Novel oxopyridine compounds and their intermediates and applications

Abstract

The present invention discloses a compound represented by formula (I), its stereoisomers, or pharmaceutically acceptable salts and key intermediates. The present invention also provides the use of the compound, its stereoisomers or pharmaceutically acceptable salts in the preparation of drugs for treating and / or preventing diseases related to FXIa receptors, especially in the preparation of drugs for treating and / or preventing cerebrovascular arterial diseases and / or peripheral arterial diseases.

Description

[0001] This application claims the priority of the invention patent with the invention name “Novel oxopyridine compounds, preparation methods and uses thereof” and patent number CN202211647390.2, filed on December 21, 2022, and is hereby expressly incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical chemistry, and in particular to oxopyridine compounds or their salts, isomers, preparation methods thereof, and use thereof in preparing drugs for treating and / or preventing diseases associated with FXIa receptors, especially in preparing drugs for treating and / or preventing cerebrovascular arterial diseases and / or peripheral arterial diseases. Background Art

[0003] Thromboembolic disease is a disease caused by abnormal blood clots formed in blood vessels during the survival of humans and animals. There are three reasons for thrombosis: damaged blood vessels, blood changes and blood stasis; it is a group of complications caused by many different diseases and different reasons. Due to the differences in various underlying diseases and the different sites of thromboembolism, thrombosis may clinically manifest as myocardial infarction, stroke, deep vein thrombosis (DVT), pulmonary embolism, atrial fibrillation and cerebral infarction, etc., especially myocardial infarction, cerebral infarction and pulmonary infarction with embolism and infarction as the main causes, which ranks first among various causes of death, claiming nearly 12 million lives each year worldwide, close to a quarter of the world's total death toll.

[0004] Coagulation factor XI (FXI) is a plasma serine protease necessary for maintaining the intrinsic pathway. After activation, it generates activated coagulation factor XIa (FXIa), which plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback activate FXI, and activated FXI in turn promotes the massive production of thrombin, thereby amplifying the coagulation cascade. Therefore, drugs targeting the FXI target can block the intrinsic pathway and inhibit the amplification of the coagulation cascade, thus having an anti-thrombotic effect. In recent years, clinical data on the association between human coagulation factor XI (FXI) deficiency or elevated FXI levels and the occurrence of thrombotic diseases, as well as antithrombotic experimental studies on animals with FXI deficiency, knockout or inhibition have shown that compared with direct FXa inhibitors, inhibition of FXI may have a lower risk of bleeding and is a new target for antithrombotic prevention and treatment.

[0005] The reported FXI inhibitors mainly include monoclonal antibodies, antisense oligonucleotides, chemical small molecules, peptides or proteins and peptide mimetics. At present, milvexian, jointly developed by BMS and Johnson & Johnson, has completed the Phase II clinical trial, and the results show that it has a lower risk of bleeding. The Phase I clinical trial of BMS's intravenous small molecule FXIa inhibitor BMS-962122 has been completed and research and development has been suspended. ONO-7684, a small molecule oral FXIa inhibitor developed by Japan's Ono Company, has entered Phase I clinical research. Monoclonal antibodies and antisense oligonucleotides need to be injected, and have the disadvantages of being expensive, slow to take effect, and potentially difficult to control.

[0006] The efficacy, pharmacokinetics and toxicity of drugs in vivo are affected by many factors and show corresponding complexity. A slight change in the chemical structure at any position may cause changes in the efficacy, pharmacokinetics and toxicity of the drug in vivo. For example, deuteration, compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetics and other properties of deuterated drugs show great contingency and unpredictability. Deuteration at certain sites has the effect of extending the half-life, such as the listed donafenib tosylate, deuterated tetrabenazine, etc., and some sites not only cannot extend the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406); on the other hand, hydrogen at certain positions on the drug molecule is not easy to be deuterated due to steric hindrance and other reasons, so the deuterated sites of the drug are unpredictable.

[0007] Bayer's FXI inhibitor Asundexian has entered Phase III clinical trials with an average terminal half-life of up to 17.8 hours. Although it has a certain advantage in bleeding risk compared to apixaban, it still has a greater bleeding risk. Therefore, the development of new FXIa small molecule inhibitors with stronger activity, better absorption, relatively faster metabolism, lower bleeding risk and better safety can make up for the shortcomings of current clinical anticoagulant and antithrombotic drugs that are prone to bleeding complications and meet unmet clinical needs. Summary of the invention

[0008] The compounds of the present invention are novel oxopyridine compounds. Most of the compounds in the examples show good anticoagulant effects and have strong FXIa inhibitory effects.

[0009] In one aspect, the present invention provides a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0010] in,

[0011] R 1is selected from halogen or trifluoromethyl;

[0012] R 2 Independently selected from NH2, NHR 7 , OH or OR 8 , where: R 7 , R 8 is selected from alkyl or cycloalkyl, R 7 , R 8 The hydrogen in the atom can be replaced by one or more deuteriums;

[0013] R 3 , R 6 independently selected from hydrogen, halogen, alkoxy, haloalkyl or CONH2;

[0014] R 4 , R 5 are independently selected from hydrogen, halogen, alkoxy or haloalkyl;

[0015] R 9 Independently selected from CH3 or CD3;

[0016] Among them, except for the following compounds:

[0017] .

[0018] Furthermore, in the above compound, its stereoisomer or pharmaceutically acceptable salt, the R 1 Selected from chloro or trifluoromethyl;

[0019] or / and R 2 Independently selected from NH2, NHR 7 , OH, OR 8 , where: R 7 , R 8 is selected from methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl, R 7 , R 8 The hydrogen in the atom can be replaced by one or more deuteriums;

[0020] or / and R 3 , R 6 independently selected from hydrogen, fluorine, chlorine, methoxy, trifluoromethyl or CONH2;

[0021] or / and R 4 , R 5 independently selected from hydrogen, fluorine, chlorine, methoxy or trifluoromethyl;

[0022] or / and R 9 Independently selected from CH3 or CD3.

