An oxopyridine compound, its preparation method and use

Abstract

The present invention discloses a compound represented by formula (I), its stereoisomers, or pharmaceutically acceptable salts. The present invention also provides the use of the compound, its stereoisomers or pharmaceutically acceptable salts in the preparation of a medicament for treating and / or preventing diseases related to the FXIa receptor, especially in the preparation of a medicament for treating and / or preventing cerebrovascular arterial diseases and / or peripheral arterial diseases, with better efficacy and higher safety.

Description

Technical Field

[0001] The present invention relates to the field of chemical drugs, and particularly to oxopyridine compounds or their salts, isomers, and their preparation methods, as well as their use in the preparation of drugs for treating and / or preventing diseases related to the FXIa receptor, especially their use in the preparation of drugs for treating and / or preventing cerebrovascular arterial diseases and / or peripheral arterial diseases, etc. Background Art

[0002] Thromboembolic diseases are diseases caused by abnormal blood clots formed in blood vessels during the survival of humans and animals. Clinically, they may manifest as myocardial infarction, stroke, deep vein thrombosis (DVT), pulmonary embolism, atrial fibrillation, and cerebral infarction, etc., claiming the lives of tens of millions of people globally every year. Coagulation factor XI (FXI) is a plasma serine protease zymogen necessary to maintain the intrinsic pathway. After activation, it generates activated coagulation factor XIa (FXIa), which plays a key role in the amplification process of the coagulation cascade reaction. Therefore, drugs targeting the FXIa target can block the intrinsic pathway and inhibit the amplification of the coagulation cascade reaction, thus having an antithrombotic effect.

[0003] The reported FXIa inhibitors mainly include monoclonal antibodies, antisense oligonucleotides, small chemical molecules, polypeptides or proteins, and polypeptide mimetics, etc. Currently, milvexian jointly developed by BMS and Johnson & Johnson has completed clinical phase II trials, and the results show a relatively low bleeding risk. The clinical phase I trial of the intravenous small molecule FXIa inhibitor BMS-962122 of BMS has been completed, and the R & D has been suspended. The small molecule oral FXIa inhibitor ONO-7684 developed by Ono Pharmaceutical Co., Ltd. of Japan has entered clinical phase I research. BAY-2433334 developed by Bayer has completed clinical phase II trials and has become the most promising small molecule FXIa inhibitor at present. Monoclonal antibodies and antisense oligonucleotides need to be administered by injection, and have the disadvantages of high price, slow onset, and possible difficulty in control. Small chemical molecules have the advantages of relatively good oral bioavailability and better patient compliance.

[0004] Therefore, the research and development of new small molecule FXIa inhibitors with high safety, good efficacy, high specificity, and strong activity may make up for the deficiencies of current clinical anticoagulant and antithrombotic drugs that are prone to bleeding complications and meet the unmet clinical needs. Summary of the Invention

[0005] The compounds of the present invention are a novel type of oxopyridine compounds, having good anticoagulant effects, in vitro affinity for FXIa, and in vivo pharmacokinetics.

[0006] On the one hand, the present invention provides a compound represented by formula (I), its stereoisomers, or a pharmaceutically acceptable salt:

[0007]

[0008] Further, the pharmaceutically acceptable salt is a metal salt.

[0009] Further, the metal salt is selected from sodium salt, potassium salt, calcium salt, lithium salt, and magnesium salt.

[0010] Further, the present invention also encompasses a pharmaceutical composition comprising the above compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the composition further contains a pharmaceutically acceptable carrier and / or excipient.

[0011] On the other hand, the present invention also relates to a method for preparing the above compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0012]

[0013] Step 1: Starting material a undergoes a substitution reaction with deuterated methane to form intermediate b;

[0014] Step 2: Intermediate b reacts with triisopropyl borate under basic conditions to form intermediate c;

[0015] Step 3: Intermediate c undergoes a coupling reaction with compound d to form intermediate e;

[0016] Step 4: Intermediate e undergoes an oxidation reaction under acidic conditions to form intermediate f;

[0017] Step 5: Intermediate f undergoes a substitution reaction with compound g under basic conditions to form intermediate h;

[0018] Step 6: Intermediate h undergoes a hydrolysis reaction under basic conditions to form the compound of formula (I).

