Novel oxopyridine compounds and their preparation and use

Abstract

The present invention discloses a compound represented by formula (I), its stereoisomer, or pharmaceutically acceptable salt, and key intermediates. The present invention further provides the use of the compound, its stereoisomer, or pharmaceutically acceptable salt in the manufacture of a medicament for treating and / or preventing a disease associated with the FXIa receptor, particularly in the manufacture of a medicament for treating and / or preventing cerebrovascular arterial disease and / or peripheral arterial disease. TIFF2025542415000028.tif41165

Description

[Technical Field]

[0001] Related Applications This application claims priority to a patent for invention entitled "Novel oxopyridine compounds and their preparation and use," filed on December 21, 2022, with patent number CN202211647390.2, which is expressly incorporated herein by reference.

[0002] The present invention relates to the field of medicinal chemistry, and more particularly to oxopyridine compounds or their salts and isomers, their preparation methods, and their use in the preparation of medicines for treating and / or preventing diseases associated with the FXIa receptor, particularly their use in the preparation of medicines for treating and / or preventing cerebrovascular arterial disease and / or peripheral arterial disease. [Background technology]

[0003] Thromboembolism is a disease caused by abnormal blood clots formed in blood vessels during human and animal life. Thrombosis is a group of complications resulting from many different diseases and causes, resulting from three factors: vascular damage, blood changes, and blood flow stagnation. Depending on the underlying disease and the location of the thrombus, thrombosis can be clinically manifested as myocardial infarction, stroke, deep vein thrombosis (DVT), pulmonary embolism, atrial fibrillation, cerebral infarction, etc. Myocardial infarction, cerebral infarction, and pulmonary infarction, which are primarily caused by embolism and infarction, are the leading causes of death, claiming approximately 12 million lives worldwide each year, accounting for nearly a quarter of the world's total deaths.

[0004] Coagulation factor XI (FXI) is a plasma serine protease zymogen required for maintaining the intrinsic pathway. Upon activation, it generates activated coagulation factor XIa (FXIa), which plays a key role in the cascade progression of the blood coagulation pathway. In the blood coagulation pathway, thrombin feedback-activates FXI, which then promotes the generation of thrombin, amplifying the cascade progression. Therefore, drugs targeting FXI can block the intrinsic pathway and inhibit the cascade progression of the blood coagulation pathway, thereby playing an antithrombotic role. Recent clinical data suggest that clotting factor XI (FXI) deficiency or elevated FXI levels are associated with the development of thrombotic disorders in humans, and experimental studies of FXI deficiency, knockout, or inhibition in animals suggest that FXI inhibition can reduce bleeding risk compared with direct FXa inhibition, making FXI a novel target for antithrombotic prevention and treatment.

[0005] Previously reported FXI inhibitors mainly include monoclonal antibodies, antisense oligomers, small chemical molecules, polypeptides or proteins, and polypeptide analogs. Currently, Milvexian, jointly developed by BMS and Johnson & Johnson, has completed Phase II clinical trials, with results showing a low risk of bleeding. BMS's intravenous small molecule FXIa inhibitor, BMS-962122, has completed Phase I clinical trials and has been discontinued. ONO-7684, a small molecule oral FXIa inhibitor developed by Ono Pharmaceuticals Japan, is currently undergoing Phase I clinical trials. Monoclonal antibodies and antisense oligomers require injection and have drawbacks, such as high cost, slow efficacy, and difficulty in control.

[0006] The in vivo efficacy, pharmacokinetics, and toxicity of drugs are influenced by multiple factors and are therefore quite complex. Even slight changes in the chemical structure at any position can cause changes in the drug's efficacy, pharmacokinetics, and toxicity in the body. For example, with regard to deuteration, changes in the pharmacokinetics and other properties of deuterated drugs compared to corresponding non-deuterated drugs are highly random and unpredictable. Deuteration at certain sites has the effect of extending half-life. Examples include commercially available drugs such as ingenol disoxate and deutetrabenazine. On the other hand, deuteration at certain sites may not extend half-life but may actually shorten it (Scott L. Harbeson, Roger D. Tung, Deuterium in Drug Discovery and Development, pp. 405-406). Meanwhile, hydrogen at certain positions on drug molecules is difficult to deuterate due to steric hindrance and other factors, so the site of deuteration of drugs can be unexpected.

[0007] Asundexian, a Bayer FXI inhibitor, has entered Phase III clinical trials and has a mean terminal half-life of 17.8 hours, which is longer than that of apixaban and has a lower bleeding risk. However, there is still a significant risk of bleeding. Therefore, by developing a new FXIa small molecule inhibitor with stronger activity, better absorption, relatively rapid metabolism, lower bleeding risk, and better safety, it can make up for the shortcomings of current clinical anticoagulant and antithrombotic drugs, which 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. Many of the compounds in the examples exhibit good anticoagulant activity and potent FXIa inhibitory activity.