[0023] Furthermore, in the above compound, its stereoisomer or pharmaceutically acceptable salt, the R 1 Selected from trifluoromethyl;

[0024] or / and R 2 Independently selected from NH2, NHR 7 , OH or OR 8 , where: R 7 , R 8 is selected from methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl or tert-butyl, R 7 , R 8 The hydrogen in the atom can be replaced by one or more deuteriums;

[0025] or / and R 3 , R 6 independently selected from hydrogen, fluorine, chlorine, methoxy, trifluoromethyl or CONH2;

[0026] or / and R 4 , R 5 independently selected from hydrogen, fluorine or chlorine;

[0027] or / and R 9 Independently selected from CH3 or CD3.

[0028] Furthermore, in the above compound, its stereoisomer or pharmaceutically acceptable salt, the R 1 Selected from trifluoromethyl;

[0029] or / and R 2 Independently selected from NH2, NHCH3, NHCD3, OH, OCH3, OCD3 or OC(CH3)3;

[0030] or / and R 3 , R 6 independently selected from fluoro, chloro, methoxy or trifluoromethyl;

[0031] or / and R 4 , R 5 independently selected from hydrogen, fluorine or chlorine;

[0032] or / and R 9 Independently selected from CH3 or CD3.

[0033] Furthermore, the above compound, its stereoisomer or pharmaceutically acceptable salt comprises the following structure:

[0034] .

[0035] In case of conflict between chemical nomenclature and structural formula in the present invention, the compound structure represented by the number shall prevail.

[0036] Furthermore, hydrogen in the structure of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt may be replaced by one or more deuterium.

[0037] Furthermore, the deuterated compounds in which hydrogen in the structure of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts is replaced by one or more deuteriums include but are not limited to the above-mentioned Compound 28, Compound 29 and Compound 30.

[0038] In another aspect, the present invention provides a method for preparing the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, comprising the following steps:

[0039] When R 2 NH2, NHR 7 OR 8 The synthetic route is as follows:

[0040] ,in,

[0041] R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 The same definition as in any one of claims 1 to 6;

[0042] Step 1: The starting material a undergoes bromination reaction to generate intermediate b;

[0043] Step 2: Intermediate b undergoes a condensation reaction with starting material c to generate intermediate c;

[0044] Step 3: The intermediate d undergoes a substitution reaction with the compound e to generate a compound of formula (1);

[0045] When R 2 When it is OH, the synthetic route is as follows:

[0046] , in,

[0047] R 1 , R3 , R 4 , R 5 , R 6 , R 7 , R 9 The same definition as in any one of claims 1 to 6;

[0048] Step 4: Compound f undergoes hydrolysis under alkaline conditions to generate a compound of formula (1).

[0049] Furthermore, the present invention also provides a key intermediate, the structure of which is shown in the following formula e:

[0050] , where R 1 is selected from halogen or trifluoromethyl, R 9 Selected from CH3 or CD3; preferably, the R 1 is selected from halogen or trifluoromethyl, R 9 Selected from CD3.

[0051] Furthermore, the above intermediate is selected from the following compounds:

[0052] 5-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one;

[0053] 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one.

[0054] The above term "halogen" includes fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.

[0055] In a third aspect, the present invention provides a pharmaceutical composition comprising any of the above-mentioned compounds, stereoisomers or pharmaceutically acceptable salts thereof, and the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0056] In a fourth aspect, the present invention also provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt in the preparation of a drug for treating and / or preventing diseases associated with FXIa receptor.

[0057] Furthermore, the above-mentioned disease associated with FXIa receptor is selected from cerebrovascular arterial disease and / or peripheral arterial disease.

[0058] Further, the above-mentioned diseases associated with FXIa receptors are selected from transient ischemic attack (TIA), ischemic stroke, including cardiogenic stroke: such as stroke caused by atrial fibrillation, non-cardiogenic stroke: such as lacunar stroke, stroke caused by large artery or small artery disease, or stroke caused by undetermined causes, cryptogenic stroke, embolic stroke, embolic stroke of undetermined origin, or events of thrombotic and / or thromboembolic origin leading to stroke or TIA, and / or conditions of peripheral arteries leading to peripheral arterial disease, including peripheral arterial occlusion, acute limb ischemia, amputation, reocclusion and restenosis after intervention (such as angioplasty, stent implantation or surgery and bypass), and / or stent thrombosis.

[0059] The term "alkyl" in the present invention represents a C1-C16 straight-chain or branched saturated alkyl group. The same explanation applies to other alkyl moieties containing "alkyl" substituents.

[0060] Beneficial effects: Compared with the prior art, the compounds of the present invention have better in vitro anticoagulant effect, and at the same time, they are highly consistent with the inhibitory effect on FXIa in vitro. In addition, in some example compounds, the compounds of the present invention have better rat injection pharmacokinetic characteristics, such as compound 21, compound 25, compound 26, and compound 27 have better AUC and Cmax, better drug efficacy; at the same time, they also have the characteristics of rapid elimination and higher safety. DETAILED DESCRIPTION

[0061] The present invention will be further described in detail below in conjunction with embodiments and test examples. The embodiments and test examples of the present invention are only used to illustrate the technical scheme of the present invention, and are not intended to limit the present invention. Any equivalent substitutions in the art made in accordance with the contents disclosed in the present invention shall fall within the protection scope of the present invention.

[0062] The compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts can be prepared by selecting the synthetic routes of the embodiments, and the conventional conditions of the reaction raw materials and the reaction solvent can be adjusted according to the needs of the substituents or the salt formation, which can be realized by those skilled in the art based on the disclosure of the present invention. In addition, the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified, and the elution solvent can be determined as a single or mixed elution solvent in combination with the reaction solvent and the common knowledge or common means of those skilled in the art unless otherwise specified.

[0063] The structures of the compounds were determined by NMR ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0064] The liquid chromatography-mass spectrometer (LC-MS) was Agilent G6120B (used with Agilent 1260 liquid phase); the nuclear magnetic resonance instrument (1 HNMR) was Bruker AVANCE-400 or Bruker AVANCE-800, NMR ( 1 H NMR) shift ( δ ) are given in parts per million (ppm), the solvent used was DMSO, the internal standard was tetramethylsilane (TMS), and the chemical shift was based on 10 -6 (ppm) is given as the unit.

[0065] The term "room temperature" in the present invention means a temperature between 10 and 30°C.

[0066] The following compounds correspond to the compounds with corresponding codes in the table of the invention content of the specification.

