3-triazolyl methyl-1,3,5-triazine-2,4-dione compounds, and preparation method and application thereof

Abstract

To provide anti-coronavirus drugs targeting 3CLpro.SOLUTION: Disclosed is a compound of formula I, a pharmaceutically acceptable salt, or a tautomer thereof. (In the formula, R1 to R4 are independently selected from the group consisting of hydrogen, methyl group, tert-butyl group, methoxy group, difluoromethyl, trifluoromethyl, trifluoromethoxy, nitro, halogen, phenyl and aromatic heterocycle; R5 is a hydrogen or halogen; and R6 is hydrogen, C1-4 alkane or C1-4 cycloalkane.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202210618258.2, filed on June 1, 2022, which is incorporated by reference for all purposes as if fully set forth herein.

[0002] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to 3-triazolylmethyl-1,3,5-triazine-2,4-dione compounds, and their preparation methods and applications. [Background technology]

[0003] COVID-19 (novel coronavirus pneumonia) is highly contagious and pathogenic, and its mutant strains, the Delta and Omicron strains, are even more infectious. The constant emergence of new mutant strains has complicated the global epidemic situation. The novel coronavirus poses a serious threat to human health, social stability, and economic development. Summary of the Invention [Problem to be solved by the invention]

[0004] 3CL pro (3C-like protease, major protease M pro 3CL, also known as 3CL, is an important nonstructural protein of coronaviruses, with similar cleavage site specificity to the 3C protease of microRNA viruses, and plays a crucial role in the replication and transcription of progeny viruses. pro 3CL has three domains. Domains I and II are primarily composed of β-sheet structures, while domain III is primarily composed of α-helical structures. The active site is located in the groove formed between domains I and II. Domain III is involved in dimerization. Compared with domain III, domains I and II of different coronaviruses show high sequence conservation, which is consistent with the active site being located in the first two domains. prouses conserved cysteine ​​and histidine as catalytic amino acids to form a catalytic duplex in which cysteine ​​is the nucleophilic attacking group and histidine is the basic group. pro is essential for viral replication and is highly conserved, making it an ideal anti-coronavirus drug target. [Means for solving the problem]

[0005] (Summary of the Invention) In one embodiment, the present application discloses a compound of Formula I, a pharmaceutically acceptable salt thereof, a diastereomer thereof, or a tautomer thereof:

[0006] [ka]

[0007] R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, methyl, tert-butyl, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, nitro, halogen, phenyl, and aromatic heterocycle; R5 is hydrogen or halogen; and R6 is hydrogen, a C1-C4 alkane, or a C1-C4 cycloalkane.

[0008] In another embodiment, the compound is [ka] is selected from the group consisting of:

[0009] In another embodiment, the pharmaceutically acceptable salt comprises one selected from the group consisting of 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, and aspartic acid.

[0010] In another embodiment, the present application discloses an anti-coronavirus pharmaceutical formulation comprising a compound of the present application.

[0011] In another embodiment, the coronavirus is the novel coronavirus SARS-CoV-2.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] 3CL pro The results of the inhibitory activity test showed that the compound of the present invention inhibits 3CL pro It has been shown that it has a strong inhibitory effect. pro IC of Compound 1, Compound 7, Compound 12, Compound 15, Compound 16, Compound 17, Compound 18, Compound 22 and Compound 23 against 50 All of the values ​​were less than 200 nM, and compound 1 had the highest inhibitory activity (IC 50 <100nM); 3CL pro Cytotoxicity tests showed that the inhibitory rates of compound 1 against A549 cells, HepG2 cells, and HEK293 cells were lower than those of PF-07321332 and S-217622 at all concentrations, indicating that it is less toxic than these two positive drugs and can be developed and applied as an anti-coronavirus drug.

[0014] The present invention provides a method for preparing 3-triazolylmethyl-1,3,5-triazine-2,4-dione compounds, which can be carried out under relatively mild conditions with low reactor requirements and low environmental pollution, and at the same time, is atom-efficient and suitable for industrial production. DETAILED DESCRIPTION OF THE INVENTION

[0015] (Detailed explanation) In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, but are not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts fall within the protection scope of the present invention.

[0016] It should be noted that terms such as "first," "second," and the like in the description of the present invention and claims, as well as in the drawings, are used to distinguish between similar items and not necessarily to describe a particular order or sequence. It should be understood that such terms may be interchanged under appropriate circumstances, such that the embodiments of the present invention described herein may be performed in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," as well as any variations thereof, are intended to cover non-exclusive inclusions; for example, a process, method, system, product, or device comprising a series of steps or units is not necessarily limited to those explicitly recited. Rather, those steps or units may include other steps or units not explicitly recited or inherent in those processes, methods, products, or devices.

[0017] The present invention will now be described in more detail in conjunction with the accompanying drawings.

[0018] The present application discloses a compound of Formula I, a pharmaceutically acceptable salt thereof, a diastereomer thereof, or a tautomer thereof.

[0019] [ka]

[0020] R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, methyl, tert-butyl, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, nitro, halogen, phenyl, and aromatic heterocycle; R5 is hydrogen or halogen; and R6 is hydrogen, a C1-C4 alkane, or a C1-C4 cycloalkane.

[0021] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0022] The pharmaceutically acceptable salt may be a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, lemon acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid, or aspartic acid.

[0023] The method for preparing the 3-triazolylmethyl-1,3,5-triazine-2,4-dione compound of the present invention is as follows.

[0024] (1) 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione (starting material) is alkylated with a bromobenzyl compound to obtain compounds a1 to a24.

