A 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound and its preparation method and application

Abstract

The present invention provides a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound and a preparation method and application thereof, which is a compound represented by formula I or a pharmaceutically acceptable salt thereof or an optical isomer thereof or an isotope-substituted form thereof, and the compound can effectively inhibit SARS-CoV-2 3CL pro activity, and can be used to prepare SARS-CoV-2 3CL pro Inhibitors block the replication and transcription of SARS-CoV-2 virus in patients. The compounds prepared by the present invention have good in vitro safety and are useful in the preparation of SARS-CoV-2 3CL pro Inhibitors have very good application prospects in drugs against SARS-CoV-2.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound for inhibiting the activity of coronavirus 3CL protease, and a preparation method and application thereof. Background Art

[0002] The ongoing COVID-19 (Corona Virus Disease 2019) pandemic has created a worrying situation, causing a large number of deaths and economic losses, and posing a huge threat to global health security. So far, its mutant strains such as Delta and Omicron are constantly emerging and have stronger transmission capabilities, but no specific drugs have been developed for SARS-CoV-2. Therefore, humans need a drug that can effectively inhibit the new coronavirus. Summary of the invention

[0003] In order to overcome the shortcomings of the above-mentioned prior art, the purpose of the present invention is to provide a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound and a preparation method and application thereof. The compound can effectively inhibit the new coronavirus and can be used as a drug for treating diseases caused by the coronavirus.

[0004] In order to achieve the above object, the present invention adopts the following technical solutions:

[0005] The present invention provides a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound for inhibiting the activity of coronavirus 3CL protease, which is a compound represented by formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer, tautomer or a mixture thereof in any proportion, including a racemic mixture, of the compound represented by formula I or a pharmaceutically acceptable salt thereof;

[0006] The structural formula of the compound of formula I is:

[0007]

[0008] wherein R1, R2, R3 and R4 are each independently selected from a hydrogen atom, a methyl group, a tert-butyl group, a methoxy group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a halogen atom, a phenyl group and an aromatic heterocyclic group;

[0009] R5 is a hydrogen atom or a halogen atom;

[0010] R6 is a hydrogen atom, or an alkane or cycloalkane having 1 to 4 carbon atoms.

[0011] The term "halogen" denotes fluorine, chlorine, bromine or iodine.

[0012] The pharmaceutically acceptable salt is a salt formed by 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compounds that inhibit the activity of coronavirus 3CL protease and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.

[0013] The representative structural formula of the compound of formula I of the present invention is shown below:

[0014]

[0015] The preparation method of the 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound for inhibiting coronavirus 3CL protease activity provided by the present invention is as follows:

[0016] (1) Using 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione as a raw material, an alkylation reaction is carried out with a benzyl bromide compound to obtain compound a;

[0017]

[0018] The molar ratio of 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione to the benzyl bromide compound is 1:1.1; the solvent used in the synthesis of compound a is acetonitrile, and the reaction is carried out under potassium carbonate and heating reflux conditions; the benzyl bromide compound is:

[0019]

[0020]

[0021] (2) removing the tert-butyl group from the compound a obtained in step (1) to obtain the corresponding compound b, and then reacting with bromoacetonitrile to obtain the corresponding compound c;

[0022]

[0023] The solvent used in the synthesis of compound b is trifluoroacetic acid; the molar ratio of compound b to bromoacetonitrile is 1:1.2; the solvent used in the synthesis of compound c is acetonitrile, and the reaction is carried out under potassium carbonate and heating reflux conditions;

[0024] (3) reacting the compound c obtained in step (2) with compound f to obtain the corresponding compound d;

[0025]

[0026] The molar ratio of compound c to compound f is 1:1.3; the catalyst used in the synthesis of compound d is acetic acid, and the solvent used is tert-butanol;

[0027] (4) reacting the compound d obtained in step (3) with sodium azide to generate a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound of formula I in which R6 is hydrogen and inhibits the activity of coronavirus 3CL protease; the solvent used in the synthesis process is N,N-dimethylformamide, and the catalyst used is zinc chloride;

[0028] Alternatively, the compound d prepared in step (3) is reacted with sodium azide to obtain the corresponding compound e, which is then further reacted with methyl trifluoromethanesulfonate or ethyl trifluoromethanesulfonate to generate a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound having a structure of formula I that inhibits the activity of coronavirus 3CL protease; the solvent used in the synthesis process is 1,4-dioxane, and the catalyst used is bisdibenzylideneacetone palladium, 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-biphenyl and potassium phosphate;

[0029] Alternatively, the compound d obtained in step (3) is reacted with an azidoalkane compound R6-N3 to generate a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound having a structure of formula I that inhibits the activity of coronavirus 3CL protease; the solvent used in the synthesis process is N,N-dimethylformamide, tetrahydrofuran and water, and the catalyst used is copper sulfate pentahydrate and sodium ascorbate.

