Compound or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and application of compound or pharmaceutically acceptable salt, hydrate, solvate or prodrug

Abstract

The invention relates to the technical field of medicines, and particularly discloses a compound or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or a pharmaceutical composition thereof, and application of the compound or the pharmaceutical composition in resisting viruses, such as coronavirus, influenza virus, respiratory syncytial virus, flaviviridae virus and filoviridae virus. The invention also relates to the application of the compound in feline coronavirus.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically, to a compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and use thereof. Background Art

[0002] Feline coronavirus (FCoV) is widespread in cats, with an estimated 40-80% of cats worldwide carrying the virus. In nature, FCoV exists as two different biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV), the latter being a mutated form of the former. The mechanism of this transformation is still not fully understood, but it is related to the cat's immune response, genetic variation of the virus, and environmental factors. Most cats infected with FECV are asymptomatic, but FIPV infection easily invades other organs and develops into infectious peritonitis (FIP).

[0003] FIP is divided into dry (non-exudative) and wet (exudative). Wet FIP ​​is characterized by a large amount of fluid accumulation in the abdominal or thoracic cavity, leading to obvious abdominal distension or difficulty breathing; while dry FIP is characterized by more local lesions, such as inflammation of the eyes, nervous system and internal organs, with various symptoms that may include weight loss, loss of appetite, fever, etc.

[0004] Incidence: ① The incidence of FIP is about 7.8-12% in cats infected with feline coronavirus; ② In a single-cat household, the infection rate of feline coronavirus is as high as 50%, and in a multi-cat environment, this ratio can rise to 80-90%; ③ In summary, the overall incidence of FIP in single cats is about 3.9-6%, and the overall incidence of FIP in multi-cats is about 6.6-10.2%

[0005] This disease is common in young cats aged 3-9 months, especially in cats that are kept in groups. The course of the disease may be sudden (more common in kittens) or slow and last for several weeks. The mortality rate of this disease is as high as 95%, and there is a certain degree of difficulty in early diagnosis. It is generally believed that only histopathological examination can provide 100% diagnosis. In terms of treatment, there is currently no specific drug for FIP. Once the infection is discovered, supportive therapy is usually adopted: forced feeding (through esophageal or gastric tube), infusion to correct dehydration, thoracentesis to relieve respiratory symptoms, etc. Immunosuppressive and anti-inflammatory drugs are also often used, such as high-dose steroids, cytotoxic drugs, etc.

[0006] In recent years, the development of antiviral drugs has brought new hope for the treatment of FIP. GS-441524 developed by Gilead has been shown to have a significant inhibitory effect on FIP virus (WO2018169946). Clinical studies have shown that GS-441524 has a very good clinical control effect on both wet and dry peritonitis. After treatment, cats treated with GS-441524 have significantly improved symptoms and a significantly increased survival rate.

[0007] However, due to its short half-life and low bioavailability, GS-441524 has a long treatment period of about 3 months and a high total cost. Currently, there is no original drug product approved for marketing in China. Summary of the invention

[0008] In order to solve the above technical problems, the present invention provides an active ingredient that can effectively inhibit virus replication and has a long half-life, and its use in antiviral, such as coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus and Filoviridae virus, especially feline coronavirus.

[0009] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:

[0010]

[0011] in,

[0012] R 1 Selected from H, -C(=O)R 5 , -C(=O)OR 5 or optionally one or more R 6 Substituted C1-C8 alkyl; preferably, R 1 is n-pentyloxycarbonyl;

[0013] R 2 Selected from H, -C(=O)R 6 、-C(=O)OR 6 、-C(=O)NR 6 R 7 、-C(=O)SR 6 、-S(O)R 6 ,

[0014] -S(O)R 6 、-S(O)(OR 6 )、-S(O)2(OR 6 ),-SONR 6 R 7 or

[0015] Y is O or S;

[0016] W 1 and W 2 Each independently selected from the group of formula Ia:

[0017]

[0018] in:

[0019] Each X is independently selected from O, OR 5 NR 5 、N(O)(R 5 )、N(OR 5 )、N(O)(OR 5 )、N-NR 5 , SS, S(O) or S(O)2; preferably, R 2 is H;

[0020] R 3 and R 4 Each independently selected from H, OR 5 、N(R 5 )2, N3, CN, NO2, S(O) n R 5 , halogen, C1-C8 alkyl, C4-C8 carbocyclylalkyl, C1-C8 substituted alkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl, C2-C8 substituted alkynyl, or arylC1-C8 alkyl; or R 3 and R 4 Form a C4-C16 carbocyclic ring, a C4-C16 unsaturated carbocyclic ring, a C4-C16 carbon-oxygen heterocyclic ring, a C4-C16 carbon-nitrogen heterocyclic ring, or a C4-C16 carbon-sulfur heterocyclic ring;

[0021] Each n is independently 0, 1, or 2;

[0022] R 5 is selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl C1-C8 alkyl, C4-C8 carbocyclyl alkyl, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 , -C(=O)SR 6 ,-SC(=O)R 6 , -S(O)R 6 , -S(O)R 6 , -S(O)(OR 6 ), -S(O)2(OR 6) or -SONR 6 R 7 ;

[0023] R 6 and R 7 Each independently selected from -CN, -OH, -OR 5 、-NR 5 R 5 , halogen, alkyl, cycloalkyl or heterocycloalkyl;

[0024] The above R 1 , R 2 , R 3 and R 4 Not H at the same time.

[0025] Preferably, the compound is one or more combinations of compounds represented by formula II to formula VI:

[0026]

[0027] in,

[0028] R 1 Selected from H, -C(=O)R 5 , -C(=O)OR 5 or optionally one or more R 6 Substituted C1-C8 alkyl; preferably, R 1 is n-pentyloxycarbonyl;

[0029] R 2 Selected from H, -C(=O)R 6 、-C(=O)OR 6 、-C(=O)NR 6 R 7 、-C(=O)SR 6 、-S(O)R 6 ,

[0030] -S(O)R 6 、-S(O)(OR 6 )、-S(O)2(OR 6 ),-SONR 6 R 7 or

[0031] Y is O or S;

[0032] W 1 and W 2 Each independently selected from the group of formula Ia:

[0033]

[0034] in:

[0035] Each X is independently selected from O, OR 5 NR 5 、N(O)(R 5 )、N(OR 5 )、N(O)(OR 5 )、N-NR 5 , SS, S(O) or S(O)2; preferably, R 2 is H;

[0036] R 5 is selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl C1-C8 alkyl, C4-C8 carbocyclyl alkyl, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 , -C(=O)SR 6 ,-SC(=O)R 6 , -S(O)R 6 , -S(O)R 6 , -S(O)(OR 6 ), -S(O)2(OR 6 ) or -SONR 6 R 7 ;

[0037] R 6 and R 7 Each independently selected from -CN, -OH, -OR 5 、-NR 5 R 5 , halogen, alkyl, cycloalkyl or heterocycloalkyl;

[0038] The above R 1 , R 2 Not H at the same time.

[0039] Preferably, the compound is one or more combinations of Compound C1 to Compound C35:

[0040]

[0041]

[0042] On the other hand, the present invention also provides a pharmaceutical composition, which comprises any of the above compounds or pharmaceutically acceptable salts thereof or hydrates thereof or solvates thereof or prodrugs thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0043] Furthermore, the pharmaceutically acceptable excipients include at least one of a binder, a filler, a disintegrant, a lubricant and a glidant.

[0044] Furthermore, the pharmaceutically acceptable carrier includes at least one of a cream, an emulsion, a gel, a liposome and a nanoparticle.

[0045] On the other hand, any of the above-mentioned compounds or their pharmaceutically acceptable salts or their hydrates or their solvates or their prodrugs or any of the above-mentioned pharmaceutical compositions provided by the present invention can be used in the preparation of oral or injectable drugs for preventing, inhibiting and treating diseases caused by viral infections.

[0046] Furthermore, the virus is a coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus and Filoviridae virus that infect mammals.

[0047] Furthermore, the coronavirus includes feline enteric coronavirus (FECV), feline infectious peritonitis virus (FIPV) or porcine epidemic diarrhea virus (PEDV).

[0048] Furthermore, the disease caused by the viral infection is feline enteritis caused by feline enteric coronavirus (FECV) infection, feline infectious peritonitis caused by feline infectious peritonitis virus (FIPV) infection, or porcine epidemic diarrhea caused by porcine epidemic diarrhea virus (PEDV) infection.

[0049] Furthermore, the compound or its pharmaceutically acceptable salt or its hydrate or its solvate or its prodrug or pharmaceutical composition is suitable for oral administration or injection administration.

[0050] Furthermore, the subject for oral administration or injection administration is a mammal, including a cat, a pig, a mouse or a dog, preferably a cat.

[0051] The compound or its pharmaceutically acceptable salt or its hydrate or its solvate or its prodrug or pharmaceutical composition provided by the present invention has at least one of the following advantages after being administered to a mammal: good oral or injectable bioavailability and a long half-life. In view of the above characteristics, the compound or its pharmaceutically acceptable salt or its hydrate or its solvate or its prodrug or pharmaceutical composition provided by the present invention can also be used to prepare oral or injectable drugs for preventing, inhibiting and treating diseases caused by viral infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The effect of the test substance / control drug on FIPV-infected CRFK cells.

[0053] Figure 2 This is the effect of GS-441524 on FIPV-infected CRFK cells.

[0054] Figure 3 The effect of compound C1 on FIPV-infected CRFK cells.

[0055] Figure 4 This is the effect of compound C2 on FIPV-infected CRFK cells.

[0056] Figure 5 This is the effect of compound C3 on FIPV-infected CRFK cells.

[0057] Figure 6 This is the effect of compound C4 on FIPV-infected CRFK cells.

[0058] Figure 7 This is the effect of compound C5 on FIPV-infected CRFK cells. DETAILED DESCRIPTION

[0059] In order to provide a clear and consistent understanding of the terms used in the specification of the present invention, some definitions are provided below. In addition, unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by ordinary technicians in the field to which the present invention belongs.

[0060] As used herein, unless otherwise indicated, the term "treat," ...

[0061] The term "pharmaceutically acceptable" as used herein means that the drugs, medicines, inert ingredients, etc. described by the term are suitable for contact with animal tissues without unusual toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio.

[0062] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a pharmaceutically acceptable compound. The salt of an ideal compound can retain or improve the biological activity and properties of the parent compound as defined in the present invention, and is biologically desirable. Pharmaceutically acceptable salts can be synthesized from a parent compound containing a basic or acidic fragment by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with a stoichiometric amount of a base or acid in water or an organic solvent or in a mixture of the two. In addition, the term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, i.e., "inner salts."

[0063] The term "prodrug" or its equivalent as used in the present invention refers to a pharmaceutical agent that is usually pharmaceutically inactive but can be directly or indirectly converted into an active form in vitro or in vivo. Prodrugs can be used to change the biodistribution or pharmacokinetics of a specific drug. Compounds are modified using a variety of groups such as esters, ethers, phosphates / salts, etc. to form prodrugs, and when the prodrug is applied to a subject, the group is cleaved by enzymatic or non-enzymatic, reduction, oxidation or hydrolysis, or otherwise releases the active compound. "Prodrugs" as used in the present invention include pharmaceutically acceptable salts, or pharmaceutically acceptable hydrates, or pharmaceutically acceptable solvates.

[0064] The term "prevention" as used in the present invention refers to starting an action in a certain way (e.g., before the onset of a disease, disorder, condition, or its symptoms) to temporarily or permanently prevent, inhibit, suppress, or reduce the risk of a subject suffering from a disease, disorder, or condition, etc. (as determined by, for example, the lack of clinical symptoms) or delaying its onset in the case of a subject susceptible to a specific disease, disorder, or condition. In some cases, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting its development into a harmful or other undesirable state. Specifically, the term "prevention" used in the present invention is used to indicate the administration of a compound or composition according to the present invention to prevent the occurrence of related diseases caused by viral infection. The term "prevention" also encompasses the administration of a compound or composition according to the present invention to prevent at least one viral infection by administering to a patient susceptible to viral infection or a patient at risk of viral infection.

[0065] The term "treatment" refers to the initiation of actions to temporarily or permanently eliminate, alleviate, inhibit, slow down or improve at least one potential cause of the disease, disorder or condition that afflicts the subject, or the symptoms associated with the disease, disorder or condition that afflict the subject, after the disease, disorder or condition or its symptoms have been diagnosed, observed. Therefore, treatment includes inhibiting (e.g., preventing or alleviating the development or further development of the disease, disorder or condition or clinical symptoms associated therewith) active disease. Specifically, the term "treatment" as used in the present invention is used to specifically indicate that a therapeutic substance including a compound or composition according to the present invention is administered to a patient who has already suffered from an infection. The term "treatment" also involves administering a compound or composition according to the present invention, optionally together with one or more antibacterial agents, to alleviate or relieve one or more symptoms associated with a viral infection; or to slow the development of a viral infection or one or more symptoms associated with a viral infection; or to reduce the severity of one or more symptoms associated with a viral infection; or to inhibit the clinical manifestations of a viral infection; or to inhibit the manifestation of adverse symptoms of a viral infection.

[0066] The term "feline coronavirus", feline coronavirus (FCoV) is the pathogen of feline infectious peritonitis (FIP), a fatal disease in domestic cats and wild cats. The FCoV virus has four main structural proteins, namely spike protein (S), membrane protein (M), small envelope protein (E) and nucleocapsid protein (N). Among them, the S protein is a glycoprotein arranged in the protrusions of the envelope, with a molecular weight of about 180 to 200 kDa. It is very important for inducing the host's antibody response and cellular immunity. Coronavirus can bind to specific cell receptors through the S protein, which is a key factor in determining the pathogenicity and tissue tropism of the virus. The S protein is a protective antigen that induces the body to produce neutralizing antibodies. At present, the relevant research on vaccines is also concentrated in the S protein area.

[0067] FCoV is divided into two serotypes: type I and type II according to the difference in S protein amino acid sequence and antibody cross-neutralization. Serotype I is the main type of epidemic strain, and its S protein is completely derived from FCoV. Serotype II FCoV is uncommon in clinical practice and is derived from dual recombination of canine coronavirus (CCoV) and FCoV. FCoV-I is widely prevalent worldwide. In the United States and some European countries, the infection rate of FCoV-I strains is as high as 80-95%; in Asia, FCoV-II is the main prevalent type, with an infection rate of up to 25%. Both serotype I and II FCoV strains have two antigenically and morphologically different biotypes (or pathological types): feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV).

[0068] The compounds and compositions provided by the present invention can be applied to a subject in any appropriate manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intracerebral parenchyma and intraventricular; nasal; vaginal; sublingual; intraocular; rectal; topical (e.g., transdermal); oral and inhalation. Deposit injections, generally administered subcutaneously or intramuscularly, can also be used to release compounds or compositions disclosed in the present invention within a limited time period.

[0069] In some embodiments, the compounds or pharmaceutical compositions provided by the present invention are suitable for oral use in the form of tablets, capsules, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. The compounds or pharmaceutical compositions for oral use can be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions can contain one or more agents, such as sweeteners, flavoring agents, colorants and preservatives to provide pharmaceutically acceptable preparations. Tablets, capsules, etc. generally contain active ingredients mixed with non-toxic pharmaceutically acceptable carriers or excipients suitable for making tablets. These carriers or excipients can be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; adhesives, such as starch, gelatin or gum arabic; and lubricants, such as magnesium stearate, stearic acid or talc.

[0070] In some embodiments, the compounds or pharmaceutical compositions provided by the present invention are in a form suitable for injection. For example, a sterile injectable aqueous or oily suspension, which can be prepared according to techniques known in the art using a suitable dispersant or wetting agent and a suspending agent. It can also be a sterile injectable solution in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used are water, Ringer's solution or isotonic sodium chloride solution. In addition, sterile oils can be used as solvents or suspension media, including synthetic monoglycerides and diglycerides.

[0071] In some embodiments, the compound or pharmaceutical composition provided by the invention is combined with a carrier material to produce a single dosage form and the amount applied varies according to the object treated and a specific mode of administration. For example, a delayed release preparation for oral administration to a feline can contain 0.001-1000mg of active substance, which is mixed with a suitable and convenient amount of carrier material, and the carrier can be 5-95wt% of the total pharmaceutical composition. The pharmaceutical composition can be prepared to provide an application amount that is easy to measure. For example, an aqueous solution for intravenous infusion can contain 3-500μg of active substance per milliliter of solution.

[0072] In some embodiments, the compounds or pharmaceutical compositions provided herein can be administered for any suitable period of time. It depends on whether the compound or pharmaceutical composition is administered prophylactically or for treating a mammal infected with a coronavirus. For example, it can be 1-100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days; it can also be 1-15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks.

[0073] In order to better understand the present invention and more clearly show how to implement the present invention, the features of the embodiments according to the present invention are now described by way of examples in conjunction with the accompanying drawings.

[0074] The present invention will be more readily understood by reference to the following examples, which are provided to illustrate the present invention and are not to be construed as limiting the scope of the present invention in any way.

[0075] Unless otherwise defined or the context clearly dictates otherwise, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Unless otherwise specified, the materials and instruments used in the present invention are conventionally commercially available.

[0076] Example

[0077] Example 1 Preparation of Compound C1:

[0078]

[0079] Compound SM was synthesized according to the method of patent WO2016069826.

[0080] To 10 mL of 2-butanone, add 1 g (3.43 mmol) of compound SM, add dropwise 0.81 g (6.86 mmol) of 2,2-dimethoxybutane, cool the system to 0-5 ° C, and add 1.18 g (6.86 mmol) of p-toluenesulfonic acid in batches. Keep the reaction warm until the TLC plate shows that the reaction is complete, add an appropriate amount of saturated sodium bicarbonate solution to the system, extract with dichloromethane, dry the extract over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product. The crude product is purified by column chromatography (ethyl acetate-petroleum ether) to obtain compound C1a (0.90 g, yield 76.0%). MS: m / z = 346.15 [M+1] + .

[0081] At 0 ℃, to 0.9g (2.61mmol) compound C1a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml) and extracted with ethyl acetate (20mL×3). The combined organic layer was then dried over sodium sulfate and concentrated in vacuo to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solid C1 (0.74g, yield: 62%).

[0082] The structure of C1 was characterized and the results are as follows:

[0083] 1 HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H),

[0084] 7.18-7.19(d,1H),5.39-5.40(d,1H),5.06-5.08(d,1H),4.68(s,1H),4.23-4.26(t,2H),3.95-3.99(d,1 H), 3.83-3.86 (d, 1H), 3.10 (s, 1H), 2.27-2.40 (m, 2H), 1.69-1.76 (m, 6H), 1.27 (s, 3H), 0.89-0.96 (m, 6H).

[0085] MS: m / z = 460.22 [M+1] + .

[0086] Example 2 Preparation of Compound C2:

[0087]

[0088] Compound SM was synthesized according to the method of patent WO2016069826.

[0089] The preparation method of C2a is the same as the preparation method of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 3,3-dimethoxypentane. Product yield 80%, MS: m / z=360.16[M+1] + .

[0090] At 0 ℃, to 0.94g (2.61mmol) compound C2a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C2 (0.80g, yield: 65%).

[0091] The structure of C2 was characterized and the results are as follows:

[0092] 1 HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H),

[0093] 7.18-7.19(d,1H),5.39-5.40(d,1H),5.06-5.08(d,1H),4.68(s,1H),4.23-4.26(t,2H),3.95-3.9 9(d,1H),3.83-3.86(d,1H),3.10(s,1H),2.27-2.40(m,2H),1.69-1.76(m,8H),0.89-0.96(m,9H).

[0094] MS: m / z = 474.23 [M+1] + .

[0095] Example 3 Preparation of Compound C3:

[0096]

[0097] Compound SM was synthesized according to the method of patent WO2016069826.

[0098] The preparation method of C3a is the same as the preparation method of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 2,2-dimethoxypentane. Product yield 79%, MS: m / z=360.16[M+1] + .

[0099] At 0 ℃, to 0.93g (2.61mmol) compound C3a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C3 (0.83g, yield: 67%).

[0100] The structure of C3 was characterized and the results are as follows:

[0101] 1 HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H),

[0102] 7.18-7.19(d,1H),5.39-5.40(d,1H),5.06-5.08(d,1H),4.68(s,1H),4.23-4.26(t,2H),3.95-3.99(d,1 H), 3.83-3.86 (d, 1H), 3.10 (s, 1H), 2.27-2.40 (m, 2H), 1.69-1.76 (m, 8H), 1.27 (s, 3H), 0.89-0.96 (m, 6H).

[0103] MS: m / z = 474.23 [M+1] +.

[0104] Example 4 Preparation of Compound C4:

[0105]

[0106] Compound SM was synthesized according to the method of patent WO2016069826.

[0107] The preparation method of C4a is the same as the preparation method of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 1,1-dimethoxycyclopentane. Product yield 73%, MS: m / z = 358.15

[0108] [M+1] + .

[0109] At 0 ℃, to 0.93g (2.61mmol) compound C4a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C4 (0.78g, yield: 63%).

[0110] The structure of C4 was characterized and the results are as follows:

[0111] 1HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H), 7.18-7.19 (d, 1H), 5.39-5.40 (d, 1H), 5.06-5.08 (d, 1H), 4.68 (s, 1H), 4.23-4.2 6(t,2H),3.95-3.99(d,1H),3.83-3.86(d,1H),3.10(s,1H),2.27-2.40(m,2H),1.69-1.76(m,6H),1.35-1.40(m,6H),0.90-0.96(t,3H).

[0112] MS: m / z = 472.22 [M+1] + .

[0113] Example 5 Preparation of Compound C5:

[0114]

[0115] Compound SM was synthesized according to the method of patent WO2016069826.

[0116] The preparation method of C5a is the same as the preparation method of C1a in Example 1, except that 2,2-dimethoxybutane is replaced with an equal molar amount of 1,1-dimethoxycyclohexane. Product yield 75%, MS: m / z = 372.16

[0117] [M+1] + .

[0118] At 0 ℃, to 0.97g (2.61mmol) compound C4a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C4 (0.84g, yield: 66%).

[0119] The structure of C5 was characterized and the results are as follows:

[0120] 1HNMR (400MHz, CDC13): δ8.10 (s, 1H), 7.26-7.27 (d, 2H), 7.18-7.19 (d, 1H), 5.39-5.40 (d, 1H), 5.06-5.08 (d, 1H), 4.68 (s, 1H), 4.23-4.2 6 (t, 2H), 3.95-3.99 (d, 1H), 3.83-3.86 (d, 1H), 3.10 (s, 1H), 2.27-2.40 (m, 2H), 1.69-1.76 (m, 6H), 1.35-1.40 (m, 8H), 0.90-0.96 (t, 3H).

[0121] MS: m / z = 486.23 [M+1] + .

[0122] Example 6 General preparation procedure of compounds C6-C10:

[0123]

[0124] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0125] The acetal intermediates C1a-C5a were respectively dissolved in a mixed solution of toluene and acetic anhydride (volume ratio of 10:1), heated to reflux, and kept warm for reaction. When TLC showed that the raw material was completely converted, the system was evaporated to dryness, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solid C6a-C10a (yield: 15-30%).

[0126] At 0 ° C, to 2.61mmol compound C6a-C10a and 0.31g (3.92mmol) pyridine in DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate. Then the mixture was stirred at 20 ° C for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml) and extracted with ethyl acetate (20mL × 3). The combined organic layer was then dried over sodium sulfate and concentrated in vacuo to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solid C6-C10.

[0127] C6, based on C1a, molar yield 11%, MS: m / z = 502.23 [M+1] + .

[0128] C7, based on C2a, molar yield 13%, MS: m / z = 516.24 [M+1] + .

[0129] C8, based on C3a, molar yield 12%, MS: m / z = 516.24 [M+1] + .

[0130] C9, based on C4a, molar yield 8%, MS: m / z = 514.23 [M+1] + .

[0131] C10, based on C5a, molar yield 7%, MS: m / z = 528.24 [M+1] + .

[0132] Example 7 General preparation procedure of compounds C11-C15:

[0133]

[0134] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0135] To a solution of compound C1a-C5a (0.098 mmol) and 1H-tetrazole (30 mg, 0.43 mmol) in anhydrous acetonitrile (1 mL) at 0°C was added 2,2-dimethyl-thiopropionic acid S-(2-{diisopropylamino-[2-(2,2-dimethyl-propionylsulfanyl)-ethoxy]-phosphanyloxy}-ethyl) ester (90 mg, 0.2 mmol) (described in J. Med. Chem, 1995, 38(20), 3941). The reaction mixture was stirred at 0°C for 1 h, then hydrogen peroxide (30%, 80 uL) was added and stirred at 0°C for 0.5 h. The reaction was quenched with sodium thiosulfate (1 M, 1 mL) and sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give compound C11a-C15a.

[0136] At 0 ° C, to 2.61mmol compound C11a-C15a and 0.31g (3.92mmol) pyridine in DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate. Then the mixture was stirred at 20 ° C for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml) and extracted with ethyl acetate (20mL×3). The combined organic layer was then dried over sodium sulfate and concentrated in vacuo to obtain a residue. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether) to obtain solid C11-C15.

[0137] C11, based on C1a, molar yield 33%, MS: m / z = 828.30 [M+1] + .

[0138] C12, based on C2a, molar yield 37%, MS: m / z = 842.32 [M+1] + .

[0139] C13, based on C3a, molar yield 31%, MS: m / z = 842.32 [M+1] + .

[0140] C14, based on C4a, molar yield 40%, MS: m / z=840.30[M+1] + .

[0141] C15, based on C5a, molar yield 38%, MS: m / z = 854.32 [M+1] + .

[0142] Example 8 General preparation procedure of compounds C16-C20:

[0143]

[0144] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0145] A pear-shaped flask (5-15 mL) was charged with C1a-C5a (20 mg), trimonomethyl phosphate (0.5-1.0 mL) was added, and the solution was cooled with an ice-water bath. Phosphorus oxychloride (40-45 mg) was added and stirred at 0°C until the reaction was complete. A solution of pyrophosphate-Bu3N (250 mg) and Bu3N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) was then added. The mixture was stirred at 0°C for 0.3-2.5 h, and then the reaction was quenched with 1.0 M ethylammonium carbonate (5 mL). The resulting mixture was stirred. The mixture was concentrated to dryness, redissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the target product were concentrated to dryness, dissolved in water (5 mL), concentrated to dryness, and dissolved again in water (5 mL). Sodium bicarbonate (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated to dryness again. This process was repeated 2-5 times. The residue was then subjected to HPLC preparative purification to afford compounds C16a-C20a.

[0146] At 0 ℃, to 2.61mmol compound C16a-C20a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C16-C20.

[0147] C16, based on C1a, molar yield 12%, MS: m / z = 540.18 [M+1] + .

[0148] C17, based on C2a, molar yield 16%, MS: m / z = 554.20 [M+1] + .

[0149] C18, based on C3a, molar yield 24%, MS: m / z = 554.20 [M+1] + .

[0150] C19, based on C4a, molar yield 21%, MS: m / z = 552.18 [M+1] + .

[0151] C20, based on C5a, molar yield 22%, MS: m / z = 565.52 [M+1] + .

[0152] Example 9 General preparation procedure of compounds C21-C25:

[0153]

[0154] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0155] A pear-shaped flask (5-15 mL) was charged with C1a-C5a (20 mg), trimethyl phosphate (0.5-1.0 mL) was added, and the solution was cooled with an ice-water bath. Phosphorus oxychloride (40-45 mg) was added and stirred at 0°C until the reaction was complete. A solution of pyrophosphate-Bu3N (250 mg) and Bu3N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) was then added. The mixture was stirred at 0°C for 0.3-2.5 h, and then the reaction was quenched with 1.0 M ethylammonium carbonate (5 mL). The resulting mixture was stirred. The mixture was concentrated to dryness, redissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the target product were concentrated to dryness, dissolved in water (5 mL), concentrated to dryness, and dissolved again in water (5 mL). Sodium bicarbonate (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated to dryness again. This process was repeated 2-5 times. The residue was then subjected to HPLC preparative purification to afford compounds C21a-C25a.

[0156] At 0 ℃, to 2.61mmol compound C21a-C25a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL×3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C21-C25.

[0157] C21, based on C1a, molar yield 22%, MS: m / z = 604.15 [M+1] + .

[0158] C22, based on C2a, molar yield 21%, MS: m / z = 618.17 [M+1] + .

[0159] C23, based on C3a, molar yield 23%, MS: m / z = 618.17 [M+1] + .

[0160] C24, based on C4a, molar yield 21%, MS: m / z = 616.15 [M+1] + .

[0161] C25, based on C5a, molar yield 22%, MS: m / z = 630.17 [M+1] + .

[0162] Example 10 General Preparation Procedure for Compounds C26-C30

[0163]

[0164] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0165] A pear-shaped flask (5-15 mL) was charged with C1a-C5a (20 mg) and trimethyl phosphate (0.5-1.0 mL) was added. The solution was cooled with an ice-water bath. Phosphorus oxychloride (40-45 mg) was added and stirred at 0°C until the reaction was complete. A solution of pyrophosphate-Bu3N (250 mg) and Bu3N (90-105 mg) in acetonitrile or DMF (1-1.5 mL) was then added. The mixture was stirred at 0°C for 0.3-2.5 h, and then the reaction was quenched with 1.0 M ethylammonium carbonate (5 mL). The resulting mixture was stirred. The mixture was concentrated to dryness, redissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the target product were concentrated to dryness, dissolved in water (5 mL), concentrated to dryness, and dissolved again in water (5 mL). Sodium bicarbonate (30-50 mg) was added and concentrated to dryness. The residue was dissolved in water and concentrated to dryness again. This process was repeated 2-5 times. The residue was then subjected to HPLC preparative purification to afford compounds C26a-C30a.

[0166] At 0 ℃, to 2.61mmol compound C26a-C30a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL × 3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C26-C30.

[0167] C26, based on C1a, molar yield 25%, MS: m / z = 668.12 [M+1] + .

[0168] C27, based on C2a, molar yield 25%, MS: m / z = 682.14 [M+1] + .

[0169] C28, based on C3a, molar yield 22%, MS: m / z = 682.14 [M+1] + .

[0170] C29, based on C4a, molar yield 25%, MS: m / z = 680.12 [M+1] + .

[0171] C30, based on C5a, molar yield 24%, MS: m / z = 694.14 [M+1] + .

[0172] Example 11 General Preparation Procedure for Compounds C31-C35

[0173]

[0174] According to the method of Examples 1-5, acetal intermediates C1a-C5a were prepared.

[0175] Compounds C16a-C20a (1.19 mmol) were dried overnight over phosphorus pentoxide in vacuo. The dried material was suspended in 4 ml of anhydrous DMF and 4.92 mmol of DIPEA. 7.34 mmol of isopropyl chloromethyl carbonate (Antiviral Chemistry & Chemotherapy 8: 557 (1997)) was added and the mixture was heated to about 25-60°C for about 30 min to 24 hours. After cooling, the reaction was filtered. The filtrate was diluted with water, extracted with dichloromethane, dried, evaporated to dryness, and purified by HPLC preparation to obtain the desired products C31a-C35a.

[0176] At 0 ℃, to 2.61mmol compound C31a-C35a and 0.31g (3.92mmol) pyridine DMF (10mL) solution, slowly add 0.59g (3.92mmol) n-pentyl chloroformate.Then the mixture was stirred at 20 ℃ for 16 hours, and TLC showed that the starting material was completely consumed. The mixture was quenched with water (20ml), and extracted with ethyl acetate (20mL × 3).Then the combined organic layer was dried over sodium sulfate, and concentrated in vacuo to obtain residue.The residue was purified by flash column chromatography (ethyl acetate / petroleum ether), to obtain solid C31-C35.

[0177] C31, based on C16a, molar yield 58%, MS: m / z = 740.29 [M+1] + .

[0178] C32, based on C17a, molar yield 60%, MS: m / z=754.30[M+1] + .

[0179] C33, based on C18a, molar yield 54%, MS: m / z = 754.30 [M+1] + .

[0180] C34, based on C19a, molar yield 59%, MS: m / z = 752.29 [M+1] + .

[0181] C35, based on C20a, molar yield 62%, MS: m / z = 766.30 [M+1] + .

[0182] Compounds C1-C5 for the treatment of feline coronavirus

[0183] 1. FIPV culture

[0184] Crandell Rees cat kidney (CRFK) cells (deposited by: Cell Bank of Typical Culture Collection Committee of Chinese Academy of Sciences, No.: 3101MAMGNO16) were inoculated in a culture bottle. When the cell density reached 70-80%, part of the culture medium was removed, and the remaining medium just covered the cells. An appropriate amount of FIP virus was added. After the virus was adsorbed on the cell surface (about 3 hours, the culture plate was gently shaken every 30 minutes to make the virus adsorbed evenly), fresh MEM culture medium without fetal bovine serum (FBS) was replaced and placed in a 37°C, 5% CO2 humidified constant temperature incubator for culture. When the cells began to produce typical lesions such as rounding, shedding, drawing, fusion, etc., until no lesions were produced (generally 2-7 days), repeated freezing and thawing method was adopted, centrifuged at 3000rpm for 10 minutes to remove cell residues, and the supernatant was collected and dispensed into cryopreservation tubes. After labeling, it was stored at -80°C for a short term or in liquid nitrogen for a long term for standby use.

[0185] 2. FIPV titer detection

[0186] 100 μL of CRFK single cell suspension was inoculated in 96-well cell culture plates. When the cell monolayer grew to a density of 70-80%, virus inoculation was performed. 100 μL of virus solution was diluted 10-fold, with a total of 6 dilution gradients, namely 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10 -6 Virus inoculation: discard the original culture medium in the 96-well plate, wash the cells twice with PBS solution, and then inoculate the virus. Set up 8 replicate wells for each virus dilution concentration, and add 100μL of virus dilution solution to each well. At the same time, set up normal control wells without virus inoculation, repeat 2 wells, and add 100μL of cell culture solution.

[0187] After virus inoculation, place the 96-well cell plate in a 37°C, 5% CO2 cell culture incubator for 1 hour. Take out the culture plate and gently shake it every 15 minutes to promote virus adsorption to cells. Transfer the 96-well cell culture plate to the incubator, add 100 μL of virus maintenance solution, and mark it. Observe the cells for CPE under an inverted microscope every day, twice a day, for 5 consecutive days. Record the number of wells with CPE and calculate the TCID of the virus according to the Reed-Mench formula. 50 .

[0188] TCID 50 = the highest logarithm of virus dilution with CPE higher than 50% + distance ratio value × logarithm of dilution multiple;

[0189] Wherein, distance ratio value = (percentage above 50% CPE - 50%) / (percentage above 50% CPE - percentage below 50% CPE).

[0190] The test results are recorded in Table 1.

[0191] Table 1 Half viral infection dose of FIPV on CRFK cells

[0192]

[0193] 3. Antiviral testing of compounds

[0194] From the test results in Table 1, we can see that the TCID of FIPV is 50 10 respectively -4.22 / 0.1mL, 1.66×10 4 When the dilution is 0.1 mL, 50% of the cells will become diseased. 50 The virus amount was diluted 166 times for in vitro antiviral test.

[0195] CRFK cells were collected by digestion and then 5 Cells / well were inoculated into 96-well plates and cultured overnight in a cell culture incubator until a monolayer of cells was formed. The test substance was diluted to multiple concentrations with culture medium. When the cells were about 80% full, the culture medium was discarded and 100 TCID 50100 μL / well of virus solution. After 2 hours of continuous culture, replace with 100 μL / well of the above-mentioned different concentrations of drug-containing serum-free culture medium, set up a positive drug control group (GS-441524, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.), a model control group and a normal control group in parallel, set up 8 replicate wells for each sample group, shake the plate crosswise to mix, and place in a cell culture incubator for continued culture. Observe the cytopathic effect, use the model group as a reference, record the cytopathic effect (CPE well number) in each sample well under a microscope, and calculate the EC 50 .

[0196] The in vitro anti-FIPV effects of GS-441524 and compounds C1-C5 are shown in Tables 2 and Figure 1 to Figure 7 .

[0197] Table 2 Effects of test substances / control drugs on FIPV-infected CRFK cells

[0198]

[0199]

[0200] From Table 2, Appendix Figure 1-7 It can be seen that the present invention tested the in vitro antiviral effect of 8 remdesivir metabolites GS-441524 and compounds C1-C5 on FIPV. After 4 hours of medication, cells were infected with 100 times the TCID50 virus amount to detect the interference of each compound on the ability of FIPV to infect cells. It was found that compounds C1 to C5 all had in vitro anti-FIPV effects, and the effect was better than GS-441524. Among them, the test result of compound C5 was the best, and its EC 50 It is 0.517μM, and its antiviral infection effect is much better than GS-441524.

[0201] Pharmacokinetic evaluation of compounds C1-C5 in rats

[0202] After a single intravenous injection / oral administration of compounds C1-C5 and GS-441524 to fasted SD male rats, blood samples were collected at 0.08h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration. Plasma was centrifuged and frozen at -20°C, and the concentrations of compounds C1-C5 and GS-441524 in plasma were determined by HPLC-MS / MS. Plasma was added to a test tube containing internal standard and methanol or acetonitrile, shaken vigorously for 5 minutes to achieve deproteinization, and then centrifuged at 6000rmp for 8 minutes. The supernatant was transferred to an automatic sampling bottle and injected into the chromatographic analysis system, and the pharmacokinetic parameters were calculated using winMolin6.3 software.

[0203] The calculation results are recorded in Table 3, where t 1 / 2 C is the half-life. The larger the value, the slower the elimination or distribution process of the active ingredient. max It is the peak drug concentration, that is, the highest blood drug concentration after administration.

[0204] Table 3 Pharmacokinetic parameters of compounds C1-C5 and GS-441524 in rats

[0205]

[0206] It can be seen from the test results in Table 3 that, compared with GS-441524, the bioavailability of injection / oral administration of compounds C1-C5 is significantly improved, with higher Cmax values ​​and t1 / 2. Combining the test results in Tables 2 and 3, it can be seen that the compounds disclosed in the present invention have outstanding antiviral properties and pharmacokinetic properties both in vitro and in vivo.

[0207] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention using the technical content disclosed above are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: The chemical structural formula of the compound is shown in Formula I: in, R 1 Selected from H, -C(=O)R 5 , -C(=O)OR 5 or optionally one or more R 6 Substituted C1-C8 alkyl; preferably, R 1 is n-pentyloxycarbonyl; R 2 selected from H, -C(=O)R 6 , -C(=O)OR 6 , -C(=O)NR 6 R 7 , -C(=O)SR 6 , -S(O)R 6 , -S(O)R 6 ,-S(O)(OR 6 ),-S(O)2(OR 6 ),-SONR 6 R 7 or Y is O or S; W 1 and W 2 Each independently selected from the group of formula Ia: in: Each X is independently selected from O, OR 5 NR 5 、N(O)(R 5 )、N(OR 5 )、N(O)(OR 5 )、N-NR 5 , SS, S(O) or S(O)2; R 3 and R 4 Each independently selected from H, OR 5 、N(R 5 )2, N3, CN, NO2, S(O) n R 5 , halogen, C1-C8 alkyl, C4-C8 carbocyclylalkyl, C1-C8 substituted alkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2-C8 alkynyl, C2-C8 substituted alkynyl, or arylC1-C8 alkyl; or R 3 and R 4 Form a C4-C16 carbocyclic ring, a C4-C16 unsaturated carbocyclic ring, a C4-C16 carbon-oxygen heterocyclic ring, a C4-C16 carbon-nitrogen heterocyclic ring, or a C4-C16 carbon-sulfur heterocyclic ring; Each n is independently 0, 1, or 2; R 5 is selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl C1-C8 alkyl, C4-C8 carbocyclyl alkyl, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 , -C(=O)SR 6 ,-SC(=O)R 6 , -S(O)R 6 , -S(O)R 6 , -S(O)(OR 6 ), -S(O)2(OR 6 ) or -SONR 6 R 7 ; R 6 and R 7 Each independently selected from -CN, -OH, -OR 5 、-NR 5 R 5 , halogen, alkyl, cycloalkyl or heterocycloalkyl; The above R 1 , R 2 , R 3 and R 4 Not H at the same time.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: The compound is one or more combinations of compounds represented by formula II to formula VI: in, R 1 Selected from H, -C(=O)R 5 , -C(=O)OR 5 or optionally one or more R 6 Substituted C1-C8 alkyl; preferably, R 1 is n-pentyloxycarbonyl; R 2 selected from H, -C(=O)R 6 , -C(=O)OR 6 , -C(=O)NR 6 R 7 , -C(=O)SR 6 , -S(O)R 6 , -S(O)R 6 、 -S(O)(OR 6 )、 -S(O)2(OR 6 )、 -SONR 6 R 7 or Y is O or S; W 1 and W 2 Each independently selected from the group of formula Ia: in: Each X is independently selected from O, OR 5 NR 5 、N(O)(R 5 )、N(OR 5 )、N(O)(OR 5 )、N-NR 5 , SS, S(O) or S(O)2; R 5 is selected from H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl C1-C8 alkyl, C4-C8 carbocyclyl alkyl, -C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 , -C(=O)SR 6 ,-SC(=O)R 6 , -S(O)R 6 , -S(O)R 6 , -S(O)(OR 6 ), -S(O)2(OR 6 ) or -SONR 6 R 7 ; R 6 and R 7 Each independently selected from -CN, -OH, -OR 5 、-NR 5 R 5 , halogen, alkyl, cycloalkyl or heterocycloalkyl; The above R 1 , R 2 Not H at the same time.

3. The compound according to claim 2 or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, characterized in that: The compound is one or more combinations of Compound C1 to Compound C35:

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.

5. The pharmaceutical composition according to claim 4, characterized in that The excipient is selected from one or more of a binder, a filler, a disintegrant, a lubricant and a glidant, and the carrier is selected from one or more of a cream, an emulsion, a gel, a liposome and a nanoparticle.

6. Use of the compound according to any one of claims 1 to 3 or its pharmaceutically acceptable salt, hydrate, solvate or prodrug, or the pharmaceutical composition according to any one of claims 4 to 5 in the preparation of a medicament for preventing, inhibiting and treating a disease caused by a virus.

7. The use according to claim 6, characterized in that The virus includes a coronavirus, an influenza virus, a respiratory syncytial virus, a Flaviviridae virus or a Filoviridae virus.

8. The use according to claim 6, characterized in that The coronavirus includes feline enteric coronavirus, feline infectious peritonitis virus or porcine epidemic diarrhea virus.

9. The use according to any one of claim 6, characterized in that The diseases caused by the virus include feline enteritis caused by feline enteric coronavirus infection, feline infectious peritonitis caused by feline infectious peritonitis virus infection, or porcine epidemic diarrhea caused by porcine epidemic diarrhea virus infection.

10. The use according to claim 6, characterized in that The compound or pharmaceutical composition is applied to mammals.

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