Novel oxopyridine compounds and preparation methods and uses thereof

Abstract

The present invention discloses a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides the use of the compound, its stereoisomer or pharmaceutically acceptable salt in the preparation of a drug for treating and / or preventing diseases associated with FXIa receptors, especially in the preparation of a drug for treating and / or preventing cerebrovascular arterial disease and / or peripheral arterial disease.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to oxopyridine compounds or their salts, isomers, and preparation methods thereof, as well as use thereof in the preparation of drugs for treating and / or preventing diseases associated with FXIa receptors, especially in the treatment and prevention of cerebrovascular arterial diseases and / or peripheral arterial diseases. Background Art

[0002] 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.

[0003] 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.

[0004] 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 small 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 Ono Co., Ltd. of Japan, has entered the Phase I clinical study. BAY-2433334 developed by Bayer has completed the Phase II clinical trial and has become the most promising small molecule FXIa inhibitor. Monoclonal antibodies and antisense oligonucleotides need to be injected, and they have the disadvantages of being expensive, slow to take effect and possibly difficult to control. Chemical small molecules have the advantages of relatively good oral bioavailability and better patient compliance. Therefore, the development of safe, effective, specific and active new FXIa small molecule inhibitors may 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

[0005] The compounds of the present invention are novel oxopyridine compounds. Most of the compounds in the examples show good anticoagulant effect and in vitro affinity for FXIa.

[0006] In one aspect, the present invention provides a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R 1 Selected from C1-C5 alkyl, wherein: the alkyl may be substituted by a substituent selected from the following: fluorine, cyano, hydroxyl, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, six-membered heterocycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazolyl, dihydrooxazolyl, phenyl or pyridyl, wherein phenyl, pyridyl, oxazolyl, oxadiazolyl, pyrazolyl, isoxazolyl and dihydrooxazolyl may be substituted by 1 to 2 substituents independently selected from the following: halogen, methyl, ethyl and cyclopropyl;

[0010] R 2 Independently selected from C1-C5 alkyl, substituted or unsubstituted aromatic group, or substituted or unsubstituted amino group, wherein the substituent is selected from alkyl, cycloalkyl or halogen;

[0011] R 3 are independently selected from hydrogen or halogen.

[0012] Furthermore, the above-mentioned halogenated C1-C4 alkyl group includes but is not limited to difluoromethyl or trifluoromethyl; the above-mentioned halogenated C1-C4 alkoxy group includes but is not limited to difluoromethoxy, trifluoromethoxy or 2,2-difluoroethoxy.

[0013] Further, in any of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof, the R 1 methyl or ethyl, wherein: methyl or ethyl may be substituted by a substituent selected from the following: C1-C4 alkoxy, C3-C6 cycloalkoxy, C3-C6 cycloalkyl, oxygen-containing six-membered heterocycloalkyl, phenyl, pyridyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazolyl or dihydrooxazolyl, wherein oxazolyl, oxadiazolyl, pyrazolyl, isoxazolyl and dihydrooxazolyl may be substituted by 1 to 2 substituents independently selected from the following: methyl, ethyl and cyclopropyl;

[0014] and / or R 2 independently selected from methyl, ethyl, propyl, phenyl, 3,4-dichlorophenyl, N,N-dimethylamino or cyclopropylamino;

[0015] and / or R 3 are independently selected from hydrogen, fluorine or chlorine.

[0016] Further, in any of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof, the R 1 is selected from methyl or ethyl, wherein: methyl or ethyl may be substituted by a substituent selected from the group consisting of methoxy, ethoxy, cyclopropyloxy, tert-butoxy, isopropyloxy, tetrahydropyranyl, 1,4-dioxanyl, furanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, oxadiazolyl, pyrazolyl, isoxazolyl, methyloxadiazolyl, methylpyrazolyl, methylisoxazolyl, cyclopropyloxadiazolyl, cyclopropylpyrazolyl, cyclopropylisoxazolyl or phenyl;

[0017] and / or R 2 independently selected from methyl, phenyl, 3,4-dichlorophenyl, N,N-dimethylamino or cyclopropylamino;

[0018] and / or R 3 are independently selected from hydrogen, fluorine or chlorine.