[0030]

[0031] Among them, the molar ratio of compound d to sodium azide is 1:1.05, the molar ratio of methyl trifluoromethanesulfonate or ethyl trifluoromethanesulfonate to compound e is 1:1.2, and the molar ratio of compound d to azidoalkane compound is 1:1.2.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention provides a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound, which has the function of inhibiting the activity of coronavirus 3CL protease. 3CL protease is an enzyme in coronavirus, and 3CL protease has been proved to be a drug discovery target for SARS, MERS and SARS-CoV-2 coronavirus. 3CL protease (3C-like protease 3CL pro , also known as major protease M pro) is an important non-structural protein in coronavirus, with a cleavage site specificity similar to that of the 3CL protease of microRNA virus, and plays an extremely critical role in the replication and transcription of progeny viruses. 3CL protease is a cysteine ​​protease of about 33kDa composed of 306 amino acids (much smaller than S protein), which can specifically recognize the 11 cleavage sites of the non-structural protein NSP4-NSP16 and cut it, thereby releasing other non-structural proteins of coronavirus. The non-structural protein NSP4-NSP16 released by self-hydrolysis and cleavage of 3CL protease is the carrier of viral genome replication and transcription, responsible for important life processes such as post-translational cleavage, modification of protein, and nucleic acid synthesis. Inhibition of 3CL protease activity can effectively block the process of RNA replication and transcription, thereby blocking the proliferation of the virus. The results of the 3CL protease inhibitory activity test show that the compounds synthesized by the present invention have a strong inhibitory effect on the activity of 3CL protease, and the preferred compounds 1, 12, 15, 16 and 17 have an IC of 2.17 for 3CL protease. 50 The values ​​were all below 200 nM, among which compound 1 had the best inhibitory activity; the results of in vitro cytotoxicity tests showed that the survival rates of HepG2 cells and HEK293 cells treated with compound 1 were higher than those of PF-07321332 and S-217622 at any concentration, and the safety of compound 1 to A549 cells was better than that of PF-07321332 and S-217622 at low concentrations, and it can be used to prepare 3CL pro Inhibitors block the replication of the new coronavirus in patients and can be developed and used as anti-coronavirus drugs.

[0034] The invention provides a method for preparing 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compounds. The synthetic method is simple to operate, has low requirements on reaction equipment, uses readily available raw materials, generates less pollution, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is the H NMR spectrum of compound 1 in deuterated MeOD of the present invention;

[0036] Figure 2 is the NMR carbon spectrum of compound 1 in deuterated MeOD of the present invention;

[0037] Figure 3 is the mass spectrum of compound 1 in the present invention;

[0038] Figure 4 The compound 1 of the present invention is 3CL pro Inhibition of kinase activity;

[0039] Figure 5 Compound 12 of the present invention is 3CLpro Inhibition of kinase activity;

[0040] Figure 6 Compound 17 of the present invention is a pro Inhibition of kinase activity;

[0041] Figure 7 is the survival rate of A549 cells after treatment with different concentrations of PF-07321332, S-217622 and compound 1;

[0042] Figure 8 is the survival rate of HEK2932 cells after treatment with different concentrations of PF-07321332, S-217622 and compound 1;

[0043] Fig. 9 is the survival rate of HepG2 cells after treatment with different concentrations of PF-07321332, S-217622 and compound 1. DETAILED DESCRIPTION

[0044] In order to enable those skilled in the art to better understand the scheme of the present invention, the technical scheme in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0045] It should be noted that the terms "first", "second", etc. in the specification and claims of the present invention and the above-mentioned drawings are used to distinguish similar objects, and are not necessarily used to describe a specific order or sequence. It should be understood that the data used in this way can be interchanged where appropriate, so that the embodiments of the present invention described herein can be implemented in an order other than those illustrated or described herein. In addition, the terms "including" and "having" and any of their variations are intended to cover non-exclusive inclusions, for example, the process, method, system, product or equipment comprising a series of steps or units is not necessarily limited to those steps or units clearly listed, but may include other steps or units that are not clearly listed or inherent to these processes, methods, products or equipment. The examples of the synthesis of the above-mentioned compounds 1-24 are given below.

[0046] Example 1

[0047] Compound 1: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0048] (1) Preparation of compound a1

[0049]

[0050] 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione (229.4 mg, 1.0 mmol), 2,4,5-trifluorobenzyl bromide (247.5 mg, 1.1 mmol) and potassium carbonate (165.8 mg, 1.2 mmol) were placed in a reactor, dissolved in 20 mL of acetonitrile, heated to reflux, stirred for 3 hours, and monitored by TLC. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained solid residue was washed with a saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected and purified by column chromatography (petroleum ether: ethyl acetate (V: V) as the mobile phase = 3: 1), and dried to obtain compound a1337.8 mg with a yield of 89.82%.

[0051] (2) Preparation of compound c1

[0052]

[0053] Step 1: Synthesis of compound b1

[0054] The obtained compound a1 (373.4 mg, 1 mmol) was placed in a reactor, 5 mL of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature overnight. The mixture was then azeotropically concentrated with toluene under reduced pressure to remove the solvent, and dried to obtain 294.8 mg of compound b1 with a yield of 92.91%.

[0055] Step 2: Synthesis of compound c1

[0056] Compound b1 (317.3 mg, 1 mmol), bromoacetonitrile (85 μL, 1.2 mmol) and potassium carbonate (165.9 mg, 1.2 mmol) were placed in a reactor, dissolved with 10 mL of acetonitrile, heated to reflux, stirred for 5 hours, and monitored by TLC. After the reaction, the resulting reaction solution was washed with a saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was collected and purified by column chromatography (petroleum ether: ethyl acetate (V: V) = 1:1 as the mobile phase), and dried to obtain compound c1280.4 mg with a yield of 78.69%.