[0025] [ka]

[0026] The molar ratio of 3-tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione to the bromobenzyl compound is 1:1. The solvent used in the synthesis of compounds a1 to a24 is acetonitrile. The reaction is carried out under reflux using potassium carbonate. The bromobenzyl compound is as follows:

[0027] JPEG2025138626000005.jpg237168JPEG2025138626000006.jpg142168

[0028] (2) The tert-butyl group is removed from Compounds A1 to A24 obtained in Step (1) to obtain the corresponding Compounds B1 to B24, which are then reacted with 3-bromopropyne to obtain the corresponding Compounds C1 to C24.

[0029] The compound of the present invention can be prepared as follows.

[0030] [ka]

[0031] The solvent used in the synthesis process of compounds b1 to b24 is trifluoroacetic acid, the molar ratio of compounds b1 to b24 to 3-bromopropyne is 1:1.2, the solvent used in the synthesis process of compounds c1 to c24 is acetonitrile, and the reaction is carried out with potassium carbonate under heating reflux conditions.

[0032] (3) Compounds c1 to c24 obtained in step (2) are reacted with 6-chloro-2-methyl-2H-indazol-5-amine or 2-methyl-5-amino-2H-indazole to give the corresponding compounds d1 to d24.

[0033] [ka]

[0034] The molar ratio of Compounds c1 to c24 to 6-chloro-2-methyl-2H-indazole-5-amine or 2-methyl-5-amino-2H-indazole is 1:1.3. The catalyst used in the process for preparing Compounds c1 to c24 is acetic acid, and the solvent used is tert-butanol.

[0035] (4) Reacting the compounds d1 to d15 obtained in step (3) with azidotrimethylsilane to obtain 3-triazolylmethyl-1,3,5-triazine-2,4-diones 1 to 15 (in Formula I, R6 is H); or Compounds d16-d20 prepared in step (3) are reacted with azidotrimethylsilane to give the corresponding compounds e16-e20, which are further reacted with methyl trifluoromethanesulfonate or ethyl trifluoromethanesulfonate to give 3-triazolylmethyl-1,3,5-triazine-2,4-diones 16-20 (in Formula I, R6 is a C1-C2 alkane); or Compounds d21 to d24 obtained in step (3) are reacted with an azidoalkane compound to give 3-triazolylmethyl-1,3,5-triazine-2,4-diones 21 to 24 (in formula I, R6 is a C3-C4 alkane or cycloalkane).

[0036] [ka]

[0037] The molar ratio of compounds d1 to d20 to azidotrimethylsilane is 1:1.5, the molar ratio of methyl trifluoromethanesulfonate or ethyl trifluoromethanesulfonate to compounds e16 to e20 is 1:1.2, and the molar ratio of compounds d21 to d24 to azidoalkane compounds is 1:1.2. The solvents used in the synthesis of compounds 1 to 15 are N,N-dimethylformamide and methanol, and the catalyst used is cuprous iodide. The solvent used in the synthesis of compounds 16 to 20 is 1,4-dioxane, and the catalysts used are bis-dibenzylideneacetone palladium, 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-bisphenol, and potassium phosphate. The solvents used in the synthesis of Compounds 21 to 24 are N,N-dimethylformamide, tetrahydrofuran, and water, and the catalysts used are copper sulfate pentahydrate and sodium ascorbate. [Example]

[0038] A synthesis example of the above compound is shown below.

[0039] 1. Preparation of Compounds 1 to 24

[0040] Example 1 Compound 1: Preparation of (E)-3-(1H-1,2,3-triazol-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

[0041] (1) Preparation of compound a1 [ka]

[0042] 3-tert-Butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione (114.7 mg, 0.5 mmol), 2,4,5-triazinefluorobenzyl bromide (112.5 mg, 0.5 mmol), and potassium carbonate (82.9 mg, 0.6 mmol) were placed in a reactor, dissolved in 10 mL of acetonitrile, heated to reflux, stirred for 1 h, and monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting solid residue was washed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic phase was collected, purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 3:1 as the mobile phase), and dried to obtain 168.9 mg of compound a1 (yield 90.47%). 1 The structure of compound a1 was confirmed by 1 H NMR spectrum.

[0043] (2) Preparation of compound c1 [ka]

[0044] Step 1: Synthesis of compound b1 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 solvent was then removed by azeotropic concentration with toluene, and the mixture was dried to obtain 298.6 mg of compound b1 (yield 94.10%).

[0045] Step 2: Synthesis of compound c1 Compound b1 (317.3 mg, 1 mmol), 3-bromopropyne (0.1 mL, 1.2 mmol), and potassium carbonate (165.9 mg, 1.2 mmol) were placed in a reactor, dissolved in 10 mL of acetonitrile, heated to reflux, and stirred. The reaction was carried out for 5 hours and monitored by TLC. After completion of the reaction, the resulting reaction solution was washed with saturated aqueous sodium chloride, extracted with ethyl acetate, and the organic phase was recovered and purified by column chromatography (petroleum ether:ethyl acetate (V:V) = 1:1 as the mobile phase). After drying, 279.9 mg of compound c1 (yield 78.78%) was obtained. 1The structure of compound c1 was confirmed by 1 H NMR spectrum.

[0046] (3) Preparation of compound d1 [ka]

[0047] Compound c1 (177.7 mg, 0.5 mmol), 6-chloro-2-methyl-2H-indazol-5-amine (118.1 mg, 0.65 mmol), and acetic acid (570 μL, 10 mmol) were placed in a reactor, 5 mL of tert-butanol was added, and the reaction mixture was stirred at 100 °C for 4 h and monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (cyclohexane:ethyl acetate (V:V) = 10:1 as the mobile phase) and dried to obtain 125.6 mg of compound d1 (yield 52.90%). 1 The structure of compound d1 was confirmed by 1 H NMR spectrum.