[0019] Further, in any of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof, the R 1 is selected from methyl or ethyl, wherein: methyl or ethyl may be substituted by a substituent selected from the group consisting of tetrahydro-2H-pyran-2-yl, methoxy, cyclobutyl, pyridin-4-yl, cyclohexaneoxy, 5-methyl-1,3,4-oxadiazol-2-yl, 1-methyl-1H-pyrazol-3-yl, 5-methylisoxazol-3-yl or phenyl;

[0020] and / or R 2 independently selected from methyl, phenyl, 3,4-dichlorophenyl, N,N-dimethylamino or cyclopropylamino;

[0021] and / or R 3 are independently selected from hydrogen, fluorine or chlorine.

[0022] Further, any of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof, comprises the following structure:

[0023]

[0024] Furthermore, hydrogen in the structure of any of the above-mentioned compounds, stereoisomers or pharmaceutically acceptable salts thereof may be replaced by one or more deuteriums.

[0025] On the other hand, the present invention also provides a method for preparing any one of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps:

[0026]

[0027] Step 1: Starting material a and starting material b undergo condensation reaction to generate intermediate c;

[0028] Step 2: Intermediate c undergoes substitution reaction with compound d to generate intermediate e;

[0029] Step 3: Intermediate e undergoes hydrolysis under alkaline conditions to generate intermediate f;

[0030] Step 4: The intermediate f undergoes a condensation reaction with the compound g to generate a compound of formula (I);

[0031] Where R 1 , R 2 , R 3 As defined in any of the above.

[0032] In a third aspect, the present invention also provides use of any one of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating and / or preventing diseases associated with FXIa receptors.

[0033] Furthermore, the above-mentioned disease associated with FXIa receptor is selected from cerebrovascular arterial disease and / or peripheral arterial disease.

[0034] Furthermore, the above-mentioned cerebrovascular arterial diseases include but are not limited to transient ischemic attack (TIA), ischemic stroke or events of thrombotic and / or thromboembolic origin leading to stroke or TIA; the above-mentioned peripheral arterial diseases include but are not limited to 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.

[0035] Furthermore, the above-mentioned ischemic stroke includes but is not limited to cardiogenic stroke, non-cardiogenic stroke, stroke caused by large artery or small artery disease, stroke caused by undetermined cause, cryptogenic stroke, embolic stroke or embolic stroke of undetermined source.

[0036] Furthermore, the aforementioned cardiogenic stroke includes but is not limited to stroke caused by atrial fibrillation; the aforementioned non-cardiogenic stroke includes but is not limited to lacunar stroke.

[0037] Beneficial effects: Compared with the prior art, the present invention has a good FXIa inhibitory effect and anti-human plasma coagulation effect, and the pharmacokinetics in rats show that it has a higher AUC and is metabolized faster, which can avoid the risk of increased bleeding due to long-term action. DETAILED DESCRIPTION

[0038] The present invention will be further described in detail below in conjunction with embodiments and experimental examples. The embodiments and experimental 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.

[0039] 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.

[0040] The structure of the compound is determined by NMR ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0041] 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 ( <h2 style=";text-align:left;direction:ltr">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.

[0042] The term "room temperature" in the present invention means a temperature between 10 and 30°C.

[0043] 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-fluoro-N-(methylsulfonyl)benzamide (Compound 1):

[0044]

[0045] Step 1: Preparation of (S)-methyl 4-(2-bromobutyramide)-2-fluorobenzoate (Intermediate c)

[0046] Add (R)-2-bromobutyric acid (400 mg, 2.39 mmol), THF5 ml, methyl 4-amino-2-fluorobenzoate (271 mg, 1.6 mmol) to a 25 ml reaction bottle, stir and cool to 0 °C, add pyridine (475 mg, 6 mmol), and dropwise add T3P (50% EA) (2.04 g, 3.2 mmol). After the addition is complete, react at room temperature for 5 h. The reaction of the raw materials is complete and the reaction is terminated. Add EA, wash with acid twice, wash with alkali once, separate the layers, and concentrate the organic phase to dryness to obtain 580 mg of the title product with a yield of 76.3% and a purity of 96.5%.

[0047] ESI-MS: m / z=318.0 (M+H) + .

[0048] Step 2: 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)butyramido)-2-fluorobenzoate (Intermediate e)

[0049] Add (S)-4-(2-bromobutyramide)-2-fluorobenzoic acid methyl ester (477mg, 1.5mmol), 6ml isopropanol, 1.5ml acetone, 4 intermediate c (371mg, 1mmol) to a 25ml reaction bottle, stir and cool to 0℃, add tetramethylguanidine (403mg, 3.5mmol) dropwise, and react at room temperature for 3h. After the reaction is completed, add EA, wash once with acid, wash once with alkali, separate the layers, and concentrate the organic phase. The concentrate is separated and purified by chromatography column (MeOH: DCM = 2: 100), the product is collected, and concentrated to obtain 500mg of the title product, with a yield of 82.2% and a purity of 98.84%.

