CN116162128A

CN116162128A - Nucleoside derivative for resisting virus infection and preparation method and application thereof

Info

Publication number: CN116162128A
Application number: CN202211513012.5A
Authority: CN
Inventors: 张天舒; 侯军旗; 张哲峰
Original assignee: Zhihe Shandong Pharmaceutical Factory Co ltd
Current assignee: Nanjing Saifosi Pharmaceutical Technology Co ltd
Priority date: 2021-11-25
Filing date: 2022-11-25
Publication date: 2023-05-26

Abstract

The invention provides a nucleoside derivative with a novel structure and a salt thereof, and further discloses a preparation method of the compound and application of the compound in antiviral drugs. The nucleoside derivative with a novel structure and the salt thereof provided by the invention have stronger antiviral effect in vivo and in vitro, and have a better medical application prospect.

Description

Nucleoside derivative for resisting virus infection and preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical chemistry, and provides an antiviral nucleoside derivative, a preparation method and application thereof.

Background

Influenza (Influnza) is an epidemic disease caused by Influenza virus, and has the characteristics of high transmission speed and strong infectivity. Typical symptoms of the infected person are fever, pain, debilitation and swelling and pain of respiratory tract, which seriously affect the health of people. Influenza virus infection is seasonal, is a high-frequency stage of cold disease in spring and winter, and causes various complications, and serious cases cause death. According to data statistics, 300-500 thousands of influenza sufferers in each year cause 25-50 thousands of deaths.

Influenza viruses are classified into influenza a (a), influenza B (B) and influenza C (C) according to their nucleoprotein and matrix protein antigens, and recently, the newly developed viruses are classified as influenza delta (D). Human influenza is mainly caused by influenza a virus and influenza b virus infection. At present, the drugs for treating cold which are already marketed are mainly classified into the following categories: m2 ion channel inhibitors, neuraminidase (NA) inhibitors and polymerase inhibitors. Currently, anti-influenza virus drugs mainly include NA inhibitors, mainly Zanamivir (zanamvir), oseltamivir (Oseltamivir), peramivir (Peramivir), and Laninamivir (Laninamivir). Zanamivir and peramivir are administered by inhalation and intravenous injection, respectively, and are extremely inconvenient for patients. Of these, oseltamivir phosphate is only an oral NA inhibitor, and is currently the preferred drug for treating influenza patients. However, with the widespread use of oseltamivir phosphate, influenza strains exhibit significant resistance to oseltamivir phosphate.

Therefore, developing an anti-influenza virus drug with high efficiency and drug resistance is still a difficult point in the research field of anti-influenza drugs, and searching for a novel anti-influenza drug is still urgent.

Disclosure of Invention

The invention solves the technical problem of providing a nucleoside derivative with a novel structure and a salt thereof, and further discloses a preparation method of the compound and application of the compound in antiviral drugs.

The invention solves the technical problem that the nucleoside derivative with a novel structure and the salt thereof have stronger antiviral effect in vivo and in vitro, and have unexpected beneficial technical effects.

The third technical problem solved by the invention is that the compound provided by the invention has a remarkable protective effect on the lung.

In order to solve the technical problems, the invention provides a compound with the following structure of formula I and pharmaceutically acceptable salts, isotopic derivatives, solvates, enantiomers and diastereomers thereof:

w is O or S;

n is 1, 2, 3, or 4;

R ₁ a monocyclic or bicyclic heterocyclyl group being hydrogen, halogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C6-C15 aryl, 3-to 6-membered ring, a monocyclic or bicyclic heteroaryl group being 5-and/or 6-membered ring;

R ₂ is hydrogen, deuterium, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy,

Ra、R _b Each independently hydrogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C3-C8 cycloalkyl, 3-to 6-membered-ring monocyclic or bicyclic heterocyclyl may independently be optionally substituted with one or more of the following groups: methyl, ethyl, halogen, cyano, amino, hydroxy, carboxyl, trifluoromethyl, mercapto, mercaptomethyl, mercaptoethyl, methoxy, ethoxy, acetyl; and Ra, R _b Are not hydrogen at the same time;

R ₃ hydrogen, halogen, cyano, hydroxymethyl, hydroxyethyl, phenyl, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy;

R ₄ hydrogen, halogen, cyano, hydroxymethyl, hydroxyethyl, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl;