[0048] (4) Preparation of Compound 1 [ka]

[0049] Compound d1 (2.4 g, 5 mmol), azidotrimethylsilane (864.1 mg, 7.5 mmol), and cuprous iodide (47.6 mg, 0.25 mmol) were placed in a reactor along with a mixture of 90 mL of N,N-dimethylformamide and 10 mL of methanol. The reaction mixture was heated and stirred overnight and monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature. The resulting reaction mixture was washed with saturated aqueous sodium chloride, extracted with ethyl acetate, and the organic phase was recovered and purified by column chromatography (dichloromethane:methanol (V:V) = 12:1 as the mobile phase) and dried to obtain 995.3 mg of compound 1 (38.44% yield).

[0050] 1H NMR (600 MHz, DMSO) δ 14.88-4.53 (m, 1H), 10.99 (s, 1H), 8.23 ​​(s, 1H), 7.83-7.50 (m, 4H), 7.12 (s, 1H), 5.23 (d, J = 54.0 Hz, 2H), 4.99 (s, 2H), 4.16 (d, J = 31.9 Hz, 3H).

[0051] 13 C NMR (151 MHz, DMSO) δ 154.87, 153.65, 151.31, 150.18, 148.58, 146.61, 145.89, 139.91, 137.12, 132.97, 127.63, 126.37, 124.56, 122.26, 121.66, 117.32, 111.72, 106.19, 55.38, 37.21, 31.15.

[0052] Example 2 Compound 2: Preparation of (E)-3-((1H-1,2,3-triazol-5-yl)methyl)-1-benzyl-6-((6-chloro-2-methyl-2H-indazol-5)-yl)imino)-1,3,5-triazine-2,4-dione

[0053] [ka]

[0054] Compound 2 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 42.23%).

[0055] 1H NMR (600 MHz, DMSO) δ 14.91-14.49 (m, 1H), 11.02 (s, 1H), 8.84 (s, 2H), 8.05 - 7.92 (m, 2H), 7.86-7.51(m, 4H), 7.10 (s, 1H), 5.25 (d, J = 53.2 Hz, 2H), 5.12 (s, 2H), 4.11 (d, J = 31.6 Hz, 3H).

[0056] 13 C NMR (151 MHz, DMSO) δ 147.66, 146.32, 143.23, 140.09, 138.21, 136.11, 135.78, 129.85, 127.56, 122.56, 122.12, 112.25, 111.12, 107.56, 107.45, 106.01, 105.56, 35.12, 34.07.

[0057] Example 3 Preparation of Compound 3: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-methylbenzyl)-1,3,5-triazine-2,4-dione

[0058] [ka]

[0059] Compound 3 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 42.75%).

[0060] 1 H NMR (600 MHz, DMSO) δ 14.85-14.39 (m, 1H), 10.89 (s, 1H), 8.32 (s, 1H), 8.12-7.83 (m, 2H), 7.66-7.45(m, 4H), 7.05 (s, 1H), 5.11 (d, J = 53.9 Hz, 2H), 4.87 (s, 2H), 4.16 (d, J = 31.2 Hz, 3H), 2.19 (s, 3H).

[0061] 13 C NMR (151 MHz, DMSO) δ 153.97, 153.27, 149.29, 147.32, 146.62, 145.31, 144.72, 136.22, 133.57, 128.43, 125.67, 124.43, 123.76, 122.16, 115.42, 111.75, 107.45, 45.88, 41.11, 21.78.

[0062] Example 4 Preparation of Compound 4: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-1-(4-(tert-butyl)benzyl)-6-(6-chloro-2-methyl)-yl-2H-indazol-5-yl)imino)-1,3,5-triazine-2,4-dione

[0063] [ka]

[0064] Compound 4 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 35.46%).

[0065] 1 H NMR (600 MHz, DMSO) δ 14.63-14.22 (m, 1H), 11.12 (s, 1H), 8.65 (s, 1H), 8.09 - 7.87 (m, 2H), 7.65-7.43(m, 4H), 7.01 (s, 1H), 5.09 (d, J = 53.8 Hz, 2H), 4.86 (s, 2H), 4.06 (d, J = 31.6 Hz, 3H), 1.33 (s, 9H).

[0066] 13C NMR (151 MHz, DMSO) δ 152.56, 147.23, 146.92, 142.45, 139.85, 135.41, 134.02, 133.58, 130.56, 127.45, 126.46, 124.25, 122.26, 119.47, 117.74, 116.85, 116.36, 116.01, 111.72, 40.22, 35.47, 31.32.

[0067] Example 5 Preparation of Compound 5: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-nitrobenzyl)-1,3,5-triazine-2,4-dione

[0068] [ka]

[0069] Compound 5 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 32.10%).

[0070] 1 H NMR (600 MHz, DMSO) δ 14.94-14.53 (m, 1H), 11.06 (s, 1H), 8.78 (s, 1H), 7.95 - 7.83 (m, 2H), 7.53 - 7.21(m, 4H), 7.07 (s, 1H), 5.12 (d, J = 53.2 Hz, 2H), 4.92 (s, 2H), 4.21 (d, J = 31.1 Hz, 3H).

[0071] 13C NMR (151 MHz, DMSO) δ 153.97, 152.85, 151.51, 150.88, 148.78, 147.11, 145.49, 140.41, 138.32, 133.57, 128.17, 125.56, 122.16, 118.52, 114.72, 109.79, 50.18, 39.91, 36.25.