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

[0010] [ka]

[0011] (where, R 1 is selected from halogen or trifluoromethyl groups, R 2 are independently NH2, NHR 7 , OH or OR 8 Selected from, with the proviso that R 7 , R 8 is selected from alkyl groups or cycloalkyl groups, and R 7 , R 8 wherein one or more hydrogen atoms may be substituted with deuterium atoms, R 3 , R 6 are independently selected from hydrogen, halogen, an alkoxy group, a halogenated alkyl group, or CONH2; R 4 , R 5 are independently selected from hydrogen, halogen, an alkoxy group, or a halogenated alkyl group; R 9 are independently selected from CH3 or CD3. However, it does not fall under the following compounds. [ka]

[0012] Furthermore, in the above compound, its stereoisomer or pharmaceutically acceptable salt, 1 is selected from chlorine and trifluoromethyl groups, or / and, R 2 are independently NH2, NHR 7 , OH, OR 8 Selected from, with the proviso that R 7 , R 8 is selected from a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopropylmethyl group, or a t-butyl group, and R 7 , R 8 wherein one or more hydrogen atoms may be substituted with deuterium atoms, or / and, R 3 , R 6are independently selected from hydrogen, fluorine, chlorine, a methoxy group, a trifluoromethyl group, or CONH2; or / and, R 4 , R 5 are independently selected from hydrogen, fluorine, chlorine, a methoxy group, and a trifluoromethyl group; or / and, R 9 is independently selected from CH3 or CD3.

[0013] Furthermore, in the above compound, its stereoisomer or pharmaceutically acceptable salt, 1 is selected from a trifluoromethyl group, or / and, R 2 are independently NH2, NHR 7 , OH or OR 8 Selected from, with the proviso that R 7 , R 8 is selected from a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopropylmethyl group, or a t-butyl group, and R 7 , R 8 wherein one or more hydrogen atoms may be substituted with deuterium atoms, or / and, R 3 , R 6 are independently selected from hydrogen, fluorine, chlorine, a methoxy group, a trifluoromethyl group, or CONH2; or / and, R 4 , R 5 are independently selected from hydrogen, fluorine or chlorine; or / and, R 9 is independently selected from CH3 or CD3.

[0014] Furthermore, in the above compound, its stereoisomer or pharmaceutically acceptable salt, 1 is selected from a trifluoromethyl group, or / and, R 2 are independently selected from NH2, NHCH3, NHCD3, OH, OCH3, OCD3, or OC(CH3)3; or / and, R 3 , R 6are independently selected from fluorine, chlorine, a methoxy group, or a trifluoromethyl group; or / and, R 4 , R 5 are independently selected from hydrogen, fluorine or chlorine; or / and, R 9 is independently selected from CH3 or CD3.

[0015] Additionally, the above compound, its stereoisomer, or pharmaceutically acceptable salt includes the following structure: [ka] [ka] [ka] [ka] [ka]

[0016] In the present invention, when the chemical name and the structural formula do not coincide, the compound structure represented by the number shall prevail.

[0017] Furthermore, one or more hydrogen atoms in the structure of the above compound, its stereoisomer or pharmaceutically acceptable salt may be replaced with deuterium atoms.

[0018] Furthermore, deuterated compounds in which one or more hydrogen atoms in the structure of the above compounds, their stereoisomers, or pharmaceutically acceptable salts are replaced with deuterium atoms include, but are not limited to, Compound 28, Compound 29, and Compound 30.

[0019] In another aspect, the present invention provides a process for preparing the above compound, a stereoisomer or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0020] R 2NH2, NHR 7 OR 8 In this case, the synthesis route is as follows: [ka] (However, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 The definitions of are the same as those in any one of claims 1 to 6.) Step 1: Starting material a undergoes a bromination reaction to produce intermediate b. Step 2: Intermediate b and starting material c undergo a condensation reaction to produce intermediate c. Step 3: Intermediate d undergoes a substitution reaction with compound e to produce a compound of formula (1).

[0021] R 2 When is OH, the synthetic route is as follows: [ka] (However, R 1 , R 3 , R 4 , R 5 ), R 6 , R 7 , R 9 The definition of is the same as the definition corresponding to any one of claims 1 to 6. Step 4: Compound f undergoes hydrolysis under alkaline conditions to produce the compound of formula (1).

[0022] Additionally, the present invention further provides a key intermediate whose structure is shown in formula e below: [ka] (where R 1 is selected from halogen or trifluoromethyl group, R 9 is selected from CH3 or CD3, and preferably,1 is selected from halogen or trifluoromethyl group, R 9 is selected from CD3.)

[0023] Furthermore, the intermediate is selected from the following compounds: 5-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone.

[0024] The term "halogen" includes fluorine, chlorine, bromine or iodine, with fluorine, chlorine or bromine being preferred.

[0025] In a third aspect, the present invention provides a pharmaceutical composition comprising any of the compounds described above, or a stereoisomer or pharmaceutically acceptable salt thereof, further comprising a pharmaceutically acceptable excipient.

[0026] In a fourth aspect, the present invention further provides the use of the above compound, a stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing a disease associated with the FXIa receptor.

