A triazole derivative and its preparation method and use

Abstract

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

Technical Field

[0001] The invention belongs to the field of chemical medicine, and specifically relates to a triazole derivative and a preparation method and use thereof. Background Art

[0002] Stroke (commonly known as "stroke") is an acute cerebrovascular disease caused by occlusion (i.e. ischemic stroke) or rupture (i.e. hemorrhagic stroke) of cerebral blood vessels. On the one hand, this disease will cause a heavy economic burden, and on the other hand, the morbidity, disability rate, recurrence rate, and mortality rate are extremely high, which seriously threatens the physical and mental health of our people. Among the sick people, up to 83% of patients suffer from ischemic stroke, and the annual recurrence rate can be as high as 17.7%. According to surveys, the elderly are generally more susceptible to the disease, but in recent years, they have gradually become younger. Among them, people with irregular diet, lack of exercise, bad habits such as smoking and drinking, or suffering from three highs, heart disease and other diseases are more likely to suffer from stroke. At present, anticoagulants and antiplatelet drugs are mainly used in clinical treatment of thrombotic diseases, but they cannot distinguish between pathological coagulation and physiological coagulation. While treating thrombosis, they can also cause serious bleeding complications (bleeding). Therefore, effective and satisfactory treatment methods for thrombotic diseases still need further discussion and research.

[0003] Coagulation factor XI (FXI) is a protease that plays a major role in the intrinsic coagulation pathway. After activation, it becomes coagulation factor XIa (FXIa), which mainly acts on the amplification stage of the coagulation cascade. In animal experiments, it was found that mice with targeted knockout of the FXI gene were still able to survive and had completely normal hemostasis function, while showing prolonged activated partial throm-boplastin time (aPTT) and normal prothrombin time (PT). Patients with congenital FXI deficiency (hemophilia c) will not show symptoms in adulthood and will not bleed spontaneously. Only some patients may have mild or moderate bleeding tendencies after trauma or surgery. Therefore, FXIa is a new target with a lower potential risk of bleeding.

[0004] FXIa is a new target for anticoagulants. The patent applications for small molecule FXIa inhibitors disclosed include CN105164112, WO2016015593, WO2017005725, WO2018041122, WO2019175043, and WO2021057818. Among them, the main ones entering clinical research are JNJ-70033093 (BMS-986177, Janssen Pharmaceuticals) and BAY-2433334 (Bayer) in clinical phase II, and ONO-5450598 (Ono Pharmaceuticals) and SHR2285 (Hengrui Medicine) in clinical phase I. The data disclosed in the early stage show that they have certain clinical effects. However, poor selectivity and poor activity are the main disadvantages of these FXIa inhibitors, and no small molecule FXIa inhibitors have been listed so far. Therefore, there is still a need to study new FXIa inhibitors.

[0005] Plasma kallikrein (PK) is associated with improved vascular permeability or other chronic inflammatory diseases. C1-INH is an endogenous inhibitor of PKa, and mutations in the SERPING1 gene in hereditary angioedema lead to its lack of function. However, people with normal function also suffer from hereditary angioedema, which is mainly attributed to the uncontrolled activity of plasma kallikrein (PK) and the production of bradykinin (BK), which leads to angioedema. In addition, plasma kallikrein (PK) first activates other factors XII in the enhancement loop, thereby expanding the initiation of the coagulation cascade, which in turn leads to increased endothelial permeability. Their activation can affect the regulatory processes of the renin-angiotensin system and fibrinolysis. Therefore, the activation of PK is an important link between the coagulation and inflammatory processes.

[0006] Most of the FXIa inhibitors currently under development are dual-target inhibitors of FXIa and PKa. For example, the FXIa inhibitor Asundexian developed by Bayer has a selectivity of only 6.7 times for PKa, so it is necessary to develop FXIa inhibitors with high selectivity for PKa. In addition, pharmacokinetic studies have shown that Asundexian is mainly metabolized to aniline and α-substituted butyric acid. Although the subsequent conversion of aniline to N-acetylated products is the main metabolic pathway, aniline may also undergo oxidative biotransformation. The oxidative metabolism of aniline / aniline groups is a recognized structural alarm, which is associated with mutagenicity, direct toxicity, methemoglobinemia, and immunosensitization toxicity. In the list of carcinogens published by the World Health Organization's International Agency for Research on Cancer in 2017, aromatic amines are on the list of Class 3 carcinogens. Aniline toxicity is the main reason for withdrawal and suspension of clinical trials in the late stages of drug development. Currently, 1 / 3 of drugs containing aromatic amines have been withdrawn from the market. Therefore, the aromatic amine structure of Asundexian is a potential toxic substance. Asundexian

[0007] Therefore, the development of anticoagulant drugs with low toxicity, reduced bleeding risk, high selectivity for FXIa and PKa dual targets, and excellent therapeutic effects has become a technical challenge that needs to be solved in this field. Summary of the invention

[0008] Purpose of the invention: The purpose of the present invention is to provide a triazole derivative and a preparation method and use thereof.

[0009] Technical solution: A compound and a pharmaceutically acceptable salt thereof, characterized in that its structure is as shown in Formula I

[0010] I

[0011] in

[0012] R1 represents H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl;

[0013] R2 represents a substituted or unsubstituted aryl group, a substituted or unsubstituted unsaturated heterocyclic group;

[0014] X represents C-OCH3 or N

[0015] R3 represents 4-chlorotriazole or 4-trifluoromethyltriazole.

[0016] The compound and pharmaceutically acceptable salt thereof are characterized in that:

[0017] The alkyl group is a C1-C20 straight chain or branched saturated aliphatic group, a C3-C20 cycloalkyl group or a C5-C20 spiroalkyl group; the substituent of the aryl group is a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 alkylthio group, a halogen group, a nitro group, a cyano group, a hydroxyl group, a carboxyl group or an amino group; the unsaturated heterocyclic group includes a partially unsaturated heterocyclic group and an aromatic heterocyclic group, and the heteroatom of the heterocyclic group is selected from nitrogen, oxygen, or sulfur.

[0018] The compound and pharmaceutically acceptable salt thereof are characterized in that:

[0019] The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, or 2,2-diethylhexyl;

[0020] The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl;

[0021] The spirocycloalkyl group is a mono-spirocycloalkyl group, a di-spirocycloalkyl group or a poly-spirocycloalkyl group;

[0022] The aryl group is a substituted phenyl or naphthyl group.

[0023] A compound and a pharmaceutically acceptable salt thereof, the structure of which is shown in Formula I

[0024] I

[0025] in

[0026] R1 represents H, ethyl or benzyl,

[0027] R2 represents a benzene ring, a benzoate, a benzoic acid or an N-containing heterocyclic ring,

[0028] X represents C-OCH3 or N,

[0029] R3 represents 4-chlorotriazole or 4-trifluoromethyltriazole.