[0057] (3) Preparation of compound d1

[0058]

[0059] Compound c1 (178.2 mg, 0.5 mmol), 6-chloro-2-methyl-2H-indazole-5-amine (118.1 mg, 0.65 mmol) and acetic acid (570 μL, 10 mmol) were placed in a reactor, dissolved in 5 mL of tert-butyl alcohol, stirred at 100°C for 4 hours, and monitored by TLC. After the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated under reduced pressure, separated and purified by column chromatography (cyclohexane: ethyl acetate (V: V) = 10: 1 as the mobile phase), and dried to obtain compound d1120.6 mg with a yield of 50.69%.

[0060] (4) Preparation of Compound 1

[0061]

[0062] Compound d1 (951.6 mg, 2 mmol), sodium azide (136.5 mg, 2.1 mmol) and zinc chloride (299.8 mg, 2.2 mmol) were placed in a reactor, dissolved in 20 mL of N,N-dimethylformamide, heated to 95 ° C under N2 protection, stirred and reacted overnight, and monitored by TLC. After the reaction was completed, it was cooled to room temperature, and 20 mL of 2M HCl solution was added to the reaction solution to precipitate a solid, which was filtered and dried to obtain compound 1361.12 mg with a yield of 34.80%. The H NMR spectrum of compound 1 in deuterated MeOD is shown in Figure 1 As shown, the NMR carbon spectrum in deuterated MeOD is as follows Figure 2 As shown in the mass spectrum Figure 3 shown.

[0063] 1 H NMR (600MHz, MeOD) δ8.16(s,1H),8.02(s,1H),7.73(s,1H),7.60-7.49(m,1H),7.26-7.12(m,1H),5.42-5.36(m,4H),4.21(s,3H).

[0064] 13 C NMR(151MHz,MeOD)δ171.19,163.46,156.48,153.88,149.98,148.60,148.41,128.39,127. 88,125.60,120.48,117.67,117.23,116.62,116.21,105.10,104.95,48.19,39.06,38.25.

[0065] MS calcd for C 20 H 14 ClF3N 10O2,[M+H] + :519; found:519.

[0066] MS calcd for C 20 H 14 ClF3N 10 O2,[M+Na] + :541; found:541.

[0067] Example 2

[0068] Compound 2: Preparation of (E)-3-((1H-tetrazol-5-yl)methyl)-1-benzyl-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-1,3,5-triazinane-2,4-dione

[0069]

[0070] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 2 is 30.54%.

[0071] 1 H NMR (600MHz, MeOD) δ9.28(s,1H),8.72(s,1H),8.03(s,1H),7.76-7.52(m,1H),7.39-7.18(m,1H),7.03(s,3H),5.75-5.53(m,4H),4.12(s,3H).

[0072] 13 C NMR(151MHz,MeOD)δ169.42,161.53,155.73,153.88,149.58,141.36,139.75,129. 12,125.94,118.19,115.47,113.45,112.53,103.02,101.87,47.17,38.56,37.78.

[0073] MS calcd for C 20 H 17 C1N 10 O2,[M+H] + :465; found:465.

[0074] Example 3

[0075] Compound 3: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-methylbenzyl)-1,3,5-triazine-2,4-dione

[0076]

[0077] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 3 is 35.23%.

[0078] 1 H NMR(600MHz,MeOD)δ9.34(s,1H),8.56(s,1H),7.92(s,1H),7.62(m,1H),7. 47-7.22(m,1H),6.98(s,2H),5.63-5.39(m,4H),4.78(s,3H),2.12(s,3H).

[0079] 13 C NMR(151MHz,MeOD)δ168.13,163.86,153.77,150.86,147.67,144.57,138.67,135 .67,123.67,113.17,111.67,109.46,105.84,101.56,47.67,38.23,35.13,21.34.

[0080] MS calcd for C 21 H 19 C1N 10 O2,[M+H] + :479; found:479.

[0081] Example 4

[0082] Compound 4: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-1-(4-(tert-butyl)benzyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1,3,5-triazine-2,4-dione

[0083]

[0084] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 4 is 36.35%.

[0085] 1 H NMR (600MHz, MeOD) δ9.43(s,1H),8.27(s,1H),7.76(s,1H),7.27-7.09(m,2H),7.02(m,2H),5.41-5.33(m,4H),4.32(s,3H),1.32(s,9H).

[0086] 13 C NMR(151MHz,MeOD)δ168.25,161.95,152.36,150.64,144.38,143.51,138.86,134.92,124 .57,121.03,117.51,113.16,110.87,107.32,105.54,101.75,46.53,38.71,35.20,21.26.

[0087] MS calcd for C 24 H 25 C1N 10 O2,[M+H] + :521; found:521.

[0088] Example 5

[0089] Compound 5: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-chlorobenzyl)-1,3,5-triazine-2,4-dione

[0090]

[0091] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 5 is 39.82%.

[0092] 1 H NMR (600MHz, MeOD) δ9.25(s,1H),8.35(s,1H),7.86(s,1H),7.31-7.11(m,2H),6.92(m,2H),5.42-5.29(m,4H),4.20(s,3H).

[0093] 13 C NMR(151MHz,MeOD)δ167.36,160.81,151.33,150.64,144.48,142.41,137.87,133. 39,125.56,118.42,113.21,110.67,106.93,105.66,100.75,46.51,42.20,41.71.

[0094] MS calcd for C 20 H 16 Cl2N 10 O2,[M+H] + :499; found:499.

[0095] Example 6

[0096] Compound 6: Preparation of (E)-3-((1H-tetrazol-5-yl)methyl)-1-(4-bromophenyl)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-1,3,5-triazine-2,4-dione

[0097]

[0098] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 6 is 41.23%.