R ₅ is hydrogen, hydroxy,

Q ₁ 、Q ₂ Each independently O, S;

R ₆ is hydrogen,

Or by reasonable means with R ₅ Are connected into a ring;

R ₇ a mono-or bicyclic heterocyclyl group being a C1-C8 linear or branched alkyl group, a C1-C8 linear or branched alkoxy group, a C1-C8 linear or branched alkylamino group, a C2-C8 linear or branched alkenyl group, a C2-C8 linear or branched alkynyl group, a C3-C8 cycloalkyl group, a C6-C15 aryl group, a (C1-C8 linear or branched alkyl) C6-C15 aryl group, a 3-to 6-membered ring, a mono-or bicyclic heteroaryl group being a 5-and/or 6-membered ring; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl may be independently optionally substituted with one or more of R ₈ Substitution;

R ₈ is hydrogen, halogen, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercapto, mercaptomethyl, mercaptoethyl, methoxy, ethoxy, acetyl,

C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic or bicyclic heteroaryl of the ring may independently optionally be substituted with one or more R ₉ Substitution;

R ₉ is hydrogen, halogen, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercaptoMethyl, mercaptoethyl, methoxy, ethoxy, acetyl,

C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic or bicyclic heteroaryl;

l is

X ₁ 、X ₂ Each independently O, S, or NH;

R ₁₀ is that

R _c 、R _d Each independently is hydrogen, halogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, or R _c 、R _d Are connected into a ring;

R ₁₁ Is hydrogen, deuterium, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic or bicyclic heteroaryl, independently optionally substituted with one or more of R ₁₈ Substitution;

R ₁₂ 、R ₁₃ are each independently C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, or R ₁₂ 、R ₁₃ The links may be optionally substituted with one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, mercapto, mercaptomethyl, mercaptoethyl, methoxy, ethoxy, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy;

R ₁₄ hydrogen, methyl, ethyl;

R ₁₅ is a C1-C8 linear or branched alkyl group, a C1-C8 linear or branched alkoxy group, a C1-C8 linear or branched alkylamino group optionally substituted with one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, mercapto, mercaptomethyl, mercaptoethyl, methoxy, ethoxy, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy;

R ₁₆ is hydrogen, cyano, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, carbonyl; wherein said alkyl, alkoxy, alkenyl, alkynyl, carbonyl groups are independently optionally substituted with one or more of R ₂₁ Substitution;

R ₁₇ is C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, independently optionally substituted with one or more of R ₂₂ Substitution;

R ₁₈ is hydrogen, deuterium, halogen, methyl, ethyl, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercapto methyl, mercapto ethyl, methoxy, ethoxy, acetyl,

(C1-C8 Linear or branched alkyl) enamine, (C1-C8 Linear or branched alkoxy) enamine, C1-C8 Linear or branched alkyl, C1-C8 Linear or branched alkoxy, C1-C8 Linear or branched alkylamino, C2-C8 Linear or branched alkenyl, C2-C8 Linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 Linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic or bicyclic heteroaryl may be independently optionally substituted with one or more of R ₁₉ Substitution;

R ₁₉ is hydrogen, deuterium, halogen, methyl, ethyl, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercapto methyl, mercapto ethyl, methoxy, ethoxy,Acetyl group,

(C1-C8 Linear or branched alkyl) enamine, (C1-C8 Linear or branched alkoxy) enamine, C1-C8 Linear or branched alkyl, C1-C8 Linear or branched alkoxy, C1-C8 Linear or branched alkylamino, C2-C8 Linear or branched alkenyl, C2-C8 Linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 Linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic or bicyclic heteroaryl may be independently optionally substituted with one or more of R ₂₀ Substitution;

R ₂₀ is hydrogen, deuterium, halogen, methyl, ethyl, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercapto methyl, mercapto ethyl, methoxy, ethoxy, acetyl,

R ₂₁ Is hydrogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C3-C8 cycloalkyl, 3-to 6-membered-ring monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered-ring monocyclic or bicyclic heteroaryl, C6-C15 aryl can independently optionally be substituted with one or more of R ₂₃ Substitution;

R ₂₂ is that

m is 1, or 2;

R ₂₃ is hydrogen, halogen, cyano, trifluoromethyl, mercapto, mercaptomethyl, mercaptoethyl, methoxy, ethoxy, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy.