[0030] Furthermore, the compound is one of the following compounds: The present invention also provides a method for preparing the aforementioned compound, which comprises the following steps:

[0031] The compound of formula AI-A and the compound of formula AI-B are subjected to a click chemistry reaction under CuOAc catalysis to obtain the target compound AI

[0032] in,

[0033] R1, X, and R2 are as defined above.

[0034] The present invention also provides the use of the aforementioned compound and its pharmaceutically acceptable salt in the preparation of a coagulation factor FXIa inhibitor and / or a plasma bradykinin kinase PKA inhibitor.

[0035] The term "alkyl" refers to a saturated aliphatic group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available connection point. The substituent is preferably one or more of the following groups independently selected from C1~C8 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro.

[0036] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituted group, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 5 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cycloalkyl; polycyclic cycloalkyls include spirocyclic, condensed and bridged cycloalkyls.

[0037] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiral cycloalkyl.

[0038] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. The aryl group can be substituted or unsubstituted, that is, it can be substituted by 0 to 4 deuterium, C1 to 4 alkyl, C1 to 4 alkoxy, C1 to 4 alkylthio, halogen, nitro, cyano, hydroxyl, carboxyl, amino and other substituents. Aryl includes spirocyclic, fused and bridged aryl groups.

[0039] The term "unsaturated heterocyclic group" refers to an unsaturated cycloalkyl group containing one or more heteroatoms, including partially unsaturated heterocyclic groups and aromatic heterocyclic groups, wherein the heteroatoms of the heterocyclic group are selected from nitrogen, oxygen, or sulfur.

[0040] The present invention also provides the use of the aforementioned compound and its pharmaceutically acceptable salt in the preparation of drugs for preventing and / or treating diseases mediated by factor XIa, and preventing and / or treating cardiovascular and cerebrovascular diseases;

[0041] Preferably, the disease is a thromboembolic disease;

[0042] More preferably, the disease is myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

[0043] The present invention also provides a medicine, which is a preparation prepared by using the aforementioned compound and its pharmaceutically acceptable salt as active ingredients and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0044] The present invention also provides a pharmaceutical composition, which comprises the aforementioned compound and a pharmaceutically acceptable salt thereof as well as a pharmaceutically acceptable carrier, diluent and excipient.

[0045] Another aspect of the present invention relates to a method for preventing and / or treating a disease mediated by Factor XIa, which comprises administering to a patient a therapeutically effective dose of the aforementioned compound or its salt, stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof, or a pharmaceutical composition comprising the same.

[0046] Another aspect of the present invention relates to a method for treating, preventing and / or treating cardiovascular and cerebrovascular diseases, which comprises administering to a patient a therapeutically effective dose of the aforementioned compound or its salt, stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof or a pharmaceutical composition containing the same, wherein the cardiovascular and cerebrovascular diseases are selected from myocardial infarction, angina pectoris, re-occlusion and restenosis after angioplasty or aortocoronary bypass surgery, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

[0047] Another aspect of the present invention relates to a drug for inhibiting factor XIa and factor PKA, which includes the aforementioned compound or its salt, stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof or a pharmaceutical composition containing the same.

[0048] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, water or oil 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 following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. Oral preparations may also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0049] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0050] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0051] Dispersible powders and granules suitable for preparing water suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents illustrate the examples above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0052] These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time.

[0053] Oral preparations 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 an oily vehicle.

[0054] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil or a mixture thereof. A suitable emulsifier can be a naturally occurring phospholipid, and the emulsion can also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.

[0055] The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents 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 the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0056] The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques using those suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in an acceptable non-toxic diluent or solvent for parenteral administration. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

[0057] The compounds of this 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.

[0058] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the optimal treatment method such as the mode of treatment, the daily dosage of the aforementioned compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0059] Beneficial effects: In order to avoid the formation of amide bonds, the present invention uses a click reaction to synthesize a series of compounds with 1,2,3-triazole as the skeleton, so as to replace the amide bonds that are easily broken during drug metabolism, and solve the toxicity problem. Surprisingly, some compounds show excellent anticoagulant activity and selectivity. Specifically: The present invention designs a small molecule inhibitor with a new structure, which solves the problem of generating aromatic amines with potential toxicity caused by the unstable amide bond breakage during asundexian metabolism by introducing a triazole skeleton. At the same time, some compounds of the present invention have higher selectivity and show excellent anticoagulant activity, and have better pharmacokinetic properties, which can be used to effectively treat and / or prevent cardiovascular and cerebrovascular diseases and thrombotic symptoms. Obviously, according to the above content of the present invention, according to the common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change can be made. The following is a further detailed description of the above content of the present invention through the specific implementation of the embodiment form. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0060] The raw materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products. The melting point was determined by a RY-1 melting point instrument from Tianjin Analytical Instrument Factory; 1H-NMR and 13C-NMR were determined by Bruker AM-600MHz, Varian 400MHz nuclear magnetic resonance instruments, with TMS as the internal standard; MS was determined by a thermo LC / MS mass spectrometer. The thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the silica gel plate used for thin layer chromatography (TLC) used a specification of 0.15 mm~0.2 mm, and the thin layer chromatography separation and purification product used a specification of 0.4 mm~0.5 mm. Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier. Unless otherwise specified in the embodiments, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere refers to a reaction bottle connected to an argon or nitrogen balloon with a volume of about 1L. Hydrogen atmosphere refers to a hydrogen balloon with a volume of about L connected to the reaction bottle. The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated 3 times. Unless otherwise specified in the embodiment, the reaction temperature is room temperature, which is 20°C~30°C. The monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the system of eluent for column chromatography used for purifying the compound and the developing agent system for thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum mystery / ethyl acetate system, D: acetone, E: dichloromethane / acetone system, F: ethyl acetate / dichloromethane system, G: ethyl acetate / dichloromethane / n-hexane, H: ethyl acetate / dichloromethane / acetone, I: petroleum ether / ethyl acetate / dichloromethane, the volume ratio of the solvent is adjusted according to the different polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment. The preparation method of the compound of the present invention comprises the following steps: The first step is a nucleophilic substitution reaction between the compound of formula AI-1 and the compound of formula AI-2 to obtain the compound of formula AI-A;

[0061] The second step is a click chemistry reaction between the compound of formula AI-A and the compound of formula AI-B under CuOAc catalysis to obtain the target compound AI.

[0062] Reagents providing alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide. The inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, saturated carbonate, sodium hydroxide and lithium hydroxide.

[0063] The conditions providing 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.

[0064] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.

[0065] General post-treatment method A (concentrate under reduced pressure to remove the solvent, add water, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter out, and spin dry).