[0050] ESI-MS: m / z=608.1(M+H) + .

[0051] Step 3: 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-fluorobenzoic acid (Intermediate f)

[0052] Add intermediate e (500 mg, 0.82 mmol) and 6 ml of methanol to a 25 ml reaction bottle, weigh lithium hydroxide (202.4 mg, 4.92 mmol) and dissolve it in 2.5 ml of water and add it dropwise to the reaction bottle. React at room temperature for 2 hours until the reaction of the raw materials is complete. Add EA, wash once with acid, wash once with saturated NaCl, separate the layers, and concentrate the organic phase to dryness to obtain 450 mg of the title product with a yield of 92.4% and a purity of 96.26%.

[0053] ESI-MS: m / z=593.1(M+H) + .

[0054] Step 4: 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-fluoro-N-(methylsulfonyl)benzamide (Compound 1)

[0055] Add intermediate f (150 mg, 0.25 mmol) and 3 ml of THF to a 25 ml reaction bottle, stir to dissolve, add CDI (122 mg, 0.75 mmol), heat to 40 °C and react for 1 h. Add methylsulfonamide (48 mg, 0.51 mmol) and DBU (114.2 mg, 0.75 mmol), react at room temperature for 2 h, and the raw materials react completely. Add EA, wash once with acid, wash once with saturated NaCl, separate the layers, concentrate the organic phase, separate and purify the concentrate by chromatography column (MeOH: DCM = 8: 100), collect the product, and concentrate to obtain 70 mg of the title product, with a yield of 41.8% and a purity of 98.15%.

[0056] ESI-MS: m / z=671.1 (M+H) + .

[0057] 1 HNMR (400 MHz, DMSO-d6) δ: 10.61 (s, 1H), 9.13 (d, 1H), 7.88 – 7.77(m, 3H), 7.69 (t, 1H), 7.47 (m, 1H), 7.25 (m, 1H), 7.14 (s, 1H), 6.53 (s,1H), 5.53 (s, 1H), 3.25 (s, 3H), 2.81 (s, 3H), 2.06 (m, 2H), 0.91 – 0.73 (m,3H).

[0058] Example 2: 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)-N-(3,4-difluorophenyl)sulfonyl)-2-fluorobenzamide (Compound 2)

[0059]

[0060] The preparation method is the same as that of Example 1, except that the methylsulfonamide in step 4 is replaced by an equal molar amount of 3,4-difluorobenzenesulfonamide to obtain the title compound with a yield of 53.6% and a purity of 97.28%.

[0061] ESI-MS: <h2 style=";text-align:left;direction:ltr"> m / z = 769.1(M+H) + .

[0062] 1HNMR (400 MHz, DMSO-d6) δ: 10.52 (s, 1H), 9.11 (d, 1H), 7.88 – 7.77(m, 4H), 7.69-7.58 (m, 2H), 7.47-7.35 (m, 2H), 7.25 (m, 1H), 7.14 (s, 1H), 6.53 (s, 1H), 5.53 (s, 1H), 2.83 (s, 3H), 2.06 (m, 2H), 0.93 – 0.75 (m, 3H).

[0063] Example 3: 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)butyramide)-N-(N,N-dimethylsulfonamido)-2-fluorobenzamide (Compound 3)

[0064]

[0065] The preparation method is the same as that of Example 1, except that the methylsulfonamide in step 4 is replaced by an equimolar amount of N,N-dimethylsulfonamide to obtain the title compound with a yield of 60.1% and a purity of 96.8%.

[0066] ESI-MS: <h2 style=";text-align:left;direction:ltr"> m / z =700.1(M+H) + .

[0067] 1 HNMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H), 9.54 (s, 1H), 9.12 (d,1H), 7.88 – 7.77 (m, 3H), 7.69 (t, 1H), 7.47 (m, 1H), 7.25 (m, 1H), 7.14 (s, 1H), 6.53 (s, 1H), 5.55 (s, 1H), 3.27 (s, 3H), 2.70 (s, 6H), 2.06 (m, 2H), 0.95 – 0.74 (m, 3H).

[0068] Example 4: 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)butyramide)-N-(N-cyclopropylsulfonamido)-2-fluorobenzamide (Compound 4)

[0069]

[0070] The preparation method is the same as that of Example 1, except that the methylsulfonamide in step 4 is replaced by an equimolar amount of N-cyclopropylaminosulfonamide to obtain the title compound with a yield of 56.5% and a purity of 97.34%.