[0027] Furthermore, the FXIa receptor-associated disease is selected from cerebrovascular arterial disease and / or peripheral arterial disease.

[0028] Furthermore, the above-mentioned FXIa receptor-related diseases are selected from peripheral arterial diseases resulting in peripheral arterial occlusion, acute limb ischemia, limb amputation, re-occlusion and restenosis after intervention (e.g., angioplasty, stent placement or surgery and bypass), and / or peripheral arterial disease including cardiogenic stroke, e.g., stroke due to atrial fibrillation, non-cardiogenic stroke, e.g., lacunar stroke, stroke due to large or small arterial disease, or stroke of undetermined cause, cryptogenic stroke, embolic stroke, embolic stroke of undetermined origin, or transient ischemic attack (TIA) including events of thrombus formation and / or thromboembolic origin leading to stroke or TIA, ischemic stroke, and / or peripheral arterial disease including peripheral arterial occlusion, acute limb ischemia, limb amputation, re-occlusion and restenosis after intervention (e.g., angioplasty, stent placement or surgery and bypass), and / or stent thrombosis.

[0029] The term "alkyl group" of the present invention refers to a C1 to C16 linear or branched saturated alkyl group. Alkyl group moieties containing other "alkyl group" substituents are to be interpreted similarly. [Effects of the Invention]

[0030] The compounds of the present invention have better in vitro anticoagulant effects than the prior art, and their inhibitory effects on FXIa are highly consistent in vitro. In addition, some example compounds of the present invention have better pharmacokinetic characteristics in rat injection. For example, Compound 21, Compound 25, Compound 26, and Compound 27 have better AUC and Cmax, better efficacy, and are rapidly eliminated, resulting in higher safety. DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention will be described in detail below with reference to examples and test examples. However, the examples and test examples of the present invention are only intended to explain the technical solutions of the present invention and are not intended to limit the present invention. Any equivalent substitutions made in the field based on the contents disclosed in the present invention are all within the scope of protection of the present invention.

[0032] The compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts can all be prepared according to the synthetic routes in the Examples. Furthermore, the usual conditions for the reaction raw materials and reaction solvents can be adjusted as needed for the substitution or salt formation. These can all be achieved by those skilled in the art based on the disclosure of the present invention. Unless otherwise specified, the column chromatography of the present invention refers to silica gel column chromatography. Unless otherwise specified, the elution solvent can be determined as a single or mixed elution solvent based on the reaction solvent and the common knowledge or conventional means of those skilled in the art.

[0033] The structure of the compound was determined by nuclear magnetic resonance ( 1 Determined by 1 H NMR or liquid chromatography-mass spectrometry (LC-MS).

[0034] The liquid chromatograph mass spectrometer (LC-MS) was an Agilent G6120B (used in combination with a liquid-phase Agilent 1260). 1 1 H NMR) is performed on a Bruker AVANCE-400 or Bruker AVANCE-800. 1 1 H NMR shifts (δ) are given in parts per million (ppm), the measurement solvent was DMSO, the internal standard was tetramethylsilane (TMS), and the chemical shifts are expressed as 10 -6 The unit is (ppm).

[0035] The term "room temperature" in the present invention refers to a temperature between 10 and 30°C.

[0036] Example 1: Preparation of Compound 1

[0037] [ka]

[0038] Step 1: (R)-2-Bromo-3-propionic acid 5 g (48.49 mmol) of concentrated sulfuric acid was added to 60 ml of water and cooled to below 5°C. 23 g (193.3 mmol) of potassium bromide and 5 g (48.49 mmol) of D-2-aminobutyric acid were added, and 5 g (72.46 mmol) of sodium nitrite dissolved in 30 ml of water was added dropwise over approximately 30 minutes while controlling the temperature below 0-5°C. After the addition was complete, the mixture was stirred overnight at 0-5°C. The next day, the reaction mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 7.5 g of an oil, which was used directly in the next step without further purification.

[0039] Step 2: Preparation of (R)-4-(2-bromobutanamido)-2-chlorobenzamide 441 mg (2.64 mmol) of (R)-2-bromo-3-propionic acid was dissolved in 4 mL of tetrahydrofuran, 300 mg (1.76 mmol) of 4-amino-2-chlorobenzamide was added, and the mixture was cooled to below 0 °C. 654 mg (8.27 mmol) of pyridinium chloride was added, followed by dropwise addition of 2.24 g (3.52 mmol) of 1-propanephosphonic anhydride (50% ethyl acetate solution) diluted with 2 mL of tetrahydrofuran. After the addition was complete, the mixture was stirred at 0-5 °C for 10 minutes and then at room temperature for 30 minutes. Upon completion of the reaction, water was added to quench the reaction, followed by extraction with EA. The organic phase was washed sequentially with 5% citric acid, saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 540 mg of crude product. 5 ml of ethyl acetate was added to the crude product, stirred at room temperature for 2 hours, filtered, the filter cake was washed with ethyl acetate, and the filter cake was dried in vacuo to obtain 430 mg of a white solid, with a yield of 76.4% and a purity of 96.55%.