[0066] 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)

[0067] 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)

[0068]

[0069] Step a: Preparation of azido-2-bromo-4-chlorobenzene (1b)

[0070] The compound 2-bromo-4-chloroaniline (1a) (20 g, 96.87 mmol) was dissolved in acetonitrile (150 mL), cooled to 0°C, and isoamyl nitrite (20.55 mL, 145.3 mmol) and trimethylsilyl azide (20.12 mL, 63.55 mmol) were slowly added dropwise in sequence. The mixture was stirred at 0°C for 5 minutes, and then the mixture was heated to room temperature and stirred for about 4 h. After the reaction of the raw materials was completed as monitored by TLC, most of the acetonitrile was removed, and the mixture was extracted with ethyl acetate and water. The organic phases were combined, washed with saturated brine, dried, concentrated, and pumped with an oil pump without spinning to obtain a brown solid 1b (25.89 g). 1 H 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).

[0071] Step b: Preparation of 1-(2-bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (1c)

[0072] 1-(2-Bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (1c)

[0073]

[0074] Compound 1b (25.89 g, 107.54 mmol) was dissolved in toluene (250 mL), and ethynyltrimethylsilane (32.34 g, 46.53 mL, 322.63 mmol) was added dropwise at room temperature. The reaction was refluxed at 110 °C overnight. After the reaction of 1b was completed, the toluene was removed by spinning in a 65 °C water bath, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate phases were combined, dried, and concentrated to obtain compound 1c (33.04 g, 92.91%). 1 H 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 of 1-(2-Bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazole (1d) 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, and refluxed at 90 °C for 40 h. After the reaction was completed as monitored by TLC, the mixture was filtered, dried by rotation, extracted with ethyl acetate and water, the organic phases were combined and concentrated, and the crude product was purified by column chromatography to obtain compound 1d (18.33 g, 68.88%). 1 H 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 (1e) 1d (18.33 g, 62.57 mmol), 2,5-dimethoxypyridine-4-boronic acid (13.74 g, 75.09 mmol), and K3PO4 (33.2 g, 156.43 mmol) were dissolved in a degassed 1,4-dioxane (160 mL) : water (40 mL) = 4:1 mixed solution, and PdCl2(dppf)•CH2Cl2 (2.55 g, 3.12 mmol) was added under argon protection. The reaction was refluxed at 90 °C for 12 h. After the reaction was completed, 1,4-dioxane was spun off, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. Compound 1e (15.37 g, 69.95%) was purified by column chromatography. 1 H NMR (400 MHz, DMSO- d 6) 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: Preparation of 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (1f) 1e (15.37 g, 43.77 mmol) and pyridine hydrobromide (70.03 g, 437.66 mmol) were dissolved in DMF (60 mL), and the mixture was stirred in an oil bath at 110 °C for 5 h. After the reaction was completed as monitored by TLC, the reaction mixture was cooled to room temperature and poured into a small amount of ice water. A white solid precipitated, which was filtered and dried to obtain compound 1f (13.59 g, 92%). 1 H NMR (400 MHz, DMSO- d6) δ11.20 (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: Preparation of 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) 1f (3 g, 8.9 mmol) and K2CO3 (3.07 g, 22.24 mmol) were dissolved in DMF (18 mL), 3-bromopropyne (0.92 mL, 10.68 mmol) was added, and the reaction was stirred at room temperature for 6 h. A large amount of water was added, and the mixture was extracted several times with a small amount of ethyl acetate. The organic phases were combined, dried, and concentrated. The crude product was purified by column chromatography to obtain 1g (1.45 g, 43.66%). 1 H 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: Preparation of 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) Compound 1g and azide benzene (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 70 / 1) as eluent to obtain compound I-1 (71 mg, white solid, yield: 53.89%). HPLC purity: 99.63%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 23 H 18 Cl2N7O2 + 494.0894, found 494.0903.

[0075] Example 2, 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) Compound 1g and methyl 2-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography, and the eluent was dichloromethane and methanol (140 / 1 to 70 / 1) to obtain compound I-2 (173.6 mg, white solid, yield: 73.7%). HPLC purity: 99.11%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 25 H20 Cl2N7O4 + 552.0948, found 552.0950.

[0076] 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)benzoate (I-3) Compound 1g and methyl 3-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 80 / 1) as eluent to obtain compound I-3 (162 mg, white solid, yield: 68.77%). HPLC purity: 99.71%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C 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] + Calculate for C 25 H 20 Cl2N7O4 + 552.0948, found 552.0954.

[0077] Example 4, 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) Compound 1g and methyl 4-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (140:1-70:1) as eluent to obtain compound I-4 (157.8 mg, yellow-white solid, yield: 76.56%). HPLC purity: 99.43%. 1 H NMR (400 MHz, DMSO- d 6) 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= 2.2Hz, 1H), 7.44 (s, 1H), 6.46 (s, 1H), 5.23 (s, 2H), 3.89 (s, 3H), 3.29 (s,3H). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 25 H 20 Cl2N7O4 + 552.0948, found 552.0959.

[0078] 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) The synthesis method is the same as I-2. I-2 is dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, lithium hydroxide monohydrate (5 equiv) is added, and stirred for 3.5 h in an ice bath. After the reaction is completed by TLC monitoring, the solvent is removed, a small amount of water is added, and the pH is adjusted to 2-3 with 4N HCl in an ice bath. Solids precipitate and are filtered to obtain compound I-5 (80 mg, white solid, yield: 74.62%). HPLC purity: 99.14%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 24 H 18 Cl2N7O4 + 538.0792, found 538.0800.

[0079] 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) The synthesis method is the same as that of I-3. I-3 was dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, lithium hydroxide monohydrate (5 equiv) was added, and the mixture was stirred for 3.5 h in an ice bath. After the reaction was completed by TLC monitoring, the solvent was removed, a small amount of water was added, and the pH was adjusted to 2-3 with 4N HCl in an ice bath. Solids precipitated and were filtered to obtain compound I-6 (87 mg, white solid, yield: 79.7%). HPLC purity: 99.66%. 1H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 24 H 18 Cl2N7O4 + 538.0792, found 538.0796.

[0080] 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) The synthesis method is the same as that of I-4. I-4 was dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, and lithium hydroxide monohydrate (5 equiv) was added. The mixture was stirred for 3.5 h under ice bath. After the reaction was completed by TLC monitoring, the solvent was removed, a small amount of water was added, and the pH was adjusted to 2-3 with 4N HCl under ice bath. Solid precipitated and was filtered to obtain compound I-7 (107 mg, white solid, yield: 79.84%). HPLC purity: 98.57%; 1 H NMR (400 MHz, DMSO- d 6) 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 = 2.4Hz, 1H), 7.38 (s, 1H), 6.46 (s, 1H), 5.21 (s, 2H), 3.27 (s, 3H). 13 C NMR (151MHz, DMSO- d 6) 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] + Calculate for C 24 H 18 Cl2N7O4 + 538.0792, found 538.0801.