A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant and a compound of formula II:

the definition of each substituent in the formula II is defined as in the formula I.

A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant and a compound of formula III:

the definition of each substituent in the formula III is defined as in the formula I.

A pharmaceutical composition comprising pharmaceutically acceptable excipients and the following compounds:

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the compound or pharmaceutically acceptable salts, isotopic derivatives, solvates, enantiomers and diastereomers thereof have the effect of resisting orthomyxoviridae viruses, paramyxoviridae viruses, coronaviruses and filoviridae viruses in human bodies or other animals.

An antiviral agent pharmaceutical composition comprising said compound and a pharmaceutically acceptable adjuvant.

Methods for treating an individual infected with an orthomyxoviridae virus, a paramyxoviridae virus, a coronavirus, a filoviridae virus comprise administering to the infected individual a therapeutically effective amount of the compound or combination thereof.

The application of the composition is that the dosage forms for treating the individual infected by the virus are injection dosage forms, respiratory tract administration dosage forms, skin administration dosage forms, mucous membrane administration dosage forms, cavity tract administration dosage forms and oral dosage forms.

The compounds and pharmaceutical compositions thereof may be used alone and/or in combination with other agents in humans or other mammals to enhance the ability of another antiviral agent to exert an antiviral effect.

The content range of the compound in the pharmaceutical composition is as follows: 0.01% -75% (W/W%).

Unless specifically stated otherwise herein, the terms used herein are all the basic meanings commonly understood by those skilled in the art.

The term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom contained in a molecule.

The term "heteroatom" refers to an oxygen, nitrogen, sulfur, boron, or phosphorus atom contained in a molecule.

The term "C1-C8 linear or branched alkyl" or in its combined terms refers to a straight or branched aliphatic hydrocarbon group containing 1 to 8 carbon atoms, preferably including methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2-methylpentanyl, 3-methylheptanyl, 3-methylpentanyl, 2-methylhexane (isoheptanyl) yl, isooctyl, and the like;

the term "C1-C8 linear or branched alkoxy" or in its combined terms refers to a group having one or more "O" atoms or "OH" groups inserted at any reasonable position of the "C1-C8 linear or branched alkyl" group, preferably including methoxy, ethoxy, isopropoxy, tert-butoxy, methylethoxy, ethylpropoxy, tert-butoxy, 2-heptanol, 1,2, 4-butanetriol, sec-butanol, 2, 5-hexanediol, (2S, 4S) - (+) -pentanediol, ethylisopropoxy, and the like;

the term "C2-C8 linear or branched alkenyl" or in its combined terms refers to a straight, branched, or cyclic aliphatic hydrocarbon group having 2 to 8 carbon atoms in the molecule, containing at least one carbon-carbon double bond, preferably including ethenyl, propenyl, allyl, trans-3-hexenyl, 2-methyl-1-butenyl, 2, 5-dimethyl-3-hexenyl, cyclopentenyl, cyclohexenyl, 1-methyl-1-cyclohexenyl, ethylenecyclohexenyl, and the like.

The term "C2-C8 linear or branched alkynyl" or in its combined terms refers to a straight, branched, or cyclic aliphatic hydrocarbon group having 2 to 8 carbon atoms in the molecule, containing at least one carbon-carbon triple bond, preferably including ethynyl, propynyl, 1-butynyl, 3-methylbutynyl, 2-pentynyl, prop-1-ynylcyclopropanyl, methyl-isopropylethynyl, and the like.

The term "C3-C8 cycloalkyl" or in its combined terms refers to a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in the molecule, which may be saturated or unsaturated, may contain one or more rings fused, and preferably includes cyclopropyl, cyclopentyl, methylcyclopentyl, n-propylcyclopentyl, 1, 3-dimethylcyclopentyl, isopropylcyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like.

The term "C6-C15 aryl" or in its combined terms refers to a group having 6 to 15 carbon atoms in the molecule with one or more benzene ring systems, which may be fused or unfused, and the fused cyclic structure may be a saturated cyclic hydrocarbon group or an unsaturated cyclic hydrocarbon group, preferably including phenyl, indenyl, indanyl, naphthyl, acenaphthenyl, 1,2,3, 4-tetrahydronaphthyl, and the like.

