CN116283908A

CN116283908A - N-aromatic methyl pyridone derivative and preparation method and application thereof

Info

Publication number: CN116283908A
Application number: CN202310228146.0A
Authority: CN
Inventors: 谢周令; 侯书增; 廖晨钟
Original assignee: Hefei University of Technology
Current assignee: Hefei University of Technology
Priority date: 2023-03-10
Filing date: 2023-03-10
Publication date: 2023-06-23

Abstract

The invention discloses an N-aromatic methyl pyridone derivative, a preparation method and application thereof, wherein the structure of the N-aromatic methyl pyridone derivative is shown as the following general formula (I). The N-aromatic methyl pyridone derivatives disclosed by the invention can effectively inhibit the activity of the blood coagulation factor XIa, and are used for preventing and treating diseases mediated by the blood coagulation factor XIa, namely cardiovascular and cerebrovascular diseases, in particular to the prevention and treatment of blood coagulation diseases or thromboembolic diseases.

Description

N-aromatic methyl pyridone derivative and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to an N-aromatic methyl pyridone derivative, a preparation method and application thereof.

Background

Common cardiovascular diseases such as stroke, thrombus and myocardial infarction are the main causes of death of the world population, and the number of deaths caused by cardiovascular diseases (CVD) is steadily rising, and the number of deaths caused by cardiovascular diseases is one third of the number of deaths worldwide. The pathological course of cardiovascular disease is closely related to thrombosis. Anticoagulants have been widely used in the treatment and prevention of thrombotic diseases. Anticoagulants are mainly divided into: traditional anticoagulant drugs and novel oral anticoagulant drugs. The traditional anticoagulants include warfarin and heparin; among the novel oral anticoagulants are the FXa inhibitors apixaban, rivaroxaban, ai Duosha, betrofloxaban and thrombin inhibitors (dabigatran etexilate), which show strong market activity for the prevention and treatment of thrombosis, however, their "bleeding risk" (bleeding risk) has limited the clinical scope of application (N Engl JMed.1991;325:153-158, blood.2003; 101:4783-4788).

Research at home and abroad proves that FXIa inhibitor is a potential medicament for treating cardiovascular and cerebrovascular diseases, especially thromboembolic diseases, and simultaneously provides a new treatment direction for overcoming remarkable hemorrhagic diseases. Thromboembolic disorders include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and thromboembolic disorders of the ventricles or peripheral circulation. Factor XI (FXI) is a plasma serine protease zymogen necessary for maintaining the endogenous pathway, and activated to form activated factor XIa (FXIa) plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback activate FXI, which in turn causes massive production of thrombin, which in turn causes a series of cascades to promote coagulation. Therefore, drugs against FXIa targets block endogenous pathways and inhibit amplification of the coagulation cascade, thus having antithrombotic effects. It was found that inhibition of FXIa factor is effective in inhibiting thrombosis in a thrombotic model (blood. 2010;116 (19): 3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of Venous Thromboembolism (VTE) (Blood 2009; 114:2878-2883), whereas severely deficient FXIa is at reduced risk of having Deep Vein Thrombosis (DVT) (Thromb Haemost 2011; 105:269-273).

FXIa is a member of the S1A serine protease (a subfamily of serine proteases) with highly conserved active sites. S1A serine proteases are mainly associated with various extracellular processes such as coagulation, digestion and immunization, including coagulation factors, plasmin, etc. FXI is a zymogen form of FXIa, containing 607 amino acid residues, that can be activated by FXIIa, thrombin, or by proteolytic cleavage at sites Ile370-Arg 369. Upon activation, FXIa forms an N-terminal heavy chain and a C-terminal light chain (Cys 484-Cys 362) via disulfide bonds, wherein the C-terminal light chain has a catalytic domain comprising an active site, wherein highly conserved trypsin-like catalytic triplets of Ser557 (195), asp462 (102) and His413 (57) can be observed. The S1, S2, S3, S4, S1 'and S2' subsites in the FXIa active site are available binding sites in the design of FXIa inhibitors, which typically bind to the S1, S1 'and S2' subsites in a significantly different manner than the binding models of other serine protease inhibitors such as thrombin, FXa and PKal inhibitors.

At present, the clinical development of FXIa inhibitors at home and abroad is very competitive, and many of the inhibitors enter clinical research stages such as BMS-986177, BAY-2433334, BMS-986209, ONO-7684, EP-7041 and the like, and are mainly used for preventing and treating diseases such as main thrombosis and the like. Clinical studies have shown that FXIa inhibitors can slow down thrombosis while the risk of bleeding is significantly reduced. In recent years, a series of FXIa inhibitor patents have been disclosed, including WO2017005725, W02018041122, WO2021233082A1, WO2021098817A1, WO2021202254A1, WO2022057849A1, etc., and research and use of FXIa inhibitors have been advanced to some extent, but there is still a great room for improvement, and there is still a need to continue to research and develop new FXIa inhibitors.

