A kind of heterocyclic amide derivative and its preparation method and use

Abstract

The present invention provides a heterocyclic amide derivative and a preparation method and use thereof, belonging to the field of chemical medicine. The heterocyclic amide derivative is a compound shown in formula I, or a salt, stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof. The heterocyclic amide derivative of the present invention can be used as a small molecule inhibitor of FXIa, and the compound has a higher activity compared with a fluorine-free compound by introducing a fluorine atom, 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.

Description

Technical Field

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

[0002] Thrombotic diseases are diseases caused by two pathological mechanisms: thrombosis and thromboembolism. There are more than 10 million patients with thrombotic diseases worldwide, and about 3% of the population in my country will develop thrombotic diseases to varying degrees each year. Thrombosis can increase the risk of cardiovascular events in patients with hypertension, hyperlipidemia and diabetes, and increase mortality. At present, the main drugs used in clinical treatment of thrombotic diseases are anticoagulants and antiplatelet drugs, but they cannot distinguish between pathological coagulation and physiological coagulation, and can cause serious bleeding complications (bleeding) while treating thrombosis, limiting their clinical application. Therefore, new anticoagulants are urgently needed.

[0003] Factor XI (FXI) is a key protease in the intrinsic coagulation pathway. After activation, factor XI becomes factor XIa (FXIa), which plays a major role in the amplification stage of the coagulation cascade. Studies have shown that mice with FXI gene silencing have a protective effect against thrombosis, but do not increase bleeding time. Patients with congenital FXI deficiency (hemophilia C) do not bleed spontaneously and do not show symptoms in adulthood. Only some patients may have a mild or moderate bleeding tendency after surgery or trauma. Epidemiological studies have shown that excessive concentrations of FXI in the blood are a risk factor for thrombosis, low concentrations of FXI have a protective effect against thrombosis, and patients with congenital FXI deficiency are less likely to develop ischemic stroke and venous thromboembolism. Animal experiments have shown that antibodies targeting FXI or FXIa and direct FXIa inhibitors have anti-thrombotic effects, but have little effect on normal hemostasis. Phase II clinical trials have shown that treatment with the antisense oligonucleotide IONIS-416858 targeting FXI can reduce the incidence of venous thromboembolism in patients undergoing elective total knee replacement, which is comparable to enoxaparin, but with a lower risk of bleeding. Therefore, genetics, epidemiology, and preclinical and clinical studies have confirmed that FXIa is a potential anticoagulant drug target with a lower 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 low oral bioavailability 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. Summary of the invention

[0005] The purpose of the present invention is to provide a heterocyclic amide derivative and a preparation method and use thereof.

[0006] The present invention provides a compound of formula I, or a salt, stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof:

[0007]

[0008] in,

[0009] n is the number of substituents R1 on the benzene ring, which is an integer from 0 to 5;

[0010] Each R1 is independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, mercapto, ester, cyano, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1 to 4;

[0011] X is selected from CR3 or N;

[0012] R3 is selected from hydrogen, C1-C8 alkyl, halogen, 3-8 membered cycloalkyl, -OR4;

[0013] R4 is selected from substituted or unsubstituted C1-C8 alkyl, 3-8 membered cycloalkyl;

[0014] Ring A is selected from a 5- to 10-membered aryl group and a 5- to 10-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1 to 2;

[0015] m is the number of substituents R2 on ring A, which is an integer from 0 to 5;

[0016] Each R2 is independently selected from substituted or unsubstituted C1-C8 alkyl, halogen, cyano, -C(O)R5, -S(O)(O)R5, -OR 5’ 、-NR6C(O)R7、5-10 membered aryl;

[0017] R5 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, -N(H)R8, -NR9R 10 ;

[0018] R 5’ Selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, -N(H)R8;

[0019] R6 is selected from hydrogen, C1-C8 alkyl;

[0020] R7 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, -N(H)R8;

[0021] R8 is selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, mercapto, ester, cyano, 3-8 membered cycloalkyl;

[0022] R9, R 10 Each is independently selected from C1 to C8 alkyl;

[0023] The substituent of the unsaturated heterocyclic group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0024] The substituent of the alkyl group is selected from C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0025] The substituent of the cycloalkyl group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0026] Further,

[0027] n is 0, 1 or 2;

[0028] Each R1 is independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, the heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 3-4;

[0029] X is selected from CR3 or N;

[0030] R3 is selected from hydrogen, C1-C4 alkyl, halogen, 3-6 membered cycloalkyl, -OR4;

[0031] R4 is selected from substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl;

[0032] Ring A is selected from phenyl, 5-10 membered unsaturated heterocyclic group, the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1-2;

[0033] m is 0, 1 or 2;

[0034] Each R2 is independently selected from substituted or unsubstituted C1-C4 alkyl, halogen, cyano, -C(O)R5, -S(O)(O)R5, -OR 5’ , -NR6C(O)R7, phenyl;

[0035] R5 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, -N(H)R8, -NR9R 10 ;

[0036] R 5’ Selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, -N(H)R8;

[0037] R6 is selected from hydrogen, C1-C4 alkyl;

[0038] R7 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -N(H)R8;

[0039] R8 is selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, mercapto, ester, cyano, 3-6 membered cycloalkyl;

[0040] R9, R 10 are independently selected from C1 to C4 alkyl;

[0041] The substituent of the unsaturated heterocyclic group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0042] The substituent of the alkyl group is selected from C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0043] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0044] Further,

[0045] n is 0, 1 or 2;

[0046] Each R1 is independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;

[0047] X is selected from CR3 or N;

[0048] R3 is selected from hydrogen, C1-C4 alkyl, halogen, 3-6 membered cycloalkyl, -OR4;

[0049] R4 is selected from substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl;

[0050] Ring A is selected from phenyl, indazolyl, indolyl, quinoxalinyl, thienyl, isoxazolyl, thiazolyl, pyrazolyl, dihydrobenzimidazolyl;

[0051] m is 0, 1 or 2;

[0052] Each R2 is independently selected from substituted or unsubstituted C1-C4 alkyl, halogen, cyano, -C(O)R5, -S(O)(O)R5, -OR 5’ , -NR6C(O)R7, phenyl;

[0053] R5 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, -N(H)R8, -NR9R 10 ;

[0054] R 5’ Selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, -N(H)R8;

[0055] R6 is selected from hydrogen, C1-C4 alkyl;

[0056] R7 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -N(H)R8;

[0057] R8 is selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, mercapto, ester, cyano, 3-6 membered cycloalkyl;

[0058] R9, R 10 are independently selected from C1 to C4 alkyl;

[0059] The substituents of the triazolyl and tetrazolyl groups are selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0060] The substituent of the alkyl group is selected from C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0061] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0062] Furthermore, the compound is represented by Formula II:

[0063]

[0064] in,

[0065] R 1a , R 1b are independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1 to 4;

[0066] The substituent of the unsaturated heterocyclic group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0067] The substituent of the alkyl group is selected from C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0068] The substituent of the cycloalkyl group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0069] X, A ring, m and R2 are as described above;

[0070] Preferably,

[0071] R 1a , R 1b are independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, the heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 3-4;

[0072] The substituent of the unsaturated heterocyclic group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0073] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0074] More preferably,

[0075] R 1a , R 1bEach of the following is independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;

[0076] The substituents of the triazolyl and tetrazolyl groups are selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0077] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0078] Furthermore, the compound is represented by formula III:

[0079]

[0080] in,

[0081] R 1b Independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1 to 4;

[0082] The substituent of the unsaturated heterocyclic group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0083] The substituent of the alkyl group is selected from C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0084] The substituent of the cycloalkyl group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0085] X, A ring, m and R2 are as described above;

[0086] Preferably,

[0087] R 1b Independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 3-4;

[0088] The substituent of the unsaturated heterocyclic group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0089] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0090] More preferably,

[0091] R 1b independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;

[0092] The substituents of the triazolyl and tetrazolyl groups are selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0093] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0094] Furthermore, the compound is represented by formula IIIa:

[0095]

[0096] in,

[0097] R 1b Independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1 to 4;

[0098] The substituent of the unsaturated heterocyclic group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0099] The substituent of the alkyl group is selected from C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0100] The substituent of the cycloalkyl group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0101] Ring A, m and R2 are as described above;

[0102] Preferably,

[0103] R 1b Independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 3-4;

[0104] The substituent of the unsaturated heterocyclic group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0105] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0106] More preferably,

[0107] R 1b independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;

[0108] The substituents of the triazolyl and tetrazolyl groups are selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0109] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0110] Furthermore, the compound is represented by formula IIIb:

[0111]

[0112] in,

[0113] R 1b Independently selected from substituted or unsubstituted C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, mercapto, ester, cyano, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, O or S, and the number of heteroatoms is 1 to 4;

[0114] The substituent of the unsaturated heterocyclic group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0115] The substituent of the alkyl group is selected from C1-C8 alkoxy, halogen, hydroxyl, amino, carboxyl, and nitro;

[0116] The substituent of the cycloalkyl group is selected from C1-C8 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0117] Ring A, m and R2 are as described above;

[0118] Preferably,

[0119] R 1bIndependently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6-membered cycloalkyl, substituted or unsubstituted 5-membered unsaturated heterocyclic group, wherein the heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 3-4;

[0120] The substituent of the unsaturated heterocyclic group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0121] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0122] More preferably,

[0123] R 1b independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, amino, carboxyl, nitro, cyano, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;

[0124] The substituents of the triazolyl and tetrazolyl groups are selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano;

[0125] The substituent of the cycloalkyl group is selected from C1-C4 alkyl, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, nitro, and cyano.

[0126] Furthermore, the compound is one of the following compounds:

[0127]

[0128]

[0129]

[0130] The present invention also provides a method for preparing the aforementioned compound, which comprises the following steps:

[0131]

[0132] The compound of formula AI-A and the compound of formula AI-B or its hydrochloride are subjected to condensation reaction under alkaline conditions and hydrolyzed to obtain the compound of formula AI;

[0133] in,

[0134] R1, n, X, A ring, R2 and m are as defined above.

[0135] The present invention also provides the use of the aforementioned compounds, or their salts, stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, hydrates, solvates, prodrugs or mixtures thereof in the preparation of coagulation factor FXIa inhibitors and / or plasma bradykinin kinase PKA inhibitors.

[0136] The present invention also provides the use of the aforementioned compound, or its salt, stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or mixture thereof in the preparation of a drug for preventing and / or treating diseases mediated by factor XIa, preventing and / or treating cardiovascular and cerebrovascular diseases;

[0137] Preferably, the disease is a thromboembolic disease;

[0138] 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.

[0139] The present invention also provides a drug, which is a preparation prepared with the aforementioned compound, or its salt, stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof as an active ingredient, and pharmaceutically acceptable excipients or auxiliary ingredients.

[0140] The present invention also provides a pharmaceutical composition, which comprises the aforementioned compound, or its salt, stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, hydrate, solvate, prodrug or a mixture thereof and a pharmaceutically acceptable carrier, diluent and excipient.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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 are 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0156] The term "alkyl" refers to a saturated aliphatic hydrocarbon 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 attachment point. The substituent is preferably one or more of the following groups independently selected from C1 to C8 alkoxy, halogen, hydroxy, amino, carboxyl, and nitro.

[0157] 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.

[0158] 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.

[0159] 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 aromatic groups.

[0160] 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.

[0161] The present invention designs a new small molecule inhibitor. The introduction of fluorine atoms has a significant improvement on the anticoagulant effect and oral absorption of the entire compound. Compared with compounds without the introduction of fluorine atoms, the compounds of the present invention have higher activity. In particular, the compounds of the present invention exhibit excellent anticoagulant activity and have better pharmacokinetic properties, and can be used to effectively treat and / or prevent cardiovascular and cerebrovascular diseases and thrombotic symptoms.

[0162] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0163] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. 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 contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0164] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0165] The melting point was determined using a RY-1 melting point apparatus from Tianjin Analytical Instrument Factory;

[0166] 1 H-NMR and 13 C-NMR was measured using a Bruker AM-600MHz / 400MHz nuclear magnetic resonance spectrometer, with TMS as the internal standard;

[0167] MS was measured using a thermo LC / MS mass spectrometer.

[0168] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.2mm. The thin layer chromatography separation and purification product uses a specification of 0.4mm-0.5mm.

[0169] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0170] Average enzyme inhibition rate and IC 50 The values ​​were determined using a Varioskan LUX multifunctional microplate reader (Thermo Fisher Scientific, USA).

[0171] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG. Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology, Anaiji, Bid Pharmaceuticals, Darui Chemicals and other companies.

[0172] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0173] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L. Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about L.

[0174] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0175] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0176] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of the eluent for column chromatography used for purifying the compound and the developing solvent system for thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / 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 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.