[0099] 1 H NMR (600MHz, MeOD) δ9.31(s,1H),8.37(s,1H),7.85(s,1H),7.28-7.08(m,2H),6.89(m,2H),5.52-5.39(m,4H),4.41(s,3H).

[0100] 13 C NMR(151MHz,MeOD)δ168.37,161.28,150.56,149.26,143.47,141.96,137.78,133. 41,124.85,117.81,114.01,110.97,106.36,105.68,100.52,46.17,42.53,40.85.

[0101] MS calcd for C 20 H 16 BrClN 10 O2,[M+H] + :543; found:543.

[0102] Example 7

[0103] Compound 7: Preparation of (E)-3-((1H-tetrazol-5-yl)methyl)-1-([1,1-biphenyl]-4-ylmethyl)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-1,3,5-triazine-2,4-dione

[0104]

[0105] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 7 is 32.51%.

[0106] 1H NMR (600MHz, MeOD) δ9.29(s,1H),8.42(s,1H),7.69(s,1H),7.60-7.44(m,5H),7.29-7.01(m,2H),6.85(m,2H),5.68-5.33(m,4H),4.20(s,3H).

[0107] 13 C NMR(151MHz,MeOD)δ167.41,161.27,149.56,148.23,144.36,141.99,141.36,138.75,132.81,129. 31,127.62,127.28,123.95,116.81,113.03,110.85,106.76,105.87,100.44,46.27,42.45,40.70.

[0108] MS calcd for C 26 H 21 C1N 10 O2,[M+H] + :541; found:541.

[0109] Example 8

[0110] Compound 8: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-(trifluoromethyl)benzyl)-1,3,5-triazine-2,4-dione

[0111]

[0112] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 8 is 33.54%.

[0113] 1 H NMR (600MHz, MeOD) δ9.23(s,1H),8.38(s,1H),7.86(s,1H),7.22-7.01(m,2H),6.84(m,2H),5.51-5.37(m,4H),4.31(s,3H).

[0114] 13C NMR(151MHz,MeOD)δ167.38,162.27,151.54,148.25,143.52,141.85,137.76,133.33, 124.75,124.11,117.88,114.00,110.94,106.35,105.53,100.58,46.26,42.48,40.76.

[0115] MS calcd for C 21 H 16 ClF3N 10 O2,[M+H] + :533; found:533.

[0116] Example 9

[0117] Compound 9: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-nitrobenzyl)-1,3,5-triazine-2,4-dione

[0118]

[0119] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 9 is 29.68%.

[0120] 1 H NMR (600MHz, MeOD) δ9.55(s,1H),8.57(s,1H),7.94(s,1H),7.39-7.11(m,2H),6.85(m,2H),5.48-5.34(m,4H),4.37(s,3H).

[0121] 13 C NMR(151MHz,MeOD)δ168.38,161.22,150.45,149.15,143.38,141.88,137.99,133. 25,124.84,117.83,113.97,110.95,106.56,105.65,100.58,46.58,42.42,40.77.

[0122] MS calcd for C 20 H 16 C1N 11 O4,[M+H] + :510; found:510.

[0123] Example 10

[0124] Compound 10: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-methoxybenzyl)-1,3,5-triazine-2,4-dione

[0125]

[0126] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 10 is 43.56%.

[0127] 1 H NMR (600MHz, MeOD) δ9.44(s,1H),8.43(s,1H),7.68(s,1H),7.24-7.02(m,2H),6.48(m,2H),5.61-5.40(m,4H),4.13(s,3H),3.40(s,3H).

[0128] 13 C NMR(151MHz,MeOD)δ168.38,163.72,151.45,148.52,143.51,141.84,137.69,133.25, 124.73,117.74,114.02,110.95,106.45,105.61,100.63,50.52,46.63,42.51,40.81.

[0129] MS calcd for C 21 H 19 C1N 10 O3,[M+H] + :495; found:495.

[0130] Embodiment 11

[0131] Compound 11: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-(trifluoromethoxy)benzyl)-1,3,5-triazine-2,4-dione

[0132]

[0133] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 11 is 39.27%.

[0134] 1H NMR (600MHz, MeOD) δ9.39(s,1H),8.41(s,1H),7.69(s,1H),7.53-7.21(m,2H),6.50(m,2H),5.57-5.39(m,4H),4.22(s,3H).

[0135] 13 C NMR(151MHz,MeOD)δ168.65,163.75,151.43,148.51,143.42,141.52,137.66,132.97, 128.92,124.53,117.46,114.00,110.51,106.45,105.16,100.36,46.52,42.26,40.53.

[0136] MS calcd for C 21 H 16 ClF3N 10 O3,[M+H] + :549; found:549.

[0137] Implementation 12

[0138] Compound 12: Preparation of E-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-fluorobenzyl)-1,3,5-triazine-2,4-dione

[0139]

[0140] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 12 is 34.40%.

[0141] 1 H NMR (600MHz, MeOD) δ9.53(s,1H),8.54(s,1H),7.91(s,1H),7.38-7.10(m,2H),6.77(m,2H),5.45-5.31(m,4H),4.32(s,3H).

[0142] 13 C NMR(151MHz,MeOD)δ169.37,162.35,151.55,149.37,142.97,141.86,137.91,133. 22,123.72,116.62,113.81,110.85,106.46,105.57,100.26,46.43,42.13,40.86.