Disclosure of Invention

The technical problem to be solved by the invention is to provide the N-aromatic methyl pyridone derivative, the preparation method and the application thereof, wherein the N-aromatic methyl pyridone derivative can effectively inhibit the blood coagulation factor XIa and has good effects on preventing and treating diseases mediated by the blood coagulation factor XIa.

The technical scheme of the invention is as follows:

an N-aromatic methyl pyridone derivative has a structure shown in the following general formula (I):

in the general formula (I),R ¹ is a group of the general formula (II):

R ² is chlorine, fluorine and C ₁ -C ₅ Alkyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or isopropoxy; r is R ³ Is hydrogen atom, C ₁ -C ₅ Alkyl, 1-difluoroethyl, 3-trifluoro-2-methoxypropan-1-yl or 3, 3-trifluoro-2-ethoxypropan-1-yl; r is R ⁴ Is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group or a hydroxyl group; x, Y, Z is a carbon atom or a nitrogen atom; ring A is a group of the following general formula (III), general formula (IV) or general formula (V):

R ¹ in the general formula (II), R ⁵ Is chloro, fluoro, trifluoromethoxy, difluoromethoxy, methoxy or C1-C5 alkyl; r is R ⁶ Is a 5-membered heterocycle, a 6-membered heterocycle, a 5-membered heteroatom-substituted heterocycle or a 6-membered heteroatom-substituted heterocycle; r is R ⁷ Is chloro, fluoro, difluoromethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy or C ₁ -C ₅ An alkyl group;

in the general formula (III) and the general formula (IV) of the ring A, R ⁸ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) NR ¹¹ R ¹² 、-NHC(O)R ¹³ 、-C(O)NHR ¹⁴ Or carboxyl, wherein, -C (O) NR ¹¹ R ¹² R in (a) ¹¹ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NR ¹¹ R ¹² R in (a) ¹² Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -NHC (O) R ¹³ R in (a) ¹³ Is hydrogen atom, halogen, alkyl, alkoxy,Amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NHR ¹⁴ R in (a) ¹⁴ Is a hydrogen atom, halogen, alkyl, alkoxy, amino, hydroxyl, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl group;

R ⁹ is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) NR ¹⁵ R ¹⁶ 、-NHC(O)R ¹⁷ 、-C(O)NHR ¹⁸ Or carboxyl, wherein, -C (O) NR ¹⁵ R ¹⁶ R in (a) ¹⁵ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NR ¹⁵ R ¹⁶ R in (a) ¹⁶ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -NHC (O) R ¹⁷ R in (a) ¹⁷ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NHR ¹⁸ R in (a) ¹⁸ Is a hydrogen atom, halogen, alkyl, alkoxy, amino, hydroxyl, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl group;

R ¹⁰ is a hydrogen atom, halogen, alkyl, alkoxy, amino, hydroxyl, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl, heteroaryl or carboxyl;

x' is a hydrogen atom or a nitrogen atom;

y' is a hydrogen atom, an oxygen atom or a nitrogen atom;

ring beta is cycloalkyl, heterocyclyl, aryl, heteroaryl, or a fused ring.

The substituent in the heterocyclic ring with 5-membered substituted heteroatom or the heterocyclic ring with 6-membered substituted heteroatom is selected from oxo, chlorine, fluorine, hydroxyl, methyl, difluoromethyl, trifluoromethyl and 2, 2-trifluoroethyl.

When the ring beta is heteroaryl, the ring beta is 5-membered heteroaryl or 6-membered heteroaryl.

The general formula (I) is represented by any one of the following formulas (I-1) to (I-4):

the general formula (I) is the following formula (I-5):

the general formula (I) is represented by any one of the following formulas (I-6) and (I-7):

in (I-6) and (I-7), the carbon atom is chiral.

A preparation method of N-aromatic methyl pyridone derivatives comprises the steps of carrying out nucleophilic substitution reaction on a compound shown in a general formula (IA) and a compound shown in a general formula (IC) to obtain a compound shown in a general formula (IB), and then carrying out coupling reaction on the compound shown in the general formula (IB) and the compound shown in a general formula (ID) to obtain a compound shown in a general formula (I), wherein the chemical reaction general formula is shown in the specification:

wherein R is ¹ 、R ² 、R ³ 、R ⁴ And (5) the alpha is hydrogen atom, alkyl, alkoxy, halogen atom, trifluoromethoxy, difluoromethoxy or nitro, and X, Y, Z and the ring A are shown in the general formula (I).

The use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of a disease mediated by factor XIa.

Use of a compound of formula (IB) for the preparation of a medicament for the treatment or prophylaxis of a disease mediated by factor XIa.

The medicine contains an effective dose of a compound shown in a general formula (I), a compound shown in a general formula (IB), a compound shown in the general formula (I) or a racemate of the compound shown in the general formula (IB), a pharmaceutically acceptable salt or prodrug thereof, a pharmaceutically acceptable carrier or excipient, or a combination of the above.

