Use of nucleoside compound in treatment of coronavirus infectious diseases

Abstract

Use of a compound represented by formula (I) or pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating coronavirus infectious diseases. The compound represented by formula (I) is used for treating patients with novel coronavirus pneumonia, and shows obvious advantages in negative conversion ratio of viral nucleic acid test, negative conversion course, and cure and hospital discharge time.

Description

Use of nucleoside compounds in treating coronavirus infectious diseases TECHNICAL FIELD

[0001] The present application relates to the new antiviral use of nucleoside compounds. BACKGROUND

[0002] Coronaviruses (CoV) are a group of enveloped, positive-sense, single-stranded RNA viruses that are widespread in humans, other mammals, and birds, and can cause diseases of the respiratory tract, intestine, liver, and nervous system. Currently, there are seven known CoVs that can cause human diseases, four of which, CoV-229E, -OC43, -NL63, and -HKU1, are prevalent in the human population and usually cause common cold symptoms. While the other three, SARS-CoV, MERS-CoV, and the novel coronavirus (2019-nCoV, or COVID-19), are highly dangerous due to their rapid onset, strong infectivity, and high mortality. Therefore, it is urgent to develop direct antiviral drugs to treat novel coronavirus infection.

[0003] SUMMARY

[0004] Compound 1 has completed phase II clinical trials as an anti-AIDS drug, and has good safety.

[0005]

[0006] The inventors determined the in vitro antiviral activity of compound 1 in MRC-5 cells infected with the novel coronavirus. The results showed that compound 1 had only weak inhibitory activity against the novel coronavirus (EC 50 of 25 μM).

[0007] However, the inventors conducted a research clinical trial directly using the compound of formula (1), and surprisingly found that, compared with the control conventional treatment, treatment of patients with novel coronavirus pneumonia using the compound of formula (1) showed obvious advantages in viral nucleic acid test conversion rate, conversion course, and cure discharge time. The inventors believe that the lack of obvious inhibitory effect of compound 1 on the virus may be related to its inability to be effectively phosphorylated in vitro.

[0008] In view of this, in one aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a coronavirus infectious disease. In another aspect, the present application provides a method for preventing or treating a coronavirus infectious disease, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0009] wherein the structure of formula (I) is as follows:

[0010]

[0011] in formula (I),

[0012] R 1 is OR 1 any group which can be metabolically released in vivo to yield a hydroxyl group, or to form an O-phospho group; OR 1 is preferably an ester group, R 1 is preferably H, R 5 -CO-, or wherein Ar is phenyl and substituted phenyl, naphthyl and substituted naphthyl, the substituents being selected from C 1-6 alkyl, F, Cl, Br, I, CN, N3, OH, NH2, OR 5 , NHR 5 ;

[0013] R 2 is selected from: H, azido, C1-C6 alkyl (e.g. methyl, ethyl), C1-C6 alkoxy (e.g. methoxy, ethoxy), C2-C6 alkynyl (e.g. ethynyl), C2-C6 alkenyl (e.g. ethenyl), halo C1-C6 alkyl (e.g. 2-chloroethyl, 2-fluoroethyl, trifluoroethyl);

[0014] R 3 is selected from H, optionally substituted R-CO-, optionally substituted R-O(C=O)-, and optionally substituted RNH-CO-, wherein R is selected from C1-C6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, etc.); wherein the substituents are selected from C1-C6 alkyl, halogen (e.g. F, Cl), CN, N3, and OR 5 .

[0015] R 4 is selected from H, OH, halogen (e.g. F), C1-C6 alkyl (e.g. methyl, ethyl), C1-C6 alkoxy (e.g. methoxy, ethoxy);

[0016] B is selected from:

[0017]

[0018] wherein X1is selected from -OH, -NH2, R 5 COO-, R 5 CONH-, R 5 O(C=O)NH-;

[0019] X2is selected from -OH, -SH, -NH2, R 5 COO-, R 5 COS-, R 5 CONH2-, R5 O(C=O)NH-;

[0020] X3is selected from H, F, -OH, and -NH2;

[0021] Y is selected from CH and N;

[0022] Z is H, -OH, or F;

[0023] R 5 selected from H, C1-C6alkyl (e.g., methyl, ethyl, propyl, isopropyl), C2-C6alkynyl (e.g., ethynyl), C2-C6alkenyl (e.g., ethenyl), haloC1-C6alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl), optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted alkoxy, CN, N3, OH, NH2, halogen (e.g., F, Cl, Br, I), and the like. 1-6 alkyl, C 1-6 alkoxy, CN, N3, OH, NH2, halogen (e.g., F, Cl, Br, I) substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted alkoxy, CN, N3, OH, NH2, halogen (e.g., F, Cl, Br, I), and the like. 1-6 alkyl, C 1-6 alkoxy, CN, N3, OH, NH2, halogen (e.g., F, Cl, Br, I) substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted alkoxy, CN, N3, OH, NH2, halogen (e.g., F, Cl, Br, I), and the like.

[0024] Preference is given to the following compounds or pharmaceutically acceptable salts thereof:

[0025]

[0026]

[0027] Pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to, for example, salts of compounds of formula (I) with hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbic palmitic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, and the like.

[0028] The compounds of formula (I) can be purchased through commercial channels or prepared by known methods.

[0029] Coronavirus infectious diseases herein refer to diseases caused by infection of viruses of the Coronaviridae family, including diseases caused by infection of humans or other animals. In particular, diseases caused by infection of humans by human coronaviruses, including but not limited to CoV-229E, -OC43, -NL63, -HKU1, SARS-CoV, MERS-CoV and the novel coronavirus (2019-nCoV, or COVID-19).

[0030] The effective amount of the compound of formula (I) for treating and preventing coronavirus infectious diseases can be determined by those skilled in the art according to the information provided herein. For example, the dosage for an adult can be 1-500 mg / day, optionally 1-50 mg / day, optionally 1-20 mg / day, optionally 1-10 mg / day, and optionally 5 mg / day. The administration can be single or multiple.

[0031] The administration can be oral or parenteral. The dosage form can be immediate release, sustained release or controlled release. The specific dosage form can be various conventional dosage forms in the art. For example, oral preparations can include tablets, hard or soft capsules, aqueous or oily suspensions, granules, emulsions, syrups or elixirs, etc. Injection preparations can include injection solutions, powder injections, etc. DETAILED DESCRIPTION

[0032] The specific embodiments of the present application are described in detail below. It should be understood that the specific embodiments described herein are intended to illustrate the present application, but not to limit the present application.

[0033] Test Example 1. Anti-novel coronavirus activity test of azithromycin phosphate amine prodrug CL-236

[0034] (I) Experimental materials and reagents

[0035] 1. Cell line: Huh 7 cells, preserved in the laboratory;

[0036] 2. Virus strain: 2019-nCoV (COVID-19);

[0037] 3. Test drug: azithromycin phosphate amine prodrug (CL-236)

[0038] 4. Positive control drug: remdesivir;

[0039] 5. Reagents: DMEM medium (Gibco), fetal bovine serum (Gibco), double antibody, trypsin, MTT (Amresco), etc.

[0040] 6. Kits: QIAamp viral RNA mini kit (52906, Qiagen), One Step TB Green PrimeScript PLUS RT-PCR Kit (Perfect Real Time) (RR096A TaKaRa)

[0041] 7. Consumables: cell culture plates, 96-well enzyme-labeled plates, etc.

[0042] 8. Instruments: multifunctional enzyme-labeled instrument, StepOnePlus fluorescence quantitative PCR instrument, carbon dioxide incubator, etc.

[0043] (B) Experimental steps

[0044] 1. Azithromycin phosphate amine prodrug CL-236 cytotoxicity assay

[0045] MTT method was used to detect the toxicity of azithromycin phosphate amine prodrug CL-236 on Huh 7 cells. MTT is a yellow dye. MTT colorimetric method is a method for detecting cell survival and growth. The detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple formazan and deposit in the cells, while dead cells do not have this function. 10% SDS (dissolved in 0.01 mol / L HCl solution) can dissolve the formazan in the cells, and the multifunctional enzyme-labeled instrument is used to measure the light absorption value at 570 nm wavelength, which can indirectly reflect the number of living cells. Within a certain range of cell number, the amount of MTT crystal formation is proportional to the number of cells. By detecting the light absorption value at 570 nm wavelength under different interferon concentrations, the survival rate of cells under the drug concentration can be calculated, and the median toxic concentration (CC 50 ) of the drug can be calculated.

[0046] Huh 7 cells were inoculated in 96-well plates one day in advance, 1×10 4(96-well plate, note that the outermost wells of the 96-well plate should not be used as experimental wells, and PBS should be added to prevent evaporation of the culture medium in other wells); observe the cell state, and when it reaches about 50%, add azithromycin phosphate amine prodrug CL-236 to the cell plate at a concentration of 100 μL / well, 2-fold dilution with DMEM medium containing 2% FBS, 6 replicates for each concentration; at the same time, set up a control group (without drug) and a blank group (without cells), and place them in a 37°C, 5% CO2 incubator; 48 h after drug addition, add 25 μL of MTT solution (5 mg / mL) to each well, continue to culture for 4 h, then add 125 μL of 10% SDS (dissolved in 0.01 mol / L HCl solution) to each well, gently blow, and place for 2 h to allow the crystals to fully dissolve. Set the blank group to zero, measure OD570, and calculate the survival rate (%) according to the following formula: survival rate (%) = OD570 of the drug group / OD570 of the control group x 100%. At the same time, calculate the half toxic concentration (CC50) of the drug.

[0047] 2. Evaluation of the inhibitory effect of azithromycin phosphate amine prodrug CL-236 on 2019-nCoV (COVID-19) virus

[0048] Antiviral activity assay was performed on Huh 7 cell model, with 3 replicates per test, and 3 repeats in total.

[0049] 1) Inoculate 5 x 10 4 Huh 7 cells per well of a 24-well cell culture plate, and incubate at 37°C, 5% CO2, until the confluence reaches 60%. Then, add 200 μL of 2019-nCoV (COVID-19) virus solution diluted with DMEM medium containing 2% FBS to each well at a multiplicity of infection (MOI) of 0.005, and incubate in a 37°C, 5% CO2 incubator for 1 h. Discard the virus solution, and add 500 μL / well of azithromycin phosphate amine prodrug CL-236 and positive control drug, 2-fold dilution from the maximum non-toxic concentration with DMEM medium containing 2% FBS. At the same time, set up a control group (without drug), and collect the supernatant virus solution 48 h after infection.

[0050] 2) RNA quantification of the collected virus using real-time RT-PCR (qRT-PCR):

[0051] Take 140 μL of the collected supernatant virus solution, and extract RNA according to the QIAamp viral RNA mini kit manual. Perform qRT-PCR detection using the One Step TB Green PrimeScript PLUS RT-PCR Kit (Perfect Real Time) kit,

[0052] Primer RBD-qF1: 5'-CAATGGTTTAACAGGCACAGG-3';

[0053] RBD-qR1: 5'-CTCAAGTGTCTGTGGATCACG-3'.

[0054] The total volume of the reaction system was 20 μL: 10 μL 2X One Step TB Green RT-PCR Buffer 4, 1.2 μL TaKaRa Ex Taq HS Mix, 0.4 μL PrimeScript PLUS RTase Mix, 0.8 μL of RBD-qF1 and RBD-qR1, 0.4 μL ROX Reference Dye (50X), 2 μL viral RNA, 4.4 μL RNase Free dH2O. The reaction parameters were: reverse transcription 42°C for 5 min, pre-denaturation 95°C for 10 s, PCR 40 cycles including denaturation 95°C for 10 s, annealing and extension 60°C for 30 s.

[0055] 3) Calculate the drug inhibition rate at each concentration. Inhibition rate (%) = 1 - experimental group viral RNA copy number / no drug group viral RNA copy number x 100%. At the same time, the half effective concentration (EC 50 ) and the therapeutic index (TI) = half toxic concentration (CC 50 ) / half effective concentration (EC 50 ) of the drug were calculated.

[0056] (III) Calculation of experimental results

[0057] Table 1. Inhibition of COVID-19 activity by azithromycin phosphate amine prodrug CL-236

[0058]

[0059] Test Example 2

[0060] A clinical trial was conducted to verify the effectiveness and safety of Compound 1 for the treatment of COVID-19 pneumonia.

[0061] Select 20 cases of patients diagnosed with new coronavirus infection by nucleic acid reagent assay, divided into azvudine (compound 1) group and clarithromycin control group, 10 cases in each group. Azvudine group treatment: 5 mg per day (oral, 5 tablets, 1 mg per tablet); Clarithromycin control group treatment: clarithromycin (oral, 2 tablets / day, 250 mg / tablet) + abidor tablets (oral 200 mg / time, 3 times / day) + interferon (5 million U, twice a day by aerosol inhalation). Measure nucleic acid changes, body temperature changes, and observe various symptoms.

[0062] The results are shown in the following table.

[0063]

[0064] The results of the clinical trial showed that among the 10 patients with new coronavirus infection, all patients in the azvudine group were nucleic acid negative, and 7 patients were discharged within 8 days.

[0065] The above clinical trial results show that compound 1 treatment of new coronavirus pneumonia shows significant clinical treatment advantages in patient nucleic acid conversion rate, conversion course, cure rate and cure course.

[0066] One of the patients who used clarithromycin support treatment for more than 20 days and still could not turn negative, turned negative 3 days after treatment with compound 1. During treatment, no drug-related adverse reactions were found.

[0067] In the in vitro test system, azvudine cannot be effectively activated by phosphatase, so the phosphoramidate prodrug of azvudine (CL-236) is used to indirectly determine its anti-new coronavirus activity. Because it is known in the trial of azvudine for the treatment of AIDS that azvudine can be effectively activated in the human body, azvudine is used directly in the human clinical trial for the treatment of new coronavirus pneumonia, rather than the phosphoramidate prodrug of azvudine.

Claims

1. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating coronavirus infectious diseases, In formula (I), R 1 is H, R 5 -CO-, or wherein Ar is phenyl, substituted phenyl, naphthyl or substituted naphthyl, and the substituent is selected from C 1-6 alkyl, F, Cl, Br, I, CN, N 3 , OH, NH 2 , OR 5 , NHR 5 ; R 2 is: H, azido, C 1 -C 6 alkyl (such as methyl, ethyl), C 1 -C 6 alkoxy (such as methoxy, ethoxy), C 2 -C 6 alkynyl (such as ethynyl), C 2 -C 6 alkenyl (such as vinyl), or halo C 1 -C 6 alkyl (such as 2-chloroethyl, 2-fluoroethyl, trifluoroethyl); R 3 is H, optionally substituted R-CO-, optionally substituted R-O(C═O)-, or optionally substituted RNH-CO-, where R is C 1 -C 6 -alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, etc.), wherein, The substituent is selected from C 1 -C 6 alkyl, halogen (such as F, Cl), CN, N 3 , and OR 5 ; R 4 is H, OH, halogen (e.g., F), C 1 -C 6 alkyl (e.g., methyl, ethyl), or C 1 -C 6 alkoxy (e.g., methoxy, ethoxy); B is selected from: Among them, X 1 is -OH, -NH 2 , R 5 CONH-, R 5 COO- or R 5 O(C=O)NH-; X 2 is OH, SH, NH 2 , R 5 COO-, R 5 COS-, R 5 CONH 2 -, or R 5 O(C=O)NH-; X 3 is H, F, OH or NH 2 ; Y is CH or N; Z is H, OH or F; R 5 Selected from H, C 1 -C 6 alkyl (such as methyl, ethyl, propyl, isopropyl), C 2 -C 6 alkynyl (such as ethynyl), C 2 -C 6 alkenyl (such as vinyl), halogenated C 1 -C 6 alkyl (such as 2-chloroethyl, 2-fluoroethyl, trifluoroethyl), optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 , OH, NH 2 , halogen (such as F, Cl, Br, I)-substituted phenyl, optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 , OH, NH 2 , halogen (such as F, Cl, Br, I)-substituted naphthyl.

2. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for preventing or treating coronavirus infectious diseases, wherein the compound of formula (I) is the following compound: Or 3. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for preventing or treating coronavirus infectious diseases, wherein the pharmaceutically acceptable salts of the compound of formula (I) include salts formed by the compound of formula (I) and the following acids: hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbyl palmitate, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine or leucine.

4. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of a medicament for preventing or treating coronavirus infectious diseases, wherein the coronavirus infectious disease is a disease caused by the infection of a virus of the family Coronaviridae, including diseases caused by infecting humans or other animals, especially diseases caused by human coronavirus infecting humans, for example, diseases caused by CoV-229E, -OC43, -NL63, -HKU1, SARS-CoV, MERS-CoV or COVID-19 infection.

5. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of a medicament for preventing or treating coronavirus infectious diseases, wherein the pharmaceutical dosage form is an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form, such as tablets, hard or soft capsules, aqueous or oily suspensions, granules, emulsions, syrups, elixirs, injections, or lyophilized powders for injection.

6. A method for preventing or treating coronavirus infectious diseases, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, In formula (I), R 1 is H, R 5 -CO-, or wherein Ar is phenyl, substituted phenyl, naphthyl or substituted naphthyl, and the substituent is selected from C 1-6 alkyl, F, Cl, Br, I, CN, N 3 ., OH, NH 2 ., OR 5 ., NHR 5 ; R 2 is: H, azido, C 1 -C 6 alkyl (such as methyl, ethyl), C 1 -C 6 alkoxy (such as methoxy, ethoxy), C 2 -C 6 alkynyl (such as ethynyl), C 2 -C 6 alkenyl (such as vinyl), or halo C 1 -C 6 alkyl (such as 2-chloroethyl, 2-fluoroethyl, trifluoroethyl); R 3 is H, optionally substituted R-CO-, optionally substituted R-O(C=O)-, or optionally substituted RNH-CO-, where R is C 1 -C 6 -alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, etc.), wherein, The substituent is selected from C 1 -C 6 alkyl, halogen (such as F, Cl), CN, N 3 , and OR 5 ; R 4 is H, OH, halogen (e.g., F), C 1 -C 6 alkyl (e.g., methyl, ethyl), or C 1 -C 6 alkoxy (e.g., methoxy, ethoxy); B is selected from: Among them, X 1 is -OH, -NH 2 , R 5 CONH-, R 5 COO- or R 5 O(C=O)NH-; X 2 is OH, SH, NH 2 , R 5 COO-, R 5 COS-, R 5 CONH 2 -, or R 5 O(C=O)NH-; X 3 is H, F, OH or NH 2 ; Y is CH or N; Z is H, OH or F; R 5 selected from H, C 1 -C 6 alkyl (such as methyl, ethyl, propyl, isopropyl), C 2 -C 6 alkynyl (such as ethynyl), C 2 -C 6 alkenyl (such as vinyl), halo-C 1 -C 6 alkyl (such as 2-chloroethyl, 2-fluoroethyl, trifluoroethyl), optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 、OH, NH 2 、halogen (such as F, Cl, Br, I)-substituted phenyl, optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 、OH, NH 2 、halogen (such as F, Cl, Br, I)-substituted naphthyl.

7. The method for preventing or treating coronavirus infectious diseases according to claim 6, wherein the compound of formula (I) is the following compound: Or 8. The method for preventing or treating coronavirus infectious diseases according to claim 6 or 7, wherein the pharmaceutically acceptable salts of the compound of formula (I) include salts formed by the compound of formula (I) and the following acids: hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbyl palmitate, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine or leucine.

9. The method for preventing or treating coronavirus infectious diseases according to any one of claims 6-8, wherein the coronavirus infectious disease is a disease caused by the infection of a virus of the family Coronaviridae, including diseases caused by the infection of humans or other animals, especially diseases caused by the infection of human coronavirus in humans, for example, diseases caused by the infection of CoV-229E, -OC43, -NL63, -HKU1, SARS-CoV, MERS-CoV or COVID-19.

10. The method for preventing or treating coronavirus infectious diseases according to any one of claims 6-8, wherein the pharmaceutical dosage form is an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form, such as tablets, hard or soft capsules, aqueous or oily suspensions, granules, emulsions, syrups, elixirs, injections, or powder for injection.