[0067] Example 1: Preparation of Compound 1

[0068]

[0069] Step 1: (R)-2-Bromo-3-propionic acid

[0070] Take 5g (48.49mmol) of concentrated sulfuric acid, add it to 60ml of water, cool it to below 5℃, add 23g (193.3mmol) of potassium bromide, 5g (48.49mmol) of D-2-aminobutyric acid, and drop 5g (72.46mmol) of sodium nitrite dissolved in 30ml of water, control the temperature below 0~5℃, and add it in about 30 minutes. After the addition, stir and react at 0~5℃ overnight. The next day, the reaction solution was extracted twice with ethyl acetate, the organic phases were combined, the organic phases were washed with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 7.5g of oil, which was directly used in the next step without purification.

[0071] Step 2: Preparation of (R)-4-(2-bromobutyramide)-2-chlorobenzamide

[0072] Take 441mg (2.64mmol) (R)-2-bromo-3-propionic acid, dissolve it in 4ml tetrahydrofuran, add 300mg (1.76mmol) 4-amino-2-chlorobenzamide, cool to below 0℃, add 654mg (8.27mmol) pyridine, and then add 2.24g (3.52mmol) 1-propylphosphoric anhydride (50% ethyl acetate solution) diluted with 2ml tetrahydrofuran dropwise. After the addition, stir at 0~5℃ for 10 minutes, and stir at room temperature for 30 minutes. After the reaction is completed, add water to terminate the reaction, add EA for extraction, wash the organic phase with 5% citric acid, saturated sodium bicarbonate, water, saturated brine, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 540mg crude product. Add 5ml ethyl acetate to the crude product and stir at room temperature for 2 hours, filter, wash the filter cake with ethyl acetate, and dry the filter cake in vacuum to obtain 430mg white solid, with a yield of 76.4% and a purity of 96.55%.

[0073] ESI-MS: m / z=319.0 (M+H) + .

[0074] Step 3: Preparation of title compound 1

[0075] Take 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one, 5 ml of isopropanol, and 2 ml of acetone, add 187 mg (1.624 mmol) of tetramethylguanidine, stir for 5 minutes, add 207 mg (0.648 mmol) (R)-4-(2-bromobutyramide)-2-chlorobenzamide, stir at room temperature overnight. After the reaction is complete, add saturated ammonium chloride to terminate the reaction, add ethyl acetate for extraction, wash the organic phase with water and saturated brine in turn, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 400 mg of crude product. Purify by column, eluent (ethyl acetate: petroleum ether = 1:2), collect the product to obtain 245 mg of white solid. The yield is 74.6%, and the purity is 96.20%.

[0076] ESI-MS: m / z=609.1(M+H) + .

[0077] 1H NMR (400 MHz, DMSO-d6) δ:10.67 (s, 1H), 9.14 (d, 1H), 7.98 – 7.72(m, 5H), 7.60 – 7.30 (m, 3H), 7.13 (s, 1H), 6.53 (s, 1H), 5.51 (dd 1H), 3.25(s, 3H), 2.14-2.04 (m, 2H), 0.78 (t, 3H).

[0078] Example 2: Preparation of Compound 2

[0079] Step 1: Preparation of (S)-methyl 2-chloro-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)benzoate

[0080] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by methyl 4-amino-2-chlorobenzoate to obtain the title compound with a purity of 96.20%.

[0081] ESI-MS: m / z=624.1(M+H) + .

[0082] Step 2: Preparation of title compound 2

[0083] Take 250 mg (0.40 mmol) of (S)-2-chloro-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxypyridin-1(2H)-yl)butyramide)benzoic acid methyl ester, add 5 ml of methanol, heat to 50°C, add 51 mg (1.215 mmol) of lithium hydroxide monohydrate dissolved in 2.5 ml of water, and stir at 50°C for 1 hour. After the reaction is completed, add 5% citric acid aqueous solution to terminate the reaction, add ethyl acetate for extraction, wash the organic phase with water and saturated brine in turn, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 245 mg of crude product. Add 5 ml of ethyl acetate and stir at room temperature for 2 hours, filter, wash the filter cake with ethyl acetate, and vacuum dry the filter cake to obtain 200 mg of white solid, with a yield of 81.9% and a purity of 97.89%.

[0084] ESI-MS: m / z=610.1(M+H) + .

[0085] 1H NMR (400 MHz, DMSO-d6) δ:12.88 (s, 1H), 10.89 (s, 1H), 9.19 (s,1H), 8.05 – 7.88 (m, 3H), 7.69 – 7.36 (m, 3H), 7.28 (s, 1H), 6.55 (s, 1H), 5.58 (dd 1H), 3.28 (s, 3H), 2.15-2.03 (m, 2H), 0.76 (t, 3H).

[0086] Example 3: Preparation of Compound 3

[0087] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-chloro-N-methylbenzamide to obtain the title compound 3 with a purity of 96.80%.

[0088] ESI-MS: m / z=623.1(M+H) + .

[0089] 1 H NMR (400 MHz, DMSO-d6) δ:10.58 (s, 1H), 9.11 (s, 1H), 7.91 – 7.66(m, 4H), 7.58 – 7.25 (m, 3H), 7.15 (s, 1H), 6.51 (s, 1H), 5.53 (dd 1H), 3.26(s, 3H), 2.88 (d, 3H), 2.12-2.01 (m, 2H), 0.79 (t, 3H).

[0090] Example 4: Preparation of Compound 4

[0091] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-chloro-benzoic acid methyl ester to obtain the title compound 4 with a purity of 97.90%.

[0092] ESI-MS: m / z=624.1(M+H) + .

[0093] 1H NMR (400 MHz, DMSO-d6) δ:10.53 (s, 1H), 9.18 (s, 1H), 7.91 – 7.75 (m, 3H), 7.56 – 7.25 (m, 3H), 7.16 (s, 1H), 6.50 (s, 1H), 5.56 (dd 1H), 4.10(s, 3H), 3.28 (s, 3H), 2.18-2.07 (m, 2H), 0.79 (t, 3H).

[0094] Example 5: Preparation of Compound 5

[0095] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-methoxy-benzamide to obtain the title compound 5 with a purity of 97.95%.

[0096] ESI-MS: m / z=605.2(M+H) + .