The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, intraperitoneal, subcutaneous, subcuticular or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.

Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.

When the compounds of the invention are administered to humans and animals in the form of a medicament, the compounds may be provided alone or in the form of a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

The invention has the advantages that:

the N-aromatic methyl pyridone derivatives of the invention can effectively inhibit the activity of the blood coagulation factor XIa, and are used for preventing and treating diseases mediated by the blood coagulation factor XIa, namely cardiovascular and cerebrovascular diseases, in particular blood coagulation diseases or thromboembolic diseases.

Detailed Description

The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The preparation of N-aromatic methyl pyridone derivatives shown in the general formula (I) and related structural identification data are given in the examples. The following examples are intended to illustrate the invention and are not intended to limit it. ¹ The H NMR spectrum was measured with a nuclear magnetic resonance apparatus (600 MHz) and the chemical shift was expressed in ppm using the tetramethylsilane internal standard (0.00 ppm). 1H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm and 0.5mm.

Column chromatography uses yellow sea silica gel of 200-300 meshes as carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, and are used without further purification, and unless otherwise indicated, commercial vendors include, but are not limited to, shanghai Shaoshan Long reagent Co., ltd, shanghai Pichia pharmaceutical technologies Co., ltd, shanghai Michelin Biochemical technologies Co., ltd, and Shanghai A Ding Shiji Co.

CDCl ₃ Deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound using an eluent system of column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a is petroleum ether and ethyl acetate system; b, a methylene dichloride and methanol system;

room temperature: 20-30 ℃.

Example 1

A preparation method of 4- (5-chloro-2-tetrazole-1-yl) phenyl-1- (3, 4-dichlorobenzyl) -5-methoxypyridine-2 (1H) ketone, which has a chemical reaction formula:

(1) Preparation of 1- (2-bromo-4-chlorophenyl) -1H-tetrazole:

2-bromo-4-chloroaniline 1a (10.0 g,48.43 mmol) was added to a 250mL reaction flask, trimethyl orthoformate (15.4 g,145.29 mmol) was added and NaN was added ₃ (9.4 g,145.29 mmol), acetic acid (20-30 mL) was added at 0deg.C, stirred for 30min, then stirred at 80deg.C for 3h, monitored by Thin Layer Chromatography (TLC), the starting material was essentially reacted, cooled to room temperature, and 50mL of saturated NaNO was added ₂ Quenching the aqueous solution, adding ethyl acetate EA (200 mL), stirring for 30min, standing for separating, back-extracting the aqueous phase with EA (100 mL. Times.2), mixing the organic phases, and sequentially extracting the organic phases with H ₂ O (100 mL. Times.2), saturated aqueous NaCl solution (100 mL), anhydrous Na ₂ SO ₄ Drying and spin dryingAfter that, column chromatography (eluent system a) gave product 1b (8.4 g), yield: 67.5%. ¹ H NMR(600MHz，DMSO-d ₆ )δ8.99(s,lH),7.83-7.82(d,J＝2.0Hz,lH),7.56-7.50(m,2H).

(2) Preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 5-dimethoxypyridine:

under nitrogen, 1c (4 g,21.8 mmol) of 2, 5-dimethoxypyridine-4-boronic acid, 1- (2-bromo-4-chlorophenyl) -1H-tetrazole 1b (4.7 g,18.2 mmol) and potassium phosphate (11.6 g,54.6 mmol) were initially charged in a 250ml reaction flask, 50ml of 1, 4-dioxane and 10ml of water were then added, and [1,1' -bis (diphenylphosphine) ferrocene was added]Palladium dichloride dichloromethane complex (445.48 mg,0.549 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 100ml of water, and using H in the organic phase ₂ O (100 mL. Times.2), saturated aqueous NaCl solution (100 mL), anhydrous Na ₂ SO ₄ After drying and spin drying, column chromatography (eluent system A) gave product 1d (3.8 g). Yield: 65.5%. ¹ HNMR(600MHz,DMSO-d ₆ )δ8.89(s,lH),7.85-7.82(d,J＝2.0Hz,1H),7.58-7.50(m,2H),7.27(dd,J＝8.4,2.1Hz,1H),6.49(s,1H),3.5(m,3H),3.67(m,3H).

(3) Preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 5-dimethoxypyridine 1d (2 g,6.3 mmol) and pyridine hydrogen bromide (10.1 g,63 mmol) were added to a 100ml reaction flask, 20ml of N, N-Dimethylformamide (DMF) was added and stirred at 100deg.C for 3H. Thin Layer Chromatography (TLC) monitoring, the raw materials basically react, cooling to room temperature, adding 100ml of water, stirring for 1h, separating out solid, suction filtering to obtain a filter cake, and drying the filter cake for 12h to obtain a crude product 1e (1.2 g). Yield: 63.16%. ¹ H NMR(600MHz,DMSO-d ₆ )δ8.89(s,1H),8.33(s,1H),7.85-7.82(d,J＝2.0Hz,1H),7.58-7.50(m,2H),6.54(m,1H),3.5(m,3H).

