – 2.00 (m, J = 7.1 Hz, 2H), 0.77 (t, J = 7.2 Hz, 3H).¹³C NMR (151 MHz, DMSO-d₆) δ 169.28, 164.95, 160.93, 159.63, 159.29, 142.64 (d, J = 11.4 Hz), 141.80, 139.55, 137.05 (q, J = 38.7 Hz), 135.57, 133.72, 133.08, 131.62, 131.07, 130.58, 127.97, 127.55, 121.97 (t, J = 267.3 Hz), 121.23, 118.44 (d, J = 13.6 Hz), 115.23, 106.67 (d, J = 28.6 Hz), 59.34, 56.61, 24.23, 10.50. HRMS (ESI, m/z) for C₂₆H₂₂ClF₄N₆O₄ ⁺[M+H]⁺, calcd 593.1322, found 593.1328.

Test example 1 measurement of Factor XIa protease Activity by the Compounds of the invention

Human FXIa (Enzyme Research Laboratories) was used to test the in vitro FXIa inhibitory activity of the compounds of the invention. The chromogenic substrate used in the invention is Boc-Glu (OBzl) -Ala-Arg-AMC (Jier Biochemical), and the substrate is hydrolyzed by FXIa to release Aminomethylcoumarin (AMC), and the inhibition strength of the compound on FXIa is obtained by measuring the change of fluorescence intensity.

The experimental procedure is outlined by preparing test compounds as 10 mM mother liquor with DMSO and then diluting to a series of concentrations with buffer (50 mMTris/HCl,100 mM sodium chloride, 5mM calcium chloride, 0.1% bovine serum albumin) at ph=7.4. In the microplate, 20. Mu.L of buffer solution, 20. Mu.L of FXIa enzyme solution (0.6 nM) and then 20. Mu.L of test compound solution were added, incubated at 37℃for 30min and 40. Mu.L of fluorogenic substrate solution (10. Mu.M) were added, immediately followed by measurement on a microplate reader, excitation wavelength of 360 nm and emission wavelength of 460 nm, data were read continuously, and compound IC ₅₀ values were obtained by fitting the data with GRAPHPAD PRISM 7, and data are shown in Table 1.

TABLE 1 IC ₅₀ data for the inhibition of FXIa by the compounds according to the invention

Example Compounds	FXIa (IC₅₀nM)	Example Compounds	FXIa (IC₅₀,nM)
				I-1	78.16	I-23	84.48
I-2	1662	(S)-I-23	43.19
				I-3	518.6	(R)-I-23	1095
I-4	160.6	I-24	378.6
				I-5	271.6	I-25	609
I-6	102.1	I-26	1327
				I-7	38.68	I-27	37.62
I-8	186.1	I-28	10.4
				I-9	226.3	I-29	33.34
I-10	1240	I-30	2.26
				I-11	1019	(S)-I-30	1.52
I-12	916.6	(R)-I-30	96.34
				I-13	2000	I-31	6860
I-14	1090	I-32	6640
				I-15	2000	I-33	12750
I-16	378.6	II-1	43.1
				I-17	534.7	II-2	14.44
I-18	1961	II-3	26.86
				I-19	1596	II-4	0.97
I-20	372.7	(S)-II-4	0.38
				I-21	496.7	(R)-II-4	101.8
I-22	258.9	Comparative example 1	4.56

The test result of FXIa enzyme activity shows that the series of compounds obtained by introducing benzyl have excellent anticoagulation activity on FXIa. The compound (S) -I-30 was excellent in anticoagulation activity, which is superior to that of comparative example 1 (asundexian). The compound (S) -II-4 has better activity and reaches the sub-nanomolar level.

Test example 2 measurement of PKa protease Activity by Compounds of the invention

Human PKa was used to test the in vitro PKa inhibitory activity of the compounds of the invention. The chromogenic substrate used in the invention is H-Pro-Phe-Arg-AMC (Jier biochemistry), and the substrate is hydrolyzed by PKa to release Aminomethylcoumarin (AMC), and the inhibition of the compound on PKa is obtained by measuring the change of fluorescence intensity.

The experimental procedure is outlined by preparing test compounds as 10mM mother liquor with DMSO and then diluting to a series of concentrations with buffer (50 mMTris/HCl,100 mM sodium chloride, 5mM calcium chloride, 0.1% bovine serum albumin) at ph=7.4. In the microplate, 20. Mu.L of buffer solution, 20. Mu.L of PKa enzyme solution (2 nM) and then 20. Mu.L of test compound solution were added, incubated at 37℃for 30min, and after 40. Mu.L of fluorogenic substrate solution (5. Mu.M) were added, immediately measured on a microplate reader, excitation wavelength was 360 nm and emission wavelength was 460 nm, data were continuously read, and compound IC ₅₀ values were obtained by fitting data with GRAPHPAD PRISM 7, and data are shown in Table 2.