[0177] The preparation method of the compound of the present invention comprises the following steps:

[0178]

[0179] The first step is to react the compound of formula AI-1 with the compound of formula AI-2 in an organic solvent under alkaline conditions to undergo a nucleophilic substitution reaction to obtain the compound of formula AI-3;

[0180] The second step is to hydrolyze the compound of formula AI-3 under acidic conditions to obtain the compound of formula AI-A;

[0181] The third step is to carry out a condensation reaction of the compound of formula AI-A and the compound of formula AI-B or its hydrochloride under alkaline conditions, and optionally hydrolyze under alkaline conditions to obtain the compound of formula AI;

[0182] 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.

[0183] 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.

[0184] The condensing agent includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-NN,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7 -benzotriazole oxide)-N,N,N',N-tetramethyluronium hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphine hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0185] 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 NN-dimethylformamide.

[0186] Example 1. Preparation of 4-(2-(4-(5-chloro-2-cyanobenzene)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamido)benzoic acid (Compound 1)

[0187]

[0188]

[0189] Step a: Preparation of (2,5-dimethoxypyridin-4-yl)boronic acid (1b)

[0190]

[0191] 2,5-Dimethoxypyridine (4.0 g, 28.8 mmol) was added to 50 mL of tetrahydrofuran, and lithium diisopropylamide (16.2 mL, 34.5 mmol) was slowly added dropwise at -78 °C, and the reaction was stirred for 2-4 hours, and triisopropyl borate (6.5 g, 34.5 mmol) was slowly added dropwise, and the reaction was stirred for 2-3 hours, and then slowly thawed to room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, stirred for 3 hours, and tetrahydrofuran was removed in vacuo. The aqueous phase was acidified with hydrochloric acid (2N), and a precipitate was usually produced, which was filtered and the filter cake was dried to obtain the title product 1b (3.9 g, yield: 74%).

[0192] Step b: Preparation of 4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile (1c)

[0193]

[0194] (2,5-dimethoxypyridin-4-yl)boronic acid 1b (4.2 g, 19.4 mmol) was added to a mixed solvent of 1,4-dioxane and water (100 mL, v / v, 4:1), followed by 2-bromo-4-chlorobenzonitrile (3.9 g, 21.3 mmol) and potassium carbonate (6.2 g, 58.2 mmol), replaced with nitrogen 3-4 times, and finally [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.6 mg, 1.9 mmol) was added. The reaction solution was heated to 80°C under nitrogen protection and stirred for 10 h. After TLC monitoring showed that the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, the solvent was removed in vacuo, 50 mL of water was added to the obtained residue, and the mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phases were washed 3-4 times with water (50 mL) and saturated sodium chloride solution (50 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA=40:1, v / v) to obtain the title product 1c as an off-white solid (3.3 g, yield: 62%).

[0195] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.98(d,J=8.2Hz,1H),7.70(d,J=8.5Hz,2H),6.86(s,1H),3.83(s,3H),3.78(s,3H).

[0196] Step c: Preparation of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile (1d)

[0197]

[0198] 1c (3.1 g, 11.3 mmol) was added to 10 mL of acetonitrile, and iodotrimethylsilane (3.4 g, 16.9 mmol) was added, and then distilled water (101.7 mg, 5.6 mmol) was added. After the addition was completed, the mixture was heated to 60°C and stirred for 10 hours. The reaction solution was poured into 20 mL of ice water, stirred for half an hour, filtered, and the filter cake was rinsed with distilled water and dried to obtain the title product 1d (2.6 g, yield: 87%). The mixture was directly used in the next step without purification.

[0199] 1H NMR (400MHz, DMSO-d6) δ7.96(dd,J=8.3,1.8Hz,1H),7.73–7.66(m,2H),7.27(s,1H),6.41(d,J=1.8Hz,1H),3.62(s,3H).

[0200] Step d: Preparation of ethyl 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetate (1e)

[0201]

[0202] 1d (3.0 g, 11.5 mmol) and cesium carbonate (5.6 g, 17.3 mmol) were added to N, N-dimethylformamide (15 mL), and ethyl bromofluoroacetate (2.6 g, 13.8 mmol) was slowly added under ice-water cooling, and the reaction was stirred for about 30 minutes. The reaction solution was poured into 40 mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure and purified to obtain the title product 1e (0.86 g, yield: 20%).

[0203] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.3Hz,1H),7.76(d,J=12Hz,1H),7.60(s,1H),6.68(s, 1H), 6.62 (s, 1H), 6.56 (s, 1H), 4.22 (q, J = 7.1Hz, 2H), 3.64 (s, 3H), 1.21 (t, J = 7.1Hz, 3H).

[0204] Step e: Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetic acid (1f)

[0205]

[0206] 1e (1.1 g, 3.4 mmol) was added to 5 mL of methanol, and 1 M lithium hydroxide (4.7 mL, 4.7 mmol) was slowly added under ice-water cooling, and the reaction was stirred for about 2 hours. Methanol was removed in vacuo, and the aqueous phase was acidified with hydrochloric acid (2 M), and a precipitate was produced, which was filtered and the filter cake was dried to obtain the title product 1f (0.9 g, yield: 88%).

[0207] 1H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.3Hz,1H),7.77(s,1H),7.73(dd,J=8.3,2.2Hz,1H),7.53(s,1H),6.61(s,1H),6.54(d,J=47.2Hz,1H),3.63(s,3H).

[0208] Steps f and g: Preparation of 4-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)benzoic acid (1)

[0209]

[0210] 1f (180 mg, 0.54 mmol), tert-butyl 4-aminobenzoate (124 mg, 0.64 mmol), HATU (305 mg, 0.80 mmol) were added to dichloromethane (2 mL), and DIPEA (103 mg, 0.80 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The dichloromethane was removed in vacuo, and 30 mL of ethyl acetate was added to the residue, which was washed with 0.5 M HCl solution for 3-4 times, then washed with 0.5 M NaHCO3 solution for 3-4 times, and finally washed with saturated saline solution. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (DCM: MeOH = 150: 1 to 50: 1, v / v) to obtain an intermediate (150 mg, yield: 55%). The intermediate (200 mg, 0.39 mmol) was added to 5 mL of ethyl acetate, and freshly prepared HCl gas was introduced at -5°C. After the reaction of the raw material was completed as monitored by TLC, solids were precipitated during the slow rotary evaporation, which was filtered and the excess HCl gas was removed by an oil pump to obtain the title product 1 as a white solid (47 mg, yield: 26%).

[0211] HPLC purity: 98.5%; 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),10.72(s,1H),7.99(d,J=8.2Hz,1H),7.93–7.90(m,2H),7.87–7.83(m, 2H),7.77(d,J=1.9Hz,1H),7.75–7.72(m,1H),7.56(s,1H),6.82(d,J=47.2Hz,1H),6.62(s,1H),3.64(s,3H); 13C NMR (151MHz, DMSO-d6) δ167.34, 163.35 (d, J = 27.1Hz), 158.97, 145.11, 142.44, 140.39, 139.90, 138.75, 135.08, 130. 69,130.47,130.23,126.64,122.43,120.19,118.39,117.30,110.76,92.95(d,J=219.1Hz),57.06; HRMS(m / z):[M+H] + Calculate for C 22 H 16 ClFN3O5 + 456.0762, found 456.0765.

[0212] Example 2, Preparation of 4-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzene (Compound 2)

[0213]

[0214] The synthetic method of Example 1 was adopted to replace the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluorobenzamide to obtain the title product 2 as a light yellow solid (56 mg, yield: 40%).

[0215] HPLC purity: 99.5%; 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.99(d,J=8.3Hz,1H),7.77–7.75(m,1H),7.75–7.66(m,3H ),7.60–7.57(m,1H),7.56(s,1H),7.55(s,2H),6.80(d,J=47.2Hz,1H),6.62(s,1H),3.65(s,3H); 13C NMR(151MHz,DMSO-d6)δ165.05,163.58(d,J=27.2Hz),159.04(d,J=21.3Hz),14 5.17,142.12(d,J=11.4Hz),140.40,139.91,138.74,135.08,131.41,131.39,13 0.48,130.23,122.46,119.05(d,J=13.8Hz),118.63,117.30,116.14(d,J=3.1Hz ),110.78,107.61(d,J=28.7Hz),93.18(d,J=219.6Hz),57.07; HRMS(m / z):[M+H] + Calculate for C 22 H 16 ClF2N4O4 + 473.0828 found 473.0822.

[0216] Example 3, Preparation of 4-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluoro-N-methylbenzamide (Compound 3)

[0217]

[0218] The title product 3 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 4-amino-2-fluoro-N-methylbenzamide.

[0219] HPLC purity: 97.7%; 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.10–8.08(m,1H),7.99(d,J=8.2Hz,1H),7.76–7.72(m,3H),7.70–7.66(m,1H),7.63 (d,J=8.3Hz,1H),7.60–7.57(m,1H),7.56(s,1H),6.79(d,J=47.2Hz,1H),6.61(s,1H),3.64(s,3H),2.75(d,J=4.6Hz,3H); 13C NMR (151MHz, DMSO-d6) δ163.99, 163.59 (d, J = 26.7Hz), 160.49, 158.92 (d, J = 21 .9Hz),145.21,141.89(d,J=11.2Hz),140.42,139.91,138.77,135.11,131.17, 130.48,130.26,122.45,119.31(d,J=14.3Hz),118.67,117.31,116.23,110.7 7,107.63(d,J=28.4Hz),93.18(d,J=283.5Hz),57.07,26.78; HRMS(m / z):[M+H] + Calculate for C 23 H 18 ClF2N4O4 + 487.0984 found 487.0973.

[0220] Example 4. Preparation of 4-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-N-ethyl-2-fluorobenzamide (Compound 4)

[0221]

[0222] The synthetic method of Example 1 was adopted to prepare the title product 4 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-N-ethyl-2-fluorobenzamide.

[0223] HPLC purity: 95.1%; 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.17–8.12(m,1H),7.99(d,J=8.3Hz,1H),7.77–7.71(m,3H),7.70–7.64(m,1H),7.63–7 .58(m,2H),7.57–7.56(m,1H),6.80(d,J=47.3Hz,1H),6.62(s,1H),3.65(s,3H),3.24(q,J=7.2Hz,2H),1.09(t,J=7.2Hz,3H); 13C NMR(151MHz,DMSO-d6)δ163.40(d,J=21.8Hz),163.29,160.43,158.88(d, J=26.7Hz),145.17,141.83,140.39,139.93,138.75,135.10,131.08,130 .49,130.24,122.47,119.65,118.65,117.30,116.17,110.79,107.61(d, J=27.9Hz),94.34(d,J=174.0Hz),57.06,34.51,15.15; HRMS(m / z):[M+H] + Calculate for C 24 H 20 ClF2N4O4 + 501.1141 found 501.1136.

[0224] Example 5. Preparation of ethyl 5-(2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-1H-indole-2-carboxylate (Compound 5)

[0225]

[0226] The title product 5 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 5-amino-1H-indole-2-carboxylic acid ethyl ester.

[0227] HPLC purity: 98.7%; 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),10.45(s,1H),8.05–8.03(m,1H),7.99( d,J=8.3Hz,1H),7.76(d,J=2.1Hz,1H),7.75–7.72(m,1H),7.53–7.45(m,2H), 7.41(d,J=8.9Hz,1H),7.14–7.12(m,1H),6.89(d,J=47.2Hz,1H),6.63(s,1H) ,4.32(q,J=7.1Hz,2H),3.64(s,3H),1.32(t,J=7.1Hz,3H).HRMS(m / z):[M+H] + calcdfor C 26 H 21 ClFN4O5 + 523.1184 found 523.1177.

[0228] Example 6. Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(2-methyl-2H-indazol-5-yl)acetamide (Compound 6)

[0229]

[0230] The synthetic method of Example 1 was adopted to prepare the title product 6 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 2-methyl-2H-indazole-5-amine.

[0231] HPLC purity: 96.6%; 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.28(s,1H),8.12(d,J=2.0Hz,1H),7.99(d,J=8.3Hz,1H),7.76–7.72(m,2H),7.6 0–7.53(m,1H),7.51(s,1H),7.42(dd,J=9.2,2.0Hz,1H),6.88(d,J=47.2Hz,1H),6.63(s,1H),4.13(s,3H),3.64(s,3H); 13 C NMR (151MHz, DMSO-d6) δ162.63 (d, J = 27.0Hz), 159.00, 146.34, 144.94, 140.35, 139.94, 138.73, 135.09, 131.45, 130.48, 130.21, 125.09,122.45,122.00,121.60,117.69,117.54,117.30,110.79,110.77,92.29(d,J=217.3Hz),57.04,40.46; HRMS(m / z):[M+H] + Calculate for C 23 H 18 ClFN5O3 + 466.1082 found 466.1087.

[0232] Example 7, Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(1-methyl-1H-indazol-5-yl)acetamide (Compound 7)

[0233]

[0234] The title product 7 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 1-methyl-1H-indazole-5-amine.

