Dihydropyrimidine compound, preparation method and application thereof, dihydropyrimidine derivative, application of dihydropyrimidine derivative, pharmaceutical composition and application of pharmaceutical composition

Abstract

The invention provides a dihydropyrimidine compound and a preparation method and application thereof, a dihydropyrimidine derivative and application thereof, and a pharmaceutical composition and application thereof, and relates to the technical field of biological medicines. The dihydropyrimidine compound provided by the invention is high in antiviral activity, particularly high in anti-HBV activity and low in toxicity, can be used for preparing antiviral drugs, and particularly has a very good application prospect when being used for preparing HBV inhibitors.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and particularly relates to a dihydropyrimidine compound, a preparation method and application thereof, a dihydropyrimidine derivative and an application thereof, and a pharmaceutical composition and an application thereof. Background Art

[0002] Hepatitis B virus (HBV) infection is a major public health problem worldwide and a cause of high mortality in liver cancer and cirrhosis. Although vaccines can be used to treat this disease, about 1.5 million people are still infected with hepatitis B every year. Currently, the main drugs for the treatment of hepatitis B are two major categories of drugs: interferon (IFN) and nucleoside analogues (NUCs). However, IFN has disadvantages such as high price and large side effects; NUCs have strong antiviral effects, but the recurrence rate is high after drug withdrawal, and there is a problem of drug resistance in long-term medication. Existing HBV treatment methods cannot completely clear the virus infection and cannot cure hepatitis B.

[0003] Through the exploration of the virus life cycle, many new strategies for the treatment of hepatitis B virus infection have been discovered, especially the HBV capsid protein inhibitors reported in recent years. The HBV capsid protein plays an important role in all processes of the virus life cycle, can completely clear covalently closed circular DNA (cccDNA), and is an important target for the research and development of anti-hepatitis B virus infection drugs.

[0004] Dihydropyrimidine HBV capsid protein inhibitors have high anti-HBV infection effects, and related compounds have entered clinical research. However, the above drugs have the problem of insufficient anti-HBV activity. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a dihydropyrimidine compound, a preparation method and application thereof, a dihydropyrimidine derivative and an application thereof, and a pharmaceutical composition and an application thereof. The dihydropyrimidine compound provided by the present invention has high anti-HBV activity.

[0006] In order to achieve the above invention purpose, the present invention provides the following technical solutions: The present invention provides a dihydropyrimidine compound having a structure shown in Formula A, Formula B or Formula C: Formula A Formula B Formula C; wherein, X includes CH or N; R1 includes any one of the following structures: ; R3 includes -H, -CH3 or -CH2CH2OH; When R3 is -H, R2 includes those without tert-butyl ester and COOH groups, those with tert-butyl ester groups or those with COOH groups; the ones without tert-butyl ester and COOH groups include any one of the following structures: ; The ones with tert-butyl ester groups include any one of the following structures: ; The ones with COOH groups include any one of the following structures: ; When R3 is -CH3, R2 includes any one of the following structures: ; When R3 is -CH2CH2OH, R2 is -CH2CH2OH.

[0007] Preferably, when X is N, R1 includes any one of the following structures: ; When X is CH, R1 includes any one of the following structures: .

[0008] The present invention also provides a preparation method of the dihydropyrimidine compounds described in the above technical solution. The preparation method of the dihydropyrimidine compounds having the structure shown in Formula A includes the following steps: subjecting Compound 2 and Compound 4 to a substitution reaction, or subjecting Compound 3 and R1-Cl to a substitution reaction to obtain the dihydropyrimidine compounds having the structure shown in Formula A; When R3 is -H and R2 is without tert-butyl ester and COOH groups, or R3 is -H and R2 is with tert-butyl ester groups, the preparation method of the dihydropyrimidine compounds having the structure shown in Formula B includes the following steps: subjecting Compound 2 and R2-NH2 to a substitution reaction to obtain the dihydropyrimidine compounds having the structure shown in Formula B where R3 is -H and R2 is without tert-butyl ester and COOH groups, or R3 is -H and R2 is with tert-butyl ester groups; When R3 is -H and R2 is with COOH groups, the preparation method of the dihydropyrimidine compounds having the structure shown in Formula B includes the following steps: subjecting the dihydropyrimidine compounds having the structure shown in Formula B where R3 is -H and R2 is with tert-butyl ester groups to a hydrolysis reaction to obtain the dihydropyrimidine compounds having the structure shown in Formula B where R3 is -H and R2 is with COOH groups; When R3 is -CH3, the preparation method of the dihydropyrimidine compound with the structure shown in Formula B comprises the following steps: subjecting Compound 5 to a substitution reaction with R2-Cl to obtain the dihydropyrimidine compound with the structure shown in Formula B where R3 is -CH3; When R3 is -CH2CH2OH, the preparation method of the dihydropyrimidine compound with the structure shown in Formula B comprises the following steps: subjecting Compound 2 to a substitution reaction with R2-NH-R3 to obtain the dihydropyrimidine compound with the structure shown in Formula B where R3 is -CH2CH2OH; The preparation method of the dihydropyrimidine compound with the structure shown in Formula C comprises the following steps: subjecting Compound 2 to a substitution reaction with Compound 6 to obtain the dihydropyrimidine compound with the structure shown in Formula C; 。

[0009] Preferably, the preparation method of Compound 3 comprises the following steps: subjecting Compound 2 to a substitution reaction with 4-aminopiperidine to obtain Compound 3.

[0010] Preferably, the preparation method of Compound 5 comprises the following steps: subjecting Compound 2 to a substitution reaction with methylammonium hydrochloride to obtain Compound 5.

[0011] Preferably, the preparation method of Compound 2 comprises the following steps: subjecting Compound 1 to a substitution reaction with N-bromosuccinimide to obtain Compound 2; Compound 1.

[0012] The present invention also provides a dihydropyrimidine derivative, comprising one or more of a pharmaceutically acceptable salt, hydrate, organic solvent clathrate, isomer and crystalline form compound of the dihydropyrimidine compound described in the above technical solution.

[0013] The present invention also provides a pharmaceutical composition, characterized by comprising an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises at least one of the dihydropyrimidine compounds described in the above technical solution and the dihydropyrimidine derivatives described in the above technical solution.

[0014] The present invention also provides the use of the dihydropyrimidine compound described in the above technical solution, the dihydropyrimidine derivative described in the above technical solution or the pharmaceutical composition described in the above technical solution in the preparation of an antiviral infection drug.

[0015] Preferably, the virus includes hepatitis B virus.

[0016] The antiviral activity of the dihydropyrimidine compounds provided by the present invention is high, especially the anti-HBV activity is high, and the toxicity is low. They can be used to prepare antiviral drugs, especially for the preparation of HBV inhibitors, and have good application prospects.

[0017] The preparation method of the dihydropyrimidine compounds provided by the present invention has a simple process, is easy to operate, has a high product yield, low production cost, and is suitable for industrial production. Description of the Drawings

[0018] Figure 1 SPR sensorgram of the dihydropyrimidine compound GLS4 prepared in the example and HBV capsid protein; Figure 2 Results diagram of the effects of the dihydropyrimidine compounds (I-3d, I-3e, I-3f), GLS4 and lamivudine (3-TC) prepared in the example on the expression of HBV capsid protein and core protein. Detailed Description of the Invention

[0019] The present invention provides a dihydropyrimidine compound having a structure shown in Formula A, Formula B or Formula C: Formula A Formula B Formula C; Wherein, X includes CH or N.

[0020] In the present invention, R1 includes any one of the following structures: .

[0021] In the present invention, when X is N, R1 includes any one of the following structures: ; Wherein, I-3b, I-3c, I-3e, I-3f, I-3g, I-3h, I-3j are the numbers of dihydropyrimidine compounds.

[0022] In the present invention, when X is CH, R1 includes any one of the following structures: .

[0023] In the present invention, R3 includes -H, -CH3 or -CH2CH2OH.

[0024] In the present invention, when R3 is -H, R2 includes no tert-butyl ester and COOH groups, contains a tert-butyl ester group or contains a COOH group.

[0025] In the present invention, the structure without tert-butyl ester and COOH groups includes any one of the following structures: 。

[0026] In the present invention, the group containing a tert-butyl ester group includes any one of the following structures: 。

[0027] In the present invention, the group containing a COOH group includes any one of the following structures: ; In the present invention, when R3 is -CH3, R2 includes any one of the following structures: 。

[0028] In the present invention, when R3 is -CH2CH2OH, R2 is -CH2CH2OH (the number of the dihydropyrimidine compound is I-3o).

[0029] The dihydropyrimidine compounds provided by the present invention have high antiviral activity, especially high anti-HBV activity, and low toxicity, and can be used to prepare antiviral drugs. In particular, they have good application prospects as HBV inhibitors.

[0030] In the present invention, the preparation method of the dihydropyrimidine compound having the structure shown in Formula A includes the following steps: subjecting Compound 2 and Compound 4 to a substitution reaction (denoted as the first substitution reaction), or subjecting Compound 3 and R1-Cl to a substitution reaction (denoted as the second substitution reaction) to obtain the dihydropyrimidine compound having the structure shown in Formula A. The preparation route is as follows: 。

[0031] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0032] In the present invention, the first substitution reaction preferably includes: mixing Compound 2, Compound 4, a first basic reagent, and a first organic solvent, and performing the first substitution reaction.

[0033] In the present invention, the molar ratio of Compound 2 to Compound 4 is preferably 1:1.1 to 1.5, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0034] In the present invention, the first basic reagent preferably includes a carbonate and / or an organic amine. The carbonate preferably includes potassium carbonate and / or sodium carbonate; the organic amine preferably includes triethylamine and / or N,N-diisopropylethylamine. In the present invention, the molar ratio of Compound 2 to the first basic reagent is preferably 1:2 to 4, and in specific embodiments, it can be 1:2, 1:2.5, 1:3, 1:3.5, or 1:4.

[0035] In the present invention, the first organic solvent preferably includes one or more of halogenated hydrocarbons, amide solvents, and lower alcohols, and may be one or more of dichloromethane (DCM), dimethylformamide (DMF), tetrahydrofuran, and absolute ethanol in specific embodiments. There is no special limitation on the amount of the first organic solvent in the present invention, as long as the first substitution reaction can proceed smoothly.

[0036] In the present invention, the mixing preferably includes: mixing compound 2 with the first organic solvent, and then adding the first basic reagent for mixing. There is no special limitation on the mixing method in the present invention, and the raw materials can be mixed evenly by using the mixing methods well-known to those skilled in the art, such as stirring and mixing.

[0037] In the present invention, the temperature of the first substitution reaction is preferably 25-50 °C, and may be 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, or 50 °C in specific embodiments; the time of the first substitution reaction is preferably 1-24 h, and may be 1 h, 2 h, 5 h, 8 h, 10 h, 12 h, 15 h, 18 h, 20 h, 22 h, or 24 h in specific embodiments.

[0038] After completing the first substitution reaction, the present invention preferably further includes: concentrating the reaction solution obtained from the first substitution reaction, adding water to the obtained concentrated solution, and then performing extraction. The obtained organic phase is successively washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The obtained filtrate is concentrated and then separated by silica gel column chromatography to obtain a dihydropyrimidine derivative having the structure shown in formula A. There is no special limitation on the concentration method in the present invention, and the concentration methods well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the organic extraction solvent for extraction preferably includes ethyl acetate, and the volume ratio of water to the organic extraction solvent is 1:1-3, and may be 1:1, 1:2, or 1:3 in specific embodiments. In the present invention, the elution method for silica gel column chromatography separation is preferably gradient elution, and the eluent used for gradient elution is preferably a mixed solvent of large polarity - small polarity; the large polarity solvent in the large polarity - small polarity mixed solvent preferably includes one or several of ethyl acetate, methanol, and dichloromethane; the small polarity solvent in the large polarity - small polarity mixed solvent preferably includes petroleum ether; the volume ratio of the large polarity solvent to the small polarity solvent is preferably 10:1-50:1, and more preferably 3:1-1:1.

[0039] In the present invention, the molar ratio of the compound 3 to R1-Cl is preferably 1:1.1 to 1.5, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5. In the present invention, the reaction conditions for the substitution reaction of the compound 3 with R1-Cl are the same as those for the substitution reaction of the compound 2 with the compound 4, and will not be elaborated herein one by one.

[0040] In the present invention, when R3 is -H and R2 does not contain a tert-butyl ester and a COOH group, or when R3 is -H and R2 contains a tert-butyl ester group, the preparation method of the dihydropyrimidine compound having the structure shown in formula B includes the following steps: subjecting the compound 2 to a substitution reaction with R2-NH2 (denoted as the third substitution reaction) to obtain a dihydropyrimidine compound having the structure shown in formula B in which R2 does not contain a tert-butyl ester and a COOH group or R2 contains a tert-butyl ester group. The preparation route is as follows: 。

[0041] In the present invention, the third substitution reaction preferably includes: mixing the compound 2, R2-NH2, a second basic reagent, and a second organic solvent, and carrying out the third substitution reaction.

[0042] In the present invention, the molar ratio of the compound 2 to R2-NH2 is preferably 1:1.1 to 1.5, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0043] In the present invention, the second basic reagent preferably includes one or more of carbonates, organic amines, and hydroxides; the carbonate preferably includes potassium carbonate and / or sodium carbonate; the organic amine preferably includes triethylamine and / or N,N-diisopropylethylamine; the hydroxide preferably includes sodium hydroxide and / or potassium hydroxide. In the present invention, the molar ratio of the compound 2 to the second basic reagent is preferably 1:2 to 4, and in specific embodiments, it can be 1:2, 1:2.5, 1:3, 1:3.5, or 1:4. In the present invention, the second basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the mass concentration of the aqueous solution of the basic reagent is preferably 5 to 20%, and in specific embodiments, it can be 5%, 10%, 15%, or 20%.

[0044] In the present invention, the second organic solvent preferably includes one or more of halogenated hydrocarbons and amide solvents, and in specific embodiments, it can be dichloromethane and / or dimethylformamide. The present invention has no special limitation on the amount of the second organic solvent, and it is only necessary to ensure the smooth progress of the third substitution reaction.

[0045] In the present invention, the mixing preferably includes: mixing Compound 2 with a second organic solvent, and then adding a second basic reagent for mixing. The present invention has no special limitation on the mixing method, and the raw materials can be mixed evenly by using a mixing method well-known to those skilled in the art, such as stirring and mixing.