[0071] ESI-MS: m / z = 712.1(M+H) + .

[0072] 1 HNMR (400 MHz, DMSO-d6) δ: 10.63 (s, 1H), 9.55 (s, 1H), 9.11 (d,1H), 7.88 – 7.77 (m, 3H), 7.71 (t, 1H), 7.46 (m, 1H), 7.27 (m, 1H), 7.16 (s,1H), 6.53 (s, 1H), 4.82 (td, 1H), 3.81 (s, 3H), 2.66 (dp, 1H), 2.03 – 1.88(m, 2H), 1.00 (t, 3H), 0.74 – 0.53 (m, 5H).

[0073] Example 5: 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)-3-phenylpropionamido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 5)

[0074]

[0075] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equimolar amount of (R)-2-bromo-3-phenylpropionic acid to obtain the title compound. The four-step reaction yield is 22.1% and the purity is 97.87%.

[0076] ESI-MS: m / z = 733.1(M+H) + .

[0077] 1HNMR (400 MHz, DMSO-d6) δ:10.88 (s, 1H), 9.18 (s, 1H), 7.81 (d, 2H),7.74 – 7.60 (m, 3H), 7.56 (m, 2H), 7.38 (m, 1H), 7.32 – 7.24 (m, 3H), 7.24 –7.14 (m, 3H), 6.43 (s, 1H), 5.92 (dd, 1H), 3.51 – 3.35 (m, 2H), 3.26 (s, 3H), 1.23 (s, 1H).

[0078] Example 6: 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)-3-phenylpropionamido)-N-(3,4-difluorophenyl)sulfonyl)-2-fluorobenzamide (Compound 6)

[0079]

[0080] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equal molar amount of (R)-2-bromo-3-phenylpropionic acid, and the methylsulfonamide in step 4 is replaced by an equal molar amount of 3,4-difluorobenzenesulfonamide to obtain the title compound. The four-step reaction yield is 19.8% and the purity is 98.25%.

[0081] ESI-MS: m / z = 831.1(M+H) + .

[0082] 1 HNMR (400 MHz, DMSO-d6) δ: 10.86 (s, 1H), 9.16 (s, 1H), 7.80 (m,3H), 7.74 – 7.60 (m, 4H), 7.56 (m, 2H), 7.42-7.38 (m, 2H), 7.32 – 7.24 (m, 3H), 7.24 – 7.14 (m, 3H), 6.44 (s, 1H), 5.92 (dd, 1H), 3.53 – 3.36 (m, 2H), 1.25 (s, 1H).

[0083] Example 7: 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)-3-phenylpropionamido)-N-(N,N-dimethylsulfonamido)-2-fluorobenzamide (Compound 7)

[0084]

[0085] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equal molar amount of (R)-2-bromo-3-phenylpropionic acid, and the methylsulfonamide in step 4 is replaced by an equal molar amount of N,N-dimethylsulfonamide to obtain the title compound. The four-step reaction yield is 24.9% and the purity is 98.51%.

[0086] ESI-MS: m / z = 762.1(M+H) + .

[0087] 1 HNMR (400 MHz, DMSO-d6) δ: 10.95 (s, 1H), 9.56 (s, 1H), 9.22 (s,1H), 7.84 (d, 2H), 7.75 – 7.62(m, 3H), 7.57 (m, 2H), 7.38 (m, 1H), 7.32 – 7.24 (m, 3H), 7.24 – 7.14 (m, 3H), 6.43 (s, 1H), 5.92 (dd, 1H), 3.51 – 3.35 (m, 2H), 2.70 (s, 6H), 1.26 (s, 1H).

[0088] Example 8: 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)-3-phenylpropionamido)-N-(N-cyclopropylsulfonamido)-2-fluorobenzamide (Compound 8)

[0089]

[0090] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equal molar amount of (R)-2-bromo-3-phenylpropionic acid, and the methylsulfonamide in step 4 is replaced by an equal molar amount of N-cyclopropylaminosulfonamide to obtain the title compound. The four-step reaction yield is 17.6% and the purity is 98.68%.

[0091] ESI-MS: m / z = 774.1(M+H) + .

[0092] 1 HNMR (400 MHz, DMSO-d6) δ: 10.98 (s, 1H), 9.59 (s, 1H), 9.20 (s,1H), 7.81 (d, 2H), 7.74 – 7.60 (m, 3H), 7.56 -7.53(m, 3H), 7.38 (m, 1H), 7.32– 7.24 (m, 3H), 7.24 – 7.14 (m, 3H), 6.43 (s, 1H), 5.92 (dd, 1H), 3.51 – 3.35(m, 2H), 2.66 (m, 1H), 1.23 (s, 1H)., 0.74 – 0.53 (m, 4H).