[0143] MS calcd for C 20 H 16 CIF 10 O2,[M+H] + :483; found:483.

[0144] Embodiment 13

[0145] Compound 13: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(3,5-dimethylbenzyl)-1,3,5-triazine-2,4-dione

[0146]

[0147] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 13 is 36.44%.

[0148] 1 H NMR (600MHz, MeOD) δ9.51(s,1H),8.50(s,1H),7.85(s,1H),7.39-7.12(m,3H),5.42-5.30(m,4H),4.21(s,3H),2.09(s,6H).

[0149] 13 C NMR(151MHz,MeOD)δ170.41,162.42,151.38,149.25,143.02,141.54,137.93,133.23, 123.77,116.28,113.65,110.88,106.35,105.82,100.24,46.50,42.19,40.84,21.90.

[0150] MS calcd for C 22 H 21 C1N 10 O2,[M+H] + :493; found:493.

[0151] Embodiment 14

[0152] Compound 14: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(3,5-dimethoxybenzyl)-1,3,5-triazine-2,4-dione

[0153]

[0154] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 14 is 42.49%.

[0155] 1 H NMR (600MHz, MeOD) δ9.48(s,1H),8.34(s,1H),7.76(s,1H),7.41-7.23(m,3H),5.41-5.31(m,4H),4.13(s,3H),3.82(s,6H).

[0156] 13 C NMR(151MHz,MeOD)δ171.53,161.73,161.44,155.87,153.85,149.63,141.12,139.63, 128.19,118.47,115.54,113.53,112.02,103.78,101.08,55.71,47.65,38.98,37.87.

[0157] MS calcd for C 22 H 21 C1N 10 O4,[M+H] + :525; found:525.

[0158] Embodiment 15

[0159] Compound 15: Preparation of (E)-3-(1H-tetrazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(3,5-difluorobenzyl)-1,3,5-triazine-2,4-dione

[0160]

[0161] The preparation method is similar to that of Example 1, except that the corresponding raw materials are replaced. The yield of the obtained compound 15 is 42.68%.

[0162] 1 H NMR (600MHz, MeOD) δ9.58(s,1H),8.21(s,1H),7.68(s,1H),7.42–7.19(m,3H),5.29–5.18(m,4H),4.12(s,3H).

[0163] 13C NMR(151MHz,MeOD)δ172.51,162.17,161.43,155.56,152.87,149.23,141.79,138. 56,127.18,114.54,112.23,112.01,102.97,100.171,55.47,47.89,38.15,37.42.

[0164] MS calcd for C 20 H 15 ClF2N 10 O2,[M+H] + :501; found:501.

[0165] Example 16

[0166] Compound 16: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-methyl-1H-tetrazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0167] (1) Preparation of compound a16

[0168] The preparation method is the same as Example 1.

[0169] (2) Preparation of compound c16

[0170] The preparation method is the same as Example 1.

[0171] (3) Preparation of compound d16

[0172] The preparation method is the same as Example 1.

[0173] (4) Preparation of compound e16

[0174] The preparation method is the same as Example 1.

[0175] (5) Preparation of Compound 16

[0176]

[0177] In a glove box, bis(dibenzylideneacetone palladium) (6.9 mg, 0.012 mmol), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-biphenyl (8.7 mg, 0.018 mmol), potassium phosphate (95.5 mg, 0.45 mmol) were placed in a reactor and dissolved in 1.5 mL of 1,4-dioxane. Take out from the glove box, stir and heat at 120°C for 5 min, then cool to room temperature, transfer to the glove box, add methyl trifluoromethanesulfonate (49.2 mg, 0.3 mmol) and compound e16 (186.8 mg, 0.36 mmol) to the reactor, and then stir and react at 70°C for 24 h. After the reaction, the reaction solution was diluted with dichloromethane solution, extracted, and the organic phase was concentrated under reduced pressure. The product was separated and purified by column chromatography (dichloromethane:methanol (V:V) = 12:1 as the mobile phase) and dried to obtain 1663.62 mg of the compound with a yield of 39.80%.

[0178] 1 H NMR (600MHz, MeOD) δ8.17(s,1H),8.01(s,1H),7.72(s,1H),7.61–7.44(m,1H),7.25–7.01(s,1H),5.41–5.32(m,4H),4.19(s,3H),3.75(s,3H).

[0179] 13 C NMR(151MHz,MeOD)δ172.46,163.23,156.46,153.62,149.10,148.55,148.34,128.88,127.52, 125.64,120.82,117.32,117.13,116.25,116.01,105.12,104.15,48.18,39.08,38.21,33.83.

[0180] MS calcd for C 21 H 16 ClF3N 10 O2,[M+H] + :533; found:533.

[0181] Embodiment 17

[0182] Compound 17: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-1, tetrazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0183]

[0184] The preparation method is similar to that of Example 16, except that the corresponding raw materials are replaced. The yield of the obtained compound 17 is 31.25%.

[0185] 1 H NMR(600MHz,MeOD)δ8.70(s,1H),8.21(s,1H),7.97(s,1H),7.55-7.34(m,1H) ,7.21-7.04(s,1H),5.45-5.22(m,4H),4.09(s,3H),3.87(s,2H),1.54(s,3H).

[0186] 13 C NMR(151MHz,MeOD)δ171.42,163.82,156.31,153.10,149.12,148.15,148.38,128.25,127.46,125 .62,120.87,117.72,117.15,116.08,115.89,105.11,104.25,48.39,39.17,38.25,33.86,15.07.