[0097] 1 H NMR (400 MHz, DMSO-d6) δ:10.68 (s, 1H), 9.14 (d, 1H), 7.95 – 7.73(m, 4H), 7.56 (m, 2H), 7.46 (d, 1H), 7.19 (dd, 1H), 7.14 (s, 1H), 6.53 (s,1H), 5.54 (dd, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.16-2.04 (m, 2H), 0.78 (t,3H).

[0098] Example 6: Preparation of Compound 6

[0099] Step 1: Preparation of (S)-methyl 4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butanamido)-2-methoxybenzoate

[0100] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced with 4-amino-2-methoxy-benzoic acid methyl ester to obtain the title compound with a purity of 97.20%. ESI-MS: m / z=620.0 (M+H) + .

[0101] Step 2: Preparation of title compound 6

[0102] Take 250mg (0.403mmol) of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxypyridin-1(2H)-yl)butyramide)-2-methoxybenzoic acid methyl ester, add 6ml of methanol, add 68mg (1.62mmol) of lithium hydroxide monohydrate dissolved in 3ml of water, and stir at 60℃ for 1 hour. After the reaction is completed, cool to room temperature, add 5% citric acid aqueous solution to terminate the reaction, add ethyl acetate for extraction, wash the organic phase with water and saturated brine in turn, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 250mg of crude product. Purify by column, eluent (dichloromethane: methanol = 50:1), collect the target product to obtain 198mg of white solid, with a yield of 81.1% and a purity of 97.66%.

[0103] ESI-MS: m / z=606.1(M+H) + .

[0104] 1 H NMR (400 MHz, DMSO-d6) δ:12.35 (s, 1H), 10.68 (s, 1H), 9.14 (d,1H), 7.93 – 7.75 (m, 3H), 7.68 (d, 1H), 7.54 (d, 1H), 7.22 – 7.10 (m, 2H), 6.54 (s, 1H), 5.54 (dd, 1H), 3.78 (s, 3H), 3.25 (s, 3H), 2.14-2.04 (m, 2H), 0.79 (t, 3H).

[0105] Example 7: Preparation of Compound 7

[0106] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-benzamide to obtain the title compound 7 with a purity of 95.21%.

[0107] ESI-MS: m / z=643.1(M+H) + .

[0108] 1H NMR (400 MHz, DMSO-d6) δ:10.80 (s, 1H), 9.13 (s, 1H), 8.12 (d,1H), 8.02 – 7.72 (m, 5H), 7.54-7.51 (m, 2H), 7.14 (s, 1H), 6.54 (s, 1H), 5.51(dd, 1H), 3.25 (s, 3H), 2.23 – 2.03 (m, 2H), 0.79 (t, 3H).

[0109] Example 8: Preparation of Compound 8

[0110] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-1,2-dibenzamide to obtain the title compound 8 with a purity of 98.69%.

[0111] ESI-MS: m / z=618.2(M+H) + .

[0112] 1 H NMR (400 MHz, DMSO-d6) δ:11.09 (s, 1H), 9.20 (s, 1H), 8.28 – 7.96 (m, 5H), 7.85 – 7.59 (m, 5H), 7.28 (s, 1H), 6.96 (s, 1H), 5.98 (dd 1H), 3.29(s, 3H), 2.23-2.15 (m, 2H), 0.80 (t, 3H).

[0113] Example 9: Preparation of Compound 9

[0114] The preparation method is the same as the preparation method of Example 2, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one is replaced with 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one to obtain the title compound 9 with a purity of 97.25%.

[0115] ESI-MS: m / z=576.1(M+H) + .

[0116] 1H NMR (400 MHz, DMSO-d6) δ:12.88 (s, 1H), 10.89 (s, 1H), 9.19 (s,1H), 8.01 – 7.85 (m, 3H), 7.68 – 7.32 (m, 3H), 7.25 (s, 1H), 6.53 (s, 1H), 5.59 (dd 1H), 3.27 (s, 3H), 2.16-2.02 (m, 2H), 0.77 (t, 3H).

[0117] Example 10: Preparation of Compound 10

[0118] The preparation method is the same as the preparation method of Example 1, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one to obtain the title compound 10 with a purity of 98.14%.

[0119] ESI-MS: m / z=575.1(M+H) + .

[0120] 1 H NMR (400 MHz, DMSO-d6) δ:10.70 (s, 1H), 9.15 (d, 1H), 7.97 – 7.71(m, 5H), 7.59 – 7.28 (m, 3H), 7.15 (s, 1H), 6.54 (s, 1H), 5.52 (dd 1H), 3.28(s, 3H), 2.15-2.03 (m, 2H), 0.78 (t, 3H).

[0121] Example 11: Preparation of Compound 11

[0122] The preparation method is the same as the preparation method of Example 7, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-trifluoromethyl-benzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one to obtain the title compound 11 with a purity of 97.46%.

[0123] ESI-MS: m / z=609.1(M+H)+ .

[0124] 1 H NMR (400 MHz, DMSO-d6) δ:10.79 (s, 1H), 9.11 (s, 1H), 8.10 (d,1H), 8.00 – 7.69 (m, 5H), 7.56-7.53 (m, 2H), 7.18 (s, 1H), 6.56 (s, 1H), 5.53(dd, 1H), 3.28 (s, 3H), 2.21 – 2.00 (m, 2H), 0.77 (t, 3H).

[0125] Example 12: Preparation of Compound 12

[0126] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2,3-difluoro-benzamide to obtain the title compound 12 with a purity of 98.27%.

[0127] ESI-MS: m / z=611.1(M+H) + .

[0128] 1 H NMR (400 MHz, DMSO-d6) δ: 10.57 (s, 1H), 9.15 (s, 1H), 7.88 – 7.81(m, 2H), 7.79 (d, J = 2.1 Hz, 2H), 7.71 (d, J = 9.1 Hz, 2H), 7.53 – 7.37 (m,1H), 7.10 (s, 1H), 6.55 (s, 1H), 5.68 (s, 1H), 3.24 (s, 3H), 2.11 (dt, J =17.0, 8.6 Hz, 2H), 0.79 (t, J = 7.2 Hz, 3H).

[0129] Example 13: Preparation of Compound 13

[0130] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3-fluoro-benzamide to obtain the title compound 13 with a purity of 98.64%.