[0040] ESI-MS: m / z = 319.0 (M+H) + .

[0041] Step 3: Preparation of Title Compound 1 200 mg (0.539 mmol) of 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone, 5 ml of isopropyl alcohol, and 2 ml of acetone were mixed, and 187 mg (1.624 mmol) of tetramethylguanidine was added. The mixture was stirred for 5 minutes, and 207 mg (0.648 mmol) of (R)-4-(2-bromobutanamido)-2-chlorobenzamide was added. The mixture was stirred overnight at room temperature. Upon completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 400 mg of crude product. The product was purified on a column using ethyl acetate:petroleum ether (1:2) as the eluent. The product was collected to give 245 mg of a white solid. The yield was 74.6% and the purity was 96.20%.

[0042] ESI-MS: m / z=609.1 (M+H) + .

[0043] 1 H 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).

[0044] Example 2: Preparation of Compound 2

[0045] Step 1: Preparation of (S)-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)butamido)benzoic acid methyl ester The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-chlorobenzoic acid methyl ester, and the title compound was prepared with a purity of 96.20%.

[0046] ESI-MS: m / z=624.1 (M+H) + .

[0047] Step 2: Preparation of Title Compound 2 250 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-oxopyridin-1(2H)-yl)butamido)benzoic acid methyl ester was taken, 5 ml of methanol was added, and the mixture was heated to 50 °C. 51 mg (1.215 mmol) of lithium hydroxide monohydrate dissolved in 2.5 ml of water was added, and the mixture was stirred at 50 °C for 1 hour. Upon completion of the reaction, the reaction was quenched by adding 5% aqueous citric acid, followed by extraction with ethyl acetate. The organic phase was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 245 mg of crude product. 5 ml of ethyl acetate was added, and the mixture was stirred at room temperature for 2 hours, filtered, the filter cake was washed with ethyl acetate, and the filter cake was dried in vacuo to obtain 200 mg of a white solid, with a yield of 81.9% and a purity of 97.89%.

[0048] ESI-MS: m / z=610.1 (M+H) + .

[0049] 1 H 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).

[0050] Example 3: Preparation of Compound 3 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-chloro-N-methylbenzamide, thereby producing the title compound 3 with a purity of 96.80%.

[0051] ESI-MS: m / z=623.1 (M+H) + .

[0052] 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).

[0053] Example 4: Preparation of Compound 4 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-chlorobenzoic acid methyl ester to prepare the title compound 4, with a purity of 97.90%.

[0054] ESI-MS: m / z=624.1 (M+H) + .

[0055] 1 H 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).

[0056] Example 5: Preparation of Compound 5 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-methoxy-benzamide, thereby producing the title compound 5 with a purity of 97.95%.

[0057] ESI-MS: m / z=605.2 (M+H) + .

[0058] 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).

[0059] Example 6: Preparation of Compound 6

[0060] Step 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)butamido)-2-methoxybenzoic acid methyl ester The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-methoxy-benzoic acid methyl ester, and the title compound was prepared with a purity of 97.20%. ESI-MS: m / z=620.0 (M+H). + .

[0061] Step 2: Preparation of Title Compound 6 250 mg (0.403 mmol) 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)butamido)-2-methoxybenzoic acid methyl ester was taken, 6 ml of methanol was added, and 68 mg (1.62 mmol) of lithium hydroxide monohydrate dissolved in 3 ml of water was added, followed by stirring at 60 °C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, quenched with 5% aqueous citric acid, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 250 mg of crude product. The product was purified by column chromatography using a mixture of methylene chloride and methanol (50:1). The product was collected to give 198 mg of a white solid, with a yield of 81.1% and a purity of 97.66%.

[0062] ESI-MS: m / z=606.1 (M+H) + .

[0063] 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).

[0064] Example 7: Preparation of Compound 7 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-trifluoromethyl-benzamide, thereby producing the title compound 7 with a purity of 95.21%.

[0065] ESI-MS: m / z=643.1 (M+H) + .

[0066] 1 H 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).

[0067] Example 8: Preparation of Compound 8 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-1,2-dibenzamide, thereby producing the title compound 8 with a purity of 98.69%.

[0068] ESI-MS: m / z=618.2 (M+H) + .

[0069] 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).

[0070] Example 9: Preparation of Compound 9 The preparation method was the same as that of Example 2, except that 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone was replaced with 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone, thereby producing the title compound 9 with a purity of 97.25%.

[0071] ESI-MS: m / z=576.1 (M+H) + .

[0072] 1 H 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).

[0073] Example 10: Preparation of Compound 10 The preparation method was the same as that of Example 1, except that in Step 3, 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone was replaced with 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone, thereby producing the title compound 10 with a purity of 98.14%.

[0074] ESI-MS: m / z=575.1 (M+H) + .

[0075] 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).