(4) Preparation of 4- (5-chloro-2-tetrazol-1-yl) phenyl-1- (3, 4-dichlorobenzyl) -5-methoxypyridin-2 (1H) one:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, and after stirring for 30min 1, 3-tetramethylguanidine (0.12 g,0.99 mmol), 4-bromomethyl-1, 2-dichlorobenzene (0.1 g,0.4 mmol) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin drying, column chromatography (eluent system A) gave product 1 (30 mg). The yield thereof was found to be 21%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.69(s,1H),7.77(dd,J＝28.3,1.5Hz,3H),7.65–7.51(m,2H),7.37(s,1H),7.27(dd,J＝8.4,2.1Hz,1H),6.49(s,1H),5.01(s,2H),3.33(s,3H).

The preparation method of the intermediate-2, 5-dimethoxy pyridine-4-boric acid 1c comprises the following steps: at-78deg.C, N ₂ Diisopropylamine (5.46 g,54 mmol) was dissolved in 20ml THF and n-butyllithium (12 ml,1.6M in n-hexane) was slowly added over 30min and stirred for 30min before the starting 2, 5-dimethoxypyridine (2.5 g,18 mmol) was slowly added to the reaction solution. After the reaction was carried out at-68℃for 2 hours, triisopropyl borate (6 g,32 mmol) was slowly added to the reaction system, the reaction was stirred at 0℃for 30 minutes and at room temperature for 1 hour, and a mixed solution of acetic acid and water (acetic acid: water=6:1) was added to the reaction system and stirring was continued for 30 minutes. A white solid precipitated and was filtered, and the filter cake was washed with water (100 ml) and dried for 12h to give product 1c (2.2 g). The yield thereof was found to be 80%.

The crude product 1e in this example represents IA in the chemical formula and the resulting product 1 represents IB in the chemical formula.

Example 2

A process for the preparation of 4- (5-chloro-2-tetrazol-1-yl) phenyl-1- (3, 4-difluorobenzyl) -5-methoxypyridin-2 (1H) one, steps (1) - (3) being as in example 1, step (4) being: 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, followed by 1, 3-tetramethylguanidine (0.12 g, 0.99)After stirring for 30min, 4-bromomethyl-1, 2-difluorobenzene (0.12 g,0.4 mmol) was added and stirred at room temperature for 2h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin-drying, column chromatography (eluent system A) gave product 2 (32 mg). The yield thereof was found to be 22%. ¹ H NMR(600MHz,DMSO-d6)δ9.72(s,1H),7.80(d,J＝28.9Hz,3H),7.48–7.28(m,3H),7.17(t,J＝6.6Hz,1H),6.51(s,1H),5.02(s,2H),3.23(s,3H).

The chemical reaction formula of the step (4) is as follows:

the products of examples 3-13 were prepared according to the preparation methods of examples 1 or 2.

The profile parameters for the products of examples 3-13 are shown in the following table:

example 14

A process for the preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -1- (3 '-fluoro- [1,1' -biphenyl ] -3-yl) methyl) -5-methoxypyridin-2 (1H) -one, steps (1) - (3) are the same as in example 1, steps (4) and (5) having the chemical formulas:

(4) Preparation of 1- (3-bromobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, 1, 3-tetramethylguanidine (0.12 g,0.99 mmol) was added and stirred for 30min, and then 1-bromo-3-bromomethylbenzene 14a (0.1 g, excess) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ Drying, spin-drying followed by column chromatography (eluent system A) gave product 14b (30 mg). The yield thereof was found to be 21%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.69(s,1H),7.80(d,J＝1.5Hz,2H),7.74(t,J＝1.4Hz,1H),7.42–7.26(m,3H),7.23–7.04(m,2H),6.47(s,1H),5.00(s,2H),3.20(s,3H).

(5) Preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -1- (3 '-fluoro- [1,1' -biphenyl ] -3-yl) methyl) -5-methoxypyridin-2 (1H) -one:

(4-fluorophenyl) boronic acid 14c (50 mg, excess), 1- (3-bromobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 14b (50 mg,0.1 mmol) and potassium phosphate (0.12 g,0.6 mmol) were charged into a 25ml reaction flask under nitrogen, and 10ml of 1, 4-dioxane and 2ml of water were added, followed by [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 10ml of water, and using H in the organic phase ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ Drying, spin-drying followed by column chromatography (eluent system B) gave product 14 (15 mg). Yield: 31%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.69(s,1H),7.80(d,J＝1.5Hz,2H),7.74(t,J＝1.4Hz,1H),7.36–7.33(m,3H),7.20–7.11(m,2H),6.47(s,1H),5.00(s,2H),3.20(s,3H).