[0131] ESI-MS: m / z=593.1(M+H) + .

[0132] 1H NMR (400 MHz, DMSO-d6) δ: 10.41 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.05 – 7.93 (m, 2H), 7.88 – 7.81 (m, 2H), 7.80 – 7.78 (m, 1H), 7.78 – 7.67(m, 2H), 7.47 (s, 1H), 7.11 (s, 1H), 6.54 (s, 1H), 5.71 (s, 1H), 3.24 (s,3H), 2.25 – 1.95 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0133] Example 14: Preparation of Compound 14

[0134] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3,5-difluoro-benzamide to obtain the title compound 14 with a purity of 98.76%.

[0135] ESI-MS: m / z=611.1(M+H) + .

[0136] 1 H NMR (400 MHz, DMSO-d6) δ: 10.37 (s, 1H), 9.13 (s, 1H), 8.13 (s,1H), 7.87 – 7.80 (m, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J= 8.6 Hz, 2H), 7.07 (s, 1H), 6.56 (s, 1H), 5.65 (s, 1H), 3.22 (s, 3H), 2.15 –1.95 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H).

[0137] Example 15: Preparation of Compound 15

[0138] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3,5-dichloro-benzamide to obtain the title compound 15 with a purity of 98.12%.

[0139] ESI-MS: m / z=643.1(M+H) + .

[0140] 1H NMR (400 MHz, DMSO-d6) δ: 10.37 (s, 1H), 9.13 (s, 1H), 8.13 (s,1H), 7.92 – 7.88 (m, 2H), 7.82-7.78 (m, 1H), 7.69 (s, 1H), 7.66-7.62(m, 2H),7.07 (s, 1H), 6.56 (s, 1H), 5.65 (s, 1H), 3.22 (s, 3H), 2.18 – 1.98 (m, 2H),0.81 (t, J = 7.2 Hz, 3H).

[0141] Example 16: Preparation of Compound 16

[0142] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3-chloro-benzamide to obtain the title compound 16 with a purity of 98.48%.

[0143] ESI-MS: m / z=609.1(M+H) + .

[0144] 1 H NMR (400 MHz, DMSO-d6) δ:10.08 (s, 1H), 9.16 (s, 1H), 8.07 (s,1H), 8.00 (s, 1H), 7.84 (m, 4H), 7.79 (d, J = 2.1 Hz, 1H), 7.50 (s, 1H), 7.10(s, 1H), 6.57 (s, 1H), 5.69 (s, 1H), 3.24 (s, 3H), 2.28 – 2.03 (m, 2H), 0.80(t, J = 7.2 Hz, 3H).

[0145] Example 17: Preparation of Compound 17

[0146] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide to obtain the title compound 17 with a purity of 97.95%.

[0147] ESI-MS: m / z=607.1(M+H) + .

[0148] 1H NMR (400 MHz, DMSO-d6) δ: 10.83 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.13 – 8.06 (m, 1H), 7.89 – 7.80 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 –7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.25 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02(m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0149] Example 18: Preparation of Compound 18

[0150] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-methoxy-N-methylbenzamide to obtain the title compound 18 with a purity of 96.25%.

[0151] ESI-MS: m / z=619.2(M+H) + .

[0152] 1 H NMR (400 MHz, DMSO-d6) δ: 10.72 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.13 – 8.06 (m, 1H), 7.89 – 7.80 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 –7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0153] Example 19: Preparation of Compound 19

[0154] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3-fluoro-N-methylbenzamide to obtain the title compound 19 with a purity of 98.20%.

[0155] ESI-MS: m / z=607.1(M+H) + .

[0156] 1 H NMR (400 MHz, DMSO-d6) δ:10.40 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H), 7.98 (t, J = 8.1 Hz, 1H), 7.89 – 7.80 (m, 2H), 7.79(dd, J = 2.1, 0.7 Hz, 1H), 7.71 (dd, J = 11.8, 1.9 Hz, 1H), 7.66 (dd, J =8.4, 2.0 Hz, 1H), 7.11 (s, 1H), 6.54 (s, 1H), 5.70 (s, 1H), 3.24 (s, 3H), 2.77 (d, J = 4.5 Hz, 3H), 2.12 (dt, J = 15.2, 7.5 Hz, 2H), 0.78 (t, J = 7.1Hz, 3H).

[0157] Example 20: Preparation of Compound 20

[0158] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2,5-difluoro-N-methylbenzamide to obtain the title compound 20 with a purity of 98.20%.

[0159] ESI-MS: m / z=625.1(M+H) + .

[0160] 1H NMR (400 MHz, DMSO-d6) δ: 10.85 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.55 (q, J = 4.6 Hz, 1H), 7.88 – 7.81 (m, 2H), 7.80 – 7.76 (m, 1H), 7.36 (d,J = 9.8 Hz, 2H), 7.12 (s, 1H), 6.54 (s, 1H), 5.48 (s, 1H), 3.25 (s, 3H), 2.75(d, J = 4.6 Hz, 3H), 2.08 (tt, J = 16.0, 8.4 Hz, 2H), 0.78 (t, J = 7.2 Hz,3H).

[0161] Example 21: Preparation of Compound 21

[0162] The preparation method is the same as the preparation method of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluorobenzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one to obtain the title compound 21 with a purity of 97.65%.

[0163] ESI-MS: m / z=596.2(M+H) + .

[0164] 1 H NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H), 9.14 (d, J = 1.0 Hz, 1H), 7.89 – 7.81 (m, 2H), 7.79 (dd, J = 2.1, 0.7 Hz, 1H), 7.74 – 7.60 (m, 2H),7.55 (d, J = 11.3 Hz, 2H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54(s, 1H), 5.53 (s, 1H), 2.16 – 2.05 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0165] The intermediate in step 3: 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one, the structural confirmation data are as follows:

[0166] ESI-MS: m / z=374.1(M+H) + .

[0167] 1 H NMR (400 MHz, DMSO-d6) δ: 11.21 (s, 1H), 9.18 (s, 1H), 7.81 (s,2H), 7.72 (s, 1H), 6.95 (s, 1H), 6.41 (s, 1H).

[0168] Example 22: Preparation of Compound 22

[0169] The preparation method is the same as the preparation method in Example 1, except that the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy- d 3 )pyridin-2(1H)-one to obtain the title compound 22 with a purity of 97.65%.