[0072] Example 6 Preparation of Compound 6: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-methoxybenzyl)-1,3,5-triazine-2,4-dione

[0073] [ka]

[0074] Compound 6 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 32.05%).

[0075] 1 H NMR (600 MHz, DMSO) δ 14.74 - 14.32 (m, 1H), 10.89 (s, 1H), 8.44 (s, 1H), 8.03 - 7.62 (m, 2H), 7.32 - 7.13(m, 4H), 6.98 (s, 1H), 5.11 (d, J = 54.3Hz, 2H), 4.76 (s, 2H), 4.23 (d, J = 31.8 Hz, 3H), 3.81 (s,3H).

[0076] 13C NMR (151 MHz, DMSO) δ 155.47, 154.55, 153.71, 152.48, 149.58, 148.61, 146.12, 142.56, 139.98, 135.65, 129.23, 126.37, 123.73, 119.63, 116.85, 111.56, 54.23, 49.52, 41.02, 39.85.

[0077] Example 7 Preparation of Compound 7: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-(trifluoromethoxy)benzyl)-1,3,5-triazine-2,4-dione

[0078] [ka]

[0079] Compound 7 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 26.36%).

[0080] 1 H NMR (600 MHz, DMSO) δ 14.35-14.12 (m, 1H), 10.65 (s, 1H), 8.23 ​​(s, 1H), 7.92 - 7.61 (m, 2H), 7.12-6.89(m, 4H), 6.73 (s, 1H), 4.96 (d, J = 53.9Hz, 2H), 4.61 (s, 2H), 4.02 (d, J = 31.2 Hz, 3H).

[0081] 13C NMR (151 MHz, DMSO) δ 156.01, 154.12, 152.45, 151.63, 149.46, 147.95, 145.48, 141.77, 138.45, 132.19, 129.45, 128.61, 125.63, 124.18, 118.17, 112.69, 111.93, 48.63, 40.14, 38.63.

[0082] Example 8 Preparation of Compound 8: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-fluorobenzyl)-1,3,5-triazine-2,4-dione

[0083] [ka]

[0084] Compound 8 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 40.42%).

[0085] 1 H NMR (600 MHz, DMSO) δ 14.93-14.52 (m, 1H), 10.94 (s, 1H), 8.56 (s, 1H), 8.12 - 7.88 (m, 2H), 7.43-7.25(m, 4H), 7.02 (s, 1H), 5.34 (d, J = 53.9 Hz, 2H), 4.85 (s, 2H), 4.09 (d, J = 31.8 Hz, 3H).

[0086] 13 C NMR (151 MHz, DMSO) δ 159.57, 153.75, 152.67, 151.54, 147.69, 144.86, 142.45, 139.73, 136.83, 134.58, 127.32, 125.72, 122.85, 118.93, 115.15, 111.12, 47.38, 40.58, 38.92.

[0087] Example 9 Preparation of Compound 9: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-chlorobenzyl)-1,3,5-triazine-2,4-dione

[0088] [ka]

[0089] Compound 9 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 38.42%).

[0090] 1 H NMR (600 MHz, DMSO) δ 14.65-14.30 (m, 1H), 10.81 (s, 1H), 8.86 (s, 1H), 8.09 - 7.56 (m, 2H), 7.23-7.09(m, 4H), 6.96 (s, 1H), 5.21 (d, J = 53.5 Hz, 2H), 4.77 (s, 2H), 3.92 (d, J = 31.5 Hz, 3H).

[0091] 13 C NMR (151 MHz, DMSO) δ 153.68, 151.12, 150.45, 149.32, 147.45, 144.75, 142.18, 139.14, 136.25, 134.24, 127.47, 125.85, 122.36, 118.47, 115.41, 111.49, 47.78, 40.49, 38.14.

[0092] Example 10 Compound 10: Preparation of (E)-3-((1H-1,2,3-triazol-5-yl)methyl)-1-(4-bromophenyl)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-1,3,5-triazine-2,4-dione

[0093] [ka]

[0094] Compound 10 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 39.77%).

[0095] 1 H NMR (600 MHz, DMSO) δ 14.77-14.42 (m, 1H), 11.01 (s, 1H), 8.93 (s, 1H), 8.17 - 7.68 (m, 2H), 7.32-7.12(m, 4H), 7.01 (s, 1H), 5.44 (d, J = 53.6 Hz, 2H), 4.86 (s, 2H), 4.01 (d, J = 31.8 Hz, 3H).

[0096] 13 C NMR (151 MHz, DMSO) δ 154.12, 153.98, 148.53, 142.23, 141.56, 139.42, 138.17, 137.45, 136.46, 130.58, 129.37, 127.41, 125.86, 122.16, 119.45, 113.98, 45.19, 40.86, 38.63.

[0097] Example 11 Preparation of Compound 11: (E)-3-((1H-1,2,3-triazol-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

[0098] [ka]

[0099] Compound 11 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 25.01%).

[0100] 1 H NMR (600 MHz, DMSO) δ 14.75-14.32 (m, 1H), 11.23 (s, 1H), 8.71 (s, 1H), 7.99 - 7.82 (m, 2H), 7.65-7.43(m, 6H), 7.40-7.31 (s, 4H), 5.13 (d, J = 53.9 Hz, 2H), 4.79 (s, 2H), 4.13 (d, J = 31.9 Hz, 3H).

[0101] 13 C NMR (151 MHz, DMSO) δ 153.74, 152.02, 148.43, 145.45,143.89, 141.43, 138.51, 136.58, 132.68, 132.42, 131.71, 129.56, 128.26, 127.78, 126.72, 119.56, 115.85, 114.74, 112.85, 111.41, 48.36, 47.58, 41.68.