[0093] Example 9: Preparation of 4-(2S)-2-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-(tetrahydro-2H-pyran-2-yl)propionamido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 9)

[0094]

[0095] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced with an equimolar amount of (2R)-2-bromo-3-(tetrahydro-2H-pyran-2-yl)propanoic acid to obtain the title compound. The four-step reaction yield is 19.6% and the purity is 98.97%.

[0096] ESI-MS: m / z = 741.1(M+H) + .

[0097] 1HNMR (400 MHz, DMSO-d6) δ: 10.58 (s, 1H), 8.77 (s, 1H), 7.85 – 7.76(m, 2H), 7.73 (d, 1H), 7.71 – 7.63 (m, 2H), 7.56 (m, 1H), 7.48 (m, 1H), 6.94(s, 1H), 4.86 (m, 1H), 3.93 (m, 1H), 3.81 (s, 3H), 3.74 – 3.57 (m, 2H), 3.38(s, 3H), 2.28 – 2.08 (m, 2H), 1.78 – 1.46 (m, 6H).

[0098] Example 10: 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)-4-methoxybutyramido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 10)

[0099]

[0100] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equimolar amount of (R)-2-bromo-4-methoxybutyric acid to obtain the title compound. The four-step reaction yield is 16.8% and the purity is 98.21%.

[0101] ESI-MS: m / z = 701.1(M+H) + .

[0102] 1 HNMR (400 MHz, DMSO-d6) δ: 10.56(s, 1H), 8.97 (s, 1H), 7.89 – 7.78(m, 2H), 7.76 (d, 1H), 7.68 (m, 2H), 7.56 (m, 1H), 7.48 (m, 1H), 6.94 (s,1H), 4.84 (m, 1H), 3.81 (s, 3H), 3.60 – 3.46 (m, 2H), 3.39 (s, 3H), 3.17 (s,3H), 2.29 – 2.08 (m, 2H).

[0103] Example 11: 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)-3-cyclobutylpropionamido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 11)

[0104]

[0105] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equimolar amount of (R)-2-bromo-4-cyclobutylbutyric acid to obtain the title compound. The four-step reaction yield is 14.8% and the purity is 97.77%.

[0106] ESI-MS: m / z = 711.1(M+H) + .

[0107] 1 HNMR (400 MHz, DMSO-d6) δ: 10.66 (s, 1H), 8.88 (s, 1H), 7.95 – 7.83(m, 2H), 7.75 (d, 1H), 7.71 (d, 1H), 7.68 (m, 1H), 7.57 (m, 1H), 7.48 (m,1H), 6.94 (s, 1H), 4.86 (td, 1H), 3.81 (s, 3H), 3.35 (s, 3H), 2.04 – 1.79 (m,3H), 1.76 – 1.65 (m, 1H), 1.69 – 1.56 (m, 3H), 1.53 – 1.37 (m, 2H).

[0108] Example 12: 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)-3-(pyridin-4-yl)propionamido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 12)

[0109]

[0110] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equimolar amount of (R)-2-bromo-3-(pyridin-4-yl)propionic acid to obtain the title compound. The four-step reaction yield is 19.4% and the purity is 97.72%.

[0111] ESI-MS: m / z = 734.1(M+H) +.

[0112] 1HNMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 9.12 (s, 1H), 8.63 – 8.54(m, 2H), 7.89– 7.75 (m, 4H), 7.71 (dd, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.23– 7.18 (m, 2H), 6.90 (s, 1H), 5.07 (td, 1H), 3.81 (s, 3H), 3.47 (dd, 1H), 3.33 (dd, 1H).

[0113] Example 13: 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)-4-(cyclohexaneoxy)butyramido)-N-(methylsulfonyl)benzamide (Compound 13)

[0114]

[0115] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equimolar amount of (R)-2-bromo-4-(cyclohexyloxy)butyric acid to obtain the title compound. The four-step reaction yield is 13.6% and the purity is 97.93%.

[0116] ESI-MS: m / z = 751.2(M+H) + .