[0046] In the present invention, the temperature of the third substitution reaction is preferably 25-50 °C, and in specific embodiments, it can be 25 °C, 30 °C, 35 °C, 40 °C, 45 °C or 50 °C; the time of the third substitution reaction is preferably 1-10 h, and in specific embodiments, it can be 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h or 10 h.

[0047] After completing the third substitution reaction, the present invention preferably further includes: concentrating the reaction solution obtained from the third substitution reaction, adding water to the obtained concentrated solution, and then performing extraction. The obtained organic phase is successively washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The obtained filtrate is concentrated and then separated by silica gel column chromatography to obtain a dihydropyrimidine compound having the structure shown in Formula B with R3 being -H and R2 being free of tert-butyl ester and COOH groups, or R3 being -H and containing a tert-butyl ester group. The present invention has no special limitation on the concentration method, and a concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the organic extraction agent used for extraction preferably includes ethyl acetate, and the volume ratio of water to the organic extraction agent is 1:1-3, and in specific embodiments, it can be 1:1, 1:2 or 1:3. In the present invention, the elution method for silica gel column chromatography separation is preferably gradient elution, and the eluent used for gradient elution is preferably a mixed solvent of large polarity - small polarity; the large polarity solvent in the mixed solvent of large polarity - small polarity preferably includes one or more of ethyl acetate, methanol and dichloromethane; the small polarity solvent in the mixed solvent of large polarity - small polarity preferably includes petroleum ether, and the volume ratio of the large polarity solvent to the small polarity solvent is preferably 30-10:1, more preferably 20-15:1.

[0048] In the present invention, when R3 is -H and R2 contains a COOH group, the preparation method of the dihydropyrimidine compound having the structure shown in Formula B includes the following steps: subjecting the dihydropyrimidine compound having the structure shown in Formula B with R3 being -H and R2 containing a tert-butyl ester group to a hydrolysis reaction to obtain a dihydropyrimidine compound having the structure shown in Formula B with R3 being -H and R2 containing a COOH group.

[0049] In the present invention, the hydrolysis reaction preferably includes: mixing a dihydropyrimidine compound having the structure shown in Formula B with R3 being -H and R2 being a tert-butyl ester group, a hydrolysis reagent, and a third organic solvent, and carrying out a hydrolysis reaction. In the present invention, the third organic solvent preferably includes dichloromethane. The present invention has no special limitation on the amount of the third organic solvent, as long as the hydrolysis reaction can proceed smoothly. In the present invention, the hydrolysis reagent preferably includes trifluoroacetic acid. The volume ratio of the third organic solvent to the hydrolysis reagent is preferably 0.5 - 2:1, and in specific embodiments, it can be 0.5:1, 1:1, or 2:1. In the present invention, the temperature of the hydrolysis reaction is preferably room temperature, and the time of the hydrolysis reaction is preferably 0.5 - 4 h, and in specific embodiments, it can be 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, or 4 h.

[0050] After completing the hydrolysis reaction, the present invention preferably further includes: concentrating the hydrolysis reaction solution obtained from the hydrolysis reaction, adding water to the obtained concentrated solution, extracting with ethyl acetate, concentrating the obtained organic phase, and then performing silica gel column chromatography separation to obtain a dihydropyrimidine compound having the structure shown in Formula B with R3 being -H and R2 being a COOH group. The present invention has no special limitation on the concentration method, and any concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the elution method for the silica gel column chromatography separation is preferably gradient elution, and the eluent used is preferably dichloromethane and methanol. The volume ratio of dichloromethane to methanol is preferably 20:1 - 5:1.

[0051] In the present invention, when R3 is -CH3, the preparation method of the dihydropyrimidine compound having the structure shown in Formula B includes the following steps: carrying out a substitution reaction (denoted as the fourth substitution reaction) between compound 5 and R2-Cl to obtain a dihydropyrimidine compound having the structure shown in Formula B with R3 being -CH3. The preparation route is as follows: 。

[0052] In the present invention, the fourth substitution reaction preferably includes: mixing compound 5, R2-Cl, a third basic reagent, and a fourth organic solvent, and carrying out the fourth substitution reaction.

[0053] In the present invention, the molar ratio of compound 5 to R2-Cl is preferably 1:1.1 - 1.5, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0054] In the present invention, the third basic reagent preferably includes one or more of carbonates, organic amines, and hydroxides; the carbonate preferably includes potassium carbonate and / or sodium carbonate; the organic amine preferably includes triethylamine and / or N,N-diisopropylethylamine; the hydroxide preferably includes sodium hydroxide and / or potassium hydroxide. In the present invention, the molar ratio of compound 5 to the third basic reagent is preferably 1:2 to 4, and in specific embodiments, it can be 1:2, 1:2.5, 1:3, 1:3.5, or 1:4. In the present invention, the third basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the mass concentration of the aqueous solution of the basic reagent is preferably 5 to 20%, and in specific embodiments, it can be 5%, 10%, 15%, or 20%.

[0055] In the present invention, the fourth organic solvent preferably includes one or more of halogenated hydrocarbons and amide solvents, and in specific embodiments, it can be dichloromethane and / or dimethylformamide. The present invention has no special limitation on the amount of the fourth organic solvent, as long as the fourth substitution reaction can proceed smoothly.

[0056] In the present invention, the mixing preferably includes: mixing compound 5 with the fourth organic solvent, and then adding the third basic reagent for mixing. The present invention has no special limitation on the mixing method, and the raw materials can be mixed evenly by using a mixing method well-known to those skilled in the art, such as stirring and mixing.

[0057] In the present invention, the temperature of the fourth substitution reaction is preferably 25 to 50 °C, and in specific embodiments, it can be 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, or 50 °C; the time of the fourth substitution reaction is preferably 1 to 10 h, and in specific embodiments, it can be 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, or 10 h.

[0058] After completing the fourth substitution reaction, the present invention preferably further includes: concentrating the reaction solution obtained from the fourth substitution reaction, adding water to the obtained concentrated solution, then performing extraction, washing the obtained organic phase successively with saturated brine, drying with anhydrous sodium sulfate and filtering, concentrating the obtained filtrate and then separating by silica gel column chromatography to obtain a dihydropyrimidine compound having the structure shown in Formula B with R3 being -CH3. The present invention has no special limitation on the concentration method, and any concentration method well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the organic extraction solvent for extraction preferably includes ethyl acetate, and the volume ratio of water to the organic extraction solvent is 1:1 to 3, and can be 1:1, 1:2 or 1:3 in specific embodiments. In the present invention, the elution method for silica gel column chromatography separation is preferably gradient elution, and the eluent used for gradient elution is preferably a mixed solvent of large polarity - small polarity; the large polarity solvent in the large polarity - small polarity mixed solvent preferably includes one or more of ethyl acetate, methanol and dichloromethane; the small polarity solvent in the large polarity - small polarity mixed solvent preferably includes petroleum ether, and the volume ratio of the large polarity solvent to the small polarity solvent is preferably 5 to 10:1, more preferably 3 to 1:1.

[0059] In the present invention, when R3 is -CH2CH2OH, the preparation method of the dihydropyrimidine compound having the structure shown in Formula B includes the following steps: reacting compound 2 with R2-NH-R3 in a substitution reaction (denoted as the fifth substitution reaction) to obtain a dihydropyrimidine compound having the structure shown in Formula B.

[0060] In the present invention, the fifth substitution reaction preferably includes: mixing compound 2, R2-NH-R3, a fourth basic reagent and a fifth organic solvent, and performing the fifth substitution reaction.

[0061] In the present invention, the molar ratio of compound 2 to R2-NH-R3 is preferably 1:1.1 to 1.5, and can be 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5 in specific embodiments.

[0062] In the present invention, the fourth basic reagent preferably includes one or more of carbonates, organic amines and hydroxides; the carbonate preferably includes potassium carbonate and / or sodium carbonate; the organic amine preferably includes triethylamine and / or N,N-diisopropylethylamine; the hydroxide preferably includes sodium hydroxide and / or sodium hydroxide. In the present invention, the molar ratio of compound 2 to the fourth basic reagent is preferably 1:2 to 4, and can be 1:2, 1:2.5, 1:3, 1:3.5 or 1:4 in specific embodiments. In the present invention, the fourth basic reagent is preferably used in the form of an aqueous solution of the basic reagent, and the mass concentration of the aqueous solution of the basic reagent is preferably 5 to 20%, and can be 10% in specific embodiments.

[0063] In the present invention, the fifth organic solvent preferably includes one or more of halogenated hydrocarbons and amide solvents, and may be dichloromethane and / or dimethylformamide in specific embodiments. There is no special limitation on the amount of the fifth organic solvent in the present invention, as long as the fifth substitution reaction can proceed smoothly.

[0064] In the present invention, the mixing preferably includes: mixing compound 2 with the fifth organic solvent, and then adding the fourth basic reagent for mixing. There is no special limitation on the mixing method in the present invention, and the raw materials can be mixed evenly by using the mixing methods well-known to those skilled in the art, such as stirring and mixing.

[0065] In the present invention, the temperature of the fifth substitution reaction is preferably 25-50°C, and may be 25°C, 30°C, 35°C, 40°C, 45°C or 50°C in specific embodiments; the time of the fifth substitution reaction is preferably 1-10 h, and may be 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h or 10 h in specific embodiments.

[0066] After completing the fifth substitution reaction, the present invention preferably further includes: concentrating the reaction solution obtained from the fifth substitution reaction, adding water to the obtained concentrated solution, then performing extraction, washing the obtained organic phase with saturated brine, drying with anhydrous sodium sulfate and filtering in sequence, concentrating the obtained filtrate and then separating by silica gel column chromatography to obtain a dihydropyrimidine compound with the structure shown in Formula B and R3 being -CH2CH2OH. There is no special limitation on the concentration method in the present invention, and the concentration methods well-known to those skilled in the art can be used, such as concentration under reduced pressure. In the present invention, the organic extraction solvent for extraction preferably includes ethyl acetate, and the volume ratio of water to the organic extraction solvent is 1:1-3, and may be 1:1, 1:2 or 1:3 in specific embodiments. In the present invention, the elution method for silica gel column chromatography separation is preferably gradient elution, and the eluent used for gradient elution is preferably a mixed solvent of large polarity - small polarity; the large polarity solvent in the mixed solvent of large polarity - small polarity preferably includes one or several of ethyl acetate, methanol and dichloromethane; the small polarity solvent in the mixed solvent of large polarity - small polarity preferably includes petroleum ether, and the volume ratio of the large polarity solvent to the small polarity solvent is preferably 5-10:1, more preferably 3-1:1.

[0067] In the present invention, the preparation method of the dihydropyrimidine compound having the structure shown in Formula C comprises the following steps: reacting compound 2 with compound 6 to obtain the dihydropyrimidine compound having the structure shown in Formula C. In the present invention, the preparation conditions of the dihydropyrimidine compound having the structure shown in Formula C are different from the preparation conditions of the dihydropyrimidine compound having the structure shown in Formula A prepared by reacting compound 2 with compound 4 only in that: compound 4 is replaced by compound 6, and other preparation conditions are the same, which will not be elaborated here one by one.

[0068] 。

[0069] In the present invention, the preparation method of compound 3 comprises the following steps: reacting compound 2 with 4-aminopiperidine (denoted as the sixth substitution reaction) to obtain compound 3, and the reaction route is as follows: 。

[0070] In the present invention, the sixth substitution reaction preferably comprises: mixing compound 2, 4-aminopiperidine and a sixth organic solvent, and carrying out the sixth substitution reaction.

[0071] In the present invention, the molar ratio of compound 2 to 4-aminopiperidine is preferably 1:1.1 - 1.5, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0072] In the present invention, the sixth organic solvent preferably comprises one or more of amide solvents, nitrile solvents and furan solvents, and in specific embodiments, it can be one or more of dimethylformamide, acetonitrile and tetrahydrofuran. The present invention has no special limitation on the dosage of the sixth organic solvent, as long as the sixth substitution reaction can proceed smoothly.

[0073] In the present invention, the temperature of the sixth substitution reaction is preferably room temperature, and the time of the sixth substitution reaction is preferably 15 - 60 min, and in specific embodiments, it can be 15 min, 20 min, 30 min, 40 min, 50 min or 60 min. The present invention preferably monitors the reaction process by TLC, and the developing agent used in the TLC is preferably dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 15:1.

[0074] After completing the sixth substitution reaction, the present invention preferably further includes: distilling the reaction solution obtained from the sixth substitution reaction to dryness under reduced pressure, adding water to the residue, extracting with ethyl acetate, washing the obtained organic phase successively with water, drying over anhydrous sodium sulfate and filtering, concentrating the obtained filtrate under reduced pressure and separating by silica gel column chromatography to obtain Compound 3. In the present invention, the eluent used for the silica gel column chromatography separation is preferably dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 25:1.

[0075] In the present invention, the preparation method of Compound 5 preferably includes the following steps: carrying out a substitution reaction (denoted as the seventh substitution reaction) between Compound 2 and methylammonium hydrochloride to obtain Compound 5, and the preparation route is as follows: 。

[0076] In the present invention, the seventh substitution reaction preferably includes: mixing Compound 2, methylammonium hydrochloride and a seventh organic solvent, and carrying out the seventh substitution reaction to obtain Compound 5.

[0077] In the present invention, the molar ratio of Compound 2 to methylammonium hydrochloride is preferably 1:1.1 - 1.5, and in specific embodiments, it can be 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0078] In the present invention, the seventh organic solvent preferably includes one or more of amide solvents, nitrile solvents and furan solvents, and in specific embodiments, it can be one or more of dimethylformamide, acetonitrile and tetrahydrofuran. The present invention has no special limitation on the dosage of the seventh organic solvent, as long as it can ensure the smooth progress of the seventh substitution reaction.

[0079] In the present invention, the temperature of the seventh substitution reaction is preferably room temperature, and the time of the seventh substitution reaction is preferably 2 - 6 h, and in specific embodiments, it can be 2 h, 3 h, 4 h, 5 h or 6 h. The present invention preferably monitors the reaction progress by TLC, and the developing agent used for the TLC is preferably dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 15:1.