[0019] Thirdly, the present invention also provides the use of any one of the above compounds, its stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing diseases related to the FⅪa receptor.

[0020] Further, the diseases related to the FⅪa receptor are selected from thrombosis and / or thromboembolism-related disorders.

[0021] Further, the diseases related to the FⅪa receptor are selected from cerebrovascular arterial diseases and / or peripheral arterial diseases.

[0022] Further, the above-mentioned cerebrovascular arterial diseases include, but are not limited to, transient ischemic attack (TIA), ischemic stroke, or events with a thrombotic and / or thromboembolic origin that lead to stroke or TIA; the above-mentioned peripheral arterial diseases include, but are not limited to, peripheral arterial occlusion, acute limb ischemia, amputation, re-occlusion and restenosis after intervention (such as angioplasty, stenting, or surgery and bypass), and / or stent thrombosis.

[0023] Further, the above-mentioned ischemic strokes include, but are not limited to, cardioembolic stroke, non-cardioembolic stroke, stroke caused by large artery or small artery diseases, stroke of undetermined cause, cryptogenic stroke, embolic stroke, or embolic stroke of undetermined origin.

[0024] Further, the above-mentioned cardioembolic strokes include, but are not limited to, strokes caused by atrial fibrillation; the above-mentioned non-cardioembolic strokes include, but are not limited to, lacunar strokes.

[0025] Beneficial effects: Compared with the prior art, the present invention has better in vitro FXIa inhibitory effect and in vitro anti-human plasma coagulation effect. In particular, in vivo pharmacokinetics in rats shows that Compound 1 has higher AUC and Cmax and a shorter half-life, indicating that when achieving the same drug effect, the dose of Compound 1 is lower than that of Compound 2 and the comparative compound, with a higher safety risk, and at the same time, it has faster metabolism, further avoiding the risk of increased bleeding due to long-term action. Detailed implementation manners

[0026] The following will further describe the present invention in detail in combination with examples and experimental examples. The examples and experimental examples of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the present invention. Any equivalent substitution in the art made in accordance with the content disclosed in the present invention belongs to the protection scope of the present invention.

[0027] The compounds, their stereoisomers or pharmaceutically acceptable salts of the present invention can all be prepared by selecting the synthetic routes of the examples, and the conventional conditions of the reaction raw materials and reaction solvents can be adjusted according to the needs of substituents or salt formation. These can all be achieved by those skilled in the art based on the disclosed content of the present invention. In addition, the column chromatography in the present invention refers to silica gel column chromatography without special instructions, and the elution solvent can be determined as a single or mixed elution solvent by combining the reaction solvent with the common knowledge or common means of those skilled in the art without special instructions.

[0028] The structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS).

[0029] The liquid chromatography-mass spectrometry (LC-MS) is Agilent G6120B (used in conjunction with the liquid phase Agilent 1260); the nuclear magnetic resonance spectrometer ( 1 HNMR) is Bruker AVANCE-400 or Bruker AVANCE-800, and the nuclear magnetic resonance ( 1 H NMR) chemical shift ( δ δ) is given in parts per million (ppm), with tetramethylsilane (TMS) as the internal standard, and the chemical shift is given in units of 10 -6 δ (ppm).

[0030] The term "room temperature" in the present invention refers to a temperature between 10 and 30 °C.

[0031] Example 1: Preparation of (S)-4-(2-(4-(5-chloro-2-propionylphenyl)-3-(methoxy-d3)-6-oxopyridazin-1(6H)-yl)-3-phenylpropanamido)-benzoic acid (Compound 1):

[0032]

[0033] Step 1: Preparation of Intermediate b

[0034] Take 6-methoxypyridazin-3-ol (2 g, 15.8 mmol), dissolve it in 40 ml of DMF, add cesium carbonate (10.3 g, 31.6 mmol), cool to 0 °C, and dropwise add deuterated iodomethane (3.5 g, 24.1 mmol). It takes about 30 minutes to add it all. After adding, stir the reaction at room temperature for 4 hours. Add EA and water, extract, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate the solvent to obtain 2.7 g of crude product. Purify it by column chromatography (eluent PE:EA = 10:1) to obtain 2 g of pure product. Yield: 88.42%, HPLC purity: 98.81%.