[0081] 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) Compound 1g and 4-azido-1H-pyrazole (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography, and the eluent was dichloromethane and methanol (140 / 1 to 30 / 1) to obtain compound I-8 (39 mg, white solid, yield: 37.77%). HPLC purity: 99.85%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151MHz, DMSO- d 6) 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] + Calculate for C 20 H 16 Cl2N9O2 + 484.0799, found 484.0801.

[0082] 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) Compound 1g and 4-azido-1-methyl-1H-pyrazole (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with the eluent being dichloromethane and methanol (100 / 1 to 40 / 1) to obtain compound I-9 (46 mg, white solid, yield: 43.29%). HPLC purity: 99.88%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 21 H 18 Cl2N9O2 + 498.0955, found 498.0961.

[0083] 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) Compound 1g and 3-azido-2-methylpyridine (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography, and the desorbent was dichloromethane and methanol (100 / 1 to 40 / 1) to obtain compound I-10 (34 mg, white solid, yield: 22%). HPLC purity 97.89%. 1 H NMR (400 MHz, DMSO- d 6) δ8.69 (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, 4.8Hz, 1H), 7.43 (s, 1H), 6.46 (s, 1H), 5.24 (s, 2H), 3.29 (s, 3H), 2.35 (s, 3H). 13 C 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] + Calculate for C 23 H 19 Cl2N8O2 + 509.1003, found 509.1009.

[0084] 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) Compound 1g and 3-azido-6-chloro-2-methylpyridine (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 40 / 1) as eluent to obtain compound I-11 (80 mg, white solid, yield: 46%). HPLC purity 95.20%. 1 H NMR (400 MHz, DMSO- d 6) 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= 8.4Hz, 1H), 7.43 (s, 1H), 6.46 (s, 1H), 5.24 (s, 2H), 3.29 (s, 3H), 2.34 (s, 3H). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 23 H 18 Cl3N8O2 + 543.0613, found 543.0620.

[0085] 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) Compound 1g and 3-azido-6-methoxy-2-methylpyridine (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 50 / 1) as eluent to obtain compound I-12 (80 mg, white solid, yield: 50.59%). HPLC purity 97.99%. 1 H 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). 13 CNMR (151 MHz, DMSO- d 6) 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] + Calculate for C 24 H 21 Cl2N8O3 + 539.1108, found 539.1118.

[0086] 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)picolinonitrile (I-13) Compound 1g and 3-azido-5-bromopyridinecarbonitrile (2 equiv) were dissolved in a mixed solvent of t-BuOH:ACN:H2O=2:1:1, and then CuSO4 (0.5 equiv) and sodium L-ascorbate (0.5 equiv) were added and stirred at room temperature for 10 h. After the reaction was completed by TLC monitoring, it was spin-dried, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography with dichloromethane and methanol (110 / 1~70 / 1) as eluent to obtain compound I-13 (138 mg, white solid, yield: 78%). HPLC purity 98.22%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 23 H 15 BrCl2N9O2 + 597.9904, found597.9909.

[0087] 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)picolinonitrile (I-14) Compound 1g and 3-azido-6-chloropyridinecarbonitrile (2 equiv) were dissolved in a mixed solvent of t-BuOH:ACN:H2O=2:1:1, and then CuSO4 (0.5 equiv) and sodium L-ascorbate (0.5 equiv) were added, and the reaction was stirred at room temperature for 10 h. After the reaction was completed by TLC monitoring, it was spin-dried, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the concentrated crude product was purified by column chromatography, and the eluent was dichloromethane and methanol (110 / 1~70 / 1) to obtain compound I-14 (125 mg, white solid, yield: 70.45%). HPLC purity 98.45%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C 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] + Calculate for C 23 H 15 Cl3N9O2 + 554.0409, found554.0416.

[0088] 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)picolinate (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) Compound 1g and 3-azidoquinolinic acid methyl ester (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 70 / 1) as eluent to obtain compound I-15 (93 mg, white solid, yield: 45.04%). HPLC purity: 98.98%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 24 H 19 Cl2N8O4 + 553.0901, found 553.0909.

[0089] 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 is the same as I-15. I-15 is dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, lithium hydroxide monohydrate (5 equiv) is added, and stirred for 3.5 h in an ice bath. After the reaction is completed by TLC monitoring, the solvent is removed, a small amount of water is added, and the pH is adjusted to 2-3 with 4N HCl in an ice bath. Solids are precipitated and filtered to obtain I-16 (38 mg, white solid, yield: 64.98%). HPLC purity 97.77%. 1 H 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 23 H 17 Cl2N8O4+ 539.0744, found 539.0752.

[0090] 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) Step a: Preparation of 1-yn-3-yl methanesulfonate (17a) Dissolve ethyl ethynyl methanol (5.23 mL, 57.6 mmol) in DCM, protect with argon, cool the reaction to 0 °C, add Et3N (12.01 mL, 86.4 mmol) dropwise to the reaction, then add a DCM solution of methanesulfonic anhydride (15.05 g, 86.4 mmol), stir and react overnight. Dilute the reaction solution with DCM, wash three times with water, dry, and concentrate to obtain a brown oil 17a (10.98 g), which is used directly in the next step. 1 H 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). Step b: 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 (17b) 1f (1.2 g, 3.56 mmol) was dissolved in isopropanol (12 mL), and tetramethylguanidine (1.37 mL, 10.68 mmol) was added. The mixture was stirred at room temperature for 30 min, and pent-1-yn-3-yl methanesulfonate (17a) (1.27 g, 7.83 mmol) was added. Under argon protection, the mixture was stirred in an oil bath at 40 °C for 6 h. After the reaction was completed, the solvent was dried by TLC, and water was added. The mixture was extracted with ethyl acetate, dried, and concentrated. The crude product was purified by column chromatography to obtain compound 17b (349 mg, 24.28%). 1 H 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: Preparation of 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) Compound 17b and azide benzene (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (140 / 1 to 100 / 1) as eluent to obtain compound I-17 (26 mg, white solid, yield: 25.09%). HPLC purity: 99.59%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C 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] + Calculate for C 25 H 22 C l2 N7O2 + 522.1207, found 522.1212.

[0091] 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) Compound 17B and methyl 2-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 80 / 1) as eluent to obtain compound I-18 (60 mg, white solid, yield: 22.53%). HPLC purity: 97.16%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 CNMR (151 MHz, DMSO- d 6) 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] + Calculate for C 27 H 24 Cl2N7O4 + 580.1261, found 580.1271.

[0092] Example 19, 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 and methyl 3-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (100 / 1 to 80 / 1) as eluent to obtain compound I-19 (143 mg, white solid, yield: 61.11%). HPLC purity: 98.46%; 1 H 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 27 H 24 Cl2N7O4 + 580.1261, found 580.1271.