[0170] ESI-MS: m / z=612.1(M+H) + .

[0171] 1 H NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H), 9.14 (d, J = 1.0 Hz, 1H), 7.97 – 7.79 (m, 2H), 7.79 (dd, J = 2.1, 0.7 Hz, 1H), 7.74 – 7.60 (m, 2H),7.55 (d, J = 11.3 Hz, 2H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54(s, 1H), 5.53 (s, 1H), 2.16 – 2.05 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0172] Example 23: Preparation of Compound 23

[0173] The preparation method is the same as the preparation method in Example 1, except that the 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3-fluorobenzamide, and the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy- d 3 )pyridin-2(1H)-one to obtain the title compound 23 with a purity of 97.65%.

[0174] ESI-MS: m / z=596.2(M+H) + .

[0175] 1 H NMR (400 MHz, DMSO-d6) δ:10.41 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.05 – 7.93 (m, 2H), 7.88 – 7.81 (m, 2H), 7.80 – 7.78 (m, 1H), 7.78 – 7.67(m, 2H), 7.47 (s, 1H), 7.11 (s, 1H), 6.54 (s, 1H), 5.71 (s, 1H), 2.25 – 1.95(m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0176] Example 24: Preparation of Compound 24

[0177] The preparation method is the same as the preparation method in Example 1, except that the 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-3-fluoro-N-methylbenzamide, and the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy- d 3 )pyridin-2(1H)-one to obtain the title compound 24 with a purity of 97.65%.

[0178] ESI-MS: m / z=610.2(M+H) + .

[0179] 1H NMR (400 MHz, DMSO-d6) δ: 10.40 (s, 1H), 9.15 (d, J = 1.0 Hz, 1H), 8.49 (d, J = 4.6 Hz, 1H), 7.98 (t, J = 8.1 Hz, 1H), 7.89 – 7.80 (m, 2H), 7.79(dd, J = 2.1, 0.7 Hz, 1H), 7.71 (dd, J = 11.8, 1.9 Hz, 1H), 7.66 (dd, J =8.4, 2.0 Hz, 1H), 7.11 (s, 1H), 6.54 (s, 1H), 5.70 (s, 1H), 2.77 (d, J = 4.5Hz, 3H), 2.12 (dt, J = 15.2, 7.5 Hz, 2H), 0.78 (t, J = 7.1 Hz, 3H).

[0180] Example 25: Preparation of Compound 25

[0181] The preparation method is the same as the preparation method of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-methylbenzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one to obtain the title compound 25 with a purity of 98.85%.

[0182] ESI-MS: m / z=610.2(M+H) + .

[0183] 1H NMR (400 MHz, DMSO-d6) δ: 10.80 (s, 1H), 9.20 – 9.08 (m, 1H), 8.10(q, J = 4.2 Hz, 1H), 7.93 – 7.81 (m, 2H), 7.78 (d, J = 2.1 Hz, 1H), 7.70 –7.58 (m, 2H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (s, 1H), 2.76 (d, J = 4.6 Hz, 3H), 2.20 – 2.02 (m, J = 7.6 Hz, 2H), 0.78(t, J = 7.2 Hz, 3H).

[0184] Example 26: Preparation of Compound 26

[0185] The preparation method is the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide to obtain the title compound 26 with a purity of 99.12%.

[0186] ESI-MS: m / z=610.2(M+H) + .

[0187] 1 H NMR (400 MHz, DMSO-d6) δ:10.79 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.06 (d, J = 3.4 Hz, 1H), 7.92 – 7.81 (m, 2H), 7.81 – 7.76 (m, 1H), 7.70 –7.60 (m, 2H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.51 (d, J = 8.6 Hz, 1H), 3.25 (s, 3H), 2.19 – 1.99 (m, J = 7.1 Hz, 2H), 0.78(t, J = 7.2 Hz, 3H).

[0188] Example 27: Preparation of Compound 27

[0189] The preparation method is the same as the preparation method of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one to obtain the title compound 27 with a purity of 98.07%.

[0190] ESI-MS: m / z=613.2(M+H) + .

[0191] 1 H NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.06 (d, J = 3.4 Hz, 1H), 7.90 – 7.76 (m, 3H), 7.71 – 7.60 (m, 2H), 7.37 (dd,J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (s, 1H), 2.09 (h, J =7.1 Hz, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0192] Example 28: Preparation of Compound 28

[0193] The preparation method is the same as the preparation method of Example 1, except that the D-2-aminobutyric acid in step 1 is replaced by (R)-2-aminobutyric acid-3,3,4,4,4-d5 acid, and the 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-benzamide to obtain the title compound 28 with a purity of 97.36%.

[0194] ESI-MS: m / z=598.2(M+H) + .

[0195] 1 H NMR (400 MHz, DMSO-d6) δ: 10.72 (s, 1H), 9.10 (d, 1H), 7.98 – 7.74 (m, 5H), 7.62 – 7.36 (m, 3H), 7.11 (s, 1H), 6.56 (s, 1H), 5.50 (dd 1H), 3.26(s, 3H).

[0196] Example 29: Preparation of Compound 29

[0197] The preparation method is the same as the preparation method of Example 1, except that 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-benzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-3,4,6-d3)-5-(methoxy)pyridin-2(1H)-one to obtain the title compound 29 with a purity of 97.66%.

[0198] ESI-MS: m / z=596.2(M+H) + .

[0199] 1 H NMR (400 MHz, DMSO-d6)δ: 10.80 (s, 1H), 9.15 (d, 1H), 7.92 – 7.82(m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.72 – 7.62 (m, 2H), 7.13 (s, 1H), 6.54(s, 1H), 5.52 (s, 1H), 3.28 (s, 3H), 2.21 – 2.03 (m, J = 7.6 Hz, 2H), 0.79(t, J = 7.2 Hz, 3H).

[0200] Example 30: Preparation of Compound 30

[0201] The preparation method is the same as the preparation method of Example 1, except that the D-2-aminobutyric acid in step 1 is replaced by (R)-2-aminobutyric acid-3,3,4,4,4-d5 acid, the 4-amino-2-chlorobenzamide in step 2 is replaced by 4-amino-2-fluoro-N-(methyl-d3)benzamide, and the 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one in step 3 is replaced by 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridin-2(1H)-one to obtain the title compound 30 with a purity of 98.62%.