[0035] ESI-MS: m / z = 144.1 (M+H) + .

[0036] Step 2: Preparation of Intermediate c

[0037] Dissolve diisopropylamine (1.7 g, 16.8 mmol) in 20 ml of THF, cool to below -60 °C, and dropwise add 6.4 ml of a 2.5 M n-butyllithium n-hexane solution over about 1 hour. After addition, stir the reaction at -60 °C for 15 minutes. Then dropwise add a 5 ml THF solution of compound b (2 g, 14.0 mmol) over about 1 hour. After addition, stir the reaction at -60 °C for 2 hours. Next, dropwise add triisopropyl borate (2.9 g, 15.4 mmol) over 30 minutes. After addition, slowly warm up to room temperature (20 °C) and stir the reaction for 30 minutes. Dropwise add a mixture of 3 g of acetic acid and 15 g of water to terminate the reaction. After addition, stir at room temperature for 30 minutes. Distill off the organic solvent, add a little water, stir at room temperature for 15 minutes, filter, wash the filter cake with water, and dry in vacuo at 70 °C to obtain 2.1 g of a solid. The yield is 80.22%, and the HPLC purity is 98.12%.

[0038] ESI-MS: m / z = 188.1 (M+H) + 。

[0039] Step 3: Preparation of intermediate e

[0040] Take compound d (2 g, 8.08 mmol) and Pd(amphos)Cl2 (86 mg, 0.12 mmol), suspend them in 20 ml of tert-amyl alcohol, heat to 85 °C, and dropwise add a mixed solution of compound c (1.8 g, 9.63 mmol), sodium carbonate (2.6 g, 24.5 mmol), and 20 ml of water over about 1 hour. After addition, react at 85 °C for 1 hour. Cool to room temperature, perform extraction treatment with EA / water, separate the aqueous layer, wash the organic layer successively with water and saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the solvent to obtain 3.6 g of a crude product. Purify by column chromatography and collect the target product to obtain 1.9 g of a pure product. The yield is 75.91%, and the purity is 98.59%.

[0041] ESI-MS: m / z = 310.1 (M+H) + 。

[0042] Step 4: Preparation of intermediate f

[0043] Take compound e (1.8 g, 5.81 mmol), anhydrous lithium chloride (1.3 g, 30.7 mmol), p-toluenesulfonic acid monohydrate (2.2 g, 11.6 mmol), and 20 ml of isopropyl alcohol, mix them, and heat under reflux for 16 hours. Cool to room temperature, evaporate half of the solvent, add 30 ml of water, stir at room temperature for 15 minutes, filter, wash the filter cake with water, and dry in vacuo at 70 °C to obtain 1.5 g of a solid. The yield is 87.29%, and the purity is 96.85%.

[0044] ESI-MS: m / z = 296.1 (M+H)+ 。

[0045] Step 5: Preparation of Methyl (S)-4-(2-(4-(5-chloro-2-propionylphenyl)-3-(methoxy-d3)-6-oxopyridazin-1(6H)-yl)-3-phenylpropanamido)benzoate (Intermediate h)

[0046] Add compound f (500 mg, 1.69 mmol), tetramethylguanidine (681 mg, 5.91 mmol), 6 ml of isopropanol, and 1.5 ml of acetone to a 25-ml reaction flask. Stir at room temperature for 15 minutes, add compound g (707 mg, 1.86 mmol), and stir the reaction overnight at room temperature. The next day, add water to terminate the reaction, extract with EA, separate the aqueous layer, and wash the organic layer successively with saturated ammonium chloride, water, saturated brine, dry over anhydrous sodium sulfate, filter, and evaporate the solvent to obtain 1.2 g of crude product. Purify by column chromatography, collect the product, and obtain 802 mg of pure product. The yield is 79.75% and the purity is 98.84%.