[0117] 1HNMR (400 MHz, DMSO-d6) δ: 10.56 (s, 1H), 9.23 (s, 1H), 7.95 – 7.87(m, 2H), 7.82 (d, 1H), 7.76 – 7.68 (m, 3H), 7.66 (d, 1H), 7.56 (dd, 1H), 6.94(s, 1H), 4.83 (m, 1H), 3.84 – 3.72 (m, 4H), 3.59 (t, 2H), 3.35 (s, 3H), 2.24– 2.04 (m, 2H), 1.81 – 1.67 (m, 2H), 1.67 – 1.59 (m, 1H), 1.63 – 1.58 (m,1H), 1.62 – 1.45 (m, 2H), 1.51 (s, 0H), 1.49 – 1.37 (m, 1H), 1.42 – 1.32 (m,1H).

[0118] Example 14: 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)-3-(5-methyl-1,3,4-oxadiazol-2-yl)propionamido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 14)

[0119]

[0120] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced with an equimolar amount of (R)-2-bromo-3-(5-methyl-1,3,4-oxadiazol-2-yl)propionic acid to obtain the title compound. The five-step reaction yield is 13.8% and the purity is 98.55%.

[0121] ESI-MS: m / z =739.1(M+H) + .

[0122] 1HNMR (400 MHz, DMSO-d6) δ: 9.56 (s, 1H), 7.98 – 7.85 (m, 2H), 7.79 (m, 1H), 7.74 – 7.65 (m, 2H), 7.58 (m, 1H), 7.48 (m, 1H), 6.83 (s, 1H), 5.18(td, 1H), 3.81 (s, 3H), 3.35 (dd, 2H), 3.29 (s, 3H), 2.52 (s, 3H).

[0123] Example 15: 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)-3-(1-methyl-1H-pyrazol-3-yl)propionamido)-2-fluoro-N-(methylsulfonyl)benzamide (Compound 15)

[0124]

[0125] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced with an equimolar amount of (R)-2-bromo-3-(1-methyl-1H-pyrazol-3-yl)propionic acid to obtain the title compound. The five-step reaction yield is 15.9% and the purity is 98.11%.

[0126] ESI-MS: m / z =737.1(M+H) + .

[0127] 1 HNMR (400 MHz, DMSO-d6) δ:10.23 (s, 1H), 7.96 – 7.86 (m, 2H), 7.78(m, 2H), 7.69 (m, 1H), 7.56 (m, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 6.86 (s,1H), 6.06 (d, 1H), 5.09 (m, 1H), 3.87 – 3.79 (m, 5H), 3.31 (s, 3H), 3.14 –3.00 (m, 2H).

[0128] Example 16: 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)-3-phenylpropionamido)-N-(methylsulfonyl)benzamide (Compound 16)

[0129]

[0130] The preparation method is the same as that of Example 1, except that the (R)-2-bromobutyric acid in step 1 is replaced by an equal molar amount of (R)-2-bromo-3-phenylpropionic acid, and the methyl 4-amino-2-fluorobenzoate is replaced by an equal molar amount of methyl 4-amino-benzoate to obtain the title compound. The five-step reaction yield is 20.2% and the purity is 98.16%.

[0131] ESI-MS: m / z =715.1(M+H) + .

[0132] 1 HNMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H), 7.95 – 7.87 (m, 2H), 7.82(d, 1H), 7.78 – 7.68 (m, 4H), 7.56 (m, 1H), 7.29 – 7.19 (m, 3H), 7.23 – 7.13 (m, 2H), 6.90 (s, 1H), 5.08 (td, 1H), 3.81 (s, 3H), 3.24 – 3.13 (m, 2H).

[0133] 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

[0134]

[0135] It was synthesized according to the method described in patent CN108026072B, with a purity of 98.5%.

[0136] ESI-MS: <h2 style=";text-align:left;direction:ltr"> m / z =593.0(M+H) + .

[0137] 1H 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).

[0138] Test Example 1: Determination of the inhibition rate of the test compound (50 nM) on coagulation factor FXIa using in vitro enzymatic assay

[0139] 1. Test samples

[0140] Example compounds 1 to 16 and comparative example 1.

[0141] ⒉Test steps

[0142] 1) Prepare the experimental buffer (50 mM HEPES, 5 mM KCl, 145 mM NaCl, 1 mg / ml PEG 8000, pH 7.4) and equilibrate to room temperature.

[0143] 2) Prepare 10X compound working solution.

[0144] 3) Prepare 0.8 nM Human FXIa working solution (2X), mix well and set aside.

[0145] 4) Add 20 μL of the FXIa working solution prepared in step 3) to all experimental wells of a 384-well plate (Coring, 3702), and centrifuge at 200 g, RT, for 10 s.