[0235] HPLC purity: 96.6%; 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.13(s,1H),8.01(s,1H),7.99(d,J=8.3Hz,1H),7.76–7.72 (m,2H),7.61(s,2H),7.52(s,1H),6.88(d,J=47.3Hz,1H),6.63(s,1H),4.01(s,3H),3.64(s,3H); 13 C NMR (151MHz, DMSO-d6) δ162.74 (d, J = 27.0Hz), 159.02, 144.97, 140.36, 139.92, 138.74, 137.60, 135.09, 132.80, 131.29, 130.47, 130.22,123.64,122.46,121.70,117.83,117.30,112.22,110.77,110.17,92.48(d,J=218.1Hz),57.04,35.88.HRMS(m / z):[M+H] + Calculate for C 23 H 18 ClFN5O3 + 466.1082 found 466.1081

[0236] Example 8. Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(quinoxalin-6-yl)acetamide (Compound 8)

[0237]

[0238] The title product 8 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with quinoxaline-6-amine.

[0239] HPLC purity: 98.7%; 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),8.89(d,J=1.9Hz,1H),8.84(d,J=1.9Hz ,1H),8.57(d,J=2.3Hz,1H),8.16(dd,J=9.1,2.4Hz,1H),8.08(d,J=9.1Hz,1H) ,7.99(d,J=8.3Hz,1H),7.76(d,J=2.1Hz,1H),7.73(dd,J=8.3,2.2Hz,1H),7. 60(s,1H),6.87(d,J=47.3Hz,1H),6.63(s,1H),3.66(s,3H).HRMS(m / z):[M+H] + calcdfor C 23 H 16 ClFN5O3 + 464.0925 found 464.0928.

[0240] Example 9. Preparation of N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamide (Compound 9)

[0241]

[0242] The title product 9 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 3-(tert-butyl)-1-phenyl-1H-pyrazole-5-amine.

[0243] HPLC purity: 98.7%; 1 H NMR(400MHz, DMSO-d6)δ10.53(s,1H),7.99(d,J=8.9Hz,1H),7.75–7.72(m,2H),7.60–7.56(m,2H),7.48–7.44(m, 2H),7.39(s,1H),7.36–7.31(m,1H),6.78(d,J=47.2Hz,1H),6.65(s,1H),6.34(s,1H),3.57(s,3H),1.28(s,9H); 13C NMR (151MHz, DMSO-d6) δ163.73 (d, J = 27.9Hz), 161.33, 158.90, 145.11, 140.36, 139.87, 139.23, 138.73, 135.12, 134.80, 130.46, 130 .25,129.53,127.38,123.61,122.50,117.92,117.26,110.77,100.57,92.72(d,J=217.9Hz),56.95,32.58,30.61; HRMS(m / z):[M+H] + Calculate for C 28 H 26 ClFN5O3 + 534.1708 found 534.1720.

[0244] Example 10. Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(4-(trifluoromethyl)phenyl)acetamide (Compound 10)

[0245]

[0246] The title product 10 was prepared by adopting the synthesis method of Example 1, except that the raw material compound tert-butyl 4-aminobenzoate was replaced with 4-(trifluoromethyl)aniline.

[0247] HPLC purity: 98.9%; 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),7.99(d,J=8.3Hz,1H),7.95(d,J=8.4Hz,2H),7.77–7.73 (m,2H),7.71(d,J=8.4Hz,2H),7.56(s,1H),6.82(d,J=47.3Hz,1H),6.62(s,1H),3.65(s,3H); 13C NMR (151MHz, DMSO-d6) δ163.54(d,J=26.9Hz),158.98,145.14,142.66,140.39,139.91,138.73,135.08,130.48,130.22,126.44(q,J=3.8H z), 124.76 (q, J = 31.9Hz), 124.75 (q, J = 271.5Hz), 122.46, 120.82, 118.51, 117.29, 110.79, 93.04 (d, J = 219.3Hz), 57.06; HRMS (m / z): [M+H] + Calculate for C 22 H 15 ClF4N3O3 + 480.0738, found 480.0737.

[0248] Example 11, Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-cyano-4-(trifluoromethyl)phenyl)-2-fluoroacetamide (Compound 11)

[0249]

[0250] The synthetic method of Example 1 was adopted, and the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 5-amino-2-(trifluoromethyl)benzonitrile to obtain the title product 11.

[0251] HPLC purity: 98.9%; 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.43(d,J=2.0Hz,1H),8.23(dd,J=8.6,2.0Hz,1H),8.14(d,J=8.5Hz,1 H),7.99(d,J=8.3Hz,1H),7.76–7.72(m,2H),7.63(s,1H),6.80(d,J=47.5Hz,1H),6.62(s,1H),3.66(s,3H); 13C NMR(151MHz,DMSO-d6)δ164.38(d,J=27.7Hz),158.99,145.35,140.47,139 .88,138.74,137.00,135.08,132.07(q,J=32.1Hz),130.48,130.24,123.79 ,123.56,122.89(q,J=271.5Hz),122.43,119.08,118.08(d,J=5.3Hz),117. 28,116.14,110.78,103.08,93.51(d,J=220.3Hz),57.10; HRMS(m / z):[M+H] + Calculate for C 23 H 14 ClF4N4O3 + 505.0690 found505.0694.

[0252] Example 12, Preparation of N-(3-(tert-butyl)-1H-pyrazol-5-yl)-2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamide (Compound 12)

[0253]

[0254] The title product 12 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 3-(tert-butyl)-1H-pyrazole-5-amine.

[0255] HPLC purity: 99.0%; 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.88(s,1H),8.04–7.94(m,1H),7.73(d,J=7.3Hz,2H ),7.44(s,1H),6.90(d,J=46.7Hz,1H),6.61(s,1H),6.29(s,1H),3.63(s,3H),1.24(s,9H); 13C NMR (151MHz, DMSO-d6) δ161.68 (d, J = 28.4Hz), 158.85, 144.79, 140.27, 139.96, 138.71, 135.09, 130.47, 130.20, 12 2.26,117.27,116.97,110.79,110.10,93.50,92.67(d,J=247.5Hz),90.42,57.03,31.19,30.37; HRMS(m / z):[M+H] + Calculate for C 22 H 22 ClFN5O3 + 458.1395, found 458.1400.

[0256] Example 13. Preparation of N-(3-(tert-butyl)isoxazol-5-yl)-2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamide (Compound 13)

[0257]

[0258] The title product 13 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 3-(tert-butyl)isoxazole-5-amine.

[0259] HPLC purity: 87.6%; 1 H NMR(400MHz,DMSO-d6)δ11.48(s,1H),7.99(d,J=8.9Hz,1H),7.78–7.68(m,2H),7.52 (s,1H),6.78(d,J=47.0Hz,1H),6.60(s,1H),6.56(s,1H),3.64(s,3H),1.29(s,9H); 13 C NMR(151MHz,DMSO-d6)δ163.23(d,J=28.4Hz),158.88,157.45,145.09,140.31,139.91,138.72,135.11,130.46,13 0.22,122.36,118.51,117.27,110.79,94.05,92.61(d,J=217.5Hz),91.66,57.05,32.54,28.79; HRMS(m / z):[M+H] + Calculate for C 22 H 21 ClFN4O4 +459.1235, found 459.1244.

[0260] Example 14. Preparation of N-(4-(tert-butyl)thiazol-2-yl)-2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamide (Compound 14)

[0261]

[0262] The title product 14 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 4-(tert-butyl)thiazole-2-amine.

[0263] HPLC purity: 97.5%; 1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.00–7.97(m,1H),7.76–7.71(m,2H),7.51(s,1H),6. 85(d,J=48.0Hz,1H),6.82(s,1H),6.60(s,1H),3.64(s,3H),1.26(s,9H); HRMS(m / z):[M+H] + Calculate for C 22 H 21 ClFN4O3S + 475.1007, found 475.1010.

[0264] Example 15. Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)yl)-2-fluoro-N-(4-(methylsulfonyl)phenyl)acetamide (Compound 15)

[0265]

[0266] The synthetic method of Example 1 was adopted to prepare the title product 15 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 3-(tert-butyl)-1-phenyl-1H-pyrazole-5-amine.

[0267] HPLC purity: 99.6%; 1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.01–7.96(m,3H),7.91–7.87(m,2H),7.76–7.76(m,1H), 7.72–7.75(m,1H),7.57(s,1H),6.81(d,J=47.3Hz,1H),6.62(s,1H),3.65(s,3H),3.17(s,3H); 13 CNMR(101MHz,DMSO-d6)δ163.66(d,J=27.0Hz),158.96,145.15,142.95,140.38,139.88,138.72,136.16,135.06,130 .45,130.21,128.49,122.44,120.71,118.58,117.27,110.75,93.13(d,J=219.1Hz),57.04,44.18; HRMS(m / z):[M+H] + Calculate for C 22 H 18 ClFN3O5S + 490.0639 found 490.0631

[0268] Example 16, Preparation of 2-(4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(3-methoxyphenyl)acetamide (Compound 16)

[0269]

[0270] The title product 16 was prepared by adopting the synthesis method of Example 1, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 3-methoxyaniline.

[0271] HPLC purity: 99.6%; 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),7.99(d,J=8.3Hz,1H),7.77–7.75(m,2H),7.51(s,1H),7.39(t,J=2.2Hz,1H),7.3 2–7.29(m,1H),7.24(t,J=8.1Hz,1H),6.82(d,J=47.2Hz,1H),6.72–6.69(m,1H),6.62(s,1H),3.72(s,3H),3.64(s,3H); 13C NMR(151MHz,DMSO-d6)δ162.90,162.72,159.88,158.95,144.99,140.34,139.94,139.52,138.73,135.08,130 .48,130.21,129.98,122.46,117.97,117.29,113.01,110.79,110.29,106.56,57.05,55.50; HRMS(m / z):[M+H] + Calculate for C 22 H 18 ClFN3O4 + 442.0970, found 442.0970.

[0272] Example 17, Preparation of 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)benzoic acid (Compound 17)

[0273]

[0274]

[0275] Step a: 1-Azido-2-bromo-4-chlorobenzene (17b)

[0276]

[0277] At 0°C, to a solution of 2-bromo-4-chloroaniline (20 g, 97 mmol) in acetonitrile (150 mL) was added isoamyl nitrite (17 g, 145 mmol), followed by dropwise addition of trimethylsilyl azide (16.7 g, 145 mmol). After 10 minutes, the ice bath was removed, the reaction mixture was warmed to room temperature, stirred at room temperature for 3 hours, and the reaction was completed. Acetonitrile was removed in vacuo, water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified to obtain the title product 17b (18 g, yield: 80%).

[0278] 1 H NMR (600MHz, CDCl3) δ7.56 (d, J = 2.3Hz, 1H), 7.32 (dd, J = 8.6, 2.3Hz, 1H), 7.10 (d, J = 8.6Hz, 1H).

[0279] Step b: 1-(2-Bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (17c)

[0280]

[0281] 17b (17 g, 73 mmol) was added to 100 mL of toluene, and then trimethylethynylsilane (21.5 g, 219 mmol) was added dropwise. The reaction was carried out at 110°C for 12 hours. After the reaction was completed, the toluene was removed in vacuo, water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified to obtain the title product 17c (23 g, yield: 92%).

[0282] 1 H NMR (600MHz, CDCl3) δ7.82 (s, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.43–7.39 (m, 2H), 0.32 (s, 9H).

[0283] Step c: 1-(2-Bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazole (17d)

[0284]

[0285] 17c (10 g, 30 mmol) was added to 100 mL of acetonitrile, and NCS (48.5 g, 363 mmol) and KF (10.5 g, 182 mmol) were added at 25 °C, and the mixture was heated to 90 °C for 40 hours. The reaction solution was directly filtered, the filtrate was spin-dried, water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified to obtain the title product 17d (6 g, yield: 67%).

[0286] 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 7.78 (d, J = 1.3Hz, 1H), 7.50 (d, J = 1.3Hz, 2H).

[0287] Step d: 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dimethoxypyridine (17e)

[0288]

[0289] 17d (6.0 g, 5.0 mmol), 2,5-dimethoxy-4-pyridineboronic acid (4.5 g, 24.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.84 g, 1.0 mmol) and sodium carbonate (5.4 g, 51.2 mmol) were added to a 1,4-dioxane aqueous solution (60 mL, v / v, 4 / 1). After the addition was completed, the reaction solution was heated to 80°C under nitrogen protection and stirred for 10 hours. The reaction solution was naturally cooled to room temperature, the solvent was removed in vacuo, 50 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phases were washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified to obtain the title product 17e (5 g, yield: 69%).

[0290] 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.76(d,J=1.3Hz,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).

[0291] Step e: 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (17f)

[0292]

[0293] 17e (5 g, 14.2 mmol) was added to 20 mL of DMF, and pyridine hydrobromide (22.8 g, 142 mmol) was added. After the addition was completed, the mixture was heated to 110°C and stirred for 4 hours. The reaction solution was poured into 20 mL of ice water, stirred for half an hour, filtered, and the filter cake was washed with distilled water and dried to obtain the title product 17f (4.2 g, yield: 87%).

[0294] 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.60(s,1H),7.74(d,J=2.3Hz,1H),7.72(s,1H),7.65(d,J=2.2Hz,1H),6.96(s,1H),6.33(s,1H),3.27(s,3H).