[0047] ESI-MS: m / z = 595.2 (M + H) + 。

[0048] Step 6: Preparation of (S)-4-(2-(4-(5-chloro-2-propionylphenyl)-3-(methoxy-d3)-6-oxopyridazin-1(6H)-yl)-3-phenylpropanamido)-2-fluorobenzoic acid (Compound 1)

[0049] Add compound h (500 mg, 0.84 mmol) and 6 ml of methanol to a 25-ml reaction flask, stir to dissolve, and cool to 0 °C. Weigh lithium hydroxide monohydrate (71 mg, 1.69 mmol), dissolve it in 3 ml of water, add it dropwise to the reaction flask. After addition, react at room temperature for 2 h. Add water to terminate the reaction, adjust the pH to weakly acidic with 5% citric acid, extract with EA, separate the aqueous layer, wash the organic layer successively with water, saturated NaCl, dry over anhydrous sodium sulfate, filter, and evaporate the solvent to obtain 490 mg of crude product. Purify by column chromatography, collect the target product, and obtain 398 mg of pure product. The yield is 81.54% and the purity is 97.38%.

[0050] ESI-MS: m / z = 581.2 (M + H) + 。

[0051] 1HNMR (400 MHz, DMSO-d6) δ: 12.76 (brs, 1H), 10.54 (s, 1H), 7.97 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.67 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.36 (m, 4H), 7.21 (m, 1H), 6.91 (s, 1H), 5.72 (m, 1H), 3.55 (m, 1H), 3.40 (m, 1H), 2.99 (brs, 2H), 1.04 (t, J = 7.1 Hz, 3H).

[0052] Example 2: Preparation of (S)-4-(2-(4-(5-chloro-2-(propanoyl-d5)-phenyl)-3-methoxy-6-oxopyridazin-1(6H)-yl)-3-phenylpropanamido)-benzoic acid (Compound 2)

[0053]

[0054] The preparation method is the same as that of Example 1. Replace the compound d in step 3 with 1-(2-bromo-4-chlorophenyl)propan-1-one 2,2,2,3,3-d5 to obtain the title compound 2 with a purity of 98.80%.

[0055] ESI-MS: m / z = 565.2 (M + H) + .

[0056] 1 HNMR (400 MHz, DMSO-d6) δ: 12.76 (brs, 1H), 10.54 (s, 1H), 7.97 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.67 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.36 (m, 4H), 7.21 (m, 1H), 6.91 (s, 1H), 5.72 (m, 1H), 3.98 (s, 3H), 3.01 (m, 2H).

[0057] 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)butanamido)-2-fluorobenzamide

[0058]

[0059] Synthesized according to the method described in Patent CN116120240, purity: 98.5%.

[0060] ESI-MS:m / z =560.0(M+H) + 。

[0061] 1 HNMR (400 MHz, DMSO-d6) δ: 12.74 (brs, 1H), 10.54 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.68 (dd, J = 8.3, 2.1 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.36 (m, 4H), 7.21 (t, J = 7.1 Hz, 1H), 6.91 (s, 1H), 5.72 (s, 1H), 3.64 (s, 3H), 3.55 (m, 1H), 3.40 (m, 1H), 2.99 (brs, 2H), 1.02 (t, J = 7.1 Hz, 3H).

[0062] Experimental Example 1: Inhibitory Effect on Coagulation Factor FXIa

[0063] 1. Test Samples

[0064] Compound 1, Compound 2 of the Example and Comparative Example 1.

[0065] 2. Test Procedures

[0066] 1) Prepare the experimental buffer (50 mM HEPES, 5 mM KCl, 145 mM NaCl, 1 mg / ml PEG8000, pH 7.4) and equilibrate to room temperature.

[0067] 2) Prepare 10X compound working solution.

[0068] 3) Prepare 0.8 nM Human FXIa working solution (2X) and mix well for later use.