[0187] MS calcd for C 22 H 18 ClF3N 10 O2,[M+H] + :547; found:547.

[0188] Embodiment 18

[0189] Compound 18: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-tetrazol-5-yl)methyl)-1-(4-(trifluoromethyl)benzyl)-1,3,5-triazine-2,4-dione

[0190]

[0191] The preparation method is similar to that of Example 16, except that the corresponding raw materials are replaced. The yield of the obtained compound 18 is 33.85%.

[0192] 1H NMR(600MHz,MeOD)δ9.34(s,1H),8.37(s,1H),7.85(s,1H),7.25-7.11(m,2 H),6.74(m,2H),5.73-5.57(m,4H),4.30(s,3H),3.95(s,2H),1.54(s,3H).

[0193] 13 C NMR(151MHz,MeOD)δ165.27,162.26,151.95,148.54,143.22,141.25,137.85,133.63,124.11 ,124.02,117.87,114.05,110.91,106.33,105.73,100.57,46.22,42.87,42.24,40.09,15.08.

[0194] MS calcd for C 23 H 20 ClF3N 10 O2,[M+H] + :561; found:561.

[0195] Embodiment 19

[0196] Compound 19: Preparation of (E)-6-(2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-tetrazol-5-yl)methyl)-1-(4-nitrobenzyl)-1,3,5-triazine-2,4-dione

[0197]

[0198] The preparation method is similar to that of Example 16, except that the corresponding raw materials are replaced. The yield of the obtained compound 19 is 34.70%.

[0199] 1 H NMR(600MHz,MeOD)δ9.74(s,1H),8.45(s,1H),7.74(s,1H),7.31-7.08(m,2 H),6.44(m,2H),5.81-5.56(m,4H),4.31(s,3H),3.94(s,2H),1.53(s,3H).

[0200] 13C NMR(151MHz,MeOD)δ168.87,161.21,152.25,148.58,143.62,141.26,137.36,133.15,124 .17,124.01,117.88,113.14,109.87,105.32,104.72,100.86,46.12,42.77,40.18,14.97.

[0201] MS calcd for C 22 H 21 N 11 O4,[M+H] + :504; found:504.

[0202] Embodiment 20

[0203] Compound 20: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-tetrazol-5-yl)methyl)-1-(4-chlorobenzyl)-1,3,5-triazine-2,4-dione

[0204]

[0205] The preparation method is similar to that of Example 16, except that the corresponding raw materials are replaced. The yield of the obtained compound 20 is 37.30%.

[0206] 1 H NMR(600MHz,MeOD)δ9.85(s,1H),8.71(s,1H),7.64(s,1H),7.40-7.12(m,2 H),6.53(m,2H),5.32-5.02(m,4H),4.11(s,3H),3.84(s,2H),1.49(s,3H).

[0207] 13 C NMR(151MHz,MeOD)δ168.21,161.52,152.85,148.34,143.14,141.36,137.35,133.42,124 .84,124.21,117.41,112.87,109.14,105.27,104.64,100.12,46.02,42.67,40.98,15.97.

[0208] MS calcd for C 22 H 20 Cl2N 10 O2,[M+H] +:528; found:528.

[0209] Embodiment 21

[0210] Compound 21: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-cyclopropyl-1H-tetrazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0211] (1) Preparation of compound a21

[0212] The preparation method is the same as Example 1.

[0213] (2) Preparation of compound c21

[0214] The preparation method is the same as Example 1.

[0215] (3) Preparation of compound d21

[0216] The preparation method is the same as Example 1.

[0217] (4) Preparation of Compound 21

[0218]

[0219] Sodium azide (598.1 mg, 9.2 mmol) and bromocyclopropane (240 μL, 3 mmol) were placed in a reactor, dissolved in 5 mL of dry DMF, stirred at 60° C. overnight, and monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with brine and tetrahydrofuran, the tetrahydrofuran layer was collected, and then washed and dried with 5% lithium chloride solution and MgSO4 to obtain cyclopropane azide.

[0220] Compound d21 (142.7 mg, 0.3 mmol), cyclopropane azide (29.9 mg, 0.36 mmol), copper sulfate pentahydrate (30.0 mg, 0.12 mmol), sodium ascorbate (23.8 mg, 0.12 mmol) were placed in a reactor, dissolved in a mixed solution of 10 mL tetrahydrofuran and 1 mL water, protected by argon, heated and stirred at 45°C overnight, and monitored by TLC. After the reaction was completed, the resulting reaction solution was concentrated under reduced pressure to remove the solvent, separated and purified by column chromatography (dichloromethane: methanol (V: V) = 12: 1 as the mobile phase), and dried to obtain 35.2 mg of compound 21 with a yield of 21.03%.

[0221] 1H NMR(600MHz,MeOD)δ8.26(s,1H),8.12(s,1H),7.78(s,1H),7.59–7.38(m,1H),7. 31–7.08(m,1H),5.41–5.30(m,4H),4.10(s,3H),2.35(s,1H),1.28-0.90(m,4H).

[0222] 13 C NMR(151MHz,MeOD)δ178.49,164.71,156.16,153.26,149.50,148.59,147.92,128.99,127.78,12 5.54,120.34,117.51,116.93,116.26,116.01,105.50,104.45,48.06,39.57,38.23,28.57,2.15.

[0223] MS calcd for C 23 H 18 ClF3N 10 O2,[M+H] + :559; found:559.