[0295] Step f: 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetate (17 g)

[0296]

[0297] 17f (4.1 g, 12 mmol) and cesium carbonate (5.9 mg, 18 mmol) were added to 15 mL of DMF, and ethyl bromofluoroacetate (2.7 g, 15 mmol) was slowly added under ice-water cooling, and the reaction was stirred for about 30 minutes. The reaction solution was poured into 20 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water and saturated brine, dried over anhydrous Na2SO4, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain the title product 17g (1.6 g, yield: 30%).

[0298] 1 H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.80(d,J=2.2Hz,1H),7.78–7.76(m,2H),7.29(s,1H), 6.54(d,J=48Hz,1H),6.53(s,1H),4.21(q,J=7.1Hz,2H),3.31(s,3H),1.21(t,J=7.1Hz,3H).

[0299] Step g: 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetic acid (17h)

[0300]

[0301] 17g (1.5g, 3.4mmol) was added to 4mL methanol, 1M lithium hydroxide (0.5mL, 0.5mmol) was slowly added under ice-water cooling, and the reaction was stirred for about 2 hours. Methanol was removed in vacuo, and the aqueous phase was acidified with hydrochloric acid (2M). A precipitate was generated, which was filtered and the filter cake was dried to obtain the title product 17h (1.3g, yield: 92%).

[0302] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),7.79(d,J=2.2Hz,1H),7.77–7.75(m,2H),7.20(s,1H),6.53(s,1H),6.45(d,J=48Hz,1H),3.28(s,3H).

[0303] Step h: tert-Butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamido)benzoate (17i)

[0304]

[0305] 17h (100 mg, 0.24 mmol), tert-butyl 4-aminobenzoate (56 mg, 0.29 mmol), HATU (138 mg, 0.36 mmol) were added to 2 mL of dichloromethane, and N,N-diisopropylethylamine (47 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The dichloromethane was removed in vacuo, 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water and saturated NaCl solution, dried without Na2SO4, and purified by column chromatography to obtain the title product 17i (105 mg, yield: 73%).

[0306] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.74(s,1H),7.89–7.81(m,4H),7.80(dd,J=8.7,2.2Hz,1H ),7.77–7.73(m,2H),7.24(s,1H),6.72(d,J=47.3Hz,1H),6.55(s,1H),3.27(s,3H),1.52(s,9H).

[0307] Step i: 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H-yl)-2-fluoroacetylamino)benzoic acid (17)

[0308]

[0309] 17i (70 mg, 0.12 mmol) was added to 5 mL of ethyl acetate, and freshly prepared HCl gas was introduced to saturation, and the reaction was stirred for 5 hours. Usually, a precipitate was produced in the reaction solution, and the solid was filtered and dried to obtain the title product 17 (20 mg, yield: 31%).

[0310] HPLC purity: 99.1%; 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),10.66(s,1H),8.72(s,1H),7.91(d,J=8.8Hz,2H),7.82(d,J=8.8Hz,2H),7 .78(d,J=2.2Hz,1H),7.75(dd,J=5.4,3.1Hz,2H),7.23(s,1H),6.74(d,J=47.4Hz,1H),6.54(s,1H),3.27(s,3H);13 C NMR(151MHz,DMSO-d6)δ167.34,163.34(d,J=27.2Hz),159.08,145.14,142.42,140.39,135.15,134.09,134.02,132.02, 131.36,130.81,130.68,127.52,126.61,124.16,122.27,120.17,116.98,92.66(d,J=215.0Hz),56.47; HRMS(m / z):[M+H] + Calculate for C 23 H 17 Cl2FN5O5,532.0591; found,532.0582.

[0311] Example 18, Preparation of 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzene (Compound 18)

[0312]

[0313] The synthetic method of Example 17 was adopted to prepare the title product 18 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluorobenzamide.

[0314] HPLC purity: 99.1%; 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.73(s,1H),7.81–7.78(m,1H),7.76–7.74(m,2H),7.72–7.69(m,1H),7.68–7 .64(m,1H),7.57(dd,J=8.6,2.0Hz,1H),7.54(s,2H),7.24(s,1H),6.71(d,J=47.4Hz,1H),6.54(s,1H),3.27(s,3H); 13CNMR (151MHz, DMSO-d6) δ165.06 (d, J = 1.5Hz), 163.55 (d, J = 27.2Hz), 159.92 (d, J = 247. 5Hz),159.07,145.20,142.10(d,J=11.3Hz),140.40,135.14,134.07,134.03,132.03,1 31.40,131.37,130.80,127.52,124.18,122.29,119.02(d,J=13.9Hz),117.21,116.12 (d, J=2.8Hz), 107.58 (d, J=28.4Hz), 92.92 (d, J=220.6Hz), 56.49; HRMS (ESI) m / z: [M+H] + Calculate for C 23 H 17 Cl2F2N6O4,548.0578; found,548.0651.

[0315] Example 19, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluoro-N-methylbenzamide (19)

[0316]

[0317] The synthetic method of Example 17 was adopted to prepare the title product 19 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluoro-N-methylbenzamide.

[0318] HPLC purity: 99.3%; 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),8.73(s,1H),8.09(t,J=4.2Hz,1H),7.81–7.78(m,1H),7.76–7.74(m,2H),7.69(dd,J=13.2,1.9H z,1H),7.63(t,J=8.4Hz,1H),7.58–7.55(m,1H),7.24(s,1H),6.71(d,J=47.4Hz,1H),6.54(s,1H),3.27(s,3H),2.75(d,J=4.6Hz,3H); 13C NMR (151MHz, DMSO-d6) δ163.97 (d, J = 2.1Hz), 163.54 (d, J = 27.2Hz), 159.65 (d, J = 247.2Hz), 159.08,145.22,141.86(d,J=11.5Hz),140.41,135.15,134.09,134.02,132.02,131.36,131 .13(d,J=4.0Hz),130.81,127.51,124.16,122.27,119.27(d,J=14.1Hz),117.19,116.20(d ,J=3.0Hz),107.60(d,J=28.3Hz),92.92(d,J=218.8Hz),56.49,26.77; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 19 Cl2F2N6O4,563.0813; found,563.0804.

[0319] Example 20, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-N-ethyl-2-fluorobenzamide (20)

[0320]

[0321] The synthetic method of Example 17 was adopted to prepare the title product 20 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-N-ethyl-2-fluorobenzamide.

[0322] HPLC purity: 98.6%; 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.73(s,1H),8.16(s,1H),7.81–7.78(m,1H),7.77–7.73(m,2H),7.69(dd,J=13.3,1.8Hz,1H),7.61(t, J=8.2Hz,1H),7.59–7.55(m,1H),7.26(s,1H),6.73(d,J=47.4Hz,1H),6.54(s,1H),3.27(s,3H),3.24(q,J=7.2Hz,2H),1.09(t,J=7.2Hz,3H); 13C NMR(151MHz,DMSO-d6)δ163.53(d,J=27.8Hz),163.42,159.60(d,J=247.3Hz),159.09, 145.24,141.75(d,J=11.4Hz),140.41,135.15,134.11,133.99,131.99,131.33,131.02 (d,J=4.2Hz),130.84,127.52,124.14,122.20,119.60(d,J=14.2Hz),117.29,116.18, 107.63(d,J=28.1Hz),92.92(d,J=218.0Hz),56.51,34.54,15.11; HRMS(ESI)m / z:[M+H] + Calculate for C 25 H 21 Cl2F2N6O4,577.0969; found,577.0962.

[0323] Example 21, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-N,N-dimethyl-2-fluorobenzamide (21)

[0324]

[0325] The synthetic method of Example 17 was adopted to prepare the title product 21 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-N,N-dimethyl-2-fluorobenzamide.

[0326] HPLC purity: 98.7%; 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.73(s,1H),7.81–7.78(m,1H),7.76–7.72(m,2H),7.70(dd,J=12.2,1.9Hz,1H),7.59(dd,J =8.5,1.9Hz,1H),7.35(t,J=8.1Hz,1H),7.24(s,1H),6.71(d,J=47.5Hz,1H),6.54(s,1H),3.28(s,3H),2.97(s,3H),2.84(s,3H); 13C NMR (151MHz, DMSO-d6) δ165.61, 163.48 (d, J = 27.4Hz), 159.06, 157.86 (d, J = 243.4H z),145.17,140.89(d,J=11.0Hz),140.39,135.13,134.05,132.05,131.38,130.79, 129.63,129.59,127.53,124.19,122.31,120.43(d,J=18.0Hz),117.17,116.62,107 .40(d,J=27.0Hz),92.85(d,J=220.2Hz),56.49,38.32,34.81; HRMS(ESI)m / z:[M+H] + Calculate for C 25 H 21 Cl2F2N6O4,577.0969; found,577.0961.

[0327] Example 22, 5-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-1-methyl-1H-indole-2-carboxylic acid (22)

[0328]

[0329] The synthetic method of Example 17 was adopted to prepare the title product 22 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 5-amino-1-methyl-1H-indole-2-carboxylic acid tert-butyl ester.

[0330] HPLC purity: 96.0%; 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H),10.42(s,1H),8.72(s,1H),8.04(s,1H),7.81–7.78(m,1H),7.76 –7.72(m,2H),7.54(s,2H),7.19(s,2H),6.82(d,J=47.4Hz,1H),6.56(s,1H),3.99(s,3H),3.27(s,3H); 13C NMR(151MHz,DMSO-d6)δ163.33,162.49(d,J=27.2Hz),159.11,144.94,140.35,137.11,135.14,134.08,134.05,132.07,131.39,131.33,130.7 9,129.61,127.54,125.43,124.19,122.32,120.05,116.24,113.92,11 1.37,109.90,93.42(d,J=210.4Hz),56.46,32.07; HRMS(ESI)m / z:[M+H] + calcdfor C 26 H 20 Cl2FN6O5,585.0856; found,585.0842.

[0331] Example 23, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(2-methyl-2H-indazol-5-yl)acetamide (23)

[0332]

[0333] The title product 23 was prepared by adopting the synthetic method of Example 17, except that the raw material compound 4-aminobenzoic acid tert-butyl ester was replaced with 2-methyl-2H-indazole-5-amine.

[0334] HPLC purity: 99.3%; 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.72(s,1H),8.28(s,1H),8.10–8.09(m,1H),7.81–7.78(m,1H),7.76–7.72(m,2H),7. 55(d,J=9.0Hz,1H),7.40(dd,J=9.2,2.0Hz,1H),7.19(s,1H),6.81(d,J=47.3Hz,1H),6.55(s,1H),4.12(s,3H),3.27(s,3H); 13C NMR (151MHz, DMSO-d6) δ162.60 (d, J = 27.2Hz), 159.09, 146.33, 144.93, 140.34, 135.12, 134.06, 134.05, 132.07, 131.43, 131.38, 130.7 8,127.54,125.07,124.19,122.31,121.97,121.59,117.53,116.19,110.71,91.62(d,J=218.5Hz),56.46,39.83; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 19 Cl2FN7O3,542.0910; found,542.0913.

[0335] Example 24, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(1-methyl-1H-indazol-5-yl)acetamide (24)

[0336]

[0337] The synthetic method of Example 17 was adopted to prepare the title product 24 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 1-methyl-1H-indazole-5-amine.

[0338] HPLC purity: 99.8%; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.73(s,1H),8.11(s,1H),8.01(s,1H),7.81–7.78(m,1H),7.76– 7.72(m,2H),7.60(s,2H),7.20(s,1H),6.80(d,J=47.4Hz,1H),6.56(s,1H),4.01(s,3H),3.27(s,3H); 13C NMR (151MHz, DMSO-d6) δ162.71 (d, J = 27.2Hz), 159.12, 144.97, 140.36, 137.59, 135.13, 134.08, 134.05, 132.79, 132.06, 131.37, 131.2 8,130.78,127.53,124.18,123.63,122.33,121.66,116.36,112.17,110.15,92.09(d,J=220.6Hz),56.46,35.89; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 19 Cl2FN7O3,542.0910; found,542.0899.

[0339] Example 25, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(quinoxalin-6-yl)acetamide (25)

[0340]

[0341] The synthetic method of Example 17 was adopted to prepare the title product 25 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with quinoxaline-6-amine.

[0342] HPLC purity: 97.5%; 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.89(d,J=1.9Hz,1H),8.84(d,J=1.9Hz,1H),8.73(s,1H),8.56(d,J=2.3Hz,1H),8.14(dd,J=9. 2,2.3Hz,1H),8.07(d,J=9.1Hz,1H),7.82–7.77(m,1H),7.76–7.74(m,2H),7.28(s,1H),6.87–6.71(m,1H),6.56(s,1H),3.29(s,3H); 13CNMR(151MHz,DMSO-d6)δ163.71(d,J=27.6Hz),159.13,146.56,145.21,144.99,143.15,140.44,139.97,139.67,135.15,134.10,134.0 3,132.03,131.37,130.81,129.95,127.52,124.98,124.17,122.31,117.71,117.20,92.92(d,J=222.2Hz),56.51; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 17 Cl2FN7O3,540.0754; found,540.0755.