[0069] 4) Add 20 μL of the FXIa working solution in step 3) to all experimental wells of a 384-well plate (Coring, 3702), centrifuge at 200 g, RT for 10 s.

[0070] 5) Add 4 μL of the compound working solution in step 2) to the corresponding experimental wells of the 384-well plate, centrifuge at 200 g, RT for 10 s, and then incubate the working plate at 25 °C for 20 min.

[0071] 6) Prepare 750 μM S-2366 working solution (2.5X) and mix well for later use.

[0072] 7) Add 16 μL of the S-2366 (brand: Chromogenix) working solution from step 6) to all the experimental wells in the 384-well plate, centrifuge at 200 g, RT for 10 s, and then place the working plate in an incubator at 37 °C for 45 min.

[0073] 8) After incubation, use EnVision to read the absorbance at OD405nm and collect the data.

[0074] Set 5 concentrations, namely: 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, and detect the IC 50 value.

[0075] 3. Data analysis

[0076] 1) Z’ factor = 1 - 3*(SD Max + SD Min ) / (Mean Max - Mean Min );

[0077] 2) CV Max = (SD Max / Mean Max )*100%;

[0078] 3) CVMin = (SD Min / Mean Min )*100%;

[0079] 4) S / B = Singal / Background;

[0080] 5) Blank control: 0.1% DMSO; Positive control: Comparative Example 1;

[0081] 6) The calculation formula of IC 50 : Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 - X)*HillSlope)).

[0082] X: Log value of compound concentration; Y: Inhibition%.

[0083] 4. Test results

[0084] The test results are shown in the following table. Under the condition of the same molar concentration, Compound 1 of the present invention has an in vitro inhibitory activity against FXIa equivalent to that of the compound in Comparative Example 1, but is superior to Compound 2.

[0085] 。

[0086] Test Example 2: Determination of Anticoagulant Effect in Human Plasma in Vitro

[0087] 1. Test Samples

[0088] Compound 1, Compound 2 of the Examples and Comparative Example 1

[0089] 2. Test Method

[0090] Using a sodium citrate (1:9) anticoagulant tube, after collecting the blood of healthy people, immediately mix it well with the anticoagulant, and centrifuge it at 4000 r / min at room temperature for 15 minutes. After centrifugation, use a pipette to aspirate the plasma sample and freeze it (-80 °C) for standby.

[0091] Weigh an appropriate amount of the compound and prepare a 10 - 100 mM stock solution with 100% DMSO (the specific concentration of the stock solution is determined according to the properties of the compound); then prepare working solutions with different concentrations using healthy human plasma as the solution (specifically: 0, 0.3, 1, 3, 10, 30, 60, 100, 300 μM), mix well; incubate at 37 °C for 3 min and then put it on the machine (model CS - 2000I) to measure APTT.

[0092] 3. Data Processing

[0093] Use GraphPad Prism software for curve fitting and calculate the EC150 value, that is, the effective concentration of the compound corresponding to a 50% prolongation of APTT relative to the blank control group.

[0094] 4. Experimental Results

[0095] The results are shown in the following table. The APTT EC150 of the tested Compound 1 is better than that of the compound in Comparative Example 1 and even better than that of Compound 2.

[0096] .

[0097] Test Example 3: Pharmacokinetic Study in Rats

[0098] 1. Test Samples

[0099] Compound 1, Compound 2 of the Examples and Comparative Example 1

[0100] 2. Preparation Method of Test Substances and Environmental Requirements

[0101] The preparation of test substances is carried out on a conventional workbench in the preparation room.

[0102] Preparation of stock solutions for the construction method: Prepared according to the dispensing regulations, using methanol as the solvent, prepare 1.00 mg / mL stock solutions of Compound 1 of the Example and Comparative Example 1 respectively.

[0103] Preparation of rat dosing solution: Prepared using 0.5% CMC-Na as the solvent. The oral dosing concentration is 30 mg / mL.

[0104] 3. Test operation

[0105] (1) Administration and sample collection

[0106] Rats were fasted for 12 h before dosing and had free access to water. 12 SD rats were used in the experiment, with 6 males and 6 females, divided into 2 groups, 6 rats in each group.