[0076] Example 11: Preparation of Compound 11 The preparation method was the same as that of Example 7, except that 4-amino-2-chlorobenzamide in step 2 was replaced with 4-amino-2-trifluoromethyl-benzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in step 3 was replaced with 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone, thereby producing the title compound 11 with a purity of 97.46%.

[0077] ESI-MS: m / z=609.1 (M+H) + .

[0078] 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).

[0079] Example 12: Preparation of Compound 12 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2,3-difluorobenzamide, thereby producing the title compound 12 with a purity of 98.27%.

[0080] ESI-MS: m / z=611.1 (M+H) + .

[0081] 1H 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).

[0082] Example 13: Preparation of Compound 13 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-3-fluorobenzamide, thereby producing the title compound 13 with a purity of 98.64%.

[0083] ESI-MS: m / z=593.1 (M+H) + .

[0084] 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), 3.24 (s, 3H), 2.25-1.95 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[0085] Example 14: Preparation of Compound 14 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-3,5-difluorobenzamide, thereby producing the title compound 14 with a purity of 98.76%.

[0086] ESI-MS: m / z=611.1 (M+H) + .

[0087] 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).

[0088] Example 15: Preparation of Compound 15 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-3,5-dichlorobenzamide, thereby producing the title compound 15 with a purity of 98.12%.

[0089] ESI-MS: m / z=643.1 (M+H) + .

[0090] 1 H 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).

[0091] Example 16: Preparation of Compound 16 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-3-chlorobenzamide, thereby producing the title compound 16 with a purity of 98.48%.

[0092] ESI-MS: m / z=609.1 (M+H) + .

[0093] 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).

[0094] Example 17: Preparation of Compound 17 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-fluoro-N-methylbenzamide, thereby producing the title compound 17 with a purity of 97.95%.

[0095] ESI-MS: m / z=607.1 (M+H) + .

[0096] 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).

[0097] Example 18: Preparation of Compound 18 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-methoxy-N-methylbenzamide, thereby producing the title compound 18 with a purity of 96.25%.

[0098] ESI-MS: m / z=619.2 (M+H) + .

[0099] 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).

[0100] Example 19: Preparation of Compound 19 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-3-fluoro-N-methylbenzamide, thereby producing the title compound 19 with a purity of 98.20%.

[0101] ESI-MS: m / z=607.1 (M+H) + .

[0102] 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 = 7.1 Hz, 3H).

[0103] Example 20: Preparation of Compound 20 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2,5-difluoro-N-methylbenzamide, thereby producing the title compound 20 with a purity of 98.20%.

[0104] ESI-MS: m / z=625.1 (M+H) + .

[0105] 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).

[0106] Example 21: Preparation of Compound 21 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-fluorobenzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in Step 3 was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, thereby producing the title compound 21 with a purity of 97.65%.

[0107] ESI-MS: m / z=596.2 (M+H) + .

[0108] 1H 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). The structural verification data for the intermediate in Step 3, 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, was as follows:

[0109] [ka]

[0110] ESI-MS: m / z=374.1 (M+H) + .

[0111] 1 H NMR(400 MHz, DMSO-d6) δ: 1H NMR(400 MHz, DMSO-d6) δ:11.21 (s, 1H), 9.18 (s, 1H), 7.81 (s, 2H), 7.72 (s, 1H), 695(s, 1H), 6.41 (s, 1H).

[0112] Example 22: Preparation of Compound 22 The preparation method was the same as that of Example 1, except that in Step 3, 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, thereby producing the title compound 22 with a purity of 97.65%.

[0113] ESI-MS: m / z=612.1 (M+H) + .

[0114] 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).

[0115] Example 23: Preparation of Compound 23 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-3-fluorobenzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in Step 3 was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, thereby producing the title compound 23 with a purity of 97.65%.

[0116] ESI-MS: m / z=596.2 (M+H) + .

[0117] 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).

[0118] Example 24: Preparation of Compound 24 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 was replaced with 4-amino-3-fluoro-N-methylbenzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in step 3 was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, thereby producing the title compound 24 with a purity of 97.65%.

[0119] ESI-MS: m / z=610.2 (M+H) + .

[0120] 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 = 4.5 Hz, 3H), 2.12 (dt, J = 15.2, 7.5 Hz, 2H), 0.78 (t, J = 7.1 Hz, 3H).

[0121] Example 25: Preparation of Compound 25 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 was replaced with 4-amino-2-fluoro-N-methylbenzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in step 3 was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, thereby producing the title compound 25 with a purity of 98.85%.

[0122] ESI-MS: m / z=610.2 (M+H) + .

[0123] 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).

[0124] Example 26: Preparation of Compound 26 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in Step 2 was replaced with 4-amino-2-fluoro-N-(methyl-d3)benzamide, thereby producing the title compound 26 with a purity of 99.12%.

[0125] ESI-MS: m / z=610.2 (M+H) + .

[0126] 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).

[0127] Example 27: Preparation of Compound 27 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 was replaced with 4-amino-2-fluoro-N-(methyl-d3)benzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in step 3 was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, thereby producing the title compound 27 with a purity of 98.07%.