[0202] ESI-MS: m / z=618.2(M+H) + .

[0203] 1H NMR (400 MHz, DMSO-d6) δ:10.78(s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.06 (d, J = 3.4 Hz, 1H), 7.92 – 7.78 (m, 3H), 7.71 – 7.60 (m, 2H), 7.37 (dd,J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (s, 1H).

[0204] Comparative Example 1: Preparation of (S)-4-(2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)butyramido)-2-fluorobenzamide

[0205]

[0206] It was synthesized according to the method described in patent CN108026072B, with a purity of 98.5%.

[0207] ESI-MS: m / z =593.1(M+H) + .

[0208] 1 H NMR (400 MHz, DMSO-d6) δ: 10.78 (s, 1H), 9.14 (s, 1H), 7.88 – 7.77(m, 3H), 7.72 – 7.61 (m, 2H), 7.55 (d, 2H), 7.37 (dd, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (dd, 1H), 3.25 (s, 3H), 2.18 – 2.00 (m, 2H), 0.78 (t, 3H).

[0209] Test Example 1: Determination of the anticoagulant effect of human plasma in vitro

[0210] 1. Test samples

[0211] Example compounds 1 to 30 and comparative example 1.

[0212] 2. Test methods

[0213] Use sodium citrate (1:9) anticoagulant tubes to collect blood from healthy individuals, mix it thoroughly with the anticoagulant immediately, and centrifuge it at 4000r / min for 15 minutes at room temperature. After centrifugation, use a pipette to draw the plasma sample and freeze it (-80℃) for later use.

[0214] Weigh an appropriate amount of compound and prepare a 10-100 mM stock solution with 100% DMSO (the specific concentration of the stock solution depends on the properties of the compound); then prepare working solutions of different concentrations using healthy human plasma as the solution (specifically: 1, 3, 10 μM), mix thoroughly; incubate at 37°C for 3 minutes and then perform APTT determination on a machine (model CS-2000I).

[0215] 3. Data processing

[0216] GraphPad Prism software was used for analysis to calculate the APTT prolongation rate at each concentration.

[0217] 4. Test results

[0218] .

[0219] The results are shown in the table above. The APTT extension rates of the tested compounds 1, 2, 5, 6, 13, 17, 21, 25, 26, and 27 at 1 μM are all better than those of the compound in comparative example 1, and the APTT extension rates are greater than 50%. The test results estimate that the EC150 of the above invention compounds is less than 1 μM.

[0220] Test Example 2: Determination of the activity of coagulation factor FXIa inhibitor

[0221] 1. Test samples

[0222] Example compounds and comparative example 1.

[0223] 2. Test steps

[0224] 1) Prepare the experimental buffer (50 mM HEPES, 5 mM KCl, 145 mM NaCl, 1 mg / ml PEG8000, pH 7.4) and equilibrate to room temperature;

[0225] 2) Prepare 10X compound working solution;

[0226] 3) Prepare 0.8nM human FXIa working solution (2X), mix well and set aside;

[0227] 4) Add 20 μL of FXIa working solution in step 3) to all experimental wells of a 384-well plate (Coring, 3702), centrifuge at 200 g, RT, for 10 s;

[0228] 5) Add 4 μL of the compound working solution in step 2) to the corresponding experimental wells in the 384-well plate, centrifuge at 200g, RT for 10 seconds, and then incubate the working plate at 25°C for 20 minutes;

[0229] 6) Prepare 750 μM S-2366 working solution (2.5X), mix well and set aside;

[0230] 7) Add 16 μL of S-2366 working solution from step 6) to all experimental wells in the 384-well plate, centrifuge at 200g, RT for 10 seconds, and then incubate the working plate at 37°C for 45 minutes;

[0231] 8) After incubation, use EnVision to read the absorbance value at OD405nm and collect the data.

[0232] 3. Data Analysis

[0233] 1) Z' factor = 1-3*(SD Max +SD Min ) / (Mean Max -Mean Min );

[0234] 2) CV Max = (SD Max / Mean Max )*100%;

[0235] 3) CVMin = (SD Min / Mean Min )*100%;

[0236] 4) S / B = Singal / Background;

[0237] 5) Blank control: 0.1% DMSO; Positive control: Comparative Example 1;

[0238] 6) IC 50 Calculation formula: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0239] X: log value of compound concentration; Y: inhibition rate (%).

[0240] Concentration setting: 5 concentrations, namely: 200nM, 40nM, 8nM, 1.6nM, 0.32nM, detection IC 50 value.

[0241] 4. Test results

[0242] The test results are shown in the following table: the tested compounds of the present invention all have a relatively obvious in vitro inhibitory effect on FXIa, and the inhibitory effect of compounds 2, 6, 17, 21, 25, 26, and 27 of the present invention on FXIa is stronger than that of the compound in comparative example 1, especially compound 2 and compound 6. The other tested inventive compounds have an inhibitory effect on FXIa equivalent to that of the comparative example.

[0243] .

[0244] Test Example 3: Pharmacokinetic Study in Rats

[0245] 1. Test samples

[0246] Comparative Example 1 and Example Compounds 2, 6, 21, 25, 26, 27, and 28.

[0247] 2. Test operation

[0248] The experiment used 48 SD rats, all male, divided into 8 groups, 6 rats in each group, namely control group 1, compound group 2, compound group 6, compound group 21, compound group 25, compound group 26, compound group 27, and compound group 28. The rats were fasted for 12 h before administration and had free access to water. Each group was given an oral gavage dose of 30 mg / kg.

[0249] Blank blood was collected before administration, and blood was collected at predetermined time points after administration: 5min, 15min, 30min, 45min, 1h, 2h, 3h, 5h, 7h, and 24h. About 0.5mL of blood was collected and placed in an EDTA-K2 tube. The plasma was separated by centrifugation and stored at -80°C. The blood concentration of the drug was detected by liquid chromatography-mass spectrometry analysis system (LC-MS / MS). Based on the plasma concentration data of the drug, the pharmacokinetic parameters were calculated using DAS 2.0 software to provide parameters such as AUC0-t, Cmax, Tmax, and t1 / 2.