TABLE 2 IC ₅₀ data on the inhibitory Activity of the inventive Compounds against PKa

Example Compounds	PKa (IC₅₀,nM)	Example Compounds	PKa (IC₅₀,nM)
				I-1	766.3	I-23	654.8
I-2	11520	(S)-I-23	643.4
				I-3	1063	(R)-I-23	7849
I-4	1968	I-24	2511
				I-5	11582	I-25	6520
I-6	412.6	I-26	8127
				I-7	832.3	I-27	774.3
I-8	2056	I-28	408.1
				I-9	3738	I-29	611.9
I-10	14390	I-30	140.8
				I-11	11131	(S)-I-30	73.13
I-12	15830	(R)-I-30	1875
				I-13	14200	I-31	47180
I-14	15830	I-32	23400
				I-15	19720	I-33	87170
I-16	6800	II-1	772.8
				I-17	2591	II-2	573.5
I-18	4844	II-3	990.9
				I-19	2144	II-4	112.2
I-20	1487	(S)-II-4	59.19
				I-21	9798	(R)-II-4	2747
I-22	822.3	Comparative example 1	42.94

The PKa enzyme activity test result shows that the introduction of benzyl can not only improve the excellent anticoagulation activity of the compound to FXIa, but also realize high selectivity to PKa. Wherein the compound (S) -II-4 had a 156-fold selectivity to FXI a/PKa as compared with comparative example 1 (asundexian).

Test example 3 Activated Partial Thromboplastin Time (APTT) determination of the Compounds of the invention

The following methods were used to determine the in vitro anticoagulation of the compounds of the invention in human plasma. The method uses Sunbio APTT kit (product number: Y115) to test, and human plasma is quality control lyophilized plasma (Sunbio).

The experimental method comprises the steps of adding 1 mL high-purity water into the freeze-dried plasma with quality control for dissolution, and mixing the plasma with light shaking. Test compounds were dissolved in DMSO and double-diluted in gradient with DMSO to prepare a series of solutions. The calcium chloride solution and APTT reagent were preheated at 37 ℃. Then, 20. Mu.L of the plasma to be measured is taken in a measuring cup, diluted test compound is added, 20. Mu.L of preheated APTT reagent is added, and the mixture is incubated at 37 ℃ for 5 min. The measuring cup was placed in the measuring channel of a semi-automatic coagulometer, then 20 μl of preheated calcium chloride solution was added, immediately measurement was performed, and the clotting time was recorded. The recorded clotting times were curve fitted using GRAPHPAD PRISM software to calculate the concentration of compound corresponding to EC _1.5x, i.e. the APTT of the 1.5-fold blank. The test results are shown in Table 3.

TABLE 3 EC _1.5x data for the in vitro anticoagulation of human plasma by the compounds of the invention

Example Compounds	EC_1.5x(μM)	Example Compounds	EC_1.5x(μM)
				I-23	25.41	(R)-I-30	29.03
(S)-I-23	13.24	II-2	1.57
				(R)-I-23	392.57	II-4	0.81
I-28	2.64	(S)-II-4	0.55
				I-30	1.41	(R)-II-4	26.86
(S)-I-30	0.75	Comparative example 1	0.82

The results of the in vitro anticoagulation activity test show that the activity of the tested compound has moderate to excellent in vitro anticoagulation activity, wherein the compounds (S) -I-30 and (S) -II-4 are both superior to that of the compound of the comparative example 1 (asundexian), and have better anticoagulation activity.

In summary, the invention provides a novel compound which can be used as an FXIa small molecule inhibitor and can effectively improve the anticoagulation effect. In addition, the compounds of the present invention are useful for the effective treatment and/or prevention of cardiovascular and cerebrovascular diseases and thrombosis symptoms.

Claims

1. A compound and a pharmaceutically acceptable salt thereof, characterized in that it is any one of the following structures

2. A pharmaceutical composition, characterized in that it is a preparation made of the compound according to claim 1 and its pharmaceutically acceptable salt, plus a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1 and its pharmaceutically acceptable salt and the pharmaceutical composition according to claim 2 in the preparation of a coagulation factor FXIa inhibitor or a plasma bradykinin kinase PKA inhibitor.

4. Use of the compound according to claim 1 and its pharmaceutically acceptable salt and the pharmaceutical composition according to claim 2 in the preparation of a drug for preventing or treating diseases mediated by factor XIa.

5. The use according to claim 4, characterized in that the disease mediated by factor XIa is a cardiovascular and cerebrovascular disease, and the cardiovascular and cerebrovascular disease is myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortocoronary bypass surgery, disseminated intravascular coagulation, stroke, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.