[0224] Embodiment 22

[0225] Compound 22: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-isopropyl-1H-tetrazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0226]

[0227] The preparation method is similar to that of Example 21, except that the corresponding raw materials are replaced. The yield of the obtained compound 22 is 32.31%.

[0228] 1 H NMR(600MHz,MeOD)δ8.16(s,1H),8.02(s,1H),7.73(s,1H),7.60-7.49(m,1H) ,7.26-7.12(m,1H),5.42–5.36(m,4H),4.21(s,3H),3.91(s,1H),1.62(s,6H).

[0229] 13C NMR(151MHz,MeOD)δ173.62,164.51,157.52,152.47,148.97,148.50,148.21,128.47,127.24,125 .74,120.42,117.65,117.28,116.61,116.24,105.43,104.82,55.17,48.28,39.07,38.47,22.50.

[0230] MS calcd for C 23 H 20 ClF3N 10 O2,[M+H] + :561; found:561.

[0231] Embodiment 23

[0232] Compound 23: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-cyclobutyl-1H-tetrazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0233]

[0234] The preparation method is similar to that of Example 21, except that the corresponding raw materials are replaced. The yield of the obtained compound 23 is 37.56%.

[0235] 1 H NMR(600MHz,MeOD)δ8.28(s,1H),8.07(s,1H),7.86(s,1H),7.71-7.34(m,1H),7. 31-7.15(m,1H),5.41-5.32(m,4H),4.18(s,3H),4.01(s,1H),2.31-1.69(m,6H).

[0236] 13 C NMR(151MHz,MeOD)δ175.62,165.53,156.47,151.05,148.87,147.51,147.02,129.92,128.31,124.32 ,120.65,118.28,117.61,116.24,115.43,105.82,104.17,55.82,48.70,39.47,38.05,27.18,14.25.

[0237] MS calcd for C 24 H20 ClF3N 10 O2,[M+H] + :573; found:573.

[0238] Embodiment 24

[0239] Compound 24: Preparation of (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-isobutyl-1H-tetrazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0240]

[0241] The preparation method is similar to that of Example 21, except that the corresponding raw materials are replaced. The yield of the obtained compound 24 is 39.22%.

[0242] 1 H NMR(600MHz,MeOD)δ8.51(s,1H),8.13(s,1H),7.84(s,1H),7.59-7.31(m,1H),7.25- 7.09(m,1H),5.51-5.25(m,4H),4.19(s,3H),3.57(s,1H),2.01(s,2H),0.92(s,6H).

[0243] 13 C NMR(151MHz,MeOD)δ174.63,163.23,156.26,153.98,149.06,148.93,148.14,128.27,127.56,125.19 ,120.39,118.23,117.94,116.61,115.91,105.15,104.90,51.41,48.18,39.05,38.24,28.42,18.06.

[0244] MS calcd for C 24 H 22 ClF3N 10 O2,[M+H] + :575; found:575.

[0245] 2. Bioactivity Assay

[0246] (1) 3CL pro Inhibitory activity test

[0247] Fluorescence resonance energy transfer was used to determine the activity of compounds against SARS-CoV-2 3CL proof the inhibitory activity.

[0248] Weigh an appropriate amount of the above compounds, prepare a solution with an appropriate concentration gradient using DMSO, and mix 5 μL of the prepared solution with 91 μL of Assay Reagent (Assay Buffer: 2019-nCoV3CL pro =90:1, purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) were added to a black 96-well plate in sequence, mixed, and incubated at 37°C in the dark for 10 minutes. Then, 4 μL of Substrate (100 μM Dabcyl-KTSAVLQSGFRKME-Edans, purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was quickly added to each well and mixed. After incubation at 37°C in the dark for 5 minutes, the signal became stable. Within 5-30 minutes, a multifunctional microplate reader (Thermo Fisher Scientific, Varioskan Flash) was used to measure the fluorescence and calculate the inhibition percentage of the sample. The excitation wavelength was 340 nm and the emission wavelength was 490 nm. The Assay Reagent without the compound was used as the 100% enzyme activity control, and the SARS-CoV-23CL was not included. pro Assay Buffer was used as a blank control, S-216722 (Shandong Xuanshuo Pharmaceutical Technology Co., Ltd.) and PF-07321332 (Jinan Jianfeng Chemical Co., Ltd.) were used as positive controls, and the rest of the treatment methods were the same. GraphPad Prism software was used to perform nonlinear regression analysis and calculate the IC values ​​of the samples (compounds 1-24 synthesized in the present invention). 50 value.

[0249]

[0250] The experimental results are shown in Tables 1 and 2 (In Table 1, IC 50 Column, A:IC 50 <200nM, B:IC 50 =200-500nM, C:IC 50 =500-1000nM, D:IC 50 >1000nM), the example compounds have an effect on 3CL pro All of them showed inhibitory activity, among which compounds 1, 12, 15, 16 and 17 had an inhibitory effect on 3CL pro The inhibitory effect was strong, IC 50 The values ​​were all below 200 nM.

[0251] Table 1 Effects of Compounds 1-24 on 3CL pro The inhibitory activity

[0252]

[0253]

[0254] Table 2 Effects of Compounds 1, 12, 17, S-217622 and PF-07321332 on 3CL pro Inhibition rate of kinase activity

[0255]

[0256] The data in Table 1-2 show that compounds 1-24 have an pro The activity of the compounds all had different degrees of inhibitory effect. At the same time, the data in Table 1 showed that the introduction of halogen atoms into the benzene ring could improve the kinase inhibitory activity of the compounds, and the direct introduction of F atoms into the benzene ring could significantly improve the activity of the compounds, while the introduction of phenyl groups into the benzene ring would weaken the activity of the compounds.