[0080] After completing the seventh substitution reaction, the present invention preferably further includes: distilling the reaction solution obtained from the seventh substitution reaction to dryness under reduced pressure, adding water, extracting with ethyl acetate, washing the obtained organic phase successively with saturated brine, drying over anhydrous sodium sulfate and filtering, concentrating the obtained filtrate under reduced pressure and separating and purifying by silica gel column chromatography to obtain Compound 5. In the present invention, the eluent used for the silica gel column chromatography separation is preferably dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 30:1 - 10:1, and in specific embodiments, it can be 30:1, 25:1, 20:1, 15:1 or 10:1.

[0081] In the present invention, the preparation method of the compound 2 preferably comprises the following steps: subjecting the compound 1 to a substitution reaction with N-bromosuccinimide (denoted as the eighth substitution reaction) to obtain the compound 2, and the reaction route is as follows: 。

[0082] In the present invention, the eighth substitution reaction preferably comprises: mixing the compound 1, N-bromosuccinimide and an eighth organic solvent, and carrying out the eighth substitution reaction.

[0083] In the present invention, the molar ratio of the compound 1 to N-bromosuccinimide is preferably 1:1.05 to 1.2, and in specific embodiments, it can be 1:1.05, 1:1.1, 1:1.15 or 1:1.2.

[0084] In the present invention, the eighth organic solvent preferably comprises a halogenated hydrocarbon and / or an amide solvent. The halogenated hydrocarbon preferably comprises carbon tetrachloride, and the amide solvent preferably comprises dimethylformamide. There is no special limitation on the dosage of the eighth organic solvent in the present invention, as long as it can ensure the smooth progress of the eighth substitution reaction.

[0085] In the present invention, the temperature of the eighth substitution reaction is preferably 50 to 90 °C, and in specific embodiments, it can be 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C or 90 °C; the time of the eighth substitution reaction is preferably 0.5 to 2 h, more preferably 0.5 h, 1 h, 1.5 h or 2 h. The present invention preferably monitors the reaction process by thin layer chromatography (TLC). The developing agent used in the thin layer chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 6:1.

[0086] After completing the eighth substitution reaction, the present invention preferably further comprises: distilling the reaction solution obtained from the eighth substitution reaction to dryness under reduced pressure, adding water to the residue, extracting with ethyl acetate, washing the obtained organic phase successively with saturated brine, drying with anhydrous sodium sulfate and filtering, and subjecting the obtained filtrate to reduced pressure concentration and then silica gel column chromatography separation to obtain the compound 2. In the present invention, the elution mode of the silica gel column chromatography separation is preferably gradient elution, and the eluent used in the gradient elution is preferably a mixed solvent of large polarity - small polarity; the large polarity solvent in the mixed solvent of large polarity - small polarity preferably comprises one or more of ethyl acetate, methanol and dichloromethane; the small polarity solvent in the mixed solvent of large polarity - small polarity preferably comprises petroleum ether, and the volume ratio of the large polarity solvent to the small polarity solvent is preferably 30:1 to 10:1, more preferably 20:1 to 15:1.

[0087] In the present invention, the preparation method of the compound 1 preferably comprises the following steps: cyclizing 2-thiazolecarboximidamide hydrochloride, 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate to obtain the compound 1, and the preparation route is as follows: 。

[0088] In the present invention, the cyclization reaction preferably comprises: mixing 2-thiazolecarboximidamide hydrochloride, 2-bromo-4-fluorobenzaldehyde, ethyl acetoacetate, a fifth basic reagent and a ninth organic solvent, and carrying out the cyclization reaction.

[0089] In the present invention, the molar ratio of 2-thiazolecarboximidamide hydrochloride to 2-bromo-4-fluorobenzaldehyde is preferably 1:1 to 2, and in specific embodiments, it can be 1:1, 1:1.5 or 1:2.

[0090] In the present invention, the molar ratio of 2-thiazolecarboximidamide hydrochloride to ethyl acetoacetate is preferably 1:1 to 2, and in specific embodiments, it can be 1:1, 1:1.5 or 1:2.

[0091] In the present invention, the fifth basic reagent preferably comprises sodium acetate. In the present invention, the molar ratio of 2-thiazolecarboximidamide hydrochloride to the fifth basic reagent is preferably 1:1.5 to 3, and in specific embodiments, it can be 1:1.5, 1:2, 1:2.5 or 1:3.

[0092] In the present invention, the ninth organic solvent preferably comprises a lower alcohol, and the lower alcohol preferably comprises absolute ethanol. There is no special limitation on the amount of the ninth organic solvent in the present invention, and it can ensure the smooth progress of the cyclization reaction.

[0093] In the present invention, the temperature of the cyclization reaction is 60 to 100 °C, and in specific embodiments, it can be 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C or 100 °C; the time of the cyclization reaction is preferably 8 to 12 h, and in specific embodiments, it can be 8 h, 9 h, 10 h, 11 h or 12 h. The present invention preferably monitors the reaction process by TLC, and the developing agent used in the TLC is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 7:1.

[0094] After completing the cyclization reaction, the present invention preferably further includes: evaporating the reaction solution obtained from the cyclization reaction to dryness under reduced pressure, adding water, extracting with ethyl acetate, washing the obtained organic phase successively with water, drying over anhydrous sodium sulfate and filtering, concentrating under reduced pressure, distilling off part of the solvent, standing, precipitating a solid, and filtering by suction to obtain Compound 1. In the present invention, the eluent used for silica gel column chromatography separation is preferably petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably 15:1. In the present invention, the temperature for standing is preferably room temperature, and the standing time is preferably 10 - 15 h, which can be 10 h, 11 h, 12 h, 13 h, 14 h or 15 h in specific embodiments.

[0095] The present invention also provides a dihydropyrimidine derivative, including one or more of pharmaceutically acceptable salts, hydrates, organic solvent compounds, isomers and crystalline compounds of the above-mentioned dihydropyrimidine compounds in the above technical solution.

[0096] In the present invention, the pharmaceutically acceptable salts preferably include one or more of hydrochloride, acetate and fumarate. The present invention has no special limitation on the hydrates, organic solvent compounds, isomers and crystalline compounds, and the hydrates, organic solvent compounds, isomers and crystalline compounds of dihydropyrimidine compounds well-known to those skilled in the art can be used.

[0097] The present invention also provides a pharmaceutical composition, including an active ingredient and a pharmaceutically acceptable excipient, and the active ingredient includes at least one of the above-mentioned dihydropyrimidine compounds and the above-mentioned dihydropyrimidine derivatives in the above technical solution.

[0098] In the present invention, the mass content of the active ingredient in the pharmaceutical composition is preferably 20 - 80%, which can be 20%, 30%, 40%, 50%, 60%, 70% or 80% in specific embodiments.

[0099] The present invention has no special limitation on the pharmaceutically acceptable excipients, and the pharmaceutically acceptable excipients well-known to those skilled in the art can be used.

[0100] In the present invention, the preparation types of the pharmaceutical composition preferably include liquid preparations, solid preparations, sprays or aerosols; the liquid preparations preferably include injections, suspensions, emulsions, solutions or syrups; the solid preparations preferably include tablets, capsules, granules or instant granules. The present invention has no special limitation on the preparation method of the pharmaceutical composition, and the preparation methods well-known in the art can be used.

[0101] In the present invention, the administration routes of the pharmaceutical composition preferably include injection, oral administration, sublingual administration or mucosal dialysis; the injection preferably includes intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.

[0102] The present invention also provides the use of the dihydropyrimidine compound, the dihydropyrimidine derivative or the pharmaceutical composition according to the above technical solution in the preparation of antiviral infection drugs. In the present invention, the virus preferably includes hepatitis B virus. The dihydropyrimidine compound, dihydropyrimidine derivative and pharmaceutical composition provided by the present invention have high antiviral activity, especially high anti-HBV activity, and low toxicity, and can be used to prepare antiviral drugs. Especially as an HBV inhibitor, it has good application prospects.

[0103] To further illustrate the present invention, the following examples are used to describe in detail the dihydropyrimidine compound provided by the present invention and its preparation method and application, the dihydropyrimidine derivative and its application, the pharmaceutical composition and its application, but they cannot be understood as limiting the protection scope of the present invention.

[0104] Comparative Example 1 Synthesis of Compound 1 (Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate): Add 400 mL of absolute ethanol, 2-thiazolecarboxamidine hydrochloride (48.89 mmol, 1.0 eq), 2-bromo-4-fluorobenzaldehyde (73.35 mmol, 1.5 eq), sodium acetate (97.81 mmol, 2 eq) and ethyl acetoacetate (73.30 mmol, 1.5 eq), reflux for 10 h, monitor the reaction by TLC (petroleum ether / ethyl acetate = 4 / 1, v / v). After the reaction is completed, evaporate to dryness under reduced pressure, add 200 mL of water, extract with ethyl acetate (200 mL each time) 3 times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate and filter. The filtrate is concentrated under reduced pressure, evaporate part of the solvent, let stand at room temperature for 12 h, precipitate a solid, filter by suction, and dry the solid component to constant weight to obtain 12.40 g of Compound 1, a yellow solid, with a yield of 60.0%.

[0105] Synthesis of Compound 2 (Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate): Add 300 mL of carbon tetrachloride, Compound 1 (29.31 mmol, 1.0 eq), and N-bromosuccinimide (32.25 mmol, 1.1 eq), reflux for 30 min, and monitor the reaction by TLC (petroleum ether / ethyl acetate = 6 / 1, v / v). After the reaction is completed, evaporate to dryness under reduced pressure, add 200 mL of water, extract 3 times with ethyl acetate (200 mL each time), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (gradient elution, petroleum ether / ethyl acetate = 20:1~15:1, v / v) to obtain 9.5 g of Compound 2 as a yellow solid with a yield of 64.4%.