[0128] ESI-MS: m / z=613.2 (M+H) + .

[0129] 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).

[0130] Example 28: Preparation of Compound 28 The preparation method was the same as that of Example 1, except that D-2-aminobutyric acid in step 1 was replaced with (R)-2-aminobutyric acid-3,3,4,4,4-d5 acid, and 4-amino-2-chlorobenzamide in step 2 was replaced with 4-amino-2-fluorobenzamide, thereby producing the title compound 28 with a purity of 97.36%.

[0131] ESI-MS: m / z=598.2 (M+H) + .

[0132] 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).

[0133] Example 29: Preparation of Compound 29 The preparation method was the same as that of Example 1, except that 4-amino-2-chlorobenzamide in step 2 was replaced with 4-amino-2-fluoro-benzamide, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone in step 3 was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl-3,4,6-d3)-5-(methoxy)pyridyl-2(1H)-ketone, thereby producing the title compound 29 with a purity of 97.66%.

[0134] ESI-MS: m / z=596.2 (M+H) + .

[0135] 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).

[0136] Example 30: Preparation of Compound 30 The preparation method was the same as that of Example 1, except that D-2-aminobutyric acid was replaced with (R)-2-aminobutyric acid-3,3,4,4,4-d5 acid in step 1, 4-amino-2-chlorobenzamide was replaced with 4-amino-2-fluoro-N-(methyl-d3)benzamide in step 2, and 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridyl-2(1H)-ketone was replaced with 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone in step 3. The title compound 30 was prepared with a purity of 98.62%.

[0137] ESI-MS: m / z=618.2 (M+H) + .

[0138] 1 H 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).

[0139] 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)butamido)-2-fluorobenzamide

[0140] [ka]

[0141] It was synthesized according to the method described in patent CN108026072B, with a purity of 98.5%.

[0142] ESI-MS: m / z = 593.1 (M+H) + .

[0143] 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).

[0144] Test Example 1: Measurement of extracorporeal anticoagulant activity in human plasma

[0145] 1. Test sample Compounds 1 to 30 of Examples and Comparative Example 1.

[0146] 2. Test Method Blood samples were collected from healthy volunteers using sodium citrate (1:9) anticoagulant tubes, immediately mixed thoroughly and uniformly with the anticoagulant, and centrifuged at 4000 r / min at room temperature for 15 minutes. After centrifugation was complete, plasma samples were drawn up with a pipette and frozen (-80°C) for use.

[0147] An appropriate amount of compound was weighed and prepared into a 10-100 mM mother solution with 100% DMSO (the specific mother solution concentration was determined according to the properties of the compound). Then, different concentrations of working solutions (specifically, 1, 3, and 10 μM, respectively) were prepared in healthy human plasma. The mixture was thoroughly mixed uniformly and incubated at 37°C for 3 minutes, after which APTT was measured using an instrument (model number CS-2000I).

[0148] 3. Data Processing The results were analyzed using GraphPad Prism software, and the APTT prolongation rate at each concentration was calculated.

[0149] 4. Test Results The results are shown in the table below. The APTT prolongation rates of the tested compounds 1, 2, 5, 6, 13, 17, 21, 25, 26, and 27 at 1 μM were all superior to the compound of Comparative Example 1. The APTT prolongation rates were greater than 50%. Based on the test results, the EC150 of the above invention compounds was predicted to be less than 1 μM. [Table 1]

[0150] Test Example 2: Measurement of coagulation factor FXIa inhibitor activity

[0151] 1. Test sample Compounds of Examples and Comparative Example 1.

[0152] 2. Testing steps 1) An experimental buffer (50 mM HEPES, 5 mM KCl, 145 mM NaCl, 1 mg / ml PEG8000, pH 7.4) was prepared and equilibrated to room temperature. 2) A 10X compound working solution was prepared. 3) Prepare a 0.8 nM human FXIa working solution (2X), mix evenly, and prepare for use. 4) 20 μL of the FXIa working solution from step 3) was added to all experimental wells of a 384-well plate (Coring, 3702), and the plate was centrifuged at 200 g, RT, for 10 s. 5) 4 μL of the compound working solution from step 2) was added to the corresponding experimental wells of the 384-well plate, and after centrifugation at 200 g and RT for 10 s, the working plate was incubated at 25° C. for 20 min. 6) A 750 μM S-2366 working solution (2.5X) was prepared, mixed uniformly, and ready for use. 7) 16 μL of the S-2366 working solution from step 6) was added to all experimental wells of the 384-well plate, and after centrifugation at 200 g and RT for 10 s, the working plate was incubated at 37° C. for 45 min. 8) After the incubation was completed, the absorbance value at OD 405 nm was read using EnVision and the data was collected.