1e in this example 14 represents IA in the chemical formula, 14b represents IB in the chemical formula, and the resulting product 14 represents I in the chemical formula.

Example 15

A process for the preparation of 3- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) methyl) -N-methyl- [1,1' -biphenyl ] -4-carboxamide, steps (1) - (3) are the same as in example 1, steps (4) and (5) of the chemical formulas:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, 1, 3-tetramethylguanidine (0.12 g,0.99 mmol) was added and stirred for 30min, and then 1-bromo-3-bromomethylbenzene 15a (0.1 g, excess) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin-drying, column chromatography (eluent system A) gave product 15b (30 mg). The yield thereof was found to be 21%. ¹ H NMR(600MHz,DMSO-d ₆ )1H NMR(600MHz,DMSO-d6)δ9.69(s,1H),7.80(d,J＝1.5Hz,2H),7.74(t,J＝1.4Hz,1H),7.42–7.26(m,3H),7.23–7.04(m,2H),6.47(s,1H),5.00(s,2H),3.20(s,3H).

(5) Preparation of 3- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) methyl) -N-methyl- [1,1' -biphenyl ] -4-carboxamide:

(4- (methylcarbamoyl) phenyl) boronic acid 15c (50 mg, excess), 1- (3-bromobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 15b (50 mg,0.1 mmol) and potassium phosphate (0.12 g,0.6 mmol) were charged under nitrogen to a 25ml reaction flask, followed by 10ml of 1, 4-dioxane and 2ml of water, and the mixture was addedInto [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 10ml of water, and using H in the organic phase ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin drying, column chromatography (eluent system B) gave product 15 (15 mg). Yield: 31%.1H NMR (600 MHz, DMSO-d) ₆ )δ10.04(s,1H),9.71(s,1H),7.83–7.73(m,2H),7.70–7.64(m,2H),7.59–7.50(m,4H),7.44–7.33(m,2H),7.21(d,J＝7.6Hz,1H),6.49(s,1H),5.09(s,2H),3.34(s,3H),2.04(s,3H).

The products of examples 16-25 were prepared according to the preparation methods of examples 14 or 15.

The profile parameters for the products of examples 16-25 are shown in the following table:

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example 26

A process for the preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -1- (6-fluoro-4 '-hydroxy- [1,1' -biphenyl ] -3-yl) methyl) -5-methoxypyridin-2 (1H) -one, steps (1) - (3) being identical to example 1, steps (4) and (5) having the chemical formulas:

(4) Preparation of 1- (3-bromo-4-fluorobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, and after stirring for 30min 1, 3-tetramethylguanidine (0.12 g,0.99 mmol), 2-bromo-4-bromomethyl-1-fluorobenzene 26a (0.1 g, excess) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin-drying, column chromatography (eluent system A) gave product 26b (40 mg). The yield thereof was found to be 30%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.72(s,1H),7.80(d,J＝28.9Hz,3H),7.48–7.28(m,3H),7.17(t,J＝6.6Hz,1H),6.51(s,1H),5.02(s,2H),3.23(s,3H).

(5) Preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -1- (6-fluoro-4 '-hydroxy- [1,1' -biphenyl ] -3-yl) methyl) -5-methoxypyridin-2 (1H) -one:

(4-hydroxyphenyl) boronic acid 26c (50 mg, excess), 1- (3-bromo-4-fluorobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 26b (50 mg,0.1 mmol) and potassium phosphate (0.12 g,0.6 mmol) were charged under nitrogen to a 25ml reaction flask, and 10ml of 1, 4-dioxane and 2ml of water were then added, followed by the addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 10ml of water, and using H in the organic phase ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin-drying, column chromatography (eluent system B) gave product 26 (11 mg). Yield: 29%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.56(s,1H),7.72(t,J＝1.4Hz,1H),7.64(s,1H),7.53–7.48(m,1H),7.47–7.43(m,1H),7.43–7.39(m,2H),7.28–7.22(m,2H),7.13(d,J＝8.7Hz,1H),7.06–6.98(m,2H),6.76(ddd,J＝8.1,2.5,1.0Hz,1H),6.35(s,1H),5.16(s,2H),3.58(s,3H).

Example 27

A process for the preparation of 4- (5-chloro-2-tetrazol-1-yl) phenyl-1- (1- (4 '-fluoro- [1,1' -biphenyl ] -3-yl) ethyl) -5-methoxypyridin-2 (1H) one, steps (1) - (3) being the same as in example 1, steps (4) and (5) of the chemical formulas:

(4) Preparation of 1- (1- (3-bromophenyl) ethyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, and after stirring for 30min 1, 3-tetramethylguanidine (0.12 g,0.99 mmol), 2-bromo-4-bromomethyl-1-fluorobenzene 27a (0.1 g, excess) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin-drying, column chromatography (eluent system A) gave product 27b (40 mg). The yield thereof was found to be 30%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.70(d,J＝1.0Hz,1H),7.80(d,J＝1.3Hz,2H),7.75(t,J＝1.4Hz,1H),7.43–7.36(m,3H),7.33(d,J＝8.3Hz,2H),6.49(s,1H),5.05(s,2H).