[0106] Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3a, GLS4): 10 mL of DMF, compound 2 (0.40 mmol, 1 eq), morpholine (0.60 mmol, 1.5 eq), and K2CO3 (0.80 mmol, 2 eq) were added, and the reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 2 / 1, v / v). After the reaction was completed, 10 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL each time) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and silica gel column chromatography (gradient elution, petroleum ether / ethyl acetate = 3:1~1:1, v / v) was used to obtain compound I-3a as a yellow solid, 160 mg, with a yield of 79.0%, m.p. 129.5~130.1 °C; 1H NMR (600 MHz, CH3OD) δ 7.83 (d, J = 3.1 Hz, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.33 – 7.27 (m, 2H), 6.98 (td, J = 8.4, 2.7 Hz, 1H), 6.05 (s, 1H), 3.97 – 3.91 (m, 3H), 3.77 (d, J = 17.0 Hz, 1H), 3.70 (q, J = 4.3 Hz, 4H), 2.52 (t, J = 4.7 Hz, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.16, 162.96, 162.19, 160.53, 146.07, 144.40, 143.19, 139.91, 139.89, 130.53, 130.48, 123.31, 123.25, 123.01, 120.19, 120.03, 114.93, 114.79, 98.17, 67.06, 59.87, 58.78, 56.77, 53.74, 14.15. HR-MS (ESI): calcd. for C 21 H 23 O4N4BrFS, [M+H] + 511.06323, found 511.06293. Example 1 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-methylpiperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3b): Add 10 mL of DMF, the compound 2 prepared in Comparative Example 1 (0.40 mmol, 1 eq), N-methylpiperazine (0.60 mmol, 1.5 eq), and K2CO3 (0.80 mmol, 2 eq), and react at room temperature for 1 h. Monitor the reaction by TLC (petroleum ether / ethyl acetate = 2 / 1, v / v). After the reaction is completed, add 10 mL of water, extract with ethyl acetate (5 mL each time) 3 times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (using gradient elution, petroleum ether / ethyl acetate = 3:1~1:1, v / v) to obtain compound I-3b, a yellow solid, with a yield of 83.3%, m.p. 184.1~185.2 °C; 1 H NMR (600 MHz, CDCl3) δ 9.66 (s, 1H), 7.85 (d, J J = 3.1 Hz,1H), 7.42 (d, J J = 3.1 Hz, 1H), 7.31 (dd, J J = 8.4, 2.6 Hz, 1H), 7.28 (dd, J J = 8.6,6.0 Hz, 1H), 6.95 (td, J J = 8.3, 2.6 Hz, 1H), 6.18 (s, 1H), 4.07 – 3.99 (m, 3H),3.90 – 3.85 (m, 1H), 2.61 (d, J J = 57.5 Hz, 8H), 2.36 (s, 3H), 1.13 (t, J J = 7.1Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.20, 163.07, 162.17, 160.52, 146.56,144.47, 143.19, 140.01, 139.98, 130.57, 130.51, 123.29, 123.23, 122.90,120.16, 120.00, 114.93, 114.79, 97.80, 59.82, 58.77, 56.39, 55.20, 53.40,46.01, 14.15. HR-MS (ESI): calcd. for C 22 H26 O2N5BrFS, [M+H] + 524.09487, found 524.09551. Example 2 Synthesis of ethyl 6-((4-acetylpiperazin-1-yl)methyl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3c): Compound I-3c was synthesized according to the preparation method of compound I-3b in Example 1, with the difference from Example 1 being that N-methylpiperazine was replaced by 1-acetylpiperazine, to obtain compound I-3c as a yellow solid, with a yield of 96.0%, m.p. 155.3~156.3 °C; 1 H NMR (600 MHz, CDCl3) δ 9.53 (s, 1H), 7.76 (d, J J = 3.1 Hz, 1H), 7.37 (d, J J = 3.1 Hz, 1H), 7.25 (dd, J J = 8.3, 2.6 Hz, 1H), 7.23 –7.20 (m, 1H), 6.89 (td, J J = 8.3, 2.6 Hz, 1H), 6.12 (s, 1H), 4.03 – 3.92 (m, 3H), 3.81 (d, J J = 17.3 Hz, 1H), 3.68 (d, J J = 29.0 Hz, 2H), 3.52 (t, J J = 5.1 Hz, 2H), 2.53 (dt, J J = 18.7, 4.9 Hz, 4H), 2.05 (s, 3H), 1.06 (t, J J = 7.1 Hz, 3H). 13CNMR (151 MHz, CDCl3) δ 169.08, 166.11, 162.89, 162.20, 160.54, 145.71,144.34, 143.17, 139.82, 139.80, 130.52, 130.47, 123.32, 123.26, 123.11,120.21, 120.05, 114.95, 114.81, 98.36, 59.92, 58.79, 56.20, 53.34, 53.01,46.35, 41.51, 21.38, 14.13. HR-MS (ESI): calcd. for C 23 H 26 O3N5BrFS, [M+H] + 552.08978, found 552.09204. Example 3 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(methoxycarbonyl)piperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3d): Compound I-3d was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that N-methylpiperazine was replaced by methyl piperazine-1-carboxylate to obtain compound I-3d, which was a yellow solid with a yield of 92.9% and m.p. 152.3~153.8 °C; 1 H NMR (600 MHz, CDCl3) δ 9.62 (s,1H), 7.82 (d, J = 3.1 Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.32 (dd, J = 8.3, 2.6 Hz,1H), 7.30 – 7.26 (m, 1H), 6.95 (td, J = 8.3, 2.6 Hz, 1H), 6.19 (s, 1H), 4.09 –3.99 (m, 3H), 3.87 (d, J = 17.3 Hz, 1H), 3.72 (s, 3H), 3.61 (s, 4H), 2.58 (t, J =5.2 Hz, 4H), 1.13 (t, J = 7.1 Hz, 3H). 1313C NMR (151 MHz, CDCl3) δ 166.15, 162.92, 162.21, 160.55, 155.94, 145.93, 144.38, 143.19, 139.87, 139.84, 130.54, 130.48, 123.32, 123.26, 123.05, 120.21, 120.05, 114.95, 114.81, 98.22, 59.90, 58.80, 56.39, 53.06, 52.71, 43.90, 14.14. HR-MS (ESI): calcd. for C 23 H 26 O4N5BrFS, [M+H] + 568.08470, found 568.08717. Example 4 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((4-(ethoxycarbonyl)piperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3e): Compound I-3e was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by ethyl piperazine-1-carboxylate to obtain compound I-3e, a yellow solid, with a yield of 96.6%, m.p. 121.5~122.4 °C; 1 1H NMR (600 MHz, CDCl3) δ 9.56 (s, 1H), 7.76 (d, J J = 3.1 Hz, 1H), 7.36 (d, J J = 3.1 Hz, 1H), 7.25 (dd, J J = 8.3, 2.6 Hz, 1H), 7.23 – 7.19 (m, 1H), 6.88 (td, J J = 8.2, 2.6 Hz, 1H), 6.12 (s, 1H), 4.09 (q, J J = 7.1 Hz, 2H), 4.02 – 3.93 (m, 3H), 3.80 (d, J J = 17.3 Hz, 1H), 3.62 – 3.47 (m, 4H), 2.59 – 2.41 (m, 4H), 1.21 (t, J J = 7.1 Hz, 3H), 1.06 (t, J J = 7.1 Hz, 3H). 1313C NMR (151 MHz, CDCl3) δ 166.16, 162.92, 162.21, 160.55, 155.55, 145.97, 144.40, 143.19, 139.87, 139.85, 130.54, 130.48, 123.32, 123.26, 123.04, 120.20, 120.04, 114.95, 114.81, 98.20, 61.49, 59.89, 58.79, 56.40, 53.43, 53.08, 43.82, 14.69, 14.14. HR-MS (ESI): calcd. for C 24 H 28 O4N5BrFS, [M+H] + 582.10035, found 582.10187. Example 5 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3f): Compound I-3f was synthesized according to the preparation method of compound I-3b in Example 1, with the difference from Example 1 only being that N-methylpiperazine was replaced by tert-butyl piperazine-1-carboxylate, to obtain compound I-3f, a yellow solid, with a yield of 77.1%, m.p. 145.1~145.4 °C; 1 1H NMR (600 MHz, CDCl3) δ 9.64 (s, 1H), 7.83 (d, J J = 3.1 Hz, 1H), 7.43 (d, J J = 3.1 Hz, 1H), 7.32 (dd, J J = 8.3, 2.6 Hz, 1H), 7.28 (dd, J = 8.6, 6.0 Hz, 1H), 6.95 (td, J J = 8.3, 2.6 Hz, 1H), 6.19 (s, 1H), 4.08 – 3.99 (m, 3H), 3.87 (d, J J = 17.4 Hz, 1H), 3.56 (q, J J = 4.4 Hz, 4H), 2.56 (d, J J = 5.4 Hz, 4H), 1.48 (s, 9H), 1.13 (t, J J = 7.1 Hz, 3H). 1313C NMR (151 MHz, CDCl3) δ 166.17, 162.94, 162.20, 160.54, 154.76, 146.08, 144.40, 143.21, 139.91, 139.88, 130.55, 130.49, 123.31, 123.25, 123.00, 120.19, 120.03, 114.95, 114.81, 98.12, 79.88, 59.88, 58.79, 56.43, 53.18, 50.86, 28.44, 14.14. HR-MS (ESI): calcd. for C 26 H 32 O4N5BrFS, [M+H] + 610.13165, found 610.13086. Example 6 Synthesis of ethyl 6-((4-benzoylpiperazin-1-yl)methyl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3g): Compound I-3g was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that N-methylpiperazine was replaced by 1-benzoylpiperazine to obtain compound I-3g, which was a yellow solid with a yield of 79.4% and a melting point of 158.5~159.4 °C; 1 1H NMR (600 MHz, CH3OD) δ 7.83 (d, J = 3.1 Hz, 1H), 7.63 (d, J = 3.2 Hz, 1H), 7.36 (dddd, J J = 17.1, 8.0, 4.6, 2.1 Hz, 5H), 7.33 – 7.27 (m, 2H), 6.98 (td, J J = 8.4, 2.7 Hz, 1H), 6.05 (s, 1H), 4.00 (d, J J = 16.9 Hz, 1H), 3.93 (q, J J = 7.1 Hz, 2H), 3.87 – 3.74 (m, 3H), 3.48 (s, 2H), 2.57 (d, J J = 69.9 Hz, 4H), 1.02 (t, J J = 7.1 Hz, 3H). 1313C NMR (151 MHz, CH3OD) δ 171.21, 166.03, 162.34, 162.00, 160.68, 145.85, 144.93, 143.22, 139.78, 135.20, 130.77, 130.71, 129.90, 128.46, 126.72, 123.73, 122.91, 119.74, 119.57, 114.93, 114.79, 98.54, 65.39, 59.87, 58.48, 55.80, 53.21, 52.73, 42.22, 13.40. HR-MS (ESI): calcd. for C 28 H 28 O3N5BrFS, [M+H] + 614.10543, found 614.10767. Example 7 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(3-hydroxyphenyl)piperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3h): Compound I-3h was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that N-methylpiperazine was replaced by 3-hydroxyphenylpiperazine to obtain compound I-3h, a yellow solid, with a yield of 62.8%, m.p. 130.2~131.1 °C; 1 1H NMR (600 MHz, CDCl3) δ 9.69 (s, 1H), 7.81 (d, J J = 3.1 Hz, 1H), 7.41 (d, J J = 3.1 Hz, 1H), 7.33 – 7.29 (m, 2H), 7.13 (t, J J = 8.1 Hz, 1H), 6.96 (td, J J = 8.3, 2.7 Hz, 1H), 6.54 (dd, J J = 8.2, 2.3 Hz, 1H), 6.44 (t, J J = 2.3 Hz, 1H), 6.34 (dd, J J = 7.9, 2.3 Hz, 1H), 6.20 (s, 1H), 4.11 – 4.01 (m, 3H), 3.92 (d, J J = 17.4 Hz, 1H), 3.30 (q, J= 3.8 Hz, 4H), 2.76 (t, J = 5.1Hz, 4H), 1.14 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.27, 162.74,162.23, 160.57, 156.99, 152.60, 146.27, 144.62, 143.27, 139.94, 139.91,130.68, 130.62, 130.02, 123.32, 123.26, 123.18, 120.21, 120.05, 115.03,114.89, 108.29, 106.95, 103.22, 98.18, 60.01, 58.73, 56.40, 53.34, 49.00,14.16. HR-MS (ESI): calcd. for C 27 H 28 O3N5BrFS, [M+H] + 602.10543, found602.10382. Example 8 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-morpholinopiperidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3i): Compound I-3i was synthesized according to the preparation method of compound I-3b in Example 1, with the difference from Example 1 only being that N-methylpiperazine was replaced by 4-morpholinopiperidine hydrochloride to obtain compound I-3i, a yellow solid, with a yield of 73.6%, m.p. 160.8~161.9 °C; 1 H NMR (600 MHz, CDCl3) δ 9.65 (s, 1H), 7.84(dd, J = 3.1, 1.0 Hz, 1H), 7.42 (dd, J = 3.2, 1.0 Hz, 1H), 7.33 – 7.25 (m, 2H),6.95 (td, J = 8.3, 2.6 Hz, 1H), 6.18 (s, 1H), 4.08 – 3.95 (m, 3H), 3.85 (d, J =17.4 Hz, 1H), 3.76 (t, J= 4.6 Hz, 4H), 3.04 – 2.96 (m, 1H), 2.93 – 2.85 (m,1H), 2.60 (t, J = 4.8 Hz, 4H), 2.35 (td, J = 11.7, 2.5 Hz, 1H), 2.27 – 2.15 (m,2H), 1.94 (ddt, J = 35.6, 12.7, 3.2 Hz, 2H), 1.68 (td, J = 12.3, 4.0 Hz, 2H),1.13 (td, J = 7.1, 1.0 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.24, 162.99,162.15, 160.50, 146.88, 144.46, 143.27, 140.08, 140.05, 130.59, 130.53,123.26, 123.20, 122.89, 120.13, 119.97, 114.93, 114.80, 97.63, 67.22, 61.75,59.79, 58.72, 56.53, 53.61, 53.29, 50.16, 28.86, 28.68, 14.21, 14.16. HR-MS(ESI): calcd. for C 26 H 32 O3N5BrFS, [M+H] + 594.13673, found 594.13898. Example 9 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3j): Compound I-3j was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by 1-(2-hydroxyethyl)piperazine to obtain compound I-3j, a yellow solid, with a yield of 48.6%, m.p. 103.4~103.7 °C; 1 H NMR (600 MHz, CDCl3) δ 9.63 (s, 1H),7.84 (d, J = 3.1 Hz, 1H), 7.42 (d, J= 3.1 Hz, 1H), 7.32 (dd, J = 8.3, 2.6 Hz, 1H),7.30 – 7.26 (m, 1H), 6.95 (td, J = 8.3, 2.6 Hz, 1H), 6.18 (s, 1H), 4.10 – 3.95(m, 3H), 3.87 (d, J = 17.4 Hz, 1H), 3.65 (t, J = 5.4 Hz, 2H), 2.79 – 2.41 (m,10H), 1.13 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.18, 163.05,162.18, 160.52, 146.38, 144.44, 143.17, 139.98, 139.95, 130.56, 130.51,123.30, 123.23, 122.95, 120.17, 120.01, 114.93, 114.79, 97.92, 59.85, 59.20,58.78, 57.79, 56.34, 53.42, 52.95, 14.16. HR-MS (ESI): calcd. forC 23 H 28 O3N5BrFS, [M+H] + 554.10543, found 554.10443. Example 10 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((4-(ethoxycarbonyl)piperidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3k): Compound I-3k was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by ethyl piperidine-1-carboxylate to obtain compound I-3k, which was a yellow solid with a yield of 85.0% and m.p. 104.4~105.6 °C; 1 H NMR (600 MHz, CDCl3) δ 9.64 (s,1H), 7.85 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.31 (dd, J= 8.4, 2.6 Hz, 1H), 7.28 (dd, J = 8.7, 6.0 Hz, 2H), 6.95 (td, J = 8.3, 2.6 Hz, 1H), 6.18 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 4.09 – 3.96 (m, 3H), 3.88 – 3.79 (m, 1H), 2.97 – 2.80 (m, 2H), 2.43 – 2.23 (m, 3H), 2.05 – 1.85 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 174.96, 166.25, 162.96, 162.17, 160.52, 146.77, 144.50, 143.33, 140.06, 140.03, 130.59, 130.53, 123.27, 123.21, 122.83, 120.14, 119.98, 114.94, 114.80, 97.76, 60.44, 59.79, 58.76, 56.76, 53.56, 53.30, 40.63, 28.47, 28.39, 14.25, 14.16. HR-MS (ESI): calcd. for C 25 H 29 O4N4BrFS, [M+H] + 581.10510, found 581.10608. Example 11 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((1,3-dioxoisoindol-2-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3l): Compound I-3l was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by phthalimide to obtain compound I-3l, a yellow solid, with a yield of 27.4%, m.p. 171.0~171.4 °C; 1 H NMR (600 MHz, CDCl3) δ 7.93 (dd, J = 5.4, 3.0 Hz, 2H), 7.76 (dd,J = 5.4, 3.0 Hz, 2H), 7.70 (d, J = 3.1 Hz, 1H), 7.47 –7.40 (m, 2H), 7.30 (dd, J = 8.1, 2.6 Hz, 1H), 7.08 (td, J = 8.2, 2.6 Hz, 1H),6.08 (d, J = 2.6 Hz, 1H), 5.31 (dd, J = 17.9, 0.7 Hz, 1H), 5.17 (dd, J = 17.9, 0.8Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 169.02, 165.29, 162.83, 162.35, 161.16, 154.11, 149.66, 143.72, 137.90, 137.88, 133.79, 132.80, 131.16, 131.10, 124.48, 123.27, 121.96, 121.90, 120.17, 120.01, 115.87, 115.73, 104.30, 60.47, 51.94, 41.00, 29.70, 14.16. HR-MS (ESI): calcd. for C 25 H 19 O4N4BrFS, [M+H] + 571.02685, found 571.02692. Example 12 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((furan-2-ylmethyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3m): Compound I-3m was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by 2-furfurylamine to obtain compound I-3m, a yellow solid, with a yield of 96.8%, m.p. 126.0~126.4 °C; 1 H NMR (600 MHz, CH3OD) δ 7.94 (d, J= 3.1 Hz, 1H), 7.73 (s, 1H), 7.49 – 7.30 (m, 3H), 7.09 (s, 1H), 6.42 – 6.27 (m, 2H), 6.11(s, 1H), 4.21 – 3.99 (m, 4H), 3.93 – 3.81 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.22, 163.16, 162.16, 160.49, 152.88, 147.85,144.29, 143.15, 142.22, 140.16, 130.68, 130.63, 123.22, 122.84, 120.08,119.93, 114.90, 114.77, 110.30, 107.72, 96.83, 59.74, 58.75, 47.19, 46.31,14.16. HR-MS (ESI): calcd. for C 22 H 21 O3N4BrFS, [M+H] + 521.04758, found 521.04926. Example 13 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((3-fluorophenylethyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3n): Compound I-3n was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that N-methylpiperazine was replaced by 3-fluorophenethylamine to obtain compound I-3n, which was a yellow solid with a yield of 65.9% and m.p. 115.0~115.4 °C; 1 H NMR (600 MHz, DMSO-d6) δ 7.97 (d, J = 3.1 Hz, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.55 (dd, J = 8.6, 2.7 Hz, 1H), 7.37 (dd, J = 8.7, 6.1 Hz, 1H), 7.29 (td, J = 7.9, 6.2 Hz, 1H), 7.21 (td, J= 8.4, 2.7 Hz, 1H), 7.11– 7.05 (m, 2H), 6.98 (td, J = 8.0, 7.3, 2.0 Hz, 1H), 6.00 (s, 1H), 4.10 – 3.98(m, 2H), 3.98 – 3.91 (m, 2H), 2.90 – 2.83 (m, 2H), 2.80 (t, J = 7.0 Hz, 2H),1.05 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.27, 163.80, 163.07,162.17, 160.50, 148.14, 144.35, 143.20, 143.16, 142.08, 142.03, 140.17,140.14, 130.63, 130.57, 130.01, 129.96, 124.44, 124.42, 123.23, 123.17,122.97, 122.89, 120.10, 119.94, 115.74, 115.60, 114.91, 114.77, 113.37,113.30, 113.23, 113.17, 96.81, 59.73, 58.79, 50.85, 47.73, 36.22, 14.18. HR-MS (ESI): calcd. for C 25 H 24 O2N4BrF2S, [M+H] + 563.07455, found 563.07428. Example 14 Synthesis of ethyl 6-((bis(2-hydroxyethyl)amino)methyl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3o): Compound I-3o was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that N-methylpiperazine was replaced by diethanolamine to obtain compound I-3o, a yellow solid, with a yield of 47.7%, m.p. 94.1~95.6 °C; 1 H NMR (600 MHz, CDCl3) δ 9.92 (s, 1H), 7.82 (d, J = 3.2Hz, 1H), 7.45 (d, J= 3.0 Hz, 1H), 7.34 – 7.27 (m, 2H), 6.97 (t, J = 8.0 Hz, 1H),6.19 (s, 1H), 4.23 (s, 2H), 4.09 – 4.02 (m, 2H), 3.78 – 3.71 (m, 4H), 2.94 –2.79 (m, 4H), 1.14 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 170.26,166.58, 166.26, 164.60, 147.02, 146.50, 143.61, 134.79, 134.73, 127.59,126.86, 123.92, 123.76, 119.08, 118.94, 64.02, 63.60, 63.14, 62.23, 61.61,59.22, 56.67, 17.82. HR-MS (ESI): calcd. for C 21 H 25 O4N4BrFS, [M+H] + 529.07380,found 529.07220. Example 15 Synthesis of ethyl 6-(((2-aminoethyl)amino)methyl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3p): Compound I-3p was synthesized according to the preparation method of compound I-3b in Example 1, with the difference from Example 1 only being that N-methylpiperazine was replaced by ethylenediamine to obtain compound I-3p, which was a yellow solid with a yield of 92.0% and m.p. 173.8~174.4 °C; 1H NMR (600 MHz, CH3OD) δ 7.87 (dd, J = 3.1, 1.4 Hz,1H), 7.76 (d, J = 3.1 Hz, 1H), 7.44 (dd, J = 8.7, 5.8 Hz, 1H), 7.35 (dd, J = 8.5,2.5 Hz, 1H), 7.04 (td, J = 8.3, 2.6 Hz, 1H), 6.07 (s, 1H), 4.50 – 4.41 (m, 2H),3.98 (q, J= 7.1 Hz, 2H), 3.45 – 3.31 (m, 4H), 1.03 (t, J = 7.1 Hz, 3H). 13C NMR(151 MHz, CH3OD) δ 165.16, 162.93, 161.97, 161.74, 161.28, 150.71, 149.11,144.12, 139.01, 138.99, 131.56, 131.50, 125.12, 121.98, 121.92, 119.79,119.63, 115.34, 115.20, 105.66, 60.40, 52.48, 49.25, 44.57, 35.63, 13.01. HR-MS (ESI): calcd. for C 19 H 22 O2N5BrFS, [M+H] + 484.06357, found 484.06412. Example 16 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3q): Compound I-3q was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by tert-butyl N-(2-aminoethyl)carbamate to obtain compound I-3q, a yellow solid, with a yield of 43.8%, m.p. 59.0~60.3 °C; 1 H NMR (600 MHz,CDCl3) δ 9.81 (s, 1H), 7.91 – 7.82 (m, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.35 –7.27 (m, 2H), 6.95 (td, J = 8.3, 2.6 Hz, 1H), 6.19 (s, 1H), 5.49 (s, 1H), 4.26– 3.99 (m, 4H), 3.40 – 3.19 (m, 2H), 2.93 – 2.73 (m, 2H), 1.41 (s, 9H), 1.13(t, J = 7.1 Hz, 3H). 1313C NMR (151 MHz, CDCl3) δ 166.20, 163.13, 162.17, 160.52, 156.33, 147.96, 144.27, 143.20, 139.98, 139.96, 130.64, 130.59, 123.23, 123.16, 122.94, 120.10, 119.94, 114.97, 114.83, 96.82, 79.23, 59.77, 58.82, 50.06, 48.06, 40.75, 28.43, 14.18. HR-MS (ESI): calcd. for C 24 H 30 O4N5BrFS, [M+H] + 584.11600, found 584.11639. Example 17 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((2-neopentanamidoethyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (I-3r): Compound I-3r was synthesized according to the preparation method of compound I-3b in Example 1, and the difference from Example 1 was only that: N-methylpiperazine was replaced by N-Boc-1,2-ethylenediamine to obtain compound I-3r, which was a yellow solid with a yield of 32.6% and m.p. 84.0~84.6 °C; 1 1H NMR (600 MHz, CDCl3) δ 9.45 (s, 1H), 7.73 (s, 1H), 7.35 (s, 1H), 7.24 (dt, J J = 11.0, 5.5 Hz, 2H), 6.93 (d, J J = 35.8 Hz, 1H), 6.08 (d, J J = 31.5 Hz, 1H), 4.11 (q, J J = 16.4, 15.9 Hz, 2H), 3.97 (dt, J J = 14.4, 7.2 Hz, 2H), 3.45 - 3.30 (m, 2H), 2.82 (s, 2H), 1.14 (s, 9H), 1.07 - 1.02 (m, 3H). 1313C NMR (151 MHz, CDCl3) δ 177.98, 165.00, 162.03, 161.32, 159.67, 146.84, 142.80, 142.16, 138.95, 129.69, 129.63, 122.19, 119.16, 119.00, 114.05, 96.34, 58.92, 57.78, 48.56, 47.28, 38.40, 37.71, 26.59, 26.50, 13.12. HR-MS (ESI): calcd. for C 24 H 30 O3N5BrFS, [M+H] + 568.12108, found 568.12183. Example 18 Synthesis of ethyl 6-((4-aminopiperidin-1-yl)methyl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (II-3): Add 7 mL of DMF, compound 2 prepared in Comparative Example 1 (2.98 mmol, 1 eq), and 4-aminopiperidine (3.59 mmol, 1.2 eq), and react at room temperature for 15 min. Monitor the reaction by TLC (dichloromethane / methanol = 15 / 1, v / v). After the reaction is completed, add 20 mL of water and extract with ethyl acetate (10 mL each time) 3 times. Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (using gradient elution, dichloromethane / methanol = 40:1 - 10:1, v / v) to obtain compound II-3, 1.13 g, yellow solid, with a yield of 72.9%, m.p. 117.9 - 118.1 °C; 1H NMR (600 MHz, CDCl3) δ 9.68 (s, 1H), 7.86 (d, J J = 3.1 Hz, 1H), 7.40 (d, J J = 3.1 Hz, 1H), 7.31 (dd, J J = 8.4, 2.6 Hz, 1H), 7.29 – 7.27 (m, 1H), 6.95 (td, J J = 8.3, 2.6 Hz, 1H), 6.18 (s, 1H), 4.08 - 3.96 (m, 3H), 3.85 (d, J J = 17.4 Hz, 1H), 2.98 - 2.75 (m, 4H), 2.40 (td, J= 11.4, 2.6 Hz, 1H), 2.3 - 2.26 (m, 1H), 1.94 (dd, J = 35.5, 12.7 Hz, 2H), 1.67 (q, J = 10.7 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.23, 163.01, 162.15, 160.50, 146.93, 144.50, 143.28, 140.08, 140.05, 130.59, 130.54, 123.25, 123.19, 122.86, 120.11, 119.95, 114.93, 114.80, 97.58, 59.77, 58.76, 56.51, 52.97, 52.68, 48.33, 35.47, 35.35, 14.16. HR - MS (ESI): calcd. for C 22 H 26 O2N5BrFS, [M + H] + 524.09487, found 524.09460. Example 19 Synthesis of ethyl 4-(2 - bromo - 4 - fluorophenyl)-6-((4-(ethylsulfonamido)piperidin - 1 - yl)methyl)-2-(thiazol - 2 - yl)-1,4 - dihydropyrimidine - 5 - carboxylate (II - 4a): Add 3 mL of DCM, compound II - 3 (0.29 mmol, 1 eq), ethylsulfonyl chloride (41 mg, 0.32 mmol, 1.1 eq) and triethylamine (87 mg, 0.86 mmol, 3 eq), react at room temperature for 1 h, monitor the reaction by TLC (petroleum ether / ethyl acetate = 1 / 3, v / v). After the reaction is completed, evaporate to dryness under reduced pressure, add 10 mL of water, extract with ethyl acetate (5 mL each time) for 3 times, combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (using gradient elution, petroleum ether / ethyl acetate = 4:1~2:1, v / v) to obtain compound II - 4a, 150 mg, yellow solid, with a yield of 85.0%, m.p. 182.0~182.1 °C; 1 H NMR (600 MHz, CDCl3) δ 9.58 (s, 1H), 7.84 (d, J = 3.1 Hz, 1H), 7.44 (d,J = 3.2 Hz, 1H), 7.32 (dd, J =8.3, 2.6 Hz, 1H), 7.27 (dd, J = 8.6, 6.1 Hz, 2H), 6.95 (td, J = 8.3, 2.7 Hz, 1H),6.18 (s, 1H), 4.14 (d, J = 8.1 Hz, 1H), 4.03 (ddt, J = 12.5, 10.8, 3.7 Hz, 3H),3.84 (d, J = 17.3 Hz, 1H), 3.41 – 3.35 (m, 1H), 3.07 (q, J = 7.4 Hz, 2H), 2.90(d, J = 11.9 Hz, 1H), 2.80 (d, J = 11.7 Hz, 1H), 2.47 (dd, J = 12.4, 9.8 Hz, 1H),2.35 (t, J = 11.2 Hz, 1H), 2.11 (s, 1H), 2.07 – 2.02 (m, 1H), 1.76 – 1.68 (m,2H), 1.40 (t, J = 7.4 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ166.18, 163.01, 162.18, 160.52, 146.36, 144.40, 143.19, 139.93, 139.91,130.55, 130.50, 123.29, 123.23, 123.03, 120.17, 120.01, 114.94, 114.80,97.92, 59.86, 58.77, 56.27, 52.71, 52.40, 50.60, 48.40, 34.05, 33.88, 14.14,8.49. HR-MS (ESI): calcd. for C 24 H 30 O4N5BrFS2, [M+H] + 616.08807, found616.08704. Example 20 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(propylsulfonamido)piperidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (II-4b): Compound II-4b was synthesized according to the preparation method of compound II-4a in Example 19, with the only difference from Example 19 being that ethylsulfonyl chloride was replaced by propylsulfonyl chloride, to obtain compound II-4b, a yellow solid, with a yield of 69.4% and m.p. 142.6~143.0 °C; 1 H NMR (600 MHz, DMSO-d6) δ 9.62(s, 1H), 7.99 (d, J = 3.1 Hz, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.56 (dd, J = 8.6, 2.7Hz, 1H), 7.38 (dd, J = 8.7, 6.1 Hz, 1H), 7.22 (td, J = 8.4, 2.7 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.02 (s, 1H), 3.94 (dd, J = 15.3, 8.3 Hz, 2H), 3.90 – 3.81 (m,2H), 3.21 – 3.14 (m, 1H), 3.01 – 2.95 (m, 2H), 2.90 (d, J = 11.6 Hz, 1H), 2.76(d, J = 11.7 Hz, 1H), 2.33 (td, J = 11.4, 2.7 Hz, 1H), 2.24 (t, J = 11.1 Hz, 1H),1.88 (d, J = 12.7 Hz, 1H), 1.83 (d, J = 12.7 Hz, 1H), 1.68 (tdd, J = 11.6, 9.7, 5.8Hz, 2H), 1.62-1.54 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13CNMR (151 MHz, DMSO-d6) δ 164.57, 161.48, 161.00, 159.35, 146.22, 143.30,142.91, 139.61, 139.59, 130.31, 130.25, 124.18, 122.00, 121.93, 119.07,118.91, 114.96, 114.82, 96.25, 58.75, 57.57, 54.98, 53.42, 51.62, 51.42,49.01, 32.64, 32.53, 16.50, 13.38, 12.14. HR-MS (ESI): calcd. forC 25 H 32 O4N5BrFS2, [M+H] + 630.10372, found 630.10400. Example 21 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(cyclopropanesulfonamido)piperidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (II-4c): Compound II-4c was synthesized according to the preparation method of compound II-4a in Example 19, and the difference from Example 19 was only that: ethylsulfonyl chloride was replaced by cyclopropylsulfonyl chloride to obtain compound II-4c, which was a yellow solid with a yield of 77.8% and m.p. 138.2~139.5 °C; 1H NMR (600 MHz, DMSO-d6) δ9.62 (s, 1H), 7.99 (d, J J = 3.2 Hz, 1H), 7.95 (d, J J = 3.2 Hz, 1H), 7.56 (dd, J J =8.6, 2.7 Hz, 1H), 7.38 (dd, J J = 8.7, 6.1 Hz, 1H), 7.28 – 7.12 (m, 2H), 6.02 (s,1H), 4.05 – 3.79 (m, 4H), 3.24 (d, J J = 9.8 Hz, 1H), 2.91 (d, J J = 11.4 Hz, 1H),2.77 (d, J J = 11.7 Hz, 1H), 2.57 (tt, J= 7.7, 5.1 Hz, 1H), 2.41 – 2.19 (m, 2H), 1.91 (dd, J = 31.0, 12.2 Hz, 2H), 1.68 – 1.55 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H), 0.97 – 0.89 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 166.18, 162.99, 162.18, 160.52, 146.39, 144.42, 143.22, 139.95, 139.93, 130.57, 130.51, 123.29, 123.23, 123.03, 120.17, 120.01, 114.95, 114.81, 97.92, 59.87, 58.77, 56.29, 52.70, 52.40, 50.60, 34.06, 33.89, 31.52, 14.15, 5.74. HR-MS (ESI): calcd. for C 25 H 30 O4N5BrFS2, [M+H] + 628.08807, found 628.08777. Example 22 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-((4-chlorophenyl)sulfamoyl)piperidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (II-4d): Compound II-4d was synthesized according to the preparation method of compound II-4a in Example 19, and the difference from Example 19 was only that: ethylsulfonyl chloride was replaced with p-chlorobenzenesulfonyl chloride to obtain compound II-4d, a yellow solid, with a yield of 45.0%, m.p. 94.3~94.5 °C; 1 H NMR (600 MHz, CDCl3) δ 9.54 (s, 1H), 7.89 - 7.82 (m, 2H), 7.80 (d, J = 3.1 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.41 (d, J = 3.1 Hz, 1H), 7.30 (dd, J = 8.3, 2.6 Hz, 1H), 7.25 (dd, J = 8.7, 6.0 Hz, 1H), 6.93 (td, J= 8.3, 2.6 Hz, 1H), 6.16 (s, 1H), 4.97 (d, J = 7.6 Hz, 1H),4.07 – 3.94 (m, 3H), 3.80 (d, J = 17.4 Hz, 1H), 3.25 (tt, J = 9.4, 5.9 Hz, 1H),2.85 – 2.68 (m, 2H), 2.42 – 2.21 (m, 2H), 1.90 – 1.80 (m, 2H), 1.68 – 1.58(m, 2H), 1.11 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 166.16, 162.96,162.17, 160.51, 146.30, 144.36, 143.15, 139.91, 139.89, 139.75, 139.17,130.54, 130.48, 129.50, 128.39, 123.28, 123.22, 123.03, 120.16, 120.00,114.93, 114.79, 97.92, 59.86, 58.75, 56.23, 52.44, 52.16, 50.50, 33.31,33.15, 14.13. HR-MS (ESI): calcd. for C 28 H 29 O4N5BrClFS2, [M+H] + 698.04909, found698.04926. Example 23 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (III-3a): Add 3 mL of DMF, the compound 2 prepared in Comparative Example 1 (0.99 mmol, 1 eq), tert-butyl glycinate (1.30 mmol, 1.3 eq), and K2CO3 (3.98 mmol, 4 eq), and react at room temperature for 3.5 h. Monitor the reaction by TLC (petroleum ether / ethyl acetate = 1 / 1, v / v). After the reaction is completed, add 20 mL of water and extract 3 times with ethyl acetate (10 mL each time). Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (using gradient elution, petroleum ether / ethyl acetate = 5:1 - 2:1, v / v) to obtain compound III-3a, 445 mg, a yellow solid, with a yield of 81.0%, m.p. 117.9 - 118.1 °C; 1H NMR (600 MHz, CDCl3) δ 9.62 (s, 1H), 7.82 (d, J = 3.1 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 7.31(ddd, J = 8.7, 4.5, 1.9 Hz, 2H), 6.95 (td, J = 8.3, 2.6 Hz, 1H), 6.18 (s, 1H),4.24 (d, J = 17.8 Hz, 1H), 4.15 (d, J = 17.7 Hz, 1H), 4.03 (td, J = 7.1 Hz, 2H),3.48 – 3.33 (m, 2H), 1.49 (s, 9H), 1.12 (t, J= 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 171.22, 166.13, 163.13, 162.17, 160.51, 147.55, 144.27, 143.12, 140.11, 140.08, 130.67, 130.61, 123.24, 123.18, 122.90, 120.10, 119.94, 114.93, 114.79, 97.08, 81.73, 59.77, 58.76, 51.81, 47.98, 28.14, 14.17. HR-MS (ESI): calcd. for C 23 H 27 O4N4BrFS, [M+H] + 553.09149, found 553.09076. Example 24 Synthesis of 6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)glycine (III-4a): Add 1 mL of DCM, 1 mL of trifluoroacetic acid and compound III-3a (135 mg, 0.27 mmol), react at room temperature for 1 h, and monitor the reaction by TLC (dichloromethane / methanol = 15 / 1, v / v). After the reaction is completed, concentrate under reduced pressure, add 10 mL of water, extract 3 times with ethyl acetate (5 mL each time), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (using gradient elution, dichloromethane / methanol = 20:1~5:1, v / v) to obtain compound III-4a, 60 mg, yellow solid, with a yield of 49.5%, m.p. 136.7~140.3 °C; 1 H NMR (600 MHz, DMSO-d6) δ 8.01 (s, 2H), 7.61 – 7.39 (m, 2H), 7.23 (s, 1H), 5.99 (s, 1H), 4.13 (s, 2H), 3.96 (d, J = 9.2 Hz, 2H), 3.44 (s, 2H), 1.06 (t, J = 6.9 Hz, 3H). 1313C NMR (151 MHz, CDCl3) δ 169.01, 166.86, 165.19, 165.13, 154.21, 153.08, 148.12, 142.07, 135.14, 135.09, 129.64, 126.02, 125.95, 124.22, 124.05, 119.78, 119.64, 109.52, 64.77, 56.24, 17.69. HR-MS (ESI): calcd. for C 19 H 19 O4N4BrFS, [M+H] + 499.02685, found 499.02621. Example 25 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-1-(tert-butoxy)-4-methyl-1-oxopentan-2-yl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (III-3b): Compound III-3b was synthesized according to the preparation method of compound III-3a in Example 23, and the difference from Example 23 was only that: tert-butyl glycinate was replaced by L-leucine tert-butyl ester hydrochloride to obtain compound III-3b, a yellow solid, with a yield of 62.0%, m.p. 125.7~126.1 °C, 1 1H NMR (600 MHz, CDCl3) δ 9.73 (s, 1H), 7.80 (d, J J = 3.1 Hz, 1H), 7.41 (d, J J = 3.1 Hz, 1H), 7.33 – 7.27 (m, 2H), 6.95 (td, J J = 8.3, 2.6 Hz, 1H), 6.19 (s, 1H), 4.16 – 4.10 (m, 2H), 4.02 (td, J J = 7.0 Hz, 2H), 3.08 (dd, J J = 8.0, 6.3 Hz, 1H), 2.04 (s, 1H), 1.49 (s, 9H), 1.25 (dt, J J = 9.0, 7.1 Hz, 2H), 1.12 (t, J J = 7.1 Hz, 3H), 0.91 (d, J J = 6.6 Hz, 3H), 0.82 (d, J= 6.6 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ174.82, 166.05, 163.00, 162.18, 160.52, 147.78, 147.65, 144.43, 143.05,142.94, 140.03, 130.64, 123.24, 122.87, 120.19, 120.09, 120.02, 119.93,114.94, 97.10, 96.80, 81.52, 61.08, 60.78, 59.74, 58.83, 46.31, 42.92, 42.80,28.12, 24.95, 24.89, 22.94, 22.85, 22.25, 14.18. HR-MS (ESI): calcd. forC 27 H 35 O4N4BrFS, [M+H] + 611.15253, found 611.15205. Example 26 Synthesis of ((6-(4-bromo-2-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-L-leucine (III-4b): Compound III-4b was synthesized according to the preparation method of compound III-4a in Example 24, with the difference from Example 24 only being that: compound III-3a was replaced with compound III-3b to obtain compound III-4b, which was a yellow solid with a yield of 74.4% and m.p. 175.7~175.9; 1 H NMR (600 MHz, CH3OD) δ 7.86 (dd, J =3.1, 1.7 Hz, 1H), 7.76 (d, J = 3.1 Hz, 1H), 7.42 (ddd, J = 8.8, 5.9, 1.7 Hz, 1H),7.33 (ddd, J = 8.4, 3.8, 2.6 Hz, 1H), 7.04 (qd, J = 8.8, 2.7 Hz, 1H), 6.05 (d, J =5.5 Hz, 1H), 4.55 – 4.44 (m, 1H), 4.29 (d, J= 16.2 Hz, 1H), 3.99 – 3.92 (m,2H), 3.61 (d, J = 39.8 Hz, 1H), 1.89 – 1.73 (m, 2H), 1.68 (dq, J = 14.4, 7.0 Hz,1H), 1.01 (td, J = 7.1, 2.5 Hz, 3H), 0.91 (ddd, J = 19.1, 10.5, 6.5 Hz, 6H). 13 C NMR (151 MHz, CH3OD) δ 165.10, 162.90, 161.98, 161.75, 161.25, 144.21,138.99, 131.49, 131.43, 125.17, 122.03, 121.96, 119.81, 119.65, 117.69,115.75, 115.30, 115.18, 61.00, 60.32, 60.13, 39.78, 24.86, 24.84, 21.58,21.50, 21.46, 13.05. HR-MS (ESI): calcd. for C 23 H 27 O4N4BrFS, [M+H] + 555.08945,found 555.09021. Example 27 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((2S,3S)-1-(tert-butoxy)-3-hydroxy-1-oxobutan-2-yl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (III-3c): Compound III-3c was synthesized according to the preparation method of compound III-3a in Example 23, and the difference from Example 23 was only that: tert-butyl glycinate was replaced by L-threonine tert-butyl ester hydrochloride to obtain compound III-3c, which was a yellow solid with a yield of 63.0% and a melting point of 90.0~90.8 °C; 1 H NMR (600 MHz, DMSO-d6) δ 9.94 (d, J = 13.9 Hz, 1H), 7.96 (dd, J = 6.1, 3.1Hz, 1H), 7.91 (d, J= 3.1 Hz, 1H), 7.55 (dd, J = 8.6, 2.7 Hz, 1H), 7.40 (dd, J =8.7, 6.1 Hz, 1H), 7.19 (tdd, J = 8.7, 6.1, 2.6 Hz, 1H), 5.99 (s, 1H), 4.80 (d, J = 5.5 Hz, 1H), 4.26 – 4.18 (m, 1H), 3.93 (dddd, J = 12.0, 10.5, 6.3, 3.8 Hz,4H), 3.17 (d, J = 5.2 Hz, 1H), 3.09 (dd, J = 9.1, 4.7 Hz, 1H), 1.40 (d, J = 5.3 Hz,9H), 1.22 (dd, J = 8.6, 6.3 Hz, 3H), 1.04 (td, J = 7.1, 1.1 Hz, 3H). 13 C NMR (151MHz, DMSO-d6) δ 172.64, 165.77, 162.76, 149.86, 144.47, 143.90, 131.45,124.97, 123.02, 120.06, 119.95, 115.89, 95.75, 80.70, 68.40, 67.91, 59.65,58.65, 49.07, 46.48, 40.43, 40.29, 40.15, 40.01, 39.87, 39.73, 39.59, 28.19,28.16, 21.01, 14.47. HR-MS (ESI): calcd. for C 25 H 31 O5N4BrFS, [M+H] + 599.11566,found 599.11542. Example 28 Synthesis of ((6-(4-bromo-2-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-D-threonine (III-4c): Compound III-4c was synthesized according to the preparation method of compound III-4a in Example 24. The difference from Example 24 was only that compound III-3a was replaced with compound III-3c to obtain compound III-4c, which was a yellow solid with a yield of 59.9% and m.p. 177.7~178.7 °C; 1 H NMR (600 MHz, CDCl3) δ 7.95 – 7.56(m, 2H), 7.59 – 7.27 (m, 2H), 6.93 (d, J = 31.1 Hz, 1H), 5.96 (t, J = 7.5 Hz,1H), 4.76 – 4.30 (m, 3H), 3.85 (dt, J = 21.3, 7.2 Hz, 2H), 3.53 (d, J = 31.8 Hz,1H), 1.54 – 1.12 (m, 3H), 1.06 – 0.63 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ170.95, 163.63, 161.83, 160.16, 159.79, 149.06, 142.77, 136.60, 130.42,125.34, 120.88, 119.15, 118.98, 114.97, 104.66, 67.60, 65.08, 64.80, 59.72,50.99, 47.59, 47.08, 19.88, 12.88, 12.86. HR-MS (ESI): calcd. forC21H23O5N4BrFS, [M+H]+ 543.05306, found 543.05286. Example 29 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-1-(tert-butoxy)-1-oxo-3-phenylpropan-2-yl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (III-3d): Compound III-3d was synthesized according to the preparation method of compound III-3a in Example 23, with the only difference from Example 23 being that tert-butyl glycinate was replaced by L-phenylalanine tert-butyl ester hydrochloride, to obtain compound III-3d, a yellow solid, with a yield of 90.6%, m.p. 57.8~58.2 °C; 1 H NMR (600 MHz, CDCl3) δ 9.61 (s, 1H), 7.84 (d, J = 3.1 Hz, 1H), 7.42 (d, J =3.1 Hz, 1H), 7.30 (ddd, J = 8.2, 6.4, 1.9 Hz, 3H), 7.26 – 7.22 (m, 3H), 7.20 –7.13 (m, 1H), 6.94 (td, J = 8.3, 2.6 Hz, 1H), 6.15 (s, 1H), 4.27 (d, J = 17.9 Hz,1H), 4.05 – 3.95 (m, 3H), 3.43 (t, J = 6.7 Hz, 1H), 3.04 (qd, J = 13.7, 6.7 Hz,2H), 1.42 (s, 9H), 1.11 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 173.14,166.06, 162.98, 162.15, 160.50, 147.60, 144.33, 143.06, 140.07, 140.05,137.12, 130.63, 130.58, 129.52, 128.41, 126.68, 123.27, 123.21, 122.85,120.12, 119.96, 114.85, 114.71, 96.85, 81.85, 63.71, 59.73, 58.78, 46.51,39.82, 28.03, 14.16. HR-MS (ESI): calcd. for C 30 H 33O4N4BrFS, [M+H] + 645.13640, found 645.13666. Example 30 Synthesis of ((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-L-phenylalanine (III-4d): Compound III-4d was synthesized according to the preparation method of compound III-4a in Example 24, and the difference from Example 24 was only that: compound III-3a was replaced with compound III-3d to obtain compound III-4d, which was a yellow solid with a yield of 45.4% and m.p. 186.1~186.3 °C; 1 H NMR (600 MHz, DMSO-d6) δ 9.76 (d, J J = 53.5 Hz, 1H), 7.99 (t, J J = 2.6 Hz, 1H), 7.94 – 7.89 (m, 1H), 7.54 (dt, J J = 8.6, 2.0 Hz, 1H), 7.36 – 7.06 (m, 7H), 5.97 (d, J J = 8.5 Hz, 1H), 4.13 (t, J J = 15.9 Hz, 1H), 3.92 (q, J J = 6.7 Hz, 3H), 3.49 (d, J J = 23.7 Hz, 1H), 3.02 – 2.86 (m, 2H), 1.03 (td, J J = 7.1, 1.4 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 173.50, 171.72, 165.50, 163.79, 162.58, 160.05, 146.10, 137.66, 133.43, 132.60, 129.92, 129.61, 129.18, 128.89, 127.02, 126.52, 121.10, 120.29, 120.13, 115.25, 115.10, 56.51, 55.53, 49.33, 35.11, 18.98. HR-MS (ESI): calcd. for C 26 H 25 O4N4BrFS, [M+H] +589.07380, found 589.07373. Example 31 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-(((S)-1-(tert-butoxy)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (III-3e): Compound III-3e was synthesized according to the preparation method of compound III-3a in Example 23, with the difference from Example 23 being only that tert-butyl glycinate was replaced by L-tyrosine tert-butyl ester hydrochloride to obtain compound III-3e, a yellow solid, with a yield of 88.4% and m.p. 75.0~75.2 °C; 1 H NMR (600 MHz, DMSO-d6) δ 9.83 (d, J = 41.9 Hz, 1H), 9.15 (d, J = 12.9Hz, 1H), 7.99 (dd, J = 3.1, 1.6 Hz, 1H), 7.93 (dd, J = 7.6, 3.1 Hz, 1H), 7.55(dt, J = 8.6, 2.3 Hz, 1H), 7.38 (ddd, J = 31.0, 8.7, 6.2 Hz, 1H), 7.19 (ddt, J =8.4, 5.4, 3.0 Hz, 1H), 7.07 – 7.02 (m, 1H), 7.03 – 6.97 (m, 1H), 6.67 – 6.61(m, 2H), 5.98 (d, J = 9.5 Hz, 1H), 4.18 – 4.03 (m, 1H), 4.01 – 3.87 (m, 3H),2.97 (d, J = 42.1 Hz, 1H), 2.87 – 2.74 (m, 2H), 1.31 (d, J = 1.1 Hz, 9H), 1.03(td, J = 7.1, 3.3 Hz, 3H). 1313C NMR (151 MHz, CDCl3) δ 173.52, 173.43, 166.18, 162.65, 162.61, 162.21, 160.55, 160.52, 155.13, 147.71, 147.65, 144.67, 144.59, 143.19, 143.13, 140.01, 139.99, 130.84, 130.78, 130.72, 130.57, 130.55, 128.36, 128.18, 123.26, 123.21, 123.15, 123.12, 120.11, 120.07, 119.95, 119.91, 115.44, 115.41, 115.01, 114.98, 114.87, 114.84, 97.15, 96.99, 81.92, 63.81, 63.36, 59.89, 58.69, 58.63, 46.54, 46.49, 38.94, 38.85, 28.07, 14.16. HR-MS (ESI): calcd. for C 30 H 33 O5N4BrFS, [M+H] + 661.13131, found 661.13269. Example 32 Synthesis of ((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-L-tyrosine (III-4e): Compound III-4e was synthesized according to the preparation method of compound III-4a in Example 24, and the difference from Example 24 was only that: compound III-3a was replaced with compound III-3e to obtain compound III-4e, which was a yellow solid with a yield of 54.7% and m.p. 156.7~156.9 °C; 1 1H NMR (600 MHz, DMSO-d6) δ 9.95 (d, J J = 108.6 Hz, 1H), 9.20 (s, 1H), 7.98 (d, J J = 45.7 Hz, 2H), 7.56 (d, J J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 7.09 (s, 2H), 6.66 (s, 2H), 5.97 (d, J= 4.3Hz, 1H), 4.15 (s, 2H), 3.99 - 3.90 (m, 2H), 3.17 (s, 2H), 2.87 (s, 1H), 1.07 - 1.00 (m, 3H). 