[0093] 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) Compound 17b and methyl 4-azidobenzoate (1.5 equiv) were weighed into a bottle, dissolved in methanol, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (160 / 1 to 80 / 1) as eluent to obtain compound I-20 (63 mg, white solid, yield: 31.26%). HPLC purity: 99.12%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6)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] + Calculate for C 27 H 24 Cl2N7O4 + 580.1261, found 580.1269.

[0094] 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) The synthesis method is the same as that of I-18. I-18 was dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, and lithium hydroxide monohydrate (5 equiv) was added. The mixture was stirred for 3.5 h under ice bath. After the reaction was completed by TLC monitoring, the solvent was removed, a small amount of water was added, and the pH was adjusted to 2-3 with 4N HCl under ice bath. Solid precipitated and was filtered to obtain compound I-21 (28 mg, white solid, yield: 57.39%). HPLC purity: 99.23%. 1 H NMR (400 MHz, DMSO- d 6) 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 = 7.2Hz, 3H). 13 C 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] + Calculate for C 26 H 22 Cl2N7O4 + 566.1105, found 566.1113.

[0095] 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) The synthesis method is the same as that of I-19. I-19 was dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, and lithium hydroxide monohydrate (5 equiv) was added. The mixture was stirred for 3.5 h in an ice bath. After the reaction was completed by TLC monitoring, the solvent was removed, a small amount of water was added, and the pH was adjusted to 2-3 with 4N HCl in an ice bath. Solids precipitated and were filtered to obtain compound I-22 (75 mg, white solid, yield: 69.87%). HPLC purity: 98.67%. 1 H NMR (400 MHz, DMSO- d 6) 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 = 7.1Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 26 H 22 Cl2N7O4 + 566.1105, found 566.1107.

[0096] 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) The synthesis method is the same as that of I-20. I-20 is dissolved in a mixed solvent of THF:MeOH:H2O=4:1:1, lithium hydroxide monohydrate (5 equiv) is added, and stirred for 3.5 h in an ice bath. After the reaction is completed by TLC monitoring, the solvent is removed, a small amount of water is added, and the pH is adjusted to 2-3 with 4N HCl in an ice bath. Solids are precipitated and filtered to obtain compound I-23 (30 mg, white solid, yield: 61.49%). HPLC purity: 97.51%. 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 26 H 22 Cl2N7O4 + 566.1105, found 566.1106.

[0097] 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 Chempartner SFC system was used for separation. The separation conditions were as follows: column temperature: 35°C, chromatographic column: DAICEL CHIRALPAK® AS (30*250mm 5μm), detection wavelength: 215 nm, back pressure: 10 MPa; mobile phase: scCO2 / methanol = 50 / 50, flow rate: 45 mL / min.

[0098] ee value: 99.28%; HPLC purity: 99.6%; 1 H NMR (400 MHz, DMSO- d 6) 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 = 8.7Hz, 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).

[0099] 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 Chempartner SFC system was used for separation. The separation conditions were as follows: column temperature: 35°C, chromatographic column: DAICEL CHIRALPAK® AS (30*250mm 5μm), detection wavelength: 215 nm, back pressure: 10 MPa; mobile phase: scCO2 / methanol = 50 / 50, flow rate: 45 mL / min.

[0100] ee value: 100%; HPLC purity: 100%; 1 H NMR (400 MHz, DMSO- d 6) 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= 7.9Hz, 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).

[0101] 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-(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, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (80 / 1 to 30 / 1) as eluent to obtain compound I-24 (37 mg, white solid, yield: 26.47%). HPLC purity 99.80%. 1 H NMR (600 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d6) δ159.20, 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] + Calculate for C 22 H 20 C l2 N9O2 + 512.1112, found 512.1120.

[0102] 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, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (140 / 1 to 70 / 1) as eluent to obtain I-25 (33 mg, white solid, yield: 25.28%). HPLC purity: 97.27%; 1 HNMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 23 H 22 C l2 N9O2 + 526.1268, found 526.1275.

[0103] 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, and CuOAc (0.2 equiv) was added. The mixture was stirred at room temperature overnight. After the reaction was completed by TLC monitoring, it was dried by spin drying, water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography with dichloromethane and methanol (80 / 1 to 30 / 1) as eluent to obtain compound I-26 (61 mg, white solid, yield: 39.77%). HPLC purity 95.21%. 1H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 23 H 20 Cl2F2N9O2 + 562.1080, found 562.1087.

[0104] 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 (27a) Take 0.5 mol / L ethynylmagnesium bromide (79.9 mL, 39.95 mmol) in a reaction bottle under argon atmosphere, place it at 0 °C, and then slowly drop phenylacetaldehyde (3.7 mL, 33.29 mmol) diluted with tetrahydrofuran (30 mL), and move to room temperature to react for 5 hours. Add saturated ammonium chloride solution (50 mL) dropwise at low temperature to quench the reaction, treat it using general post-treatment method A, and purify the crude product by column chromatography (PE / EtOAc, v / v, 30 / 1) to obtain a yellow oil (2.64 g, yield: 54.2%). 1 H 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 of 1-phenyl-3-butyn-2-yl methanesulfonate (27b) Intermediate 27a (2.63 g, 17.99 mmol) was weighed and dissolved in dichloromethane (30 mL), protected by argon, and placed at 0 °C. Triethylamine (3.75 mL, 26.99 mmol) and methanesulfonic anhydride (4.8 g, 26.99 mmol) diluted in dichloromethane were then added dropwise and reacted for 5 hours. The reaction was quenched by adding water and treated with general post-treatment method A to obtain a crude brown oil (4.03 g, yield: 100%). 1 H 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 of Azidobenzene (27c) Weigh aniline (0.5 g, 5.37 mmol) and dissolve it in acetonitrile (5 mL), place it at 0 °C, then add isoamyl nitrite (943.43 mg, 8.05 mmol) and sodium trimethylsilylazide (927.83 mg, 8.05 mmol) dropwise, and move to room temperature to react for 4 hours. Use general post-treatment method A to obtain a crude brown oil (626 mg, yield: 97.88%), which is directly used 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 (27d) Weigh the intermediate 1f (1 g, 2.97 mmol) and dissolve it in 10 mL isopropanol / acetone solution (v / v, 4 / 1), then add tetramethylguanidine (1.02 g, 8.9 mmol), stir at room temperature for half an hour, then add the intermediate 27b (1.46 g, 6.53 mmol), and heat to 40 °C in an oil bath under argon atmosphere for 5 hours. Use the general post-treatment method A, and the crude product is purified by column chromatography (PE / EtOAc, v / v, 6 / 1) to obtain a yellow solid (0.26 g, yield: 18.84%). 1 H NMR (400 MHz, DMSO- d 6) 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: Preparation of 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 µmol) was weighed and dissolved in methanol (2 mL), and intermediate 27c (38.4 mg, 322.35 µmol) and cuprous acetate (5.27 mg, 42.98 µmol) were added. The mixture was reacted at 30 °C for 5 hours under argon atmosphere. The crude product was purified by column chromatography (DCM / MeOH, v / v, 120 / 1 - 70 / 1) using general post-treatment method A to obtain a white solid (35 mg, yield: 27.87%). HPLC purity: 97.17%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d6) δ158.92, 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] + Calculate for C 30 H 24 Cl2N7O2 + 584.1363, found 584.1373.