(5) 4- (5-chloro-2-tetrazol-1-yl) phenyl-1- (1- (4 '-fluoro- [1,1' -biphenyl ] -3-yl)

Preparation of ethyl) -5-methoxypyridin-2 (1H) one:

(4-fluorophenyl) boronic acid 27a (50 mg, excess), 1- (3-bromobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 27b (50 mg,0.1 mmol) and potassium phosphate (0.12 g,0.6 mmol) were charged into a 25ml reaction flask under nitrogen, followed by 10ml of 1, 4-dioxane and2ml of water, 1' -bis (diphenylphosphine) ferrocene was added]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 10ml of water, and using H in the organic phase ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ After drying and spin-drying, column chromatography (eluent system B) gave product 27 (10 mg). Yield: 23%. ¹ H NMR(600MHz,Chloroform-d)δ8.56(s,1H),8.26–8.18(m,2H),7.63(dd,J＝8.4,1.8Hz,1H),7.57(d,J＝8.4Hz,1H),7.50(ddd,J＝8.9,5.0,1.7Hz,3H),7.36(dd,J＝7.3,2.1Hz,1H),7.21–7.18(m,1H),7.15(d,J＝2.6Hz,1H),6.72(s,1H),6.58(s,1H),5.34(t,J＝4.9Hz,1H),4.91(s,1H),3.23(s,3H).

The products of examples 28-32 were prepared according to the methods of preparation of examples 26 or 27.

The profile parameters for the products of examples 28-32 are shown in the following table:

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example 33

A process for the preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -1- (1- (4 '-hydroxy- [1,1' -biphenyl ] -3-yl) -1-ethyl) -5-methoxypyridin-2 (1H) one, steps (1) - (3) being identical to example 1, steps (4) and (5) according to the chemical formulas:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, and after stirring for 30min 1, 3-tetramethylguanidine (0.12 g,0.99 mmol), 1-bromo-3- (1-bromoethyl) benzene 33a (0.1 g, excess) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ Drying, spin-drying followed by column chromatography (eluent system A) gave product 33b (40 mg). The yield thereof was found to be 30%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.70(s,1H),9.56(d,J＝2.0Hz,1H),7.83–7.72(m,3H),7.16(s,1H),7.01(s,1H),6.85(d,J＝8.0Hz,2H),6.49(s,1H),6.14(q,J＝7.2Hz,1H),3.18(s,3H),1.73(d,J＝7.2Hz,3H).

(5) Preparation of 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -1- (1- (4 '-hydroxy- [1,1' -biphenyl ] -3-yl) -1-ethyl) -5-methoxypyridin-2 (1H) one:

(4-hydroxyphenyl) boronic acid 33c (50 mg, excess), 1- (3-bromobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 33b (50 mg,0.1 mmol) and potassium phosphate (0.12 g,0.6 mmol) were charged into a 25ml reaction flask under nitrogen, 10ml of 1, 4-dioxane and 2ml of water were then added, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 10ml of water, and using H in the organic phase ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ Drying, spin-drying followed by column chromatography (eluent system B) gave product 33 (10 mg). Yield: 23%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.70(s,1H),9.56(d,J＝2.0Hz,1H),7.83–7.72(m,3H),7.49–7.32(m,5H),7.16(s,1H),7.01(s,1H),6.85(d,J＝8.0Hz,2H),6.49(s,1H),6.14(q,J＝7.2Hz,1H),3.18(s,3H),1.73(d,J＝7.2Hz,3H).

Example 34

A process for the preparation of 4- (5-chloro-2-tetrazol-1-yl) phenyl-1- (1- (2, 4-difluoro- [1, 1-biphenyl ] -3-yl) -1-ethyl) -5-methoxypyridin-2 (1H) one, steps (1) - (3) being identical to example 1, step (4) and step (5) in the chemical formulas:

4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 1e (0.1 g,0.33 mmol) was added to a 50ml reaction flask and dissolved in 10ml DMF, and after stirring for 30min 1, 3-tetramethylguanidine (0.12 g,0.99 mmol), 1-bromo-3- (1-bromoethyl) benzene 34a (0.1 g, excess) was added and stirred for 2H at room temperature. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete. Quench with 20ml water and extract twice with 20ml EA. The organic phase is successively treated with H ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ Drying, spin-drying followed by column chromatography (eluent system A) gave product 34b (40 mg). The yield thereof was found to be 30%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.70(s,1H),9.56(d,J＝2.0Hz,1H),7.83–7.72(m,3H),7.16(s,1H),7.01(s,1H),6.85(d,J＝8.0Hz,2H),6.49(s,1H),6.14(q,J＝7.2Hz,1H),3.18(s,3H),1.73(d,J＝7.2Hz,3H).