[0146] 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.

[0147] 6) Prepare 750 μM S-2366 working solution (2.5X), mix well and set aside.

[0148] 7) Add 16 μL of the 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.

[0149] 8) After incubation, use EnVision to read the absorbance value at OD405nm and collect the data.

[0150] 3. Data Analysis

[0151] 1) Z' factor = 1-3*(SD Max +SD Min ) / (Mean Max -Mean Min );

[0152] 2) CV Max = (SD Max / Mean Max )*100%;

[0153] 3) CVMin = (SD Min / Mean Min )*100%;

[0154] 4) S / B = Singal / Background;

[0155] 5) Blank control: 0.1% DMSO; Positive control: Comparative Example 1;

[0156] 6) IC 50 Calculation formula: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0157] X: log value of compound concentration; Y: Inhibition%.

[0158] 4. Test results

[0159] The test results are shown in the table below, which show that under the same molar concentration conditions, the compounds of the present invention have stronger in vitro inhibitory activity against FXIa than the compounds of Comparative Example 1.

[0160]

[0161] Test Example 2: Determination of the activity of coagulation factor FXIa inhibitor (IC 50 )

[0162] The inhibitory effects of compounds 1, 3, 8 and the compound of comparative example 1 on human coagulation factor FXIa were determined by in vitro enzymatic assay. Five concentrations were set, namely: 200 nM, 40 nM, 8 nM, 1.6 nM, and 0.32 nM. IC 50 value.

[0163] The test reagents and operating methods are as described in Test Example 1.

[0164] The test results are shown in the table below, which show that compounds 1, 3, and 8 of the present invention have strong in vitro inhibitory activity against FXIa.

[0165]

[0166] Test Example 3: Determination of the anticoagulant effect of human plasma in vitro

[0167] 1. Test samples

[0168] Example compounds 1, 3, 8 and comparative example 1.

[0169] ⒉Test methods

[0170] 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.

[0171] Weigh an appropriate amount of compound and prepare it into a 10-100 mM stock solution with 100% DMSO (the specific concentration of the stock solution is determined by the properties of the compound); then prepare working solutions of different concentrations using healthy human plasma as the solution (specifically: 0, 0.3, 1, 3, 10, 30, 60, 100, 300 μM), mix thoroughly; incubate at 37°C for 3 min, and then perform APTT determination on a machine (model CS-2000I).

[0172] 3. Data Processing

[0173] GraphPad Prism software was used for curve fitting and EC150 value was calculated, i.e., the effective concentration of the compound corresponding to 50% extension of APTT relative to the blank control group.

[0174] 4. Experimental results

[0175] The results are shown in the following table. The APTT EC150 of the tested compounds 1, 3, and 8 are all better than that of the compound in comparative example 1.

[0176]

[0177] Test Example 4: Pharmacokinetic study in rats

[0178] 1. Test samples

[0179] Example compound 1 and comparative example 1.

[0180] ⒉ Preparation method and environmental requirements of test substances

[0181] The preparation of test substances was carried out on the conventional workbench in the preparation room.

[0182] Preparation of stock solutions of the proposed method: Prepare according to the pharmaceutical preparation regulations, using methanol as solvent to prepare 1.00 mg / mL stock solutions of Example Compound 1 and Comparative Example 1, respectively.

[0183] Preparation of dosing solution for rats: 0.5% CMC-Na was used as solvent. The injection concentration was 3 mg / mL.

[0184] ⒊Test operation

[0185] (1) Dosage regimen

[0186] Twelve SD rats were used in the experiment, half of which were male and half were female, and were divided into 4 groups, with 3 rats in each group. The dosage for each group was 3 mg / kg.

[0187] (2) Medication administration and sample collection

[0188] Rats were fasted for 12 hours before administration and had free access to water. Twelve SD rats were used in the experiment, half male and half female, divided into 4 groups, 3 rats in each group. Group 1 was the comparative example 1-♀ group, with a dose of 3 mg / kg; Group 2 was the comparative example 1-♂ group, with a dose of 3 mg / kg; Group 3 was the compound 1-♀ group, with a dose of 3 mg / kg; Group 4 was the compound 1-♂ group, with a dose of 3 mg / kg.

[0189] Blank blood was collected before administration, and blood was collected at predetermined time points after administration: <h2 style=";text-align:left;direction:ltr"> 2min、5min、10min、15min、30min、 <h2 style=";text-align:left;direction:ltr"> 45 min, 1 h, 2 h, 3 h, 5 h, 7 h, 24 h, About 0.5 mL of blood was collected and placed in an EDTA-K2 tube. The plasma was separated by centrifugation and stored at -80°C.