[0107] Blank blood was collected before dosing, and blood was collected at the predetermined time points after dosing: 2 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 5 h, 7 h, 24 h, Approximately 0.5 mL of blood was collected, placed in an EDTA-K2 tube, centrifuged to separate plasma, and stored at -80 °C.

[0108] (2) Animal disposal

[0109] After the experiment, all animals were euthanized according to the institutional SOP.

[0110] (3) Instruments

[0111] Liquid chromatography-mass spectrometry tandem analysis system (LC-MS / MS), including Shimadzu LC-20AD series binary pumps and SIL-20AC autosampler, as well as AB API-4000 Q-Trap mass detector (including ESI ion source), chromatographic column: ODS-C18 (4.6×50 mm, 3 µm).

[0112] (4) Sample treatment

[0113] Standard curve sample treatment: 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 14000 g for half an hour, and take the supernatant for LC-MS / MS detection.

[0114] Rat plasma sample treatment: 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 14000 g for half an hour, and take the supernatant for detection.

[0115] (5) Pharmacokinetic analysis

[0116] According to the plasma concentration data of the drug, DAS 2.0 software was used to calculate the pharmacokinetic parameters.

[0117] 4. Results

[0118] The experimental results of the pharmacokinetic study of oral administration in rats are shown in the following table. Compared with Comparative Example 1, Example Compound 1 has better absorption, and the AUC (0-t) , Cmax are significantly increased, indicating that to achieve the same drug effect, the dosage of Example Compound 1 is lower. However, both Cmax and AUC of Example Compound 2 are comparable to those of the compound in Comparative Example 1, proving that not all deuterated positions have the effect of enhancing the drug effect.

[0119] At the same time, unexpectedly, compared with Comparative Example 1 and Compound 2, Compound 1 has a shorter half-life and exhibits pharmacokinetic characteristics of rapid elimination, indicating that the potential bleeding safety risk of Compound 1 is also lower, and it also proves that not all deuterated positions have the effect of prolonging the half-life.

[0120] .

[0121] The above embodiments are only one of the preferred embodiments of the present invention and should not be used to limit the protection scope of the present invention. Any meaningless modifications or polishings made on the main design concept and spirit of the present invention, as long as the technical problems solved are still consistent with those of the present invention, should be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I), its stereoisomers or pharmaceutically acceptable salts: 。 2. The compound, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that, The salt is a metal salt.

3. The compound, stereoisomer or pharmaceutically acceptable salt according to claim 2, characterized in that, The metal salt is selected from sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3, its stereoisomer or pharmaceutically acceptable salt, characterized in that, The composition further contains a pharmaceutically acceptable carrier and / or excipient.

5. A process for preparing the compound, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: ； Step 1: The starting material a undergoes a substitution reaction with deuterated methane to form intermediate b; Step 2: Intermediate b reacts with triisopropyl borate under alkaline conditions to form intermediate c; Step 3: Intermediate c undergoes a coupling reaction with compound d to form intermediate e; Step 4: Intermediate e undergoes an oxidation reaction under acidic conditions to form intermediate f; Step 5: Intermediate f undergoes a substitution reaction with compound g under alkaline conditions to form intermediate h; Step 6: Intermediate h undergoes a hydrolysis reaction under alkaline conditions to form the compound of formula (I).

6. Use of the compound according to any one of claims 1 to 3, its stereoisomers or pharmaceutically acceptable salts or the composition according to claim 4 in the preparation of a medicament for treating and / or preventing diseases related to the FⅪa receptor.

7. The application according to claim 6, characterized in that, The diseases related to the FⅪa receptor are selected from thrombosis and / or thromboembolism-related disorders.

8. The application according to claim 6, wherein The diseases related to the FⅪa receptor are selected from cerebrovascular arterial diseases and / or peripheral arterial diseases.

9. The application according to claim 6, characterized in that, The diseases related to the FⅪa receptor are selected from transient ischemic attack, ischemic stroke or peripheral arterial diseases.

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