(5) Preparation of 4- (5-chloro-2-tetrazol-1-yl) phenyl-1- (1- (2, 4-difluoro- [1, 1-biphenyl ] -3-yl) -1-ethyl) -5-methoxypyridin-2 (1H) one:

(4-hydroxyphenyl) boronic acid 34c (50 mg, excess), 1- (3-bromobenzyl) -4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) one 34b (50 mg,0.1 mmol) and potassium phosphate (0.12 g,0.6 mmol) were charged into a 25ml reaction flask under nitrogen, 10ml of 1, 4-dioxane and 2ml of water were then added, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride dichloromethane complex (10 mg,001 mmol) and the mixture was stirred at 80℃for 12h. Thin Layer Chromatography (TLC) monitoring, starting material was essentially complete and cooled to room temperature. The reaction mixture was cooled and filtered through celite and the filter cake was washed with EA. Extracting the filtrate twice after adding 10ml of water, and using H in the organic phase ₂ O (10 mL. Times.2), saturated aqueous NaCl solution (10 mL), anhydrous Na ₂ SO ₄ Drying, spin-drying followed by column chromatography (eluent system B) gave product 34 (15 mg). Yield: 32%. ¹ H NMR(600MHz,DMSO-d ₆ )δ9.68(s,1H),7.87–7.71(m,3H),7.56(td,J＝9.0,6.6Hz,1H),7.49–7.15(m,6H),7.01(s,1H),6.49(s,1H),6.16(q,J＝7.3Hz,1H),3.17(s,3H),1.73(d,J＝7.1Hz,3H).

The products of examples 35-38 were prepared according to the methods of preparation of examples 33 or 34.

The profile parameters for the products of examples 35-38 are shown in the following table:

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biological evaluation of Compounds

1. Assay of Factor XIa protease Activity by Compounds of the invention

1. Test method

The activity of the factor XI inhibitor was measured by the chromogenic substrate method. Due to the action of the coagulation factor XI activator, the coagulation factor XI is converted into the coagulation factor XI a, the generated coagulation factor XI a has proteolytic enzyme activity, then peptide bonds can be cut at the carboxyl end of Arg in a chromogenic substrate L-pyroglutamyl-L-propyl-L-arginine-pNA, p-nitroaniline PNA with specific absorption at 405nm wavelength is released, the free PNA is yellow, and the corresponding enzymatic activity can be measured by monitoring the change of absorption value at 405 nm.

2. Reagent, consumable and instrument

Factor XIa protease (Human FXI a mother liquor) used in the experiment was purchased from Haematologic Technologies inc company at a concentration of 2.1mg/mL; factor XIa-specific substrates were purchased from HYPHEN BioMed, cat No. CS-21 (66); tris buffer was purchased from emerging organisms; naCl was purchased from Alatine; blocking Buffer (BSA) was purchased from bisharp.

TBS-BSA buffer (50 mM Tris/HCl, pH 7.4,100mM NaCl,5mM CaCl) ₂ 0.605.7g Tris, 0.5844g NaCl, 0.1g BSA, 0.55492g CaCl were weighed out in 0.1% BSA) ₂ Dissolving in 80mL of ultrapure water, regulating the pH to 7.4 by concentrated hydrochloric acid, and fixing the volume to 100mL.

Multifunctional microplate reader was purchased from Biomek; an electronic balance; an analytical balance; 96-well plate

3. Compound formulation

The compound was dissolved in DMSO, 1mM, and stored at 2-8deg.C.

4. Test method

a, weighing 5mg of coagulation factor XIa specific substrate CS-21 (66) (molecular weight is 502.5), dissolving the coagulation factor XIa specific substrate CS-21 into 2.5mg/mL of substrate mother liquor by using 2mL of distilled water, diluting the substrate mother liquor into 0.5mg/mL (molar concentration is about 1 mM) of substrate reaction liquor by using 0.5mL of water for 5 times, and storing the substrate mother liquor at 4 ℃.

b: mu.L of the Human FXI a mother liquor (2.1 mg/mL) was taken up, diluted to 10nM solution by adding TBS-BSA buffer, then 0.2mL was taken up from 10nM solution and diluted to 1nM of the Human FXI a reaction solution by adding 1.8mM of LTBS-BSA buffer, and the Human FXI a mother liquor was stored at-20 ℃.

c: dilution of the sample solution (to 5 concentrations).

d: mu.L of the reaction solution of Human F XI a (1 nM) and 50. Mu.L of the sample solution (product of the example) were pipetted and mixed uniformly in a 96-well plate, incubated at room temperature for 60min, then 50. Mu.L of the substrate reaction solution (1 mM) was added thereto, the detection was carried out at a405nM wavelength for 1 hour, and the absorbance was measured and scanned once per minute. Wherein the negative control is 50. Mu.L TBS-BSA buffer+50. Mu.L Human FXI a reaction solution+50. Mu.L substrate reaction solution; the blank was 50. Mu.L TBS-BSA buffer + 50. Mu.L sample solution + 50. Mu.L substrate reaction.