[0190] (3) Animal disposal

[0191] At the end of the experiment, all animals were euthanized according to institutional SOP.

[0192] (4) Instruments

[0193] Liquid chromatography-mass spectrometry analysis system (LC-MS / MS) includes Shimadzu LC-20AD series binary pump and SIL-20AC autosampler and AB API-4000 Q-Trap mass spectrometer detector (including ESI ion source), chromatographic column: ODS-C18 (4.6×50 mm, 3 µm).

[0194] (5) Sample processing

[0195] Standard curve sample processing: Prepare a series of working solutions containing different concentrations of comparative example 1 and compound 1. Take 20 μL of the working solution, add 100 μL of blank plasma sample, vortex mix, then add 300 μL of acetonitrile solution containing 40 ng / mL propranolol internal standard, vortex mix, centrifuge at 4°C and 14000g for half an hour, and take the supernatant for LC-MS / MS detection.

[0196] Treatment of rat plasma samples: Take 20 μL of acetonitrile, add 100 μL of plasma sample, vortex mix, then add 300 μL of acetonitrile solution containing 40 ng / mL propranolol internal standard, vortex mix, centrifuge at 4°C and 14000g for half an hour, and take the supernatant for detection.

[0197] (6) Pharmacokinetic analysis

[0198] According to the plasma concentration data of drugs, DAS 2.0 software was used to calculate the pharmacokinetic parameters.

[0199] 4. Results

[0200] The experimental results of the pharmacokinetic study of injection administration in rats are shown in the following table. Compound 1 has a better AUC and a shorter half-life, indicating that Compound 1 can have a lower dosage than Comparative Example 1. At the same time, it has the characteristics of rapid elimination, which reduces the risk of bleeding caused by long-term non-elimination of the drug during use, and the medication process is more controllable.

[0201]

[0202] 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 or a pharmaceutically acceptable salt thereof represented by formula (I): ； in, R 1 methyl or ethyl, wherein: methyl is substituted by a substituent selected from the group consisting of tetrahydro-2H-pyran-2-yl, cyclobutyl, pyridin-4-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1-methyl-1H-pyrazol-3-yl, or phenyl; ethyl may be substituted by a substituent selected from the group consisting of methoxy or cyclohexaneoxy; R 2 is selected from methyl, 3,4-dichlorophenyl, N,N-dimethylamino or cyclopropylamino; R 3 Selected from hydrogen or fluorine.

2. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that The compound is selected from the following structures: 。 3. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 2, characterized in that: The hydrogen in the compound or pharmaceutically acceptable salt may be replaced by one or more deuterium.

4. A method for preparing the compound or pharmaceutically acceptable salt according to claim 1, characterized in that: The method comprises the following steps: ； Step 1: Starting material a and starting material b undergo condensation reaction to generate intermediate c; Step 2: Intermediate c undergoes substitution reaction with compound d to generate intermediate e; Step 3: Intermediate e undergoes hydrolysis under alkaline conditions to generate intermediate f; Step 4: The intermediate f undergoes a condensation reaction with the compound g to generate a compound of formula (I); Where R 1 , R 2 , R 3 As defined in claim 1.

5. Use of the compound or pharmaceutically acceptable salt according to any one of claims 1 to 2 in the preparation of a FXIa receptor inhibitor.

6. The use according to claim 5, characterized in that The disease associated with the FXIa receptor inhibitor is selected from cerebrovascular arterial disease and / or peripheral arterial disease.

7. The use according to claim 5, characterized in that The disease associated with the FXIa receptor inhibitor is selected from anticoagulation.

8. The use according to claim 5, characterized in that The disease associated with the FXIa receptor inhibitor is selected from transient ischemic attack (TIA), ischemic stroke, thrombosis and / or thromboembolism leading to stroke or TIA, or a disorder of peripheral arteries leading to peripheral arterial disease.

9. The use according to claim 8, characterized in that The ischemic stroke is selected from cardiogenic stroke and non-cardiogenic stroke; the cardiogenic stroke is selected from stroke caused by atrial fibrillation; the non-cardiogenic stroke is selected from lacunar stroke, stroke caused by large artery or small artery disease, stroke caused by undetermined cause, cryptogenic stroke, and embolic stroke; the peripheral arterial disease leading to peripheral arterial disease is selected from peripheral arterial occlusion, acute limb ischemia, amputation, reocclusion and restenosis after intervention, or stent thrombosis.

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