13 C NMR (151 MHz, DMSO - d6) δ 165.71, 162.50, 162.03, 160.39,156.30, 149.55, 144.44, 143.96, 140.96, 131.42, 130.63, 130.58, 128.41,124.87, 122.98, 120.03, 119.87, 115.94, 115.80, 115.46, 95.80, 63.36, 63.19,59.65, 58.54, 55.37, 38.60, 14.45. HR - MS (ESI): calcd. for C 26 H 25 O5N4BrFS, [M + H] + 605.06871, found 605.06818. Example 33 Synthesis of di - tert - butyl ((6 - (2 - bromo - 4 - fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol - 2 - yl)-3,6 - dihydropyrimidin - 4 - yl)methyl)-L - aspartate (III - 3f): Compound III - 3f was synthesized according to the preparation method of compound III - 3a in Example 23, with the difference from Example 23 only being that tert - butyl glycinate was replaced by D - aspartic acid di - tert - butyl ester hydrochloride to obtain compound III - 3f, a yellow solid, with a yield of 56.5%, m.p. 60.1~61.2 °C; 1 H NMR (600MHz, CH3OD) δ 7.78 (dd, J = 5.5, 3.1 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.37 (ddd, J =18.7, 8.7, 6.0 Hz, 1H), 7.28 (dt, J = 8.5, 2.3 Hz, 1H), 6.97 (tdd, J = 8.4, 5.6,2.6 Hz, 1H), 6.02 (d, J = 8.2 Hz, 1H), 4.15 - 3.98 (m, 2H), 3.92 (q, J= 7.1 Hz, 2H), 3.47 (d, J = 47.9 Hz, 1H), 2.68 - 2.50 (m, 2H), 1.38 (d, J = 3.9 Hz, 9H), 1.33 (d, J = 1.9 Hz, 9H), 1.02 (td, J = 7.1, 1.2 Hz, 3H). 13 C NMR (151 MHz, CH3OD) δ 172.30, 170.40, 166.00, 162.37, 162.14, 162.12, 160.72, 143.21, 140.10, 131.06, 130.95, 128.53, 128.48, 123.69, 122.64, 119.50, 119.33, 114.83, 114.69, 81.60, 80.95, 80.93, 65.26, 59.66, 58.18, 51.77, 38.38, 27.02, 27.00, 26.94, 26.85, 13.19. HR - MS (ESI): calcd. for C 29 H 37 O6N4BrFS, [M + H]+ 669.15753, found 669.15619. Example 34 Synthesis of ((6 - (2 - bromo - 4 - fluorophenyl) - 5 - (ethoxycarbonyl) - 2 - (thiazol - 2 - yl) - 3,6 - dihydropyrimidin - 4 - yl)methyl) - L - aspartic acid (III - 4f): Compound III - 4f was synthesized according to the preparation method of compound III - 4a in Example 24, and the difference from Example 24 was only that: compound III - 3a was replaced with compound III - 3f to obtain compound III - 4f, which was a yellow solid with a yield of 74.4%, m.p. 186.7~187.2 °C; 1 H NMR (600 MHz, CH3OD) δ 7.79 (dd, J = 62.5, 3.0 Hz, 2H), 7.48 (dd, J = 8.8, 5.9 Hz, 1H), 7.33 (dd, J = 8.4, 2.5 Hz, 1H), 7.05 (td, J= 8.3, 2.6 Hz, 1H), 6.06 (s, 1H), 4.58 - 4.44 (m, 2H), 3.97 (q, J = 7.1 Hz, 3H), 3.11 - 2.86 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CH3OD) δ 172.98, 170.64, 165.08, 162.91, 161.44, 161.24, 144.17, 139.03, 131.63, 131.57, 125.30, 121.94, 121.88, 119.73, 119.56, 115.35, 115.21, 105.29, 60.33, 57.99, 52.38, 48.17, 33.53, 13.06. HR - MS (ESI): calcd. for C 21 H 19 O6N4BrFS, [M + H] + 555.01668, found 555.01630. Example 35 Synthesis of ethyl 4-(2 - bromo - 4 - fluorophenyl)-6-(((R)-1-(tert - butoxy)-6-(tert - butoxycarbonyl)amino)-1 - oxohex - 2 - yl)amino)methyl)-2-(thiazol - 2 - yl)-1,4 - dihydropyrimidine - 5 - carboxylate (III - 3g): The compound III - 3g was synthesized according to the preparation method of compound III - 3a in Example 23, and the difference from Example 23 was only that: tert - butyl glycinate was replaced with N (6)-Boc - L - lysine tert - butyl ester hydrochloride, to obtain compound III - 3g, a yellow solid, with a yield of 64.8%, m.p. 58.6~60.5 °C; 1 H NMR (600 MHz, CDCl3) δ 9.70 (s, 1H), 7.85 (d, J = 3.1Hz, 1H), 7.42 (d, J = 3.1 Hz, 1H), 7.30 (dt, J = 8.1, 2.5 Hz, 2H), 6.95 (td, J =8.3, 2.6 Hz, 1H), 6.18 (s, 1H), 4.19 (d, J= 17.9 Hz, 1H), 4.13 - 3.95 (m, 3H), 3.09 (dt, J = 27.8, 7.1 Hz, 3H), 2.14 - 1.91 (m, 1H), 1.78 - 1.68 (m, 1H), 1.67 - 1.55 (m, 2H), 1.49 (s, 11H), 1.43 (s, 9H), 1.12 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CH3OD) δ 166.09, 162.13, 162.09, 157.12, 143.30, 140.19, 130.93, 128.52, 123.64, 122.74, 119.55, 119.50, 119.34, 114.81, 114.66, 81.21, 78.43, 65.26, 62.00, 60.13, 59.61, 39.80, 32.66, 29.37, 27.41, 27.00, 22.92, 13.17. HR - MS(ESI): calcd. for C 32 H 44 O6N5BrFS, [M + H]+ 726.21538, found 726.21454. Example 36 Synthesis of ((6-(2 - bromo - 4 - fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol - 2 - yl)-3,6 - dihydropyrimidin - 4 - yl)methyl)-D - lysine (III - 4g): Compound III - 4g was synthesized according to the preparation method of compound III - 4a in Example 24, with the difference from Example 24 only being that: compound III - 3a was replaced with compound III - 3g to obtain compound III - 4g, which was a yellow solid with a yield of 64.4% and m.p. 204.6~205.5 °C; 1 H NMR (600 MHz, CH3OD) δ 7.85 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 3.1 Hz, 1H), 7.41 - 7.29 (m, 2H), 7.01 (dtd, J = 11.0, 8.2, 2.6 Hz, 1H), 6.14 (d, J = 4.3 Hz, 1H), 4.25 - 4.16 (m, 1H), 4.02 (q,J = 7.1Hz, 3H), 3.13 (d, J = 37.5 Hz, 1H), 2.89 (dt, J = 23.1, 7.0 Hz, 2H), 1.83-1.62(m, 4H), 1.61-1.46 (m, 2H), 1.14 (td, J = 7.1, 1.1 Hz, 3H). 13 C NMR (151 MHz,CH3OD) δ 167.92, 164.10, 162.44, 144.97, 141.40, 132.65, 132.60, 125.43,124.58, 121.77, 121.73, 121.61, 121.57, 116.90, 116.76, 65.51, 61.76, 48.93,40.96, 40.90, 29.07, 28.91, 23.97, 23.81, 15.64. HR-MS (ESI): calcd. forC 23 H 28 O4N5BrFS, [M+H] + 568.10239, found 568.10156. Example 37 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((methylamino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (IV-3): Add 8 mL of DMF, compound 2 prepared in Comparative Example 1 (4.97 mmol, 1 eq), methylamine hydrochloride (5.97 mmol, 1.2 eq) and K2CO3 (19.9 mmol, 4 eq), react at room temperature for 2 h, monitor the reaction by thin layer chromatography (dichloromethane / methanol = 15 / 1, v / v), add 50 mL of water, extract 3 times with ethyl acetate (25 mL each time), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter by suction, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography (using gradient elution, dichloromethane / methanol = 30:1~10:1, v / v) to obtain compound IV-3, 2.15 g, yellow solid, with a yield of 95.5%, m.p. 228.7~229.1 °C; 1 H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 3.1 Hz, 1H),7.41-7.32 (m, 1H), 7.25 (dt, J= 8.3, 3.8 Hz, 2H), 6.90 (s, 1H), 6.10 (d, J = 4.0Hz, 1H), 4.16 - 3.91 (m, 4H), 2.48 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H). 13 C NMR (151MHz, CDCl3) δ 168.15, 165.09, 161.31, 157.86, 150.01, 142.76, 142.26, 130.37, 130.31, 129.69, 129.63, 123.10, 122.03, 119.63, 119.46, 119.11, 118.95, 114.47, 114.33, 114.00, 108.98, 58.87, 52.49, 51.27, 13.13. HR - MS (ESI): calcd. for C 18 H 19 O2N4BrFS, [M + H] + 455.03702, found 455.03812. Example 38 Synthesis of ethyl 4-(2 - bromo - 4 - fluorophenyl)-6-((N - methylacetamido)methyl)-2-(thiazol - 2 - yl)-1,4 - dihydropyrimidine - 5 - carboxylate (IV - 4a): 6 mL of DCM, compound IV - 3 (0.66 mmol, 1 eq) and acetyl chloride (0.79 mmol, 1.2 eq) were added, and the reaction was carried out at room temperature for 3 h. TLC (ethyl acetate / petroleum ether = 1 / 1, v / v). After the reaction was completed, 10 mL of water was added, and the mixture was extracted 3 times with ethyl acetate (5 mL each time). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (gradient elution, ethyl acetate / petroleum ether = 3:1 - 1:1, v / v) was used to obtain compound IV - 4a, 120 mg, yellow solid, with a yield of 36.6%, m.p. 61.7 - 62.6 °C; 1 H NMR (600 MHz, CDCl3) δ 9.48 (s, 1H), 7.85 (dd, J = 20.7, 3.1 Hz, 1H), 7.52 - 7.40 (m, 1H), 7.39 - 7.34 (m, 1H), 7.34 - 7.29 (m, 1H), 7.00 (dtd, J= 34.9, 8.2, 2.6 Hz, 1H), 6.25 - 6.10 (m, 1H), 5.04 - 4.78 (m, 2H), 4.07 (dq, J = 16.6, 6.9 Hz, 2H), 3.11(d, J = 91.6 Hz, 3H), 2.24 (d, J = 23.1 Hz, 3H), 1.13 (td, J = 7.1, 3.7 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 172.34, 165.26, 162.76, 162.40, 161.20, 145.52, 144.56, 143.92, 143.54, 140.13, 130.49, 130.44, 124.84, 123.18, 122.61, 120.44, 120.28, 120.14, 119.98, 115.72, 115.58, 115.03, 114.89, 105.95, 76.79, 60.18, 58.47, 52.35, 52.15, 36.81, 21.79, 21.41, 14.04. HR - MS (ESI): calcd. for C 20 H 21 O3N4BrFS, [M + H] + 497.04758, found 497.04932. Example 39 Synthesis of ethyl 4-(2 - bromo - 4 - fluorophenyl)-6 - ((N - methyl pivaloylamino)methyl)-2 - (thiazol - 2 - yl)-1,4 - dihydropyrimidine - 5 - carboxylate (IV - 4b): Compound IV - 4b was synthesized according to the preparation method of compound IV - 4a in Example 38, and the difference from Example 38 was only that: acetyl chloride was replaced by tert - butyl formyl chloride to obtain compound IV - 4b, a yellow solid, with a yield of 31.8%, m.p. 69.4 - 70.3 °C; 1 H NMR (600 MHz, CDCl3) δ 9.15 (s, 1H), 7.74(d, J = 3.1 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.24 (dd, J = 8.3, 2.7 Hz, 1H), 6.90 (td, J= 8.3, 2.7 Hz, 1H), 6.12 (s, 1H), 5.04 - 4.86 (m, 2H), 4.04 - 3.93 (m, 2H), 3.18(s, 3H), 1.29 (s, 9H), 1.08 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ179.24, 165.15, 161.46, 161.20, 159.55, 145.05, 143.70, 142.28, 138.71,138.69, 129.51, 129.45, 122.22, 122.15, 121.77, 119.14, 118.97, 114.00,113.87, 99.10, 59.14, 57.41, 46.19, 38.00, 36.39, 27.00, 13.09. HR - MS (ESI):calcd. for C 23 H 27 O3N4BrFS, [M + H]+ 539.09453, found 539.09497. Example 40 Synthesis of ethyl 4-(2 - bromo - 4 - fluorophenyl)-6-((4 - methyl - N - methylbenzamido)methyl)-2-(thiazol - 2 - yl)-1,4 - dihydropyrimidine - 5 - carboxylate (IV - 4c): Compound IV - 4c was synthesized according to the preparation method of compound IV - 4a in Example 38, and the difference from Example 38 was only that: acetyl chloride was replaced by p - methylbenzoyl chloride, to obtain compound IV - 4c, a yellow solid, with a yield of 34.9%, m.p. 81.6~82.3 °C; 1 H NMR (600 MHz, CH3OD) δ 7.86 - 7.77(m, 1H), 7.72 - 7.58 (m, 1H), 7.52 - 7.26 (m, 4H), 7.20 (t, J = 9.0 Hz, 1H), 7.13(d, J = 7.9 Hz, 1H), 7.06 - 6.94 (m, 1H), 6.11 - 5.91 (m, 1H), 5.05 (d, J = 17.1 Hz,1H), 4.33 (s, 1H), 4.00 - 3.82 (m, 2H), 3.05 (d, J = 20.5 Hz, 3H), 2.29 (d,J = 14.6 Hz, 3H), 0.99 (dt, J = 49.2, 6.8 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 173.51, 166.15, 162.53, 162.25, 160.59, 145.43, 144.74, 143.97, 143.47, 140.62, 139.90, 139.02, 131.92, 130.59, 129.08, 128.84, 127.65, 127.38, 123.23, 122.87, 120.17, 120.01, 115.58, 115.44, 115.09, 114.95, 105.44, 60.26, 58.51, 53.63, 34.48, 21.44, 21.41, 14.10, 14.02. HR-MS (ESI): calcd. for C 26 H 25 O3N4BrFS, [M + H] + 573.07888, found 573.07953. Example 41 Synthesis of ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-fluoro-N-methylbenzamido)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (IV-4d): Compound IV-4d was synthesized according to the preparation method of compound IV-4a in Example 38, and the difference from Example 38 was only that: acetyl chloride was replaced with p-fluorobenzoyl chloride to obtain compound IV-4d, a yellow solid, with a yield of 38.3%, m.p. 83.7~84.2 °C; 1 H NMR (600 MHz, CDCl3) δ 7.88 (dd, J = 9.7, 3.1 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.51 (d, J = 16.3 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.34 - 7.30 (m, 1H), 7.16 - 7.11 (m, 1H), 7.06 (dd, J = 9.8, 7.3 Hz, 1H), 6.98(td, J = 8.2, 2.7 Hz, 1H), 6.24 – 6.02 (m, 1H), 5.21 (d, J= 24.3 Hz, 1H), 4.88 –4.68 (m, 1H), 4.13 - 3.95 (m, 2H), 3.13 (d, J = 12.2 Hz, 3H), 1.11 (dt, J = 49.3, 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 173.08, 172.46, 166.12, 165.08, 164.64, 162.97, 162.82, 162.38, 162.27, 161.15, 160.61, 155.81, 149.91, 144.04, 143.44, 133.20, 132.58, 132.51, 130.57, 130.51, 129.94, 129.59, 129.54, 125.04, 120.22, 120.06, 115.71, 115.57, 115.32, 115.17, 115.09, 114.95, 105.57, 60.39, 60.31, 58.50, 52.02, 34.58, 14.07. HR-MS (ESI): calcd. for C 25 H 22 O3N4BrF2S, [M + H] + 577.05381, found 577.05432. Test Example 1 The dihydropyridine compounds prepared in each example were tested for anti-HBV activity as follows: Serial dilutions of each compound (the solvent was MEM medium containing non-essential amino acids, additionally containing 10% fetal bovine serum and 1% penicillin / streptavidin, and the concentration was diluted in a five-fold concentration gradient starting from the maximum non-toxic concentration, with a total of 6 - 7 concentration gradients) were incubated with HepAD38 cells for 3 days and then replaced with a drug-containing medium once (the drug concentration was the same as the aforementioned concentration gradient). On the 6th day, the cells were collected for a pharmacodynamic evaluation experiment, including extracting intracellular HBV core DNA and then detecting the content of intracellular HBV core DNA by fluorescence real-time quantitative PCR (qPCR) method, calculating the inhibition rate, and finally calculating the half-maximal effective concentration (EC 50 ) using the Reed-Muench method. The results are shown in Table 1.