[0105] Example 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) 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) Step a: Preparation of 4-azido-1H-pyrazole (28a) Weigh 4-aminopyrazole (1 g, 12.03 mmol) and dissolve it in 6 mol / L hydrochloric acid (10 mL). Place it at 0 °C, slowly drop sodium nitrite (1.1 g, 16.01 mmol) in water (5 mL), stir for half an hour, then drop sodium azide (1.11 g, 17.09 mmol) in water (5 mL), and move to room temperature to react for 3 hours. Use general post-treatment method A to obtain a crude orange solid (1.04 g, yield: 79.14%), which is 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-phenylethyl)-4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (I-28) The preparation method is the same as that of I-27, except that intermediate 27c is replaced by intermediate 28a to obtain a white solid (yield: 26.63%). HPLC purity: 99.73%; 1 H NMR (600 MHz, DMSO- d 6) 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). 13 C 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] + Calculate for C 27 H 22 Cl2N9O2 + 574.1268, found 574.1287.

[0106] Example 29, 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) Step a: Preparation of methyl 4-azidobenzoate (29a) Weigh 4-aminobenzoic acid methyl ester (0.5 g, 3.31 mmol) and dissolve it in acetonitrile (5 mL), place it at 0 ° C, then add isoamyl nitrite (0.74 mL, 4.96 mmol) and sodium trimethylsilylazide (0.69 mL, 4.96 mmol) dropwise, and move to room temperature to react for 4 hours. Use general post-treatment method A to obtain a crude orange solid (0.58 g, yield: 98.21%), which is directly used in the next step. Step b: 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) The preparation method is the same as that of I-27, except that intermediate 27c is replaced by intermediate 29a to obtain a yellow solid (yield: 53.23%). HPLCpurity: 95.51%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C 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] + Calculate for C 32 H 26 Cl2N7O4 + 642.1418, found 642.1416.

[0107] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (I-30) Weigh I-29 (147 mg, 228.79 µmol) and dissolve it in 6 mL THF / MeOH / H2O solution (v / v / v, 4 / 1 / 1), add lithium hydroxide (27.39 mg, 1.14 mmol), and react at room temperature for 3 hours. After vacuum concentration, add 2 mL of distilled water, adjust the pH to about 3 with 2 mol / L HCl, and solid precipitates. After filtering, dry it to obtain a white solid (120 mg, yield: 83.45%). HPLC purity: 97.83%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 31 H 24 Cl2N7O4 + 628.1261, found 628.1255.

[0108] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Enantiomer 1) The Chempartner SFC system was used for separation. The separation conditions were as follows: column temperature: 35°C, chromatographic column: DAICEL CHIRALPAK® REGIS (30*250mm 10μm), detection wavelength: 215 nm, back pressure: 10MPa; mobile phase: scCO2 / (methanol / acetonitrile, 0.1% 7M ammonia methanol) = 50 / 50, flow rate: 45 mL / min.

[0109] ee value: 100%; HPLC purity: 100%; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0110] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Enantiomer 2) The Chempartner SFC system was used for separation. The separation conditions were as follows: column temperature: 35°C, chromatographic column: DAICEL CHIRALPAK® REGIS (30*250mm 10μm), detection wavelength: 215 nm, back pressure: 10MPa; mobile phase: scCO2 / (methanol / acetonitrile, 0.1% 7M ammonia methanol) = 50 / 50, flow rate: 45 mL / min.

[0111] ee value: 99.46%; HPLC purity: 99.7%; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0112] 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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 31a The compound 2-bromo-4-chloroaniline (30 g, 140.3 mmol) was dissolved in toluene (200 mL), and bis(boronic acid) pinacol ester (40.6 g, 159.8 mmol) and potassium acetate (37.1 g, 377.8 mmol) were added in sequence, and the atmosphere was replaced with nitrogen 3-4 times. Under nitrogen protection, PdCl2(dppf)•CH2Cl2 (3.6 g, 4.4 mmol) was quickly added, and the temperature was raised to 90 °C and stirred for 12 h. After the reaction solution was cooled to room temperature, the reaction solution was spin-dried. The crude product was purified by silica gel column chromatography to obtain the compound (24.7 g, yield: 67%). 1 H 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). Step b: Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline 31b Compound 31a (24.7 g, 97.3 mmol) was dissolved in a mixed solution of degassed 1,4-dioxane (200 mL) and water (50 mL), and then 4-chloro-6-methoxypyrimidine (14.1 g, 97.3 mmol) and potassium acetate (23.9 g, 243.4 mmol) were added, and the mixture was replaced with nitrogen 3-4 times. PdCl2(dppf)•CH2Cl2 (2.4 g, 2.9 mmol) was quickly added under nitrogen protection, heated to 80 °C, and stirred for 12 h. The TLC monitored the complete consumption of compound 1a, and the reaction solution was cooled to room temperature, dried by rotation, and then extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed three times with a saturated saline solution, dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain compound 31b as a white solid (14.7 g, yield: 64%). 1 H 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). Step c: Preparation of 4-(2-azido-5-chlorophenyl)-6-methoxypyrimidine (31c) Compound 31b (10 g, 42.4 mmol) was dissolved in 100 mL of acetonitrile, the reaction solution was cooled to 0 °C, and isoamyl nitrite (7.5 g, 63.6 mmol) and trimethylsilyl azide (8.3 g, 63.6 mmol) were slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was continued for 10 hours. A solid precipitated, which was filtered and dried to obtain compound 31c (10.3 g, yield: 88%). It was directly used in 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 (31d) Compound 31c (10.3 g, 39.5 mmol) and ethynyltrimethylsilane (7.0 g, 71.1 mmol) were dissolved in 100 mL toluene solution, refluxed at 110 °C for 12 hours, and concentrated under reduced pressure to remove the organic solvent. 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 obtain a crude product, which was purified by column chromatography to obtain compound 31d (12 g, yield: 84%).