[0153] 3. Data Analysis 1) Z' factor = 1-3*(SD Max +SD Min ) / (Mean Max -Mean Min ), 2) CV Max = (SD Max / Mean Max )*100%, 3) CVMin = (SD Min / Mean Min )*100%, 4) S / B = Signal / Background, 5) Blank: 0.1% DMSO, Positive control: Comparative Example 1, 6) IC 50 Formula: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) X: logarithmic value of compound concentration, Y: inhibition rate (%). Concentration settings: 200nM, 40nM, 8nM, 1.6nM, 0.32nM, and IC 50 The value was detected.

[0154] 4. Test Results The test results are shown in the table below. All of the tested compounds of the present invention had significant in vitro inhibitory activity against FXIa. The inhibitory activity of compounds 2, 6, 17, 21, 25, 26, and 27 of the present invention against FXIa was stronger than that of the compound of Comparative Example 1. In particular, compounds 2 and 6 were more pronounced. The other tested compounds of the present invention had FXIa inhibitory activity equivalent to that of the comparative examples.

[0155] [Table 2]

[0156] Test Example 3: Pharmacokinetic study in rats

[0157] 1. Test sample Comparative Example 1 and compounds 2, 6, 21, 25, 26, 27, and 28 of Examples.

[0158] 2. Test Procedure In the experiment, 48 SD rats, all male, were used and divided into 8 groups of 6 rats each: Comparative Example 1 group, Compound 2 group, Compound 6 group, Compound 21 group, Compound 25 group, Compound 26 group, Compound 27 group, and Compound 28 group. The rats were fasted for 12 hours before administration and allowed to drink water ad libitum. Each group was then forced to receive oral administration of 30 mg / kg of compound.

[0159] A blank blood sample was collected before administration, and approximately 0.5 mL of blood was collected at specified time points after administration: 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 5 h, 7 h, and 24 h. The blood was placed in an EDTA-K2 tube, and the plasma was centrifuged and stored at -80°C. The blood concentration of the drug was detected using a liquid chromatography-mass spectrometry system (LC-MS / MS). Pharmacokinetic parameters were calculated using DAS 2.0 software based on the plasma concentration data of the drug, providing parameters such as AUC0-t, Cmax, Tmax, and t1 / 2.

[0160] 3. Test Results The experimental results of the pharmacokinetic study of oral administration to rats are shown in the table below. Compounds 2, 6, 21, 25, 26, and 27 of the examples have better absorption than Comparative Example 1, and the AUC (0-t) In particular, Compounds 21, 25, 26, and 27 showed significantly improved AUC and Cmax compared to Comparative Example 1 at the same dose, which meant that the dose of the compounds of this example could be lower to achieve similar efficacy.

[0161] At the same time, Compounds 21, 25, 26, and 27 have the pharmacokinetic characteristics of shorter half-life and faster elimination compared to Comparative Example 1 and Compound 28. This explains their lower safety risk of potential bleeding, and proves that not all deuterium positions have the effect of extending half-life. In particular, the present invention relates to compounds having R 9 and / or R 2 It has been unexpectedly discovered that deuterated compounds containing positions have superior pharmacokinetic results.

[0162] [Table 3]

[0163] Test Example 4: Effects of repeated administration to rats on general condition and food intake

[0164] 1. Test drug Compounds 2, 21, 25, 26, and 27 of Comparative Example 1 and Examples.

[0165] 2. Testing method Seventy healthy adult SD rats were randomly divided into seven groups, half of which were male and half of which were female. Each group consisted of 10 rats and was divided into the blank group, comparative example 1 group, compound 2 group, compound 21 group, compound 25 group, compound 26 group, and compound 27 group. Each group was forced to administer drugs to the rats once a day for 14 consecutive days, as per the administration method in the table below. The blank group was administered the same volume of solvent, and the effects of the drugs on the rats' general condition and food intake were observed and recorded after administration.

[0166] [Table 4]

[0167] 3. Test Results In a study of the general condition of rats in each group that had been given oral administration for 14 consecutive days, more than one-third of the rats in the comparison example 1 group showed piloerection and decreased activity, while no obvious abnormalities were observed in any of the other groups.

[0168] The observation results of food intake of rats in each group who were given oral administration for 14 consecutive days are shown in the table below.

[0169] [Table 5]

[0170] As can be seen from the above table, the rats in Comparative Example 1 group showed a significant decrease in food intake within 24 hours after the final administration compared to the blank group (P<0.001). The rats in Compound 2, Compound 21, Compound 25, Compound 26, and Compound 27 groups showed almost the same food intake as the blank group within 24 hours after the final administration, with no statistical difference. This proves that the compounds of the present invention are safer and have a lower risk of tissue toxicity.

[0171] The above example is merely one of the preferred embodiments of the present invention and should not be used to limit the protection scope of the present invention. Any technical problem solved by any change or adaptation that has no substantial meaning made in the main design concept and spirit of the present invention is still consistent with the present invention and should all be included in the protection scope of the present invention.