[0107] HBV core DNA inhibition rate (%) = [1 - 2 ^ (HBV Ct control group - HBV Ct drug group)] × 100%; Among them, HBV Ct control group represents the Ct value of HBV core DNA in the control group; HBV Ct drug group represents the Ct values of HBV core DNA at different concentrations in the experimental group samples, and ^ represents the power.

[0108] The compounds prepared in the examples were serially diluted with complete culture medium, and a total of 8 concentrations were set (the solvent was MEM medium containing non-essential amino acids, additionally containing 10% fetal bovine serum and 1% penicillin / streptavidin, and the concentrations were 100 μM, 50 μM, 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, 0.00064 μM). They were added to HepAD38 cells, and the drug-containing medium was changed every 3 days (the drug concentration was the same as the aforementioned gradient concentration). After 6 days of drug action in each group, the cytopathic effect was observed to determine the cytotoxicity, the maximum non-toxic concentration was determined, and the median toxic concentration (CC 50 ) was calculated using the Reed-Muench method, and the selectivity index (SI = CC 50 / EC 50 ) was calculated. The results are shown in Table 1.

[0109] Table 1 Anti-HBV activity and cytotoxicity test results of dihydropyridine compounds

[0110] The activity experimental data in Table 1 show that the dihydropyridine compounds provided by the present invention have high antiviral activity, especially compounds I-3c, I-3d, I-3e, and I-3f have good anti-tumor activity. The dihydropyridine compounds provided by the present invention can be further studied and developed as drug lead molecules to improve their drug-likeness.

[0111] The CC 50 values of each compound vary to some extent. Among them, compound I-3f has low cytotoxicity and strong activity and is the most potential HBV inhibitor.

[0112] Test Example 2 The HBV capsid protein was immobilized on the surface of the CM5 chip, and then dihydropyridine compounds at different concentrations (3.12 μM, 6.25 μM, 12.5 μM, 25 μM, 50 μM) were passed over the chip surface. The sensorgrams of the interaction between the compounds and the HBV capsid protein were recorded using surface plasmon resonance technology, as shown in Figure 1 . It can be seen that the dihydropyridine compounds provided by the present invention have good interaction with the HBV capsid protein.

[0113] Test Example 3 Using a culture medium (MEM medium containing non-essential amino acids, supplemented with 10% fetal bovine serum and 1% penicillin / streptavidin) as a solvent, the dihydropyridine compounds (I-3d, I-3e, I-3f, GLS4) and lamivudine (3-TC) were serially diluted 5-fold starting from 10 μM and applied to the cells, with a total of 5 concentrations (2 μM, 0.4 μM, 0.08 μM, 0.016 μM, 0 μM) set. After 3 days of treatment with each compound on HepAD38 cells, the culture medium containing the drug was replaced once. On the 6th day, the cells were harvested and subjected to Western blot and particle gel assay respectively to test the effect of the compounds on the HBc protein and HBV capsid content. See Figure 2 , it can be seen that each compound can inhibit HBV activity in a dose-dependent manner, further indicating the anti-HBV potential of the dihydropyridine compounds provided by the present invention.

[0114] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A dihydropyrimidine compound, characterized in that: It has a structure shown in Formula A, Formula B or Formula C: Formula A Formula B Formula C; wherein X comprises CH or N; R1 includes any of the following structures: ； R3 includes -H, -CH3 or -CH2CH2OH; When the R3 is -H, R2 includes no tert-butyl ester and COOH group, tert-butyl ester group or COOH group; the tert-butyl ester and COOH group-free group includes any one of the following structures: ； The tert-butyl ester group includes any one of the following structures: ； The COOH-containing group includes any one of the following structures: ； When the R3 is -CH3, R2 includes any one of the following structures: ； When said R3 is -CH2CH2OH, R2 is -CH2CH2OH.

2. The dihydropyrimidine compound according to claim 1, characterized in that When X is N, R1 includes any one of the following structures: ； When X is CH, R1 includes any one of the following structures: 。 3. The method for preparing the dihydropyrimidine compound according to claim 1 or 2, characterized in that: The preparation method of the dihydropyrimidine compound having the structure shown in formula A comprises the following steps: performing a substitution reaction on compound 2 and compound 4, or performing a substitution reaction on compound 3 and R1-Cl, to obtain a dihydropyrimidine compound having the structure shown in formula A; When R3 is -H and R2 does not contain tert-butyl ester and COOH group, or R3 is -H and R2 contains tert-butyl ester group, the preparation method of the dihydropyrimidine compound having the structure shown in formula B comprises the following steps: subjecting compound 2 to a substitution reaction with R2-NH2 to obtain a dihydropyrimidine compound having the structure shown in formula B, wherein R3 is -H and R2 does not contain tert-butyl ester and COOH group, or R3 is -H and R2 contains tert-butyl ester group; When R3 is -H and R2 is a COOH group, the preparation method of the dihydropyrimidine compound having a structure shown in formula B comprises the following steps: subjecting the dihydropyrimidine compound having a structure shown in formula B, wherein R3 is -H and R2 is a tert-butyl ester group, to a hydrolysis reaction to obtain a dihydropyrimidine compound having a structure shown in formula B, wherein R3 is -H and R2 is a COOH group; When R3 is -CH3, the preparation method of the dihydropyrimidine compound having the structure shown in formula B comprises the following steps: subjecting compound 5 to a substitution reaction with R2-Cl to obtain a dihydropyrimidine compound having the structure shown in formula B in which R3 is -CH3; When R3 is -CH2CH2OH, the preparation method of the dihydropyrimidine compound having the structure shown in formula B comprises the following steps: subjecting compound 2 to a substitution reaction with R2-NH-R3 to obtain a dihydropyrimidine compound having the structure shown in formula B, wherein R3 is -CH2CH2OH; The preparation method of a dihydropyrimidine compound having a structure shown in Formula C comprises the following steps: subjecting Compound 2 to a substitution reaction with Compound 6 to obtain a dihydropyrimidine compound having a structure shown in Formula C; 。 4. The preparation method according to claim 3, characterized in that: The preparation method of the compound 3 comprises the following steps: Compound 2 is subjected to a substitution reaction with 4-aminopiperidine to obtain compound 3.

5. The preparation method according to claim 3, characterized in that: The preparation method of compound 5 comprises the following steps: Compound 2 is subjected to a substitution reaction with methylamine hydrochloride to obtain compound 5.

6. The preparation method according to any one of claims 3 to 5, characterized in that The preparation method of the compound 2 comprises the following steps: Compound 1 is subjected to a substitution reaction with N-bromosuccinimide to obtain compound 2; Compound 1.

7. A dihydropyrimidine derivative, comprising one or more of the pharmaceutically acceptable salts, hydrates, organic solvates, isomers and crystalline compounds of the dihydropyrimidine compound according to claim 1 or 2.

8. A pharmaceutical composition, characterized in that The invention comprises an active component and a pharmaceutically acceptable excipient, wherein the active component comprises at least one of the dihydropyrimidine compound according to claim 1 or 2 and the dihydropyrimidine derivative according to claim 7.

9. Use of the dihydropyrimidine compound according to claim 1 or 2, the dihydropyrimidine derivative according to claim 7 or the pharmaceutical composition according to claim 8 in the preparation of an antiviral infection drug.

10. The use according to claim 9, characterized in that: The viruses include hepatitis B virus.

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