The term "(C1-C8 linear or branched alkyl) C6-C15 aryl" or in its combined terms means "C1-C8 linear or branched alkyl" and "C6-C15 aryl" are as defined above, specifically meaning "C6-C15 aryl" is a group substituted with a linear or branched hydrocarbon group containing 1 to 8 carbon atoms, preferably including benzyl, phenylpropyl, (2, 2-dimethylpropyl) phenyl, benzisopropyl, n-pentylphenyl, 4-isobutylphenyl, 4-n-butylbenzyl, and the like.

The term "3-to 6-membered ring monocyclic or bicyclic heterocyclic group" or in its combined terms refers to a group containing 1 to more heteroatoms in the molecule, having a stable 3-to 6-membered ring system, each ring having 3 to 6 ring atoms, which group has a single or two ring systems, and the ring systems may be saturated or unsaturated, preferably including aziridinyl, pyrrolyl, piperazinyl, pyrazinyl, furan, morpholinyl, tetrahydrothienyl, octahydroindolyl, and the like.

The term "heteroatom" refers to a nitrogen atom, a sulfur atom, an oxygen atom, a phosphorus atom, a boron atom, and the like.

The term "5-and/or 6-membered ring monocyclic or bicyclic heteroaryl" or in its combined terms refers to a monocyclic or bicyclic group containing 1 to more heteroatoms in the molecule, having a stable 5-to 6-membered-aromatic ring system, each ring having 5 to 6 ring atoms, preferably including pyrrolyl, thienyl, pyrazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 5,6,7, 8-tetrahydroquinolinyl, and the like.

The term "C1-C8 linear or branched alkylamino" or in its combined terms means the insertion of "N", "NH", or "NH" at any reasonable position of the "C1-C8 linear or branched alkyl" group ₂ "radical group" preferably includes methylamino, isopropylamino, 3-methylazetidinyl, diisopropylamino, N, N-dimethylbutylamino, N, N-dimethylbutyl, N, N-diethylethylenediamine, N-ethylpiperidino, N-ethylisopropyl, N, N, N' -trimethylethylenediamine, N, N-dimethylcyclohexylamino, and the like.

The term "enamine" or in its combined terms refers to a group containing one or more "- (c=n) -" groups in the group.

The term "(C1-C8 linear or branched alkyl) enamine" or in its combined terms refers to a group in which the "enamine" is substituted with one or more "C1-C8 linear or branched alkyl" groups, preferably including 5-methylpentane-1-enamine, 5-methyl-3-ethyl-pentan-1-enamine, 5-methyl-2-methyl-pentan-1-enamine, and the like.

The term "(C1-C8 linear or branched alkoxy) enamine" or in its combined terms refers to a group in which the "enamine" is substituted with one or more "C1-C8 linear or branched alkoxy" groups, preferably including 5-methoxypentane-1-enamine, 5-methoxy-3-ethyl-pentan-1-enamine, 5-methoxy-2-methyl-pentan-1-enamine, and the like.

The term "(C1-C8 linear or branched alkylamino) enamine" or in its combined terms refers to a group in which the "enamine" is substituted with one or more "C1-C8 linear or branched alkylamino" groups, preferably including 6-methylaminopentane-1-vinylamine, 6-methylamino-3-ethyl-pentane-1-vinylamine, 6-methylamino-2-methyl-pentane-1-vinylamine, and the like.

The term "(C3-C8 cycloalkyl) enamine" or in its combined terms refers to a group in which the "enamine" is substituted with one or more "C3-C8 cycloalkyl" groups, preferably including cyclopropyl-1-enamine, cyclopentyl-1-enamine, cyclohexyl-1-enamine, cyclopropyl-1-propenylamine, cyclopentenyl-1-enamine, and the like.

The term "(3-to 6-membered ring mono-or bicyclic heterocyclyl) enamine" or in its combined terms refers to a group in which the "enamine" is substituted with one or more "3-to 6-membered ring mono-or bicyclic heterocyclyls", preferably including pyrrolyl-1-vinylamine, aziridinyl-1-vinylamine, furyl-1-vinylamine, morpholinyl-1-acrylamido, pyrazinyl-1-acrylamido, tetrahydrothiophenyl-1-vinylamine, and the like.

The term "compound of formula I", "compound provided herein" or similar terms includes any subgroup of compounds of formula I and compounds of formula I, including all possible stereoisomers, cis-trans isomers, pharmaceutically acceptable salts, solvates, isotopic derivatives, and metal complexes.