[0250] 3. Test results

[0251] The experimental results of the pharmacokinetic study of oral administration in rats are shown in the following table. Compared with the comparative example 1, the example compounds 2, 6, 21, 25, 26, and 27 have better absorption, AUC (0-t) Especially for Compound 21, Compound 25, Compound 26, and Compound 27, at the same dosage, AUC and Cmax were significantly improved compared with Comparative Example 1, indicating that the same drug efficacy was achieved with a lower dosage of the compound in this example.

[0252] At the same time, compared with Comparative Example 1 and Compound 28, Compound 21, Compound 25, Compound 26, and Compound 27 have shorter half-lives and have rapid elimination pharmacokinetic characteristics, indicating that their potential safety risks of bleeding are also lower, and it also proves that not all deuterated positions have the effect of extending the half-life. In particular, the present invention unexpectedly found that the general structure (I) containing R 9 and / or R 2 Deuterated compounds at the 3 position have more advantageous pharmacokinetic results.

[0253] .

[0254] Test Example 4: Effects of continuous drug administration on general state and food intake in rats

[0255] 1. Experimental drugs

[0256] Comparative Example 1 and Example Compound 2, Compound 21, Compound 25, Compound 26, and Compound 27.

[0257] 2. Experimental plan

[0258] 70 healthy adult SD rats were randomly divided into 7 groups, each group had half male and half female, and divided into blank group, comparative example group 1, compound group 2, compound group 21, compound group 25, compound group 26, and compound group 27, with 10 rats in each group. The drugs were administered orally by gavage. The administration schedule was shown in the table below. The drugs were administered continuously for 14 days, once a day. The blank group was administered with the same volume of solvent. After administration, the effects of the drugs on the general state and food intake of the rats were observed and recorded.

[0259] .

[0260] 3. Test results

[0261] In the study of the general condition of rats after continuous oral administration for 14 days, more than 1 / 3 of the rats in the control group 1 showed piloerection and hypoactivity; no obvious abnormalities were found in the other groups.

[0262] The results of the observation of the food intake of rats in each group after continuous intragastric administration for 14 days are shown in the following table:

[0263] .

[0264] As can be seen from the table above, compared with the blank group, the food intake of rats in the control group 1 was significantly reduced within 24 hours after the last administration (P<0.001); the food intake of rats in the compound 2 group, compound 21 group, compound 25 group, compound 26 group, and compound 27 group within 24 hours after the last administration was basically the same as that of the blank group, with no statistical difference. This proves that the compounds of the present invention are safer and have a lower risk of tissue toxicity.

[0265] The above embodiment is only one of the preferred implementation modes of the present invention and should not be used to limit the protection scope of the present invention. Any changes or modifications that are made to the main design concept and spirit of the present invention and have no substantive significance, and the technical problems they solve are still consistent with the present invention, should be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I), its stereoisomer or pharmaceutically acceptable salt: ， in, R 1 Selected from trifluoromethyl; R 2 Selected from NH2, NHR 7 or OH, where: R 7 is selected from methyl, ethyl or propyl, R 7 The hydrogen in the atom can be replaced by one or more deuteriums; R 3 , R 4 , R 5 are independently selected from hydrogen, R 6 Selected from fluorine; R 9 Selected from CD3.

2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, characterized in that: The R 2 Selected from NH2, NHCH3, NHCD3 or OH.

3. A compound represented by formula (I), its stereoisomer or pharmaceutically acceptable salt: ， in, R 1 Selected from trifluoromethyl; R 9 Selected from CH3; R 2 Selected from OH, R 3 , R 4 , R 5 are independently selected from hydrogen, R 6 is selected from fluorine, chlorine or methoxy.

4. A compound represented by formula (I), its stereoisomer or pharmaceutically acceptable salt: ， in, R 1 Selected from trifluoromethyl; R 9 Selected from CH3; R 2 is selected from NH2, NHCH3 or NHCD3, R 3 , R 4 , R 5 are independently selected from hydrogen, R 6 is selected from fluoro or methoxy; Among them, except for the following compounds: 。 5. A compound, a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following structures: , , , , , , , , , or .

6. The compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt, characterized in that: The hydrogen in the compound, its stereoisomer or pharmaceutically acceptable salt may be replaced by one or more deuterium.

7. A method for preparing the compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt, characterized in that: The following steps are involved: When R 2 NH2 or NHR 7 The synthetic route is as follows: ， Where R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 The same definition as in any one of claims 1 to 6; Step 1: The starting material a undergoes bromination reaction to generate intermediate b; Step 2: Intermediate b undergoes a condensation reaction with starting material c to generate intermediate d; Step 3: The intermediate d undergoes a substitution reaction with the compound e to generate a compound of formula (1); When R 2 When it is OH, the synthetic route is as follows: ， Where R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 The same definition as in any one of claims 1 to 6; Step 4: Compound f undergoes hydrolysis under alkaline conditions to generate a compound of formula (1).

8. A key intermediate, characterized in that: The structure is shown in formula e below: , where R 1 Selected from trifluoromethyl, R 9 Selected from CD3.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt, characterized in that: The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt in the preparation of a medicament for treating and / or preventing diseases associated with FXIa receptor.

11. The use according to claim 10, characterized in that The disease associated with FXIa receptor is selected from cerebrovascular arterial disease and / or peripheral arterial disease.

12. The use according to claim 10, characterized in that The disease associated with FXIa receptor is selected from thromboembolism.

13. The use according to claim 10, characterized in that The disease associated with FXIa receptor is selected from transient ischemic attack (TIA), ischemic stroke, thrombosis and / or thromboembolism leading to stroke or TIA, peripheral arterial disorders leading to peripheral arterial disease.

14. The use according to claim 13, characterized in that The ischemic stroke includes cardiogenic stroke and non-cardiogenic stroke; the cardiogenic stroke includes stroke caused by atrial fibrillation; the non-cardiogenic stroke includes lacunar stroke, stroke caused by large artery or small artery disease, or stroke caused by undetermined causes, cryptogenic stroke, and embolic stroke; the peripheral arterial disorders that lead to peripheral arterial disease include peripheral arterial occlusion, acute limb ischemia, amputation, re-occlusion and restenosis after intervention, and stent thrombosis.

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