[0113] 1 H NMR (600 MHz, DMSO- d 6) 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 (31e) 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 of acetonitrile and reacted at 80 °C for 6 hours. The organic solvent was removed by concentration under reduced pressure. 100 mL of water was added to the obtained residue, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified to obtain 31e (5 g, yield: 52%). 1 H NMR (400 MHz, DMSO- d 6) 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 (31f) To a solution of compound 31e (5 g, 15.4 mmol) in acetic acid (5 mL), slowly dropwise add 48% aqueous hydrobromic acid solution (16.5 mL, 146.3 mmol). Heat to 80 °C and react for 2.5 hours. After the reaction solution is cooled, rotary evaporate to dryness, then add ethyl acetate, and then dilute with saturated sodium bicarbonate solution, separate the layers, collect the organic phase, and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product 31f (4.6 g, yield: 97%), which is used directly in the next step without purification. 1H NMR (400MHz, DMSO- d 6) 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)phenyl)-3-(pent-1-yn-3-yl)pyrimidin-4(3H)-one (31 g) The preparation method was the same as 17 b, except that 1f was replaced by 31f to give a white solid (773 mg, yield 64%). 1 H NMR (400 MHz, DMSO- d 6) 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)

[0114] The preparation method is the same as I-17, except that 17b is replaced by intermediate 31g to obtain a white solid (60 mg, yield 46%). HPLC purity: 99.13%; 1 H NMR (400 MHz, DMSO- d 6) 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); 13 C 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] + Calculate for C 23 H 19 Cl2N8O + 493.1053, found 493.1064.

[0115] 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 I-31 except that 27c is replaced by 28a. A white solid (68 mg, yield 53%) is obtained. HPLC purity: 97.43%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C 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] + Calculate for C 20 H 17 Cl2N 10 O + 483.0958, found 483.0968.

[0116] 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) The preparation method is the same as I-31 except that 27c is replaced by 4-azido-1-methyl-1H-pyrazole to obtain a white solid (69 mg, yield 52%). HPLC purity: 99.57%; 1 H NMR (400 MHz, DMSO- d 6) 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 (151MHz, DMSO- d 6) 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] + Calculate for C 21 H 19 Cl2N 10 O + 497.1115, found 497.1126.

[0117] 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 ac: Same as Step ac of I-27 Step d: Preparation of N-(2-bromo-4-chlorophenyl)formamide (34a) 2-Bromo-4-chloroaniline (50 g, 242.17 mmol) and sodium formate (8.23 g, 121.08 mmol) were weighed and added to formic acid (44.58 g, 968.68 mmol) and reacted at 25 °C for 23 hours under argon. After the reaction was completed, an appropriate amount of ethyl acetate was added, and the organic layer was washed with water and saturated NaHCO3, dried, and concentrated to obtain a gray solid 34a (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 (34b) Weigh compound 34a (39 g, 166.33 mmol) and dissolve it in 450 mL of tetrahydrofuran. Control the temperature at 0 °C, add triethylamine (100.99 g, 997.97 mmol), and then drop POCl3 (51 g, 332.66 mmol) in 200 mL of dry tetrahydrofuran into the reaction system for 1 hour. After the reaction is completed, pour the reaction solution into ice water, add potassium carbonate, stir for 5 minutes, extract with tertiary methyl ether, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a brown solid 34b (36 g, yield: 100%), which is directly used in the next step. Step f: Preparation of 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (34c) Compound 34b (27 g, 124.73 mmol) was weighed and added to a toluene solution (490 mL) of 2-diazo-1,1,1-trifluoroethane (0.5 M), and Ag2CO3 (6.88 g, 24.95 mmol), 4A molecular sieves (14.72 g) and DMF (100 mL) were added, and the mixture was reacted in an oil bath at 40 °C for 16 hours. Celite was spread on the mixture, and the solid was removed by filtration. The filtrate was treated with general post-treatment method A to obtain a crude product, which was purified by column chromatography (PE / EtOAc, v / v, 100 / 1) to obtain a dark red oil 34c (28.5 g, yield: 69.98%). 1 H 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: Preparation of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dimethoxypyridine (34d) Intermediate 34c (21 g, 64.32 mmol), 2,5-dimethoxypyridine-4-boronic acid (14.12 g, 77.18 mmol), and K3PO4 (27.84 g, 160.8 mmol) were weighed and dissolved in 200 mL 1,4-dioxane / H2O solution (v / v, 4 / 1), and PdCl2(dppf)•CH2Cl2 (2.63 g, 3.22 mmol) was added. The mixture was refluxed at 85 °C for 12 h under argon atmosphere. The crude product was purified by column chromatography (PE / EtOAc, v / v, 20 / 1) according to the general work-up method A to obtain 34d as a white solid (19.2 g, yield: 46.94%). 1 H NMR (400 MHz, DMSO- d 6) 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 (34e) Intermediate 34d (16.82 g, 43.72 mmol) and pyridinium hydrobromide (69.95 g, 437.17 mmol) were weighed and dissolved in DMF (60 mL) and refluxed at 110 °C for 4 hours. General workup method B was used to obtain an off-white solid 34e (14.7 g, yield: 90.7%). 1 H NMR (600 MHz, DMSO- d 6) 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 (34f) The preparation method is the same as that of intermediate 27d, except that intermediate 1f is replaced by intermediate 34e to obtain the intermediate (yield: 15.3%). 1 H NMR (400 MHz, DMSO- d 6) 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)

[0118] The preparation method is the same as I-27, except that intermediate 27d is replaced by intermediate 34f to obtain a white solid (yield: 27.33%). HPLC purity: 100%; 1 H 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 31 H 24 ClF3N7O2 + 618.1627, found618.1662.

[0119] Example 35, 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) 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, except that intermediate 27c is replaced by intermediate 28a to obtain a white solid (yield: 28.75%). HPLC purity: 97.13%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) δ158.90, 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] + Calculate for C 28 H 22 ClF3N9O2 + 608.1532, found 608.1573.

[0120] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoate (II-3) The preparation method is the same as II-1, except that intermediate 27c is replaced by intermediate 29a to obtain a yellow solid (yield: 65.3%). HPLC purity: 99.8%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151 MHz, DMSO- d 6) 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] + Calculate for C 33 H26 ClF3N7O4 + 676.1681, found 676.1718.

[0121] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (II-4) The preparation method is the same as I-30, except that I-29 is replaced by II-3 to obtain a white solid (yield: 91.2%). HPLC purity: 100%; 1 H NMR (400 MHz, DMSO- d 6) 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). 13 C NMR (151MHz, DMSO- d 6) 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] + Calculate for C 32 H 24 ClF3N7O4 + 662.1525, found662.1528.

[0122] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Enantiomer 1)

[0123]

[0124] The Chempartner SFC system was used for separation. The separation conditions were as follows: column temperature: 35 °C, chromatographic column: DAICELCHIRALPAK® REGIS (30*250mm 10μm), detection wavelength: 215 nm, back pressure: 10 MPa; mobile phase: scCO2 / (methanol / acetonitrile, 0.1% 7M ammonia methanol) = 50 / 50, flow rate: 45 mL / min.