[0343] Example 26, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoro-N-(4-(methylsulfonyl)phenyl)acetamide (26)

[0344]

[0345] The synthetic method of Example 17 was used to prepare the title product 26 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-(methylsulfonyl)aniline.

[0346] HPLC purity: 99.3%; 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.73(s,1H),7.98–7.93(m,2H),7.91–7.86(m,2H),7.82–7.77( m,1H),7.76–7.74(m,2H),7.25(s,1H),6.73(d,J=47.4Hz,1H),6.54(s,1H),3.28(s,3H),3.16(s,3H); 13 C NMR(151MHz,DMSO-d6)δ163.66(d,J=27.5Hz),159.07,145.19,142.97,140.40,136.17,135.14,134.07,134.04,132.04,1 31.37,130.80,128.50,127.53,124.19,122.30,120.70,117.17,92.86(d,J=222.3Hz),56.49,44.21; HRMS(ESI)m / z:[M+H]+ Calculate for C 23 H 19 Cl2FN5O5S,566.0468; found,566.0456.

[0347] Example 27, Preparation of 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzoic acid (Compound 27)

[0348]

[0349] The synthetic method of Example 17 was used to replace the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-(methylsulfonyl)aniline to obtain an intermediate, and then the tert-butyl ester was hydrolyzed with HCl gas to obtain the title product 27.

[0350] HPLC purity: 97.6%; 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),10.78(s,1H),8.73(s,1H),7.85(t,J=8.6Hz,1H),7.79(dd,J=8.6,2.2Hz,1 H),7.76–7.69(m,3H),7.62(dd,J=8.7,2.0Hz,1H),7.25(s,1H),6.71(d,J=47.4Hz,1H),6.54(s,1H),3.28(s,3H); 13 C NMR (151MHz, DMSO-d6) δ164.99 (d, J = 3.3Hz), 163.75 (d, J = 27.3Hz), 161.92 (d, J = 255.5 Hz),159.06,145.23,143.95(d,J=11.5Hz),140.41,135.14,134.07,134.03,133.14,1 32.03,131.38,130.80,127.52,124.18,122.29,117.31,115.92(d,J=3.3Hz),114.60( d, J=10.2Hz), 108.03 (d, J=27.6Hz), 92.98 (d, J=217.3Hz), 56.50; HRMS (ESI) m / z: [M+H] + Calculate for C 23 H 16 Cl2F2N5O5,550.0496; found,550.0487.

[0351] Example 28, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-2-fluoroacetamide (28)

[0352]

[0353] The synthetic method of Example 17 was adopted to prepare the title product 28 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 1-(difluoromethyl)-1H-indazol-5-amine.

[0354] HPLC purity: 98.5%; 1 H NMR (400MHz, DMSO-d6) δ10.70–10.56(m,1H),8.73(s,1H),8.40(d,J=0.6Hz,1H),8.30–8.26(m,1H),8.06(d,J=58.4Hz,1H),7.80( q,J=1.8Hz,2H),7.78(d,J=2.2Hz,1H),7.75(dd,J=5.3,3.0Hz,2H),7.22(s,1H),6.79(d,J=47.4Hz,1H),6.56(s,1H),3.28(s,3H); 13 CNMR(101MHz,DMSO-d6)δ163.04(d,J=27.1Hz),159.09,145.03,140.35,138.68,135.39,135.11,134.05,134.02,133.77,132.03,131.35,130. 76,127.51,125.57,124.16,123.50,122.31,116.66,112.88,111.95(t, J=245.3Hz),92.59(d,J=219.6Hz),111.00,56.45; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 17 Cl2F3N7O3,578.0722; found,578.0713.

[0355] Example 29, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acetamide (29)

[0356]

[0357] The title product 29 was prepared by using the synthesis method of Example 17, replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-(methylsulfonyl)aniline.

[0358] HPLC purity: 99.1%; 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.54(s,1H),10.32(s,1H),8.72(s,1H),7.81–7.78(m,1H),7.76–7.74(m,2H ),7.43(d,J=1.8Hz,1H),7.19–7.12(m,2H),6.85(d,J=8.4Hz,1H),6.76(d,J=44.0Hz,1H),6.54(s,1H),3.26(s,3H); 13 C NMR(151MHz,DMSO-d6)δ162.27(d,J=27.2Hz),159.08,155.98,144.92,140.33,135.13,134.07,134.04,132.05,131.67,131.37,13 0.78,130.02,127.53,126.98,124.18,122.30,116.21,113.77,108.63,102.39,91.98(d,J=207.8Hz),56.45; HRMS(ESI)m / z:[M+H] + Calculate for C 23 H 17 Cl2FN7O4,544.0703; found,544.0707.

[0359] Example 30, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)benzoic acid (Compound 30)

[0360]

[0361] Step a: 1-(2-Bromo-4-chlorophenyl)-1H-tetrazole (30b)

[0362]

[0363] Sodium azide (0.94 g, 14.53 mmol) was first added to a reaction flask, followed by 10 ml of acetic acid, then 2-bromo-4-chloroaniline (1.00 g, 4.84 mmol), and finally triethyl orthoformate (2.42 mL, 14.53 mmol), and the mixture was reacted at 80°C for 10 hours. The acetic acid was removed in vacuo, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the title product 30b (1.1 g, yield: 87%).

[0364] 1 H NMR (600MHz, CDCl3) δ9.00 (s, 1H), 7.84 (d, J = 2.1Hz, 1H), 7.55 (dd, J = 8.5, 2.1Hz, 1H), 7.51 (d, J = 8.5Hz, 1H).

[0365] Step b: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dimethoxypyridine (30c)

[0366]

[0367] 30b (3.8 g, 14.6 mmol), 2,5-dimethoxypyridin-4-yl (2.7 g, 14.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.60 g, 0.73 mmol) and sodium carbonate (4.66 g, 43.9 mmol) were added to a 1,4-dioxane aqueous solution (60 mL, v / v, 4 / 1). After the addition was completed, the reaction solution was heated to 80°C under nitrogen protection and stirred for 10 hours. The reaction solution was naturally cooled to room temperature, the solvent was removed in vacuo, 50 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phases were washed with water and saturated NaCl solution, dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 30c (2.6 g, yield: 56%).

[0368] 1 H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 7.82 (d, J = 1.4Hz, 2H), 7.73 (d, J = 2.5Hz, 2H), 6.84 (s, 1H), 3.81 (s, 3H), 3.40 (s, 3H).

[0369] Step c: 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (30d)

[0370]

[0371] 30c (0.50 g, 1.57 mmol) was added to 5 mL of acetonitrile, iodotrimethylsilane (0.47 g, 2.36 mmol) was added, and distilled water (14.2 mg, 0.78 mmol) was added. After the addition, the mixture was heated to 60°C and stirred for 10 hours. The reaction solution was poured into 6 mL of ice water, stirred for half an hour, filtered, and the filter cake was washed with distilled water and dried to obtain the title product 30d (430 mg, yield: 89%).

[0372] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.80(d,J=1.1Hz,2H),7.72(t,J=1.4Hz,1H),6.95(s,1H),6.40(s,1H),3.24(s,3H).

[0373] Step d: Ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetate (30e)

[0374]

[0375] 30d (320 mg, 1.05 mmol) and cesium carbonate (858 mg, 2.63 mmol) were added to 5 mL of N,N-dimethylformamide, and ethyl bromofluoroacetate (389 mg, 2.11 mmol) was slowly added under ice-water cooling, and the reaction was stirred for about 30 minutes. The reaction solution was poured into 10 mL of water, extracted with ethyl acetate (10 mL×3), and the organic phases were combined, washed with water and saturated NaCl solution, dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 30e (120 mg, yield: 28%).

[0376] 1 H NMR(600MHz,DMSO-d6)δ9.76(s,1H),7.85(d,J=2.3Hz,2H),7.82(d,J=1.8Hz,1H),7.28(s,1H ),6.60(s,1H),6.53(d,J=47.2Hz,1H),4.23–4.18(m,2H),3.26(s,3H),1.21(t,J=7.2Hz,3H).

[0377] Step e: 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetic acid (30f)

[0378]

[0379] 30e (100 mg, 0.24 mmol) was added to 2 mL of methanol, and 1 M lithium hydroxide (0.37 mL, 0.37 mmol) was slowly added under ice-water cooling, and the reaction was stirred for about 2 hours. The methanol was removed in vacuo, and the aqueous phase was acidified with hydrochloric acid (2 M), and a precipitate was precipitated, which was filtered and dried to obtain the title product 30f (83 mg, 88%).

[0380] 1 H NMR (600MHz, DMSO-d6) δ9.77(s,1H),7.85(d,J=2.2Hz,2H),7.82(d,J=1.8Hz,1H),7.24(s,1H),6.60(s,1H),6.45(d,J=47.2Hz,1H),3.17(s,3H).

[0381] Step f: tert-Butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetamide)benzoate (30 g)

[0382]

[0383] 30f (50 mg, 0.132 mmol), tert-butyl 4-aminobenzoate (30.5 mg, 0.158 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (75 mg, 0.197 mmol) were added to 2 mL of dichloromethane, and N,N-diisopropylethylamine (17.5 mg, 0.197 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Dichloromethane was removed in vacuo, 10 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (10 mL×3), the organic phases were combined, and then washed with water, saturated sodium bicarbonate solution, dilute hydrochloric acid solution, and saturated brine, dried over anhydrous Na2SO4, and purified by column chromatography to obtain 30 g (64 mg, yield: 87%) of the title product.

[0384] 1 H NMR (600MHz, DMSO-d6) δ10.70(s,1H),9.77(s,1H),7.89(d,J=8.8Hz,2H),7.85(t,J=4.4Hz,4 H),7.83–7.82(m,1H),7.17(s,1H),6.78–6.67(m,1H),6.62(s,1H),3.17(s,3H),1.54(s,9H).

[0385] Step g: 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)benzoic acid (30)

[0386]

[0387] 30 g (200 mg, 0.36 mmol) was added to 5 mL of ethyl acetate, and freshly prepared HCl gas was introduced. After the reaction was completed, solids were precipitated during slow rotary evaporation. The solids were filtered and dried to obtain the title product 30 (27 mg, yield: 15%).

[0388] HPLC purity: 98.6%; 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),10.66(s,1H),9.73(s,1H),7.92–7.89(m,2H),7.84–7. 82(m,4H),7.80–7.79(m,1H),7.22(s,1H),6.72(d,J=47.3Hz,1H),6.59(s,1H),3.24(s,3H); 13 C NMR(151MHz,DMSO-d6)δ167.34,163.29(d,J=27.5Hz),158.99,144.85,144.41,142.42,139.95,135.71,132.43,131.3 6,131.25,130.93,130.68,127.97,126.61,122.70,120.16,117.26,92.77(d,J=228.0Hz),56.46; HRMS(ESI)m / z:[M+H] + Calculate for C 22 H 17 ClFN6O5,499.0933; found,499.0921.

[0389] Example 31, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzamide (Compound 31)

[0390]

[0391] The synthetic method of Example 30 was adopted to prepare the title product 31 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluorobenzamide.

[0392] HPLC purity: 98.6%; 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.74(s,1H),7.83–7.79(m,3H),7.72–7.63(m,2 H),7.58–7.55(m,3H),7.23(s,1H),6.69(d,J=47.4Hz,1H),6.59(s,1H),3.24(s,3H); 13 C NMR (151MHz, DMSO-d6) δ165.05, 163.51 (d, J = 27.6Hz), 159.92 (d, J = 247.6Hz), 158.98,144.87,144.48,142.10(d,J=11.4Hz),139.96,135.70,132.44,131.4 0,131.37,131.27,130.92,127.98,122.73,119.03(d,J=13.7Hz),117.52,116 .12,107.58(d,J=28.5Hz),92.97(d,J=220.8Hz),56.47; HRMS(ESI)m / z:[M+H] + calcdfor C 22 H 17 ClF2N7O4,516.0998; found,516.0991.

[0393] Example 32, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluoro-N-methylbenzamide (Compound 32)

[0394]

[0395] The synthetic method of Example 30 was adopted to obtain the title product 32 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluoro-N-methylbenzamide.

[0396] HPLC purity: 93.8%; 1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.74(s,1H),8.14–8.05(m,1H),7.83–7.79(m,3H),7.71–7.61(m,2H ),7.58–7.55(m,1H),7.23(s,1H),6.69(d,J=47.4Hz,1H),6.59(s,1H),3.24(s,3H),2.75(d,J=4.5Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ163.94,163.59,159.65(d,J=247.0Hz),158.98,144 .87,144.48,141.86(d,J=11.6Hz),139.96,135.70,132.44,131.37,131.27, 131.12,130.92,127.98,122.72,119.30(d,J=14.3Hz),117.42,116.18,107 .58(d,J=28.3Hz),92.67(d,J=106.6Hz),56.47,26.77; HRMS(ESI)m / z:[M+H] + Calculate for C 23 H 19 ClF2N7O4,530.1155; found,530.1152.

[0397] Example 33, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluoro-N-ethylbenzamide (Compound 33)

[0398]

[0399] The synthetic method of Example 30 was adopted to obtain the title product 33 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-N-ethyl-2-fluorobenzamide.