[0257] Compounds 1, 12, 15, 16 and 17 have an effect on 3CL pro IC 50 The values ​​were all less than 200 nM, indicating that the 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compounds of the present invention have an inhibitory effect on coronavirus 3CL pro Has inhibitory activity. Figure 4-6 The three compounds with the best inhibitory activity, 1, 12 and 17, were shown to inhibit 3CL pro The inhibitory effect of compound 1 was better than that of compounds 12 and 17, and it can be developed and applied as an anti-coronavirus drug.

[0258] (2) Compound cytotoxicity test

[0259] The MTT method was used to evaluate the in vitro cytotoxicity of compounds 1, 12, and 17. HepG2, HEK293, and A549 cells in the logarithmic growth phase were obtained and digested with trypsin to prepare cell suspensions. The cell density was adjusted to 5×10 4 / mL, 180μL per well was inoculated into a sterile 96-well cell culture plate, and cultured in a 37°C, 5% CO2 constant temperature incubator for 24 hours. After the cells are attached to the bottom of the well plate, 20μL of the drug solution with a concentration gradient is added to each well, and 6 replicate wells are set up in parallel. A zero adjustment group (without cells and drug group) and a control group (without drug group) are also set up. After incubating in a 37°C, 5% CO2 constant temperature incubator for 24 hours, 20μL of 5g / LMTT solution is added to each well and culture is continued for 4 hours. After the culture is completed, the culture solution in the well is gently aspirated, 100μL of DMSO is added to each well, and the well is placed on a shaker for low-speed shaking for 10 minutes to fully dissolve the crystals. The absorbance value (OD 490nm ), and the cell survival rate was calculated. The results are shown in Tables 3-5 and Figure 7-Figure 9 .

[0260]

[0261] Table 3 Survival rate of A549 cells after treatment with different concentrations of tested drugs

[0262]

[0263] Table 4 Survival rate of HEK293 cells after treatment with different concentrations of tested drugs

[0264]

[0265] Table 5 Survival rate of HepG2 cells after treatment with different concentrations of tested drugs

[0266]

[0267]

[0268] Tables 3-5 show the survival rates of A549 cells, HEK293 cells and HepG2 cells at different concentrations of PF-07321332, S-217622, ​​representative compounds 1, 12 and 17. Figure 7-Figure 9 It can be seen that the safety of compound 1 on HepG2 cells and HEK293 cells is better than PF-07321332 and S-217622 at any concentration, and the safety on A549 cells is better than PF-07321332 and S-217622 at low concentrations. The survival rates of the three tested cells treated with compound 12 and compound 17 at concentrations of 400nM and 200nM were slightly lower than those of PF-07321332 and S-217622, ​​but at concentrations of 12.5nM and lower, the survival rates of HEK293 and HepG2 cells were higher than those of PF-07321332 and S-217622, ​​but lower than those of compound 1. Based on the above data, compound 1 has good inhibitory activity and safety against 3CL proteases and can be further studied.

[0269] The above contents are only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound, characterized in that: It is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the structural formula of the compound of formula I is: Among them, R1, R3 and R4 are F atoms, R2 is a hydrogen atom; R5 is a chlorine atom; and R6 is a hydrogen atom.

2. The 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound according to claim 1, characterized in that: The pharmaceutically acceptable salt of the compound of formula I is a salt formed by the compound of formula I and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.

3. A method for preparing a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound according to any one of claims 1 to 2, characterized in that: The following steps are involved: (1) Using 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione as a raw material, an alkylation reaction is carried out with a benzyl bromide compound to obtain compound a; (2) removing the tert-butyl group from compound a to obtain compound b, and then reacting compound b with bromoacetonitrile to obtain compound c; (3) reacting compound c with compound f to obtain compound d; (4) reacting compound d with sodium azide to obtain a compound of formula I; 。 4. The method for preparing 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compounds according to claim 3, characterized in that: Step (1) is specifically as follows: dissolving 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione, a benzyl bromide compound and potassium carbonate in acetonitrile, heating under reflux to react, and obtaining compound a.

5. The method for preparing 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compounds according to claim 3, characterized in that: Step (2) specifically comprises: dissolving compound a in trifluoroacetic acid, stirring, and removing trifluoroacetic acid to obtain compound b; dissolving compound b, bromoacetonitrile and potassium carbonate in acetonitrile, heating under reflux to react, and obtaining compound c; and step (3) specifically comprises: dissolving compound c, compound f and acetic acid in tert-butanol, stirring for reaction, and obtaining compound d.

6. The method for preparing 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compounds according to claim 3, characterized in that: In step (4), compound d is reacted with sodium azide to obtain a compound of formula I, specifically, compound d, sodium azide and zinc chloride are dissolved in N,N-dimethylformamide, and heated to react to obtain a compound of formula I.

7. Use of a 3-tetrazolylmethyl-1,3,5-triazine-2,4-dione compound according to any one of claims 1-2 in the preparation of anti-coronavirus drugs, characterized in that: The coronavirus is the new coronavirus SARS-CoV-2.

8. The use according to claim 7, characterized in that: The dosage form of the medicine is tablet, capsule, granule, syrup, premix, micropill, ointment or injection.

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