Claims

1. A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (where, R １ is selected from halogen or trifluoromethyl groups, R ２ are independently ２ , N.H.R. ７ , OH or OR ８ Selected from, with the proviso that R ７ , R ８ is selected from alkyl groups or cycloalkyl groups, and R ７ , R ８ wherein one or more hydrogen atoms may be substituted with deuterium atoms; R ３ , R ６ are independently hydrogen, halogen, an alkoxy group, a halogenated alkyl group, or CONH ２ Selected from R ４ , R ５ are independently selected from hydrogen, halogen, an alkoxy group, or a halogenated alkyl group; R ９ are independently CH ３ or CD ３ Selected from.) However, it does not fall under the following compounds. 【Chemistry 2】

2. R １ is selected from chlorine and trifluoromethyl groups, or / and, R ２ are independently ２ , N.H.R. ７ , OH, OR ８ Selected from, with the proviso that R ７ , R ８ is selected from a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopropylmethyl group, or a t-butyl group, and R ７ , R ８ wherein one or more hydrogen atoms may be substituted with deuterium atoms; or / and, R ３ , R ６ are independently hydrogen, fluorine, chlorine, a methoxy group, a trifluoromethyl group, or CONH ２ Selected from or / and, R ４ , R ５ are independently selected from hydrogen, fluorine, chlorine, a methoxy group, and a trifluoromethyl group; or / and, R ９ are independently CH ３ or CD ３ 2. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

3. R １ is selected from a trifluoromethyl group, or / and, R ２ are independently ２ , N.H.R. ７ , OH or OR ８ Selected from, with the proviso that R ７ , R ８ is selected from a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopropylmethyl group, or a t-butyl group, and R ７ , R ８ wherein one or more hydrogen atoms may be substituted with deuterium atoms; or / and, R ３ , R ６ are independently hydrogen, fluorine, chlorine, a methoxy group, a trifluoromethyl group, or CONH ２ Selected from or / and, R ４ , R ５ are independently selected from hydrogen, fluorine or chlorine; or / and, R ９ are independently CH ３ or CD ３ 2. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

4. R １ is selected from a trifluoromethyl group, or / and, R ２ are independently ２ , NHCH ３ , NHCD ３ , OH, OCH ３ , OCD ３ or OC(CH ３ ) ３ Selected from or / and, R ３ , R ６ are independently selected from fluorine, chlorine, a methoxy group, or a trifluoromethyl group; or / and, R ４ , R ５ are independently selected from hydrogen, fluorine or chlorine; or / and, R ９ are independently CH ３ or CD ３ The compound according to any one of claims 1 to 3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

5. The compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt, wherein the compound is selected from the following structures: 【Transformation 3】 【Chemistry 4】 【Transformation 5】

6. The compound, its stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein one or more hydrogen atoms in the compound, its stereoisomer, or pharmaceutically acceptable salt may be substituted with deuterium atoms.

7. The compound, its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 6, characterized in that the method for producing the compound comprises the following steps: R ２ NH ２ , N.H.R. ７ OR ８ In this case, the synthesis route is as follows: 【Transformation 6】 (However, R １ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ The definitions of are the same as those in any one of claims 1 to 6. Step 1: Starting material a undergoes a bromination reaction to produce intermediate b. Step 2: Intermediate b and starting material c undergo a condensation reaction to produce intermediate c. Step 3: Intermediate d undergoes a substitution reaction with compound e to produce a compound of formula (1). R ２ When is OH, the synthetic route is as follows: 【Transformation 7】 (However, R １ , R ３ , R ４ , R ５ , R ６ , R ７ , R ９ The definitions of are the same as those in any one of claims 1 to 6. Step 4: Compound f is hydrolyzed under alkaline conditions to produce a compound of formula (1).

8. A key intermediate characterized by the structure shown in formula e below. 【Transformation 8】 (R １ is selected from halogen and trifluoromethyl groups, R ９ is CH ３ or CD ３ Preferably, the R １ is selected from halogen and trifluoromethyl groups, R ９ is a CD ３ Selected from.)

9. 9. The intermediate according to claim 8, selected from the following compounds: 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone, 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-(methoxy-d3)pyridyl-2(1H)-ketone.

10. A pharmaceutical composition comprising the compound, its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable auxiliary material.

11. Use of the compound according to any one of claims 1 to 6, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing a disease associated with the FXIa receptor.

12. 10. The use according to claim 9, characterized in that the disease associated with the FXIa receptor is selected from cerebrovascular arterial disease and / or peripheral arterial disease, more preferably the disease associated with the FXIa receptor is selected from transient ischemic attack (TIA), ischemic stroke (cardiogenic stroke, e.g. stroke due to atrial fibrillation; non-cardiogenic stroke, e.g. lacunar stroke, stroke due to large or small arterial disease, or stroke of undetermined cause; cryptogenic stroke; embolic stroke; embolic stroke of undetermined origin; or events of thrombotic and / or thromboembolic origin leading to stroke or TIA), and / or peripheral arterial pathology leading to peripheral arterial disease (peripheral arterial occlusion, acute limb ischemia, limb amputation, re-occlusion and restenosis after intervention (e.g. angioplasty, stent placement or surgery and bypass), and / or stent thrombosis).

Images