[0102] Example 12 Preparation of Compound 12: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(4-(trifluoromethyl)benzyl)-1,3,5-triazine-2,4-dione

[0103] [ka]

[0104] Compound 12 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 27.52%).

[0105] 1H NMR (600 MHz, DMSO) δ 14.89-14.56 (m, 1H), 11.10 (s, 1H), 8.64 (s, 1H), 8.19 - 7.92 (m, 2H), 7.52-7.36(m, 4H), 7.14 (s, 1H), 5.46 (d, J = 53.8 Hz, 2H), 4.92 (s, 2H), 4.13 (d, J = 31.7 Hz, 3H).

[0106] 13 C NMR (151 MHz, DMSO) δ 155.12, 152.83, 148.58, 142.52, 141.76, 139.79, 137.85, 135.56, 131.03, 129.46, 128.73, 126.86, 125.87, 124.41, 123.38, 119.24, 113.16, 46.10, 41.78, 40.23.

[0107] Example 13 Preparation of Compound 13: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(3,5-dimethylbenzyl)-1,3,5-triazine-2,4-dione

[0108] [ka]

[0109] Compound 13 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 26.44%).

[0110] 1H NMR (600 MHz, DMSO) δ 14.91-14.45 (m, 1H), 11.05 (s, 1H), 8.45 (s, 1H), 8.15- 7.89 (m, 2H), 7.74-7.56(m, 3H), 7.12 (s, 1H), 5.15 (d, J = 54.1 Hz, 2H), 4.93 (s, 2H), 4.21 (d, J = 31.5 Hz, 3H), 2.21-2.19 (s, 6H).

[0111] 13 C NMR (151 MHz, DMSO) δ 153.76, 151.23, 149.58, 145.59, 143.53, 141.81, 139.52, 135.45, 133.76, 129.57, 128.53, 123.89, 121.43, 120.83, 117.36, 115.81, 47.25, 45.43, 43.57, 25.69.

[0112] Example 14 Preparation of Compound 14: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(3,5-dimethoxybenzyl)-1,3,5-triazine-2,4-dione

[0113] [ka]

[0114] Compound 14 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 24.93%).

[0115] 1H NMR (600 MHz, DMSO) δ 14.96-14.51 (m, 1H), 11.09 (s, 1H), 8.64 (s, 1H), 8.22- 7.72 (m, 2H), 7.63-7.51(m, 3H), 7.21 (s, 1H), 5.13 (d, J = 54.2 Hz, 2H), 4.89 (s, 2H), 4.11 (d, J = 31.4 Hz, 3H), 3.81 (s, 6H).

[0116] 13 C NMR (151 MHz, DMSO) δ 161.45, 155.75, 152.41, 149.47, 145.15, 143.78, 141.47, 135.12, 132.49, 128.57, 126.47, 121.74, 119.38, 115.56, 109.53, 104.41, 54.13, 45.58, 43.76, 41.15.

[0117] Example 15 Preparation of Compound 15: (E)-3-(1H-1,2,3-triazol-5-yl)methyl)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-1-(3,5-difluorobenzyl)-1,3,5-triazine-2,4-dione

[0118] [ka]

[0119] Compound 15 was prepared in the same manner as compound 1 (Example 1) using different starting materials (yield 26.78%).

[0120] 1 H NMR (600 MHz, DMSO) δ 14.86-14.47 (m, 1H), 10.95 (s, 1H), 8.35 (s, 1H), 7.78-7.21 (m, 5H), 7.15 (s, 1H), 5.65 (d, J = 54.2 Hz, 2H), 4.84 (s, 2H), 4.11 (d, J = 31.7 Hz, 3H).

[0121] 13 C NMR (151 MHz, DMSO) δ 159.47, 155.82, 154.73, 148.78, 146.45, 143.61, 141.83, 137.82, 132.41, 128.85, 126.49, 120.53, 118.88, 116.52, 109.62, 106.87, 52.98, 41.91, 39.15.

[0122] Example 16 Preparation of Compound 16: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-methyl-1H-1,2,3-triazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0123] (1) Preparation of compound a16 The preparation method was the same as in Example 1.

[0124] (2) Preparation of compound c16 The preparation method was the same as in Example 1.

[0125] (3) Preparation of compound d16 The preparation method was the same as in Example 1.

[0126] (4) Preparation of compound e16 The preparation method was the same as that of Compound 1 in Example 1.

[0127] (5) Preparation of Compound 16 [ka]

[0128] Bisdibenzylideneacetonepalladium (6.9 mg, 0.012 mmol), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-bisphenyl (8.7 mg, 0.018 mmol), and potassium phosphate (95.5 mg, 0.45 mmol) were added to a reaction vessel containing 1.5 mL of 1,4-dioxane and stirred at 120 °C for 5 min, then cooled to room temperature. Methyl trifluoromethanesulfonate (49.2 mg, 0.3 mmol) and compound e16 (186.4 mg, 0.36 mmol) prepared in step (4) were added, and the reaction mixture was stirred at 70 °C for 24 h. After the reaction was completed, the reaction solution was diluted and extracted with dichloromethane solution. The organic phase was concentrated under reduced pressure, separated and purified by column chromatography (dichloromethane:methanol (V:V) = 12:1 as the mobile phase), and dried to obtain 33.6 mg of compound 16 (yield 21.03%).

[0129] 1 H NMR (600 MHz, DMSO) δ 11.95-10.12 (m, 1H), 8.10 (s, 1H), 7.74-7.41 (m, 4H), 7.01 (s, 1H), 5.45 (d, J = 53.9 Hz, 2H), 4.85 (s, 2H), 4.22 (d, J = 31.7 Hz, 6H).

[0130] 13 C NMR (151 MHz, DMSO) δ 156.78, 154.72, 153.51, 149.43, 148.85, 146.45, 145.89, 143.82, 141.71, 137.82, 134.53, 131.74, 125.71, 122.86, 121.46, 116.78, 112.16, 107.82, 55.18, 37.51, 35.05, 31.76.

[0131] Example 17 Preparation of Compound 17: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0132] [ka]

[0133] Compound 17 was prepared in the same manner as compound 16 (example 16) using different starting materials (yield 23.52%).

[0134] 1 H NMR (600 MHz, DMSO) δ 11.78-10.23 (m, 1H), 8.17 (s, 1H), 7.45-7.31 (m, 4H), 6.98 (s, 1H), 5.75 (d, J = 53.8 Hz, 2H), 4.65 (s, 2H), 4.17 (d, J = 31.7 Hz, 5H), 2.23 (s, 3H).

[0135] 13 C NMR (151 MHz, DMSO) δ 157.47, 154.56, 153.63, 149.12, 148.78, 146.86, 145.75, 143.46, 142.25, 137.74, 135.76, 131.58, 125.43, 122.86, 121.74, 117.73, 114.63, 109.39, 54.52, 35.23, 34.47, 31.25, 15.36.

[0136] Example 18 Preparation of Compound 18: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-1,2,3-triazol-5-(yl)methyl)-1-(4-(trifluoromethyl)benzyl)-1,3,5-triazine-2,4-dione

[0137] [ka]

[0138] Compound 18 was prepared in the same manner as compound 16 (example 16) using different starting materials (yield 22.41%).

[0139] 1 H NMR (600 MHz, DMSO) δ 11.07-10.96 (m, 1H), 7.56 (s, 1H), 7.49-7.14 (m, 4H), 6.67 (s, 1H), 5.48 (d, J = 53.7 Hz, 2H), 4.27 (s, 2H), 4.11 (d, J = 31.5 Hz, 3H), 2.24 (s, 1H), 1.61 (s, 3H), 1.04 (s, 3H).

[0140] 13 C NMR (151 MHz, DMSO) δ 159.13, 154.35, 153.25, 149.31, 148.35, 146.35, 145.64, 143.67, 142.15, 138.75, 136.58, 132.96, 127.24, 123.85, 121.46, 118.45, 114.42, 108.74, 54.96, 36.24, 33.57, 31.85, 28.75, 15.32.

[0141] Example 19 Preparation of Compound 19: (E)-6-(2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1-(4-fluorobenzyl)-1,3,5-triazine-2,4-dione

[0142] [ka]

[0143] Compound 19 was prepared in the same manner as compound 16 (example 16) using different starting materials (yield 24.70%).

[0144] 1 H NMR (600 MHz, DMSO) δ 10.97-10.76 (m, 1H), 7.78 (s, 1H), 7.56-7.24 (m, 5H), 6.34 (s, 1H), 5.67 (d, J = 53.6 Hz, 2H), 4.24 (s, 2H), 4.01 (d, J = 31.7 Hz, 3H), 2.12 (s, 1H), 1.46 (s, 3H), 1.14 (s, 3H).

[0145] 13 C NMR (151 MHz, DMSO) δ 159.32, 154.56, 153.76, 149.24, 148.75, 146.24, 145.42, 143.74, 142.57, 138.58, 136.97, 132.35, 127.24, 121.46, 118.75, 114.46, 108.35, 54.74, 36.35, 33.68, 31.46, 28.68, 15.57.

[0146] Example 20 Preparation of Compound 20: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1-(4-fluorobenzyl)-1,3,5-triazine-2,4-dione

[0147] [ka]

[0148] Compound 20 was prepared in the same manner as compound 16 (example 16) using different starting materials (yield 23.76%).

[0149] 1H NMR (600 MHz, DMSO) δ 10.89-10.66 (m, 1H), 7.56 (s, 1H), 7.45-7.14 (m, 4H), 6.64 (s, 1H), 5.23 (d, J = 53.7 Hz, 2H), 4.46 (s, 2H), 4.13 (d, J = 31.5 Hz, 3H), 2.23 (s, 1H), 1.26 (s, 3H), 1.09 (s, 3H).

[0150] 13 C NMR (151 MHz, DMSO) δ 159.46, 154.85, 153.35, 149.86, 148.46, 146.35, 145.46, 143.35, 142.25, 138.47, 136.63, 132.85, 127.58, 121.85, 118.25, 114.86, 108.35, 54.85, 36.46, 33.75, 31.68, 28.86, 15.24.

[0151] Example 21 Preparation of Compound 21: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-cyclopropyl-1H-1,2,3-triazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0152] (1) Preparation of compound a21 The preparation method was the same as in Example 1.

[0153] (2) Preparation of compound c21 The preparation method was the same as in Example 1.

[0154] (3) Preparation of compound d21 The preparation method was the same as in Example 1.

[0155] (4) Preparation of Compound 21 [ka]

[0156] Sodium azide (598.1 mg, 9.2 mmol) and bromocyclopropane (240 μL, 3 mmol) were placed in a reactor and dissolved in 5 mL of dry DMF. The reaction mixture was stirred at 60° C. overnight and monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature and extracted with brine and tetrahydrofuran. The tetrahydrofuran layer was collected, washed with 5% lithium chloride solution, and dried over MgSO4 to obtain azidocyclopropane.

[0157] Compound d21 (142.4 mg, 0.3 mmol), azidocyclopropane (29.9 mg, 0.36 mmol), copper sulfate pentahydrate (30.0 mg, 0.12 mmol), and sodium ascorbate (23.8 mg, 0.12 mmol) were placed in a reactor and dissolved in a mixture of 10 mL of tetrahydrofuran and 1 mL of water under argon protection. The mixture was heated and stirred at 45 °C overnight and monitored by TLC. After completion of the reaction, the resulting reaction solution was concentrated under reduced pressure to remove the solvent. The mixture was then purified by column chromatography (dichloromethane:methanol (V:V) = 12:1 as the mobile phase) and dried to obtain 35.2 mg of compound 21 (yield 21.03%).

[0158] 1 H NMR (600 MHz, DMSO) δ 11.01-10.36 (m, 1H), 7.98 (s, 1H), 7.56-7.25 (m, 4H), 7.12 (s, 1H), 5.38 (d, J = 53.7 Hz, 2H), 4.76 (s, 2H), 4.52 (d, J = 31.5 Hz, 3H), 2.56 (s, 1H), 1.21 (s, 2H), 0.86 (s, 2H).

[0159] 13C NMR (151 MHz, DMSO) δ 158.45, 155.86, 154.56, 149.86, 148.43, 146.76, 145.41, 143.78, 142.52, 138.47, 136.71, 132.78, 127.78, 123.52, 121.02, 118.57, 114.18, 108.75, 54.13, 36.85, 33.54, 31.17, 2.15.

[0160] Example 22 Preparation of Compound 22: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-isopropyl-1H-1,2,3-triazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0161] [ka]

[0162] Compound 22 was prepared in the same manner as compound 21 (example 21) using different starting materials (yield 21.30%).

[0163] 1 H NMR (600 MHz, DMSO) δ 11.21-10.76 (m, 1H), 7.68 (s, 1H), 7.36-7.15 (m, 4H), 6.88 (s, 1H), 5.18 (d, J = 53.6 Hz, 2H), 4.36 (s, 2H), 4.01 (d, J = 31.7 Hz, 3H), 2.16 (s, 1H), 1.71 (s, 3H), 1.06 (s, 3H).

[0164] 13C NMR (151 MHz, DMSO) δ 158.32, 154.86, 153.78, 149.12, 148.03, 146.54, 145.15, 143.36, 142.22, 138.67, 136.63, 132.53, 127.85, 123.32, 121.45, 118.80, 114.53, 108.67, 54.14, 36.56, 33.24, 31.09, 28.14.

[0165] Example 23 Preparation of Compound 23: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-isobutyl-1H-1,2,3-triazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0166] [ka]

[0167] Compound 23 was prepared in the same manner as compound 21 (example 21) using different starting materials (yield 19.22%).

[0168] 1 H NMR (600 MHz, DMSO) δ 10.34-10.32 (m, 1H), 7.63 (s, 1H), 7.25-7.11 (m, 4H), 6.56 (s, 1H), 5.27 (d, J = 53.7 Hz, 2H), 4.25 (s, 2H), 4.04 (d, J = 31.2 Hz, 3H), 2.16 (s, 1H), 1.16 (s, 3H), 1.24 (s, 3H), 0.81 (s, 2H).

[0169] 13C NMR (151 MHz, DMSO) δ 159.26, 154.67, 153.36, 149.17, 148.58, 146.37, 145.57, 143.36, 142.36, 138.58, 136.25, 132.48, 127.24, 123.69, 121.36, 118.58, 114.68, 108.35, 54.66, 36.96, 33.24, 31.68, 28.46, 19.78.

[0170] Example 24 Preparation of Compound 24: (E)-6-(6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(1-cyclobutyl-1H-1,2,3-triazol-5-yl)methyl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4-dione

[0171] [ka]

[0172] Compound 24 was prepared in the same manner as compound 21 (example 21) using different starting materials (yield 17.56%).

[0173] 1 H NMR (600 MHz, DMSO) δ 10.78-10.12 (m, 1H), 7.45 (s, 1H), 7.15-7.01 (m, 4H), 6.16 (s, 1H), 5.54 (d, J = 53.5 Hz, 2H), 4.42 (s, 2H), 4.11 (d, J = 31.4 Hz, 3H), 2.31 (s, 1H), 1.82 (s, 3H), 1.46 (s, 3H).

[0174] 13C NMR (151 MHz, DMSO) δ 158.56, 154.12, 153.16, 149.67, 148.36, 146.37, 145.27, 143.19, 142.19, 138.53, 136.48, 132.49, 127.19, 123.95, 121.10, 118.56, 114.57, 108.47, 54.95, 36.26, 33.96, 31.35, 28.36, 15.64.

[0175] 2. Bioactivity Assay

[0176] (1) 3CL pro Inhibitory activity test SARS-CoV-2 3CL pro The inhibitory activity of the compounds against the β-glucanase was measured using fluorescence resonance energy transfer.

[0177] 10 μL of compound solution prepared at various concentrations (final concentrations: 1000, 500, 250, 125, 62.5, 31.25, 15.63, 7.81, 3.90, 1.95 nM in DMSO) and SARS-CoV-2 3CL pro The mixture was mixed with 40 μL of the fluorogenic substrate Dabcyl-KTSAVLQSGFRKME-Edans (Shanghai Biyuntian Biotechnology Co., Ltd., final concentration: 0.5 μM, diluted in Tris-HCl buffer (20 mM Tris-HCl, 100 mM NaCl, 1 mM EDTA, pH 7.4)) and added to a black 96-well plate. The mixture was then incubated at 37°C for 10 minutes. The reaction was initiated by adding 50 μL of the fluorescent substrate Dabcyl-KTSAVLQSGFRKME-Edans (Shanghai Biyuntian Biotechnology Co., Ltd., final concentration: 20 μM). The reaction was then incubated for 10 minutes and measured using a multifunctional microplate reader (Thermo Fisher Scientific Co., Ltd., Varioskan Flash) for fluorescence detection (excitation wavelength: 340 nm, emission wavelength: 490 nm). Fluorescence values ​​were recorded and the inhibition rate of the sample was calculated. DMSO without compound was used as an enzyme activity control, and SARS-CoV-2 3CL was used as a blank control. proThe same treatment method was used as in the case of Tris-HCl buffer containing no HCl. 50 Values ​​were calculated by nonlinear regression analysis using GraphPad Prism software.

[0178] Inhibition rate (%) = (RFU 酵素活性対照 -RFU 試料 ) / (RFU_ 酵素活性対照 -RFU_ ブランク対照 )×100%

[0179] The experimental results are shown in Tables 1 and 2 (in Table 1, IC 50 Column A:IC 50 <100nM, B:IC 50 =200-500nM, C: 500-1000nM, D: >1000nM), and the compounds of the examples were all 3CL pro Among them, Compound 1, Compound 7, Compound 12, Compound 15, Compound 16, Compound 17, Compound 18, Compound 22 and Compound 23 have inhibitory activity against IC 50 Values ​​less than 100 nM and 3CL pro It has a strong inhibitory effect against

[0180] [Table 1]

[0181] [Table 2]

[0182] The data in Tables 1 and 2 show that compounds 1 to 24 are all 3CL pro The results showed that the 3CL pro IC of Compound 1, Compound 7, Compound 12, Compound 15, Compound 16, Compound 17, Compound 18, Compound 22 and Compound 23 against 50 All values ​​were below 200 nM, and the coronavirus 3CL proThe inhibitory activity of 3-triazolylmethyl-1,3,5-triazine-2,4-diketone against Specifically, 3CL pro IC of Compound 1, Compound 12, and Compound 17 against 50 The inhibitory activities were 96.60 nM, 177.8 nM, and 123.2 nM, respectively, and compound 1 had the best inhibitory activity (IC 50 <100 nM) and could be developed and applied as an anti-coronavirus drug.

[0183] (2) 3CL pro Cytotoxicity test The in vitro cytotoxicity of compounds 1, 12, and 17 was evaluated by the MTT assay. HepG2, HEK293, and A549 cells were harvested in the logarithmic growth phase, digested with trypsin, and cell suspensions were prepared. The cell density was 5 × 10 4 The solution was adjusted to a cell count / mL and inoculated into a sterilized 96-well cell culture plate at 180 μL per well. The plate was then incubated at 37°C in a 5% CO2 incubator for 24 hours. After the cells attached to the bottom of the well plate, 20 μL of a gradient drug solution was added to each well. Six duplicate wells were set up in parallel, including a blank group (no cells, no compound) and a control group (no compound). After 24 hours of incubation at 37°C in a 5% CO2 incubator, 20 μL of 5 g / L MTT solution was added to each well and incubated for 4 hours. After incubation, the culture medium in the wells was gently aspirated, and 100 μL of DMSO was added to each well. The wells were shaken at low speed for 10 minutes to completely dissolve the crystals. Cell viability was then calculated. The results are shown in Tables 3–5.

[0184] Cell viability (%) = (OD value of sample group - OD value of blank group) / (OD value of control group - OD value of blank group)

[0185] [Table 3]

[0186] [Table 4]

[0187] [Table 5]

[0188] Tables 3 to 5 show the inhibitory rates of PF-07321332, S-217622, ​​and representative compounds 1, 12, and 17 against A549, HEK293, and HepG2 cells at various concentrations. These data show that the inhibitory rates of compound 1 against A549, HepG2, and HEK293 cells were lower than those of PF-07321332 and S-217622 at all concentrations. Compounds 12 and 17 at 400 nM and 200 nM were slightly more toxic than PF-07321332 and S-217622 against the three cell types tested. However, when A549, HEK293, and HepG2 cells were treated at 12.5 nM or less, cell viability was higher than that of PF-07321332 and S-217622. In summary, compound 1 possesses the characteristics of good inhibitory activity and low toxicity against 3CL proteases and can be further studied.

[0189] The above content is intended to explain the technical idea of ​​the present invention, and does not limit the protection scope of the present invention. Any modifications made based on the technical solutions proposed based on the technical idea of ​​the present invention are included in the scope of the claims of the present invention.

Claims

1. A compound of Formula I, a pharmaceutically acceptable salt thereof, or a tautomer thereof. 【Chemical 1】 (In the formula, R １ , R ２ , R ３ and R ４ are independently selected from the group consisting of hydrogen, methyl, tert-butyl, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, nitro, halogen, phenyl, and aromatic heterocycles; R ５ is hydrogen or halogen; and R ６ is hydrogen, a C1-C4 alkane, or a C1-C4 cycloalkane.

2. The compound is 【Chemistry 2】 【change】 2. The compound of claim 1 selected from the group consisting of:

3. 10. The compound of claim 1, wherein the pharmaceutically acceptable salt comprises one selected from the group consisting of 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, and aspartic acid.

4. 10. An anti-coronavirus pharmaceutical formulation comprising the compound of claim 1.

5. The anti-coronavirus pharmaceutical preparation according to claim 4, wherein the coronavirus is the novel coronavirus SARS-CoV-2.

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