The half Inhibitory Concentration (IC) of the product of the examples of the invention on FXIa was determined ₅₀ ) The test results are specifically shown in Table A belowThe illustration is:

table A

Examples	IC ₅₀ (nM)	Examples	IC ₅₀ (nM)
				6	<200	24	<1
9	22.45	25	<1
				15	5.39	29	5.31
16	5.58	30	4.74
				19	3.03	32	8.8
20	17.38	33	<1
				23	<1	36	1.45

From the semi-inhibitory concentrations of Table A, the products prepared in examples of the present invention have good inhibitory effects on FXIa activity, wherein the products prepared in examples 23, 24 and 25 can better inhibit FXIa activity.

Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. An N-aromatic methyl pyridone derivative, characterized in that: the structure is shown as the following general formula (I):

in the general formula (I), R ¹ Is a group of the general formula (II):

in the general formula (III) and the general formula (IV) of the ring A, R ⁸ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) NR ¹¹ R ¹² 、-NHC(O)R ¹³ 、-C(O)NHR ¹⁴ Or carboxyl, wherein, -C (O) NR ¹¹ R ¹² R in (a) ¹¹ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NR ¹¹ R ¹² R in (a) ¹² Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -NHC (O) R ¹³ R in (a) ¹³ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NHR ¹⁴ R in (a) ¹⁴ Is a hydrogen atom, halogen, alkyl, alkoxy, amino, hydroxyl, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl group;

R ⁹ is hydrogen atom, halogen, alkyl, alkoxy, amino, hydroxyl, amino, nitro, chloro, cycloalkylHeterocyclic, aryl, heteroaryl, -C (O) NR ¹⁵ R ¹⁶ 、-NHC(O)R ¹⁷ 、-C(O)NHR ¹⁸ Or carboxyl, wherein, -C (O) NR ¹⁵ R ¹⁶ R in (a) ¹⁵ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NR ¹⁵ R ¹⁶ R in (a) ¹⁶ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -NHC (O) R ¹⁷ R in (a) ¹⁷ Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxy, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl, -C (O) NHR ¹⁸ R in (a) ¹⁸ Is a hydrogen atom, halogen, alkyl, alkoxy, amino, hydroxyl, amino, nitro, chloro, cycloalkyl, heterocyclyl, aryl or heteroaryl group;

x' is a hydrogen atom or a nitrogen atom;

y' is a hydrogen atom, an oxygen atom or a nitrogen atom;

ring beta is cycloalkyl, heterocyclyl, aryl, heteroaryl, or a fused ring.

2. An N-aromatic picolinine derivative according to claim 1, wherein: the substituent in the heterocyclic ring with 5-membered substituted heteroatom or the heterocyclic ring with 6-membered substituted heteroatom is selected from oxo, chlorine, fluorine, hydroxyl, methyl, difluoromethyl, trifluoromethyl and 2, 2-trifluoroethyl.

3. An N-aromatic picolinine derivative according to claim 1, wherein: when the ring beta is heteroaryl, the ring beta is 5-membered heteroaryl or 6-membered heteroaryl.

4. An N-aromatic picolinine derivative according to claim 1, wherein: the general formula (I) is represented by any one of the following formulas (I-1) to (I-4):

5. an N-aromatic picolinine derivative according to claim 1, wherein: the general formula (I) is the following formula (I-5):

6. an N-aromatic picolinine derivative according to claim 1, wherein: the general formula (I) is represented by any one of the following formulas (I-6) and (I-7):

in (I-6) and (I-7), the carbon atom is chiral.

7. The method for preparing the N-aromatic methyl pyridone derivative according to claim 1, wherein the method comprises the following steps: nucleophilic substitution reaction is carried out on the compound shown in the general formula (IA) and the compound shown in the general formula (IC) to obtain a compound shown in the general formula (IB), and then coupling reaction is carried out on the compound shown in the general formula (IB) and the compound shown in the general formula (ID) to obtain a compound shown in the general formula (I), wherein the chemical reaction general formula is shown in the specification:

8. Use of a compound of general formula (I) according to claim 7 for the preparation of a medicament for the treatment or prophylaxis of diseases mediated by factor XIa.

9. Use of a compound of formula (IB) according to claim 7 for the manufacture of a medicament for the treatment or prophylaxis of a disease mediated by factor XIa.

10. The medicament as claimed in claim 8 or 9, wherein: the medicine contains an effective dose of a compound shown in a general formula (I), a compound shown in a general formula (IB), a compound shown in the general formula (I) or a racemate of the compound shown in the general formula (IB), a pharmaceutically acceptable salt or prodrug thereof, a pharmaceutically acceptable carrier or excipient, or a combination of the above.