[0125] ee value: 100%; HPLC purity: 100%; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0126] 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-phenylethyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Enantiomer 2)

[0127]

[0128] The Chempartner SFC system was used for separation. The separation conditions were as follows: column temperature: 35 °C, chromatographic column: DAICELCHIRALPAK® REGIS (30*250mm 10μm), detection wavelength: 215 nm, back pressure: 10 MPa; mobile phase: scCO2 / (methanol / acetonitrile, 0.1% 7M ammonia methanol) = 50 / 50, flow rate: 45 mL / min.

[0129] ee value: 99.1%; HPLC purity: 99.6%; 1 H NMR (400 MHz, DMSO- d 6) 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).

[0130] Comparative Example 1

[0131] 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)-2-fluorobenzamide (asundexian)

[0132] 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

[0133]

[0134] The synthesis was carried out using a method similar to that reported in the literature by Asundexian. The crude product was purified by silica gel column chromatography to obtain the target compound (114 mg, white solid, 73%). HPLC purity: 99.03%. 1 H NMR (400 MHz, DMSO- d 6) δ10.76 (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). 13 C NMR (151 MHz, DMSO- d 6) 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 C 26 H 22 ClF4N6O4 + [M+H] + , calcd 593.1322, found 593.1328.

[0135] Test Example 1: Determination of the activity of the compounds of the present invention on Factor XIa protease

[0136] The in vitro FXIa inhibitory activity of the compounds of the present invention was tested using human FXIa (Enzyme Research Laboratories). The chromogenic substrate used in the present invention is Boc-Glu(OBzl)-Ala-Arg-AMC (Gill Biochemicals). The substrate is hydrolyzed by FXIa to release aminomethylcoumarin (AMC). By measuring the change in fluorescence intensity, the inhibitory strength of the compound on FXIa is obtained.

[0137] The experimental operation is briefly described as follows: the test compound is prepared into a 10 mM stock solution with DMSO, and then diluted into a series of concentrations with a pH = 7.4 buffer (50 mMTris / HCl, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% bovine serum albumin). In the microplate, add 20 μL of buffer solution, 20 μL of FXIa enzyme solution (0.6 nM), and then add 20 μL of the test compound solution, incubate at a constant temperature of 37 ° C for 30 min, add 40 μL of fluorescent substrate solution (10 μM), and immediately measure on the microplate reader, with an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Read the data continuously, and fit the data with GraphPad Prism 7 to obtain the compound IC 50 Values, data see Table 1.

[0138] Table 1. IC values ​​of the inhibitory activity of the compounds of the present invention on FXIa 50 data

[0139] Example compounds <![CDATA[FXIa (IC 50 nM)]]> Example compounds <![CDATA[FXIa (IC 50 ,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 results of the FXIa enzyme activity test showed that the series of compounds obtained by introducing benzyl groups had excellent anticoagulant activity against FXIa. Compound (S)-I-30 had excellent anticoagulant activity, which was better than comparative example 1 (asundexian). Compound (S)-II-4 had even better activity, reaching the sub-nanomolar level.

[0140] Test Example 2: Determination of the activity of the compounds of the present invention on PKa protease

[0141] The in vitro PKa inhibitory activity of the compounds of the present invention was tested using human PKa. The chromogenic substrate used in the present invention is H-Pro-Phe-Arg-AMC (Gill Biochemical), and the substrate is hydrolyzed by PKa to release aminomethylcoumarin (AMC). By measuring the change in fluorescence intensity, the inhibitory strength of the compound on PKa is obtained.

[0142] The experimental operation is briefly described as follows: the test compound is prepared into a 10 mM stock solution with DMSO, and then diluted into a series of concentrations with a pH = 7.4 buffer (50 mMTris / HCl, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% bovine serum albumin). In the microplate, add 20 μL of buffer solution, 20 μL of PKa enzyme solution (2 nM), and then add 20 μL of the test compound solution, incubate at a constant temperature of 37 ° C for 30 min, add 40 μL of fluorescent substrate solution (5μM), and immediately measure on the microplate reader, with an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Read the data continuously, and fit the data with GraphPad Prism 7 to obtain the compound IC 50 Values, data see Table 2.

[0143] Table 2. IC values ​​of the inhibitory activity of the compounds of the present invention on PKa 50 data

[0144] Example compounds <![CDATA[PKa (IC 50 ,nM)]]> Example compounds <![CDATA[PKa (IC 50 ,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 results of the PKa enzyme activity test showed that the introduction of benzyl groups not only improved the compound's excellent anticoagulant activity against FXIa, but also achieved high selectivity for PKa. Compared with Comparative Example 1 (asundexian), the selectivity of compound (S)-II-4 for FXIa / PKa reached 156 times.

[0145] Test Example 3: Activated Partial Thromboplastin Time (APTT) Determination of the Compounds of the Invention

[0146] The following method is used to determine the in vitro anticoagulant effect of the compound of the present invention in human plasma. This method uses the APTT kit (Cat. No.: Y115) of Sunbio Company for testing, and the human plasma is the quality control freeze-dried plasma (Sunbio Company).

[0147] Experimental method: Add 1 mL of high-purity water to the quality control freeze-dried plasma to dissolve it and shake it gently to mix. The test compound was dissolved with DMSO, and the test compound was diluted two-fold with DMSO to prepare a series of solutions. First, preheat the calcium chloride solution and APTT reagent at 37°C. Then take 20μL of the plasma to be tested in a measuring cup, add the diluted test compound, and then add 20μL of preheated APTT reagent, and incubate at 37°C for 5 min. Place the measuring cup in the measuring channel of the semi-automatic coagulation instrument, and then add 20μL of preheated calcium chloride solution, measure immediately, and record the coagulation time. The recorded coagulation time was curve fitted using GraphPad Prism7 software to calculate the EC 1.5x , which is the concentration of the compound corresponding to 1.5 times the APTT of the blank control. The test results are shown in Table 3.

[0148] Table 3. EC of the compounds of the present invention on the anticoagulant effect of human plasma in vitro 1.5x data

[0149] Example compounds <![CDATA[EC 1.5x (μM)]]> Example compounds <![CDATA[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 above in vitro anticoagulant activity test results show that the tested compounds have moderate to excellent in vitro anticoagulant activity, among which compounds (S)-I-30 and (S)-II-4 are better than comparative example 1 (asundexian) and have better anticoagulant activity.

[0150] In summary, the present invention provides a novel compound that can be used as a small molecule inhibitor of FXIa, which can effectively enhance the anticoagulant effect. In addition, the compound of the present invention can be used to effectively treat and / or prevent cardiovascular and cerebrovascular diseases and thrombotic symptoms.

Claims

1. A compound and a pharmaceutically acceptable salt thereof, characterized in that: It is any of the following structures 2. A pharmaceutical composition, characterized in that: A preparation comprising the compound according to claim 1 and a pharmaceutically acceptable salt thereof, and 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: Factor XIa-mediated diseases are cardiovascular and cerebrovascular diseases, such as 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.

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