[0400] HPLC purity: 97.9%; 1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.74(s,1H),8.19–8.13(m,1H),7.85–7.81(m,3H),7.73–7.61(m,2H),7 .59–7.57(m,1H),7.23(s,1H),6.69(d,J=47.4Hz,1H),6.59(s,1H),3.30–3.23(m,5H),1.09(t,J=7.2Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ163.48(d,J=27.2Hz),163.31,159.60(d,J=247.0Hz),158.97,1 44.87,144.47,141.76(d,J=11.4Hz),139.96,135.70,132.44,131.37,131.28,131.06(d ,J=4.3Hz),130.92,127.97,122.73,119.66(d,J=14.2Hz),117.46,116.14(d,J=2.8Hz) ,107.59(d,J=28.3Hz),92.95(d,J=229.1Hz),56.47,34.53,15.14; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 21 ClF2N7O4,544.1311; found,544.1306.

[0401] Example 34, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluoro-N,N-dimethylbenzamide (Compound 34)

[0402]

[0403] The synthetic method of Example 30 was adopted to obtain the title product 34 by replacing the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluoro-N,N-dimethylbenzamide.

[0404] HPLC purity: 99.5%; 1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.76(s,1H),7.85–7.81(m,3H),7.74–7.70(m,1H),7.62–7.59(m,1H),7.3 7(t,J=8.2Hz,1H),7.25(s,1H),6.79–6.63(m,1H),6.61(s,1H),3.26(s,3H),2.99(s,3H),2.85(d,J=1.3Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ165.62,163.44(d,J=27.2Hz),158.98,157.86(d,J=243.5Hz),1 44.87,144.47,140.88(d,J=10.8Hz),139.96,135.69,132.44,131.38,131.27,130.92,1 29.61(d,J=5.3Hz),127.98,122.72,120.43(d,J=18.1Hz),117.43,116.62(d,J=2.8Hz) ,107.40(d,J=27.1Hz),92.97(d,J=211.0Hz),56.48,38.32,34.82; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 21 ClF2N7O4,544.1311; found,544.1316.

[0405] Example 35. Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzoic acid (Compound 35)

[0406]

[0407] The synthetic method of Example 30 was adopted to replace the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluorobenzoic acid tert-butyl ester to obtain the title product 35.

[0408] HPLC purity: 97.3%; 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.74(s,1H),7.88–7.79(m,4H),7.74–7.70(m,1 H),7.63–7.61(m,1H),7.25(s,1H),6.68(d,J=47.4Hz,1H),6.59(s,1H),3.24(s,3H); 13 C NMR (151MHz, DMSO-d6) δ164.99 (d, J = 3.7Hz), 163.70 (d, J = 27.4Hz), 161.92 (d, J = 255 .3Hz),158.98,144.86,144.52,143.93(d,J=11.5Hz),139.98,135.70,133.14,132.4 2,131.36,131.26,130.93,127.97,122.70,117.62,115.92(d,J=3.0Hz),114.61(d, J=10.2Hz), 108.03 (d, J=27.8Hz), 93.15 (d, J=221.0Hz), 60.25; HRMS (ESI) m / z: [M+H] + Calculate for C 22 H 15 ClF2N6O5,517.0839; found,517.0832.

[0409] Example 36, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-N-(2,2-difluoroethyl)-2-fluorobenzamide (Compound 36)

[0410]

[0411] 35 (30 mg, 0.058 mmol) was added to a reaction flask, followed by 1 mL of acetonitrile, followed by 2,2-difluoroethylamine hydrochloride (4.5 uL, 0.063 mmol), N-methylimidazole (16 uL, 0.203 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (24 mg, 0.087 mmol), and the mixture was stirred at room temperature for 16 hours. The acetonitrile was removed in vacuo, 60 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with water, saturated NaCl solution, saturated NaHCO3 solution (10 mL × 3), and dilute hydrochloric acid solution (10 mL × 3), dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 36 (15 mg, yield: 45%).

[0412] HPLC purity: 98.8%; 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),9.76(s,1H),8.56–8.54(m,1H),7.85–7.81(m,2H),7.74(d,J=13.2Hz,1H),7.68(t,J=8.3 Hz,1H),7.62–7.57(m,1H),7.26(s,1H),6.70(d,J=47.3Hz,1H),6.61(s,1H),6.30–5.95(m,1H),3.71–3.61(m,2H),3.25(s,3H); 13 C NMR (151MHz, DMSO-d6) δ164.25, 163.58 (d, J = 27.8Hz), 160.62, 158.98, 144.86, 144. 51,142.37(d,J=11.5Hz),139.97,135.71,132.43,131.36,131.26,131.24,130.93,1 27.98,122.70,118.42(d,J=13.8Hz),117.52,116.22,114.91(t,J=241Hz),107.62(d ,J=27.8Hz),93.02(d,J=225.3Hz),56.47,41.95(t,J=26.2Hz); HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 18 ClF4N7O4,580.1123; found,580.1120.

[0413] Example 37, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-N-(2,2,2-trifluoroethyl)-2-fluorobenzamide (Compound 37)

[0414]

[0415] The synthetic method of Example 36 was adopted to obtain the title product 37 by replacing the raw material compound 2,2-difluoroethylamine hydrochloride with 2,2,2-trifluoroethylamine.

[0416] HPLC purity: 98.6%; 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.77(s,1H),8.84(s,1H),7.85–7.82(m,3H),7.75(d,J=13.2Hz,1H),7 .69–7.64(m,2H),7.27(s,1H),6.71(d,J=47.3Hz,1H),6.62(d,J=3.1Hz,1H),4.10–4.05(m,2H),3.26(s,3H); 13 C NMR(151MHz,DMSO-d6)δ164.37,163.60(d,J=27.1Hz),160.61,158.97,144.87,144.4 9,142.53(d,J=11.4Hz),139.96,135.70,132.44,131.37,131.27,131.17(d,J=3.6Hz ),130.92,127.98,125.18(q,J=321.63Hz),122.72,118.27(d,J=13.8Hz),117.57,11 6.24,107.65(d,J=27.8Hz),93.03(d,J=223.8Hz),56.47,40.50; HRMS(ESI)m / z:[M+H] + calcdfor C 24 H 18 ClF5N7O4,598.1029; found,598.1022.

[0417] Example 38, Preparation of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)-N-cyclopropyl-2-fluorobenzamide (Compound 38)

[0418]

[0419] The synthetic method of Example 36 was adopted to prepare the title product 38 by replacing the raw material compound 2,2-difluoroethylamine hydrochloride with cyclopropylamine.

[0420] HPLC purity: 93.9%; 1H NMR (400MHz, DMSO-d6) δ10.72(s,1H),9.76(s,1H),8.25(s,1H),7.85–7.81(m,3H),7.69(d,J=13.6Hz,1H),7.62–7.56(m,2H ),7.25(s,1H),6.70(d,J=47.4Hz,1H),6.61(s,1H),3.25(s,3H),2.81(d,J=7.6Hz,1H),0.68(d,J=6.9Hz,2H),0.54(s,2H); 13 C NMR (151MHz, DMSO-d6) δ164.97, 163.56, 159.50 (d, J = 247.5Hz), 158.98, 144. 87,144.48,141.70(d,J=11.0Hz),139.96,135.70,132.43,131.37,131.26,13 0.93,130.86,127.98,122.71,119.85(d,J=14.7Hz),117.56,116.09,107.60( d,J=28.3Hz),92.99(d,J=212.4Hz),56.47,23.42,6.27; HRMS(ESI)m / z:[M+H] + Calculate for C 25 H 20 ClF2N7O4,556.1311; found,556.1315.

[0421] Example 39, Preparation of 4-(2-(4-(5-chloro-2-(4-trifluoromethyl-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)benzoic acid (Compound 39)

[0422]

[0423] Step a: N-(2-bromo-4-chlorophenyl)formamide (39b)

[0424]

[0425] 2-Bromo-4-chloroaniline (50 g, 242 mmol), formic acid (45 g, 968 mmol), and sodium formate (8 g, 121 mmol) were added to a reaction flask and reacted at room temperature for 16 hours under argon protection. The reaction solution was diluted with ethyl acetate (200 mL), washed with water (200 mL × 3) and saturated sodium bicarbonate solution (200 mL × 3) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Solids precipitated and were filtered to obtain the title product 39b (49.8 g, yield: 88%).

[0426] Step b: 2-Bromo-4-chloro-1-isocyanobenzene (39c)

[0427]

[0428] 39b (50 g, 212 mmol) was added to a reaction flask, 500 mL of anhydrous tetrahydrofuran was added, and then triethylamine (65 g, 638 mmol) was added. Under Ar protection, the reaction system was cooled to 0°C, the system temperature was maintained, POCl3 (39 g, 255 mmol) dissolved in 250 mL of anhydrous tetrahydrofuran was slowly added dropwise to the reaction solution, and 0°C was maintained after the addition, and the reaction was allowed to proceed for 12 hours. After the reaction was completed, the reaction solution was poured into ice water at 0°C to quench, extracted with petroleum ether (150 mL×3), the organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title product 39c (40.4 g, yield: 87%).

[0429] Step c: 1-(2-Bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (39d)

[0430]

[0431] 39c (10 g, 46 mmol), 2-diazo-1,1,1-trifluoroethane (182 mL, 0.3-0.4 M toluene solution), silver carbonate (3.8 g, 13.9 mmol) and 4A molecular sieves (5.5 g) were added to a reaction bottle, DMF (60 mL) was added, heated to 40°C, reacted for 16 hours, the reaction solution was filtered, the filtrate was spin-dried, water (50 mL) was added, and extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (80 mL), dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 39d (7.2 g, yield: 47%).

[0432] Step d: 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dimethoxypyridine (39e)

[0433]

[0434] 39d (32.7 g, 100 mmol), 2,5-dimethoxypyridin-4-yl (22.0 g, 120 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (8 mg, 10 mmol) and sodium carbonate (26.5 g, 250 mmol) were added to a 1,4-dioxane aqueous solution (v / v, 4 / 1, 300 mL). After the addition was completed, the reaction solution was heated to 80°C under nitrogen protection and stirred for 16 hours. The reaction solution was naturally cooled to room temperature, the solvent was removed in vacuo, 200 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with a saturated NaCl solution (200 mL), dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 39e (26.2 g, yield: 68%).

[0435] Step e: 4-(5-Chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-pyridone (39f)

[0436]

[0437] 39e (21 g, 54.6 mmol) was added to 200 mL of DMF, and pyridine hydrobromide (87.4 g, 546 mmol) was added. After the addition was completed, the mixture was heated to 110° C. under argon protection and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into 200 mL of ice water, stirred for half an hour, filtered, and the filter cake was rinsed with distilled water and dried to obtain the title product 39f (16 g, yield: 79%).

[0438] Step f: Ethyl 2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetate (39 g)

[0439]

[0440] 39f (10 g, 27 mmol) and cesium carbonate (13.2 g, 40.5 mmol) were added to 60 mL of N,N-dimethylformamide, the reaction system was cooled to 0°C, ethyl bromofluoroacetate (7.5 g, 40.5 mmol) was slowly added dropwise at 0°C, and the reaction was stirred at 0°C for about 30 minutes. The reaction solution was poured into 300 mL of water, extracted with ethyl acetate (60 mL×3), the organic phases were combined, washed with saturated NaCl solution (300 mL), dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 39g (3.3 g, yield: 26%).

[0441] 1 H NMR(400MHz,DMSO-d6)δ9.27(s,1H),7.86–7.84(m,2H),7.81(t,J=1.4Hz,1H),7 .27(s,1H),6.62–6.45(m,2H),4.20(q,J=7.2Hz,2H),3.24(s,3H),1.19(m,3H).

[0442] Step g: 2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetic acid (39h)

[0443]

[0444] 39g (1.8g, 3.8mmol) was added to 10mL methanol, cooled to 0°C, 1M lithium hydroxide (5.7mL, 5.7mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. Methanol was removed in vacuo, and the aqueous phase was acidified with hydrochloric acid (2M). A precipitate was produced, which was filtered and dried to obtain the title product 39h (0.53g, yield: 30%).

[0445] Step h: tert-Butyl 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-fluoroacetylamino)benzoate (39i)

[0446]

[0447] 39h (150 mg, 0.34 mmol) and tert-butyl 4-aminobenzoate (78 mg, 0.40 mmol) were added to a reaction flask, and 1.5 mL of acetonitrile was added, followed by N-methylimidazole (96 uL, 1.18 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (141 mg, 0.50 mmol), and the mixture was stirred at room temperature for 16 hours. The acetonitrile was removed in vacuo, 60 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, and purified by column chromatography to obtain the title product 4a-8 (173 mg, yield: 73%).

[0448] 1H NMR (400MHz, DMSO-d6) δ10.69(s,1H),9.29(s,1H),7.89(d,J=8.9Hz,2H),7.86–7.80 (m,5H),7.23(s,1H),6.72(d,J=47.3Hz,1H),6.62(s,1H),3.23(s,3H),1.54(s,9H).

[0449] Step i: 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxo-pyridin-1(2H)-yl)-2-fluoroacetylamino)benzoic acid (39)

[0450]

[0451] 39i (170 mg, 0.27 mmol) was added to 5 mL of ethyl acetate and freshly prepared HCl gas was introduced. After the reaction was completed, solid was precipitated and filtered and dried to obtain the title product 39 (85 mg, yield: 55%).

[0452] HPLC purity: 98.4%; 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),10.68(s,1H),9.29(s,1H),7.94–7.90(m,2H),7.87–7. 85(m,3H),7.84–7.81(m,2H),7.23(s,1H),6.73(d,J=47.5Hz,1H),6.62(s,1H),3.23(s,3H); 13 C NMR(151MHz, DMSO-d6)δ167.32,163.31(d,J=27.2Hz),159.02,144.81,142.44,140.15,137.18(q,J=38.6Hz),135.54,133.59,132.39,131.42 ,130.88,130.66,127.82,127.66,126.60,122.67,121.11(q,J=267.3Hz),120.13,116.84,92.71(d,J=214.5Hz),56.26; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 17 ClF4N5O5,566.0854; found,566.0850.

[0453] Example 40, 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxo-pyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzoic acid (40)

[0454]

[0455] The synthetic method of Example 39 was adopted to replace the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluorobenzoic acid tert-butyl ester to obtain the title product 40.

[0456] HPLC purity: 99.1%; 1 H NMR (400MHz, DMSO-d6) δ13.08(s,1H),10.81(s,1H),9.29(s,1H),7.94–7.85(m,3H),7.82–7.81(m,1H),7.74(dd ,J=13.4,2.0Hz,1H),7.64(dd,J=8.7,2.0Hz,1H),7.26(s,1H),6.70(d,J=47.4Hz,1H),6.62(s,1H),3.23(s,3H); 13 C NMR(151MHz,DMSO-d6)δ164.99(d,J=3.4Hz),163.73(d,J=27.2Hz),161.92(d,J=255.4Hz),1 59.02,144.93,143.94(d,J=11.6Hz),140.19,137.19(q,J=38.6Hz),135.55,133.58,133.12, 132.37,131.42,130.90,127.81,127.66,122.65,121.10(q,J=266.7Hz),117.26,115.91,11 4.59(d,J=10.1Hz),108.01(d,J=27.5Hz),93.14(d,J=178.2Hz),56.28; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 16 ClF5N5O5,584.076; found,584.072.

[0457] Example 40a, 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxo-pyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzoic acid (Enantiomer 1)

[0458] Nexera UC SFC-UV system was used for separation. The separation conditions were as follows: column temperature: 40°C, chromatographic column: DAICEL OD-H 4.6mm ID×150mm L.5μm, detection wavelength: 242nm, back pressure: 20MPa; mobile phase: scCO2 / methanol=80 / 20, flow rate: 3mL / min.

[0459] HPLC purity: 99.7%; 1 H NMR(400MHz,DMSO-d6)δ13.07(s,1H),10.80(s,1H),9.29(s,1H),7.94–7.85(m,3H),7.82–7.81(m,1H),7.73(dd ,J=13.4,2.0Hz,1H),7.64(dd,J=8.7,2.0Hz,1H),7.25(s,1H),6.70(d,J=47.4Hz,1H),6.62(s,1H),3.22(s,3H)

[0460] Example 40b, 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxo-pyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzoic acid (Enantiomer 2)

[0461] Nexera UC SFC-UV system was used for separation. The separation conditions were as follows: column temperature: 40°C, chromatographic column: DAICEL OD-H 4.6mm ID×150mm L.5μm, detection wavelength: 242nm, back pressure: 20MPa; mobile phase: scCO2 / methanol=80 / 20, flow rate: 3mL / min.

[0462] HPLC purity: 99.9%; 1 H NMR(400MHz,DMSO-d6)δ13.08(s,1H),10.80(s,1H),9.29(s,1H),7.94–7.85(m,3H),7.82–7.80(m,1H),7.74(dd ,J=13.4,2.0Hz,1H),7.64(dd,J=8.7,2.1Hz,1H),7.26(s,1H),6.70(d,J=47.4Hz,1H),6.61(s,1H),3.23(s,3H)

[0463] Example 41, 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxo-pyridin-1(2H)-yl)-2-fluoroacetylamino)-2-fluorobenzamide (41)

[0464]

[0465] The synthetic method of Example 39 was adopted to replace the raw material compound 4-aminobenzoic acid tert-butyl ester with 4-amino-2-fluorobenzamide to obtain the title product 41.

[0466] HPLC purity: 96.5%; 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.30(s,1H),7.86–7.81(m,3H),7.74–7.66(m,2 H),7.63–7.58(m,3H),7.25(s,1H),6.70(d,J=47.4Hz,1H),6.63(s,1H),3.23(s,3H); 13 C NMR (151MHz, DMSO-d6) δ165.06, 163.54 (d, J = 27.2Hz), 159.93 (d, J = 247.7Hz), 159.03, 144.90, 142. 11(d,J=11.4Hz),140.17,137.19(q,J=38.7Hz),135.55,133.59,132.37,131.40(d,J=4.5Hz),131. 36,130.89,127.81,127.65(d,J=2.9Hz),122.66,121.11(q,J=267.3Hz),118.99(d,J=13.8Hz),117 .11,116.11(d,J=2.9Hz),107.57(d,J=28.4Hz),92.99(d,J=230.7Hz),56.27; HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 17 ClF5N6O4,583.092; found,583.090.

[0467] Example 42, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetylamino)benzoic acid (42)

[0468]

[0469] Step a: 2-amino-5-chlorophenylboronic acid pinacol ester (42b)

[0470]

[0471] The compound 2-bromo-4-chloroaniline (30.0 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 mixture was replaced with nitrogen 3-4 times. Under nitrogen protection, PdCl2(dppf)·CH2Cl2 (3.57 g, 4.36 mmol) was quickly added, 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 compound 42b (24.68 g, yield: 67.1%).

[0472] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=2.6Hz,1H),7.13(dd,J=8.6,2.6Hz,1H),6.53(d,J=8.6Hz,1H),4.75(s,2H),1.33(s,12H).

[0473] Step b: 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline (42c)

[0474]

[0475] Compound 42b (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, stirred for 12 h, and the compound 42b was completely consumed by TLC monitoring. 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 3 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 42c as a white solid (14.7 g, yield: 64.3%).

[0476] 1H NMR (400MHz, CDCl3) δ8.78(d,J=1.1Hz,1H),7.49(d,J=2.5Hz,1H),7.15(dd,J=8.7, 2.4Hz,1H),6.99(d,J=1.1Hz,1H),6.67(d,J=8.6Hz,1H),5.35(s,2H),4.02(s,3H).

[0477] Step c: 4-(2-azido-5-chlorophenyl)-6-methoxypyrimidine (42d)

[0478]

[0479] Compound 42c (10 g, 42.4 mmol) was dissolved in 100 mL of acetonitrile, 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 in sequence, stirred at 0°C for 5 min, and then heated to room temperature and stirred for about 10 h. Solid precipitated, and the reaction solution was filtered to obtain a light yellow solid, which was dried to obtain compound 42d (10.33 g, yield: 88.3%). It was directly used in the next step without column chromatography purification.

[0480] Step d: 4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine (42e)

[0481]

[0482] Compound 42d (10.3 g, 39.5 mmol) was dissolved in toluene solution, ethynyltrimethylsilane (7.0 g, 71.1 mmol) was added dropwise, and the mixture was heated to 110°C in an oil bath, stirred under reflux for 12 h, and the reaction mixture was completely reacted by TLC monitoring, and then the reaction mixture was cooled to room temperature. The reaction mixture was spin-dried, water was added, and the mixture was 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 42e as a light yellow solid (12 g, yield: 84.4%).

[0483] 1 H NMR (600MHz, DMSO-d6) δ8.65 (s, 1H), 8.36 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.82 (dd ,J=8.5,2.4Hz,1H),7.75(d,J=8.4Hz,1H),6.54(s,1H),3.89(s,3H),0.26(s,9H).

[0484] Step e: 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine (42f)

[0485]

[0486] Compound 42e (10.7 g, 29.6 mmol) was dissolved in 100 mL of acetonitrile, and NCS (29.1 g, 217.7 mmol) and silica gel (29.7 g) were added in sequence. The oil bath was heated to 80 ° C and stirred under reflux for 6 h. After the raw materials were completely consumed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the reaction solution was spin-dried. 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 then purified by column chromatography to obtain compound 42f as a light yellow solid (4.98 g, yield: 52.3%), which was used in the next step.

[0487] 1 H NMR(400MHz,DMSO-d6)δ8.75–8.71(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).

[0488] Step f: 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)-one (42 g)

[0489]

[0490] To a 4 mL acetic acid solution of compound 42f (5.0 g, 15.4 mmol), a 48% aqueous solution of hydrobromic acid (16.6 mL, 146.3 mmol) was slowly added dropwise. The oil bath reaction was heated to 80°C and stirred under reflux for about 2.5 h. The raw material reaction was complete. After the reaction solution was cooled, the reaction solution was rotary evaporated to dryness, and then ethyl acetate was added, and then a saturated sodium bicarbonate solution was added to dilute, and the organic phase was collected and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product as a brown solid 42 g (4.6 g, yield: 96.8%), which was used directly in the next step without purification.

[0491] 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.02(s,1H),7.84(d,J=2.5Hz,1H),7.77(dd,J=8.5,2.4Hz,1H),7.71–7.68(m,1H),6.17(s,1H).

[0492] Step g: 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroethyl ester (42h)

[0493]

[0494] Compound 42g (2.0g, 6.5mmol) was dissolved in DMF, cesium carbonate (2.5g, 7.8mmol) was added, and then ethyl bromofluoroacetate (924μL, 7.79mmol) was slowly added under ice bath conditions, and the reaction was carried out at room temperature for 3h. After the reaction of the raw materials was detected to be complete, the reaction solution was poured into ice water, and the pH was adjusted to 3-4 with 1M HCl solution. Solids precipitated, and the solids were filtered and dried to obtain a crude product, which was then purified by column chromatography to obtain compound 42h as a white solid (854mg, yield: 31.9%).

[0495] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.48(s,1H),7.96(d,J=2.4Hz,1H),7.84(dd,J=8.5,2 .4Hz,1H),7.76(d,J=8.5Hz,1H),6.65(s,2H),4.22(q,J=7.1Hz,2H),1.19(t,J=7.1Hz,3H).

[0496] Step h: 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetic acid (42i)

[0497]

[0498] Compound 42h (300 mg, 0.73 mmol) was dissolved in 3 mL of anhydrous methanol, and 1 M aqueous lithium hydroxide solution (1.09 mL) was slowly added dropwise under ice bath conditions, and the reaction was carried out at room temperature for about 1 h. The reaction solution was spin-dried, water was added to the residue, and the pH was adjusted to 3-4 with 1 M HCl solution. Solids precipitated, which were filtered and dried to obtain crude product 42i as a white solid (252 mg, yield: 90%).

[0499] 1H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.43(s,1H),7.96(d,J=2.4Hz,1H),7.83(dd,J=8.5,2.3Hz,1H),7.75(d,J=8.5Hz,1H),6.63(s,2H).

[0500] Step i: tert-Butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetylamino)benzoate (42j)

[0501]

[0502] Compound 42i (252 mg, 0.66 mmol) was dissolved in a dichloromethane solution, and tert-butyl p-aminobenzoate (152 mg, 0.79 mmol), HATU (374 mg, 0.39 mmol) were added in sequence, and DIPEA (163 μL) was added at room temperature. The reaction was carried out for about 12 h. TLC monitored that the raw material reaction was complete, and the reaction solution was spin-dried. A saturated sodium bicarbonate solution was added to the residue, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with 0.5 M HCl and saturated brine for 3-4 times, respectively, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. Compound 42j was purified by column chromatography as a white solid (200 mg, yield: 54.4%).

[0503] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),8.82(s,1H),8.47(s,1H),7.97(d,J=2.4Hz,1H),7.87(d,J=8.8Hz,2H),7.8 3(d,J=2.3Hz,1H),7.81(d,J=8.7Hz,2H),7.76(d,J=8.5Hz,1H),6.80(d,J=46.4Hz,1H),6.64(s,1H),1.52(s,9H).

[0504] Step j: 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetylamino)benzoic acid (42)

[0505]

[0506] Compound 42j (100 mg) was weighed and dissolved in about 5 mL of EA solution, and freshly prepared HCl gas was introduced under ice bath conditions. TLC monitored the complete reaction of the raw material, and the reaction solution was spin-dried to obtain compound 42 as a white solid (54 mg, yield: 60.2%).

[0507] HPLC purity: 95.1%; 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.80(s,1H),8.47(s,1H),7.96(d,J=2.3Hz,1H),7.91(d,J=8.6Hz,2H), 7.83(dd,J=8.5,2.4Hz,1H),7.80(d,J=8.7Hz,2H),7.75(d,J=8.5Hz,1H),6.80(d,J=46.4Hz,1H),6.63(s,1H); 13 C NMR(151MHz,DMSO-d6)δ167.34,162.65(d,J=25.8Hz),159.60,159.40,151.77,142.25,135.63,134.64,134.29,1 33.49,131.59,131.01,130.72,129.00,126.78,124.84,120.24,115.26,91.37(d,J=221.1Hz); HRMS(m / z):[M+H] + Calculate for C 21 H 14 Cl2FN6O4 + 503.0437, found 503.0433.

[0508] Example 43, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetamide)-2-fluorobenzamide (43)

[0509]

[0510] Compound 42i (100 mg, 0.260 mmol) was dissolved in dichloromethane solution, 4-amino-2-fluoroaniline (48 mg, 0.31 mmol), HATU (148 mg, 0.39 mmol) were added in sequence, and DIPEA (64 μL) was added in the end. The reaction was carried out at room temperature for about 12 h, and the reaction of the raw materials was completed by TLC monitoring. The reaction solution was washed with 0.5 M HCl, saturated sodium bicarbonate solution and saturated brine in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (DCM: MeOH = 100: 1 to 40: 1) to obtain 43 as a white solid (17 mg, yield: 12.6%).

[0511] HPLC purity:95.2%; mp:214.6~215.2℃; 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.80(s,1H),8.47(s,1H),7.96(d,J=2.4Hz,1H),7.84(dd,J=8.6,2. 4Hz,1H),7.75(d,J=8.5Hz,1H),7.70–7.64(m,2H),7.55–7.53(m,3H),6.79(d,J=46.4Hz,1H),6.64(s,1H); 13 C NMR(151MHz,DMSO-d6)δ165.09,162.87(d,J=25.9Hz),159.90(d,J=248.0Hz),159 .66,159.40,151.80,141.88(d,J=11.3Hz),135.63,134.63,134.29,133.50,131. 60,131.43(d,J=3.9Hz),131.02,129.00,124.84,119.23(d,J=14.0Hz),116.20(d ,J=2.9Hz),115.27,107.70(d,J=28.3Hz),91.41(d,J=221.6Hz); HRMS(m / z):[M+H] + calcdfor C 21 H 14 Cl2F2N7O3 + 520.0503, found 520.0499.

[0512] Example 44, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetylamino)-2-fluoro-N-methylbenzamide (44)

[0513]

[0514] The preparation method is similar to that of the target compound 43. The raw material 4-amino-2-fluoroaniline is replaced with N-methyl-2-fluoro-4-aminobenzamide, and the target compound 44 is prepared and purified as a white solid (22 mg, yield: 15.8%).

[0515] HPLC purity: 95.5%; 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.81(s,1H),8.47(s,1H),8.12–8.08(m,1H),7.96(d,J=2.3Hz,1H),7.84(dd,J=8.5,2.4Hz,1H),7.76(d, J=8.5Hz,1H),7.69–7.64(m,1H),7.63(d,J=8.4Hz,1H),7.54(dd,J=8.6,2.0Hz,1H),6.80(d,J=46.4Hz,1H),6.64(s,1H),2.75(d,J=4.6Hz,3H); 13 C NMR (151MHz, DMSO-d6) δ163.96, 162.86 (d, J = 26.1Hz), 159.66, 159.64 (d, J = 247.3H z),159.40,151.80,141.66(d,J=11.3Hz),135.62,134.64,134.28,133.51,131.59, 131.19(d,J=4.2Hz),131.02,129.00,124.85,119.51(d,J=14.2Hz),116.26(d,J=2. 8Hz), 115.28, 107.70 (d, J = 28.3Hz), 91.40 (d, J = 221.3Hz), 26.77; HRMS (m / z): [M+H] + Calculate for C 22 H 16 Cl2F2N7O3 + 534.0659, found 534.0652.

[0516] Example 45, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoroacetylamino)-N-ethyl-2-fluorobenzamide (45)

[0517]

[0518] The preparation method is similar to that of the target compound 43, except that the raw material 4-amino-2-fluoroaniline is replaced with N-ethyl-2-fluoro-4-aminobenzamide to prepare and purify the target compound 45 as a white solid (25 mg, yield: 17.5%).

[0519] HPLC purity: 95.1%; 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.82(s,1H),8.47(d,J=1.0Hz,1H),8.15( q,J=5.4Hz,1H),7.97(d,J=2.3Hz,1H),7.84(dd,J=8.5,2.4Hz,1H),7.76(d,J=8 .5Hz,1H),7.70–7.61(m,1H),7.61(d,J=8.3Hz,1H),7.54(dd,J=8.5,1.9Hz,1H) ,6.80(d,J=46.4Hz,1H),6.65(s,1H),3.30–3.19(m,2H),1.09(t,J=7.2Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ163.28,162.83(d,J=25.9Hz),159.64,159.56(d,J=24 7.0Hz),159.38,151.79,141.54(d,J=12Hz),135.59,134.64,134.23,133.51, 131.57,131.10,131.02,129.00,124.85,119.88(d,J=14.1Hz),116.20,115.2 8,107.67(d,J=28.3Hz),91.40(d,J=221.1Hz),34.51,15.13; HRMS(m / z):[M+H] + Calculate for C 23 H 18 C l2 F2N7O3 + 548.0816, found 548.0808.

[0520] Example 46, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoro-N-(4-(methylsulfonyl)phenyl)acetamide (46)

[0521]

[0522] Using a similar synthetic route to target compound 43, replacing the raw material 4-amino-2-fluoroaniline with 4-(methylsulfonyl)aniline, the target compound 46 was prepared and purified as a white solid (31 mg, yield: 22.2%).

[0523] HPLC purity: 93.7%; 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.80(s,1H),8.48(s,1H),7.96(d,J=2.4Hz,1H),7.94–7.91(m,2H),7.90–7 .87(m,2H),7.84(dd,J=8.5,2.3Hz,1H),7.75(d,J=8.5Hz,1H),6.81(d,J=46.4Hz,1H),6.64(s,1H),3.16(s,3H); 13 CNMR(151MHz,DMSO-d6)δ162.97(d,J=26.0Hz),159.65,159.40,151.83,142.77,136.36,135.63,134.64,134.29, 133.50,131.60,131.02,129.00,128.56,124.84,120.80,115.27,91.40(d,J=221.3Hz),44.19; HRMS(m / z):[M+H] + Calculate for C 21 H 16 Cl2FN6O4S + 537.0315, found 537.0305.

[0524] Example 47, 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluoro-N-(quinoxalin-6-yl)acetamide (47)

[0525]

[0526] The synthetic route of target compound 43 was adopted, and the raw material 4-amino-2-fluoroaniline was replaced by 6-aminoquinoxaline to prepare and purify target compound 47 as a white solid (34 mg, yield: 25.5%).

[0527] HPLC purity: 95.6%; 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.90(d,J=1.9Hz,1H),8.85(d,J=1.9 Hz,1H),8.83(s,1H),8.53(d,J=2.2Hz,1H),8.52(s,1H),8.13(dd,J=9.1,2. 3Hz,1H),8.08(d,J=8.9Hz,1H),7.98(d,J=2.3Hz,1H),7.85(dd,J=8.5,2.4H z,1H),7.77(d,J=8.5Hz,1H),6.88(d,J=46.4Hz,1H),6.67(d,J=0.9Hz,1H); 13 C NMR (151MHz, DMSO-d6) δ163.03 (d, J = 26.1Hz), 159.66, 159.45, 151.85, 146.64, 145.12, 143.14, 140.05, 139.52, 135.61, 134. 67,134.25,133.54,131.59,131.06,130.06,129.03,124.93,124.89,117.86,115.33,91.48(d,J=222.6Hz); HRMS(m / z):[M+H] + Calculate for C 22 H 14 Cl2FN8O2 + 510.0523, found 510.0518.

[0528] Example 48, 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)acetamide)benzoic acid (48)

[0529]

[0530] Using a similar synthetic route to compound 43, the raw material in step g was replaced with tert-butyl bromoacetate to prepare the target compound 48 as an off-white solid (33 mg, yield: 36.8%). HPLC purity: 98.0%; 1H NMR (400MHz, DMSO-d6) δ12.72(s,1H),10.73(s,1H),8.78(s,1H),8.31(s,1H),7.94(d,J=2.4Hz,1H),7. 95–7.86(m,2H),7.84–7.79(m,1H),7.74(d,J=8.5Hz,1H),7.71–7.63(m,2H),6.49(s,1H),4.76(s,2H). 13 C NMR(151MHz,DMSO-d6)δ167.34,165.73,160.52,159.21,153.14,142.94,135.67,135.40,134.20, 133.49,131.22,131.02,130.83,129.19,126.02,124.89,118.88,113.98,49.29.HRMS(m / z):[M+H] + Calculate for C 21 H 15 Cl2N6O4 + 485.0532, found 485.0519.

[0531] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0532] Test Example 1: Determination of the activity of the compounds of the present invention on Factor XIa protease

[0533] 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 Biochemical), and 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.

[0534] The experimental operation is briefly described as follows: the test compound is prepared into a 10mM stock solution with DMSO, and then diluted into a series of concentrations with a buffer solution (50mMTris / HCl pH 7.4, 100mM sodium chloride, 5mM calcium chloride, 0.1% bovine serum albumin). In the microplate, add 20μL of buffer solution, 20μL of FXIa enzyme solution (0.6nM), and then add 20μL of the test compound solution, incubate at a constant temperature of 37°C for 30min, add 40μL of fluorescent substrate solution (10μM), and immediately measure on an ELISA reader, with an excitation wavelength of 360nm and an emission wavelength of 460nm. Read the data continuously, and fit the data with GraphPad Prism 7 to obtain the compound IC 50 Values, data see Table 1.

[0535] Table 1. IC values ​​of the inhibitory activity of the compounds of the present invention on FXIa 50 data

[0536] Example compounds <![CDATA[FXIa(IC 50 ,nM)]]> Example compounds <![CDATA[FXIa(IC 50 ,nM)]]> 17 7.3 33 27.6 18 9.3 34 221.3 19 30.1 35 20.5 20 24.3 36 55.7 21 396.1 37 114.0 22 5.5 38 133.5 23 34.2 39 5.7 24 18.2 40 12 25 17.3 40a 8.2 27 6.6 40b 8.9 30 3.8 41 65.9 31 34.1 48 201.5 32 40.1

[0537] As can be seen from Table 1, the compounds of the present invention have a certain inhibitory effect on FX1a protease activity, and the compounds with introduced fluorine atoms have a better inhibitory effect on FX1a protease activity than the compounds without introduced fluorine atoms. Among them, compounds 17, 18, 22, 27, 30, 39, 40, 40a and 40b have excellent inhibitory effects.

[0538] Test Example 2: Activated Partial Thromboplastin Time (APTT) Determination of the Compounds of the Invention

[0539] 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).

[0540] 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. Dissolve the test compound with DMSO, and dilute the test compound in a two-fold gradient with DMSO to prepare a series of solutions. First preheat the calcium chloride solution and APTT reagent at 37°C. Then take 20 μL of the plasma to be tested in a measuring cup, add the diluted test compound, and then add 20 μL of preheated APTT reagent, and incubate at 37°C for 5 minutes. Place the measuring cup in the measuring channel of the semi-automatic coagulation meter, then add 20 μL of preheated calcium chloride solution, measure immediately, and record the coagulation time. Use GraphPad Prism 7 software to fit the recorded coagulation time and 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 2.

[0541] Table 2. EC of the compounds of the present invention on the anticoagulant effect of human plasma in vitro 1.5x data

[0542] Example compounds <![CDATA[EC 1.5x (μM)]]> Example compounds <![CDATA[EC 1.5x (μM)]]> 17 2.57 40 1.26 22 1.69 40a 1.20 27 2.93 40b 1.23 30 0.78 48 7.23 39 2.70

[0543] It can be seen from Table 2 that the compounds of the present invention have a good in vitro anticoagulant effect in human plasma. Compared with the compounds without the introduction of fluorine atoms, the compounds of the present invention after the introduction of fluorine atoms have a better anticoagulant effect.

[0544] In summary, the present invention provides a new compound that can be used as a small molecule inhibitor of FXIa. The compound introduces fluorine atoms, which have higher activity than compounds without fluorine, 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.

Claims

1. A compound or a salt thereof, characterized in that: The compound is one of the following compounds:

2. Use of the compound or salt thereof according to claim 1 in the preparation of a coagulation factor FXIa inhibitor and / or a plasma bradykinin kinase PKA inhibitor.

3. Use of the compound or salt thereof according to claim 1 in the preparation of a medicament for preventing and / or treating diseases mediated by factor XIa.

4. The use according to claim 3, characterized in that: The disease is a cardiovascular and cerebrovascular disease.

5. The use according to claim 3, characterized in that: The disease is a thromboembolic disease.

6. The use according to claim 5, characterized in that: 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.

7. A drug, characterized in that: The drug is a preparation prepared by using the compound or salt thereof as claimed in claim 1 as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

8. A pharmaceutical composition, characterized in that: The invention comprises the compound or salt thereof according to claim 1 and a pharmaceutically acceptable carrier, diluent and excipient.

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