The term "solvate" refers to a complex of a compound of the present invention with a suitable solvent, such as water, ethanol, acetone, methanol, acetic acid, and the like, by coordination bonds.

The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable acid salts obtained by treating the compounds of the present invention with a suitable acid, and includes organic acid salts and inorganic acid salts, and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, perchloric acid, and the like; organic acids such as acetic acid, propionic acid, succinic acid, maleic acid, lactic acid, oxalic acid, succinic acid, citric acid, tartaric acid, proline, aspartic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Similarly, pharmaceutically acceptable metal salts or forms thereof which may be combined with amines to form salts, such as sodium, potassium, magnesium, zinc, iron, calcium, ammonium and the like, may be obtained by treatment with suitable organic or inorganic bases and are included within the scope of the present invention.

The absolute configuration of the term "enantiomer, diastereomer" may be determined using methods of characterization known in the art, such as X-ray diffraction (X Ray Diffraction), NMR (Nuclear Magnetic Resonance), and the like, as are well known in the art. Preferably, the compositions of the present invention comprise stereoisomers of the compounds described above in a single configuration. By "single configuration stereoisomer" is meant that the molecule is substantially free of other enantiomers, diastereomers, specifically at least 90% of the same isomer, and up to 10% of the other isomeric forms.

Stereoisomers of the compounds and intermediates thereof provided herein may be obtained by methods well known in the art, for example, by preparative chromatography (Preparative Chromatography) apparatus, such as by separation using a chromatographic column of chiral stationary phase. Or salifying the compound with an acid or a base having optical activity, selectively crystallizing, separating, dissociating, and purifying to obtain a single stereoisomer of the compound and an intermediate thereof, such as L-tartaric acid, L-malic acid, S-mandelic acid, L-phenylalanine, L-camphoric acid, L-arginine, L-proline, L-glutamic acid, and the like, and using a base such as R-phenethylamine, S-phenethylamine, R-strychnine, S-brucine, D-ephedrine, L-Meng Chun, L-phenylalaninol, and the like.

When the structure of the compound used above and below contains a phosphorus (P) atom, the phosphorus atom of the compound is represented as having a chiral center according to the Cahn-Ingold-Prelog rule, and is represented as "R configuration" or "S configuration". If not indicated as chiral center, the compounds are indicated as a mixture of "R configuration" and "S configuration".

The compounds provided herein also include isotopic derivatives of formula I, meaning that one or more atoms in the intermediate or compound are replaced by an isotope of that atom, an isotope of formula I including, but not limited to, deuterium (D), ¹³ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ F、 ³¹ P, etc., and the choice of use of the isotopic derivatives of the compounds provided by the present invention depends on the field of application of the compounds, such as the use of deuterated isotopic derivatives can significantly improve the stability of the compound molecule while increasing the half-life of the compound molecule in vivo.

The term "composition" may be a composition prepared by intimately bringing into association an effective amount of the compound (including the compound or solvates, salts, isotopic derivatives, etc.) as active ingredient with pharmaceutically acceptable carriers, diluents, excipients, taste-masking agents, shaping agents, lubricants, stabilizers, solubilizers, co-solvents, buffering agents, emulsifiers, colorants, binders, disintegrants, fillers, preservatives, suspending agents, coating materials, anti-binders, permeation promoters, pH adjusting agents, buffers, or adjuvants.

The term "pharmaceutically acceptable excipients" is intended to include a variety of combinations depending on the form of administration desired. For example, in the case of preparing an oral dosage form composition, dosage forms such as suspensions, syrups, and solutions may be formulated with diluents such as water, oils, alcohols, etc.; the preparation of pill, capsule, powder, tablet, etc. can use solid steroid such as starch, sugar, kaolin, lubricant, adhesive, etc.; pH adjusters such as hydrochloric acid, sodium bicarbonate, phosphate buffer, etc. may be used in preparing the injection; surfactants such as polyoxyethylene castor oil, lecithin, etc., suspending agent gelatin, methylcellulose, sodium carboxymethylcellulose, etc., isotonic regulator such as sodium chloride, glucose, etc.

The term "therapeutically effective amount" means that the active ingredient is administered in the range of about 0.01 to 750mg/kg, more preferably in the range of about 0.10 to 500mg/kg, at suitable intervals per day, in one or more dosage forms administered to a subject in need thereof to produce the desired therapeutic result in vivo. Further, the expected therapeutic effect can be obtained by judging the change in the dose due to factors such as the severity of the disease, the age and weight of the subject to be administered, and the like. By "desired therapeutic effect" is meant that the proliferation of the virus is significantly inhibited by administering to the subject a therapeutically effective amount of a compound or combination thereof.

The compounds of the present invention may be used alone and/or in combination with other agents to enhance the ability of another antiviral agent to exert an antiviral effect in a human or other mammal.

Detailed Description

The compounds of the present invention are synthesized according to the following method:

embodiment one:

s-2: s-1 (27.2 g,0.1 mol) was added to 300mL of methylene chloride under nitrogen protection, triethylamine (30.4 g,0.3 mol) was added, isobutyl chloroformate (13.7 g,0.1 mol) was slowly added under ice bath, the reaction was stirred at room temperature for 3 hours, methanol solution of ammonia gas (2.0M, 50 mL) was added under ice bath, the reaction was continued at room temperature for 5 hours, concentration was reduced under reduced pressure, the resulting residue was added to 500mL of DMF solvent, 2,4, 6-collidine (36.4 g,0.3 mol) was slowly added under ice bath and reacted with cyanuric chloride (55.3 g,0.3 mol) for 16 hours at room temperature, DMF was distilled off under reduced pressure, 500mL of water was added, extraction was performed with 600mL of ethyl acetate, the saturated brine was used for 500mL washing the organic phase, concentration was performed, and the product was recrystallized with ethanol/water to give compound S-2 (11.1 g, 44%), ESI-MS (+: m/z= 254.14).

Embodiment two:

s-4: s-3 (11.1 g,0.1 mol) was added to 1000mL of water, sodium persulfate (71.4 g,0.3 mol) and silver nitrate (1.7 g,0.01 mol) were added, heated to reflux for 8 hours, cooled and concentrated, the resulting residue was added to 200mL of ethanol, stirred for 2 hours, filtered, the filtrate was concentrated, and the compound S-4 (5.5 g, 50%) was isolated by column chromatography as ESI-MS (+): m/z=110.10.

S-5: s-4 (5.5 g,50 mmol) was added to 100mL of toluene under nitrogen protection, 20mL of a toluene solution of rhodium acetylacetonate dicarbonyl (5.2 g,20 mmol) and N-Bn-Yanphos ligand (1.2 g) was added, benzoic acid (2.4 g,20 mmol) was added, the reaction mixture was transferred to an autoclave, carbon monoxide (3.0 bar) and hydrogen (3.0 bar) were introduced, the reaction was kept under pressure and reflux for 48 hours, cooled to room temperature, magnesium monoperoxyphthalate hexahydrate (40.4 g,0.1 mol) in methanol (50 mL) and phosphoric acid buffer solution (pH=6.5, 50 mL) were added under ice bath, the reaction was continued for 2 hours under heating, the organic phase was separated by cooling, concentrated, and the compound S-5 (0.8 g, 12%) was separated by column chromatography, ESI-MS (+): m/z= 137.09.

S-6: s-5 (1.4 g,10.0 mol) was added to 20mL of methanol, 2mL of water, sodium hydroxide (0.8 g,20.0 mol) was added, the mixture was heated to reflux for 2 hours, the pH was adjusted to 5 to 6 with hydrochloric acid (0.1M), and the mixture was concentrated to give compound S-6 (0.3 g, 20%) as a liquid phase by ESI-MS (+): M/z= 156.22.

Embodiment III:

s-7: s-2 (2.5 g,10.0 mmol) was added to 10mL of ethyl acetate under nitrogen, 5mL of ethyl acetate hydrochloride solution was added, and the mixture was stirred at room temperature for 1 hour and neutralized to basicity with triethylamine for use.

S-6 (1.5 g,10.0 mmol) was added to 50mL of tetrahydrofuran, HOBt (1.4 g,10.0 mmol), EDCI (1.9 g,10.0 mmol), triethylamine (3.0 g,30.0 mmol), stirred at room temperature for 2 hours, the above-mentioned solution of S-2 in ethyl acetate was added, the reaction was continued at room temperature for 4 hours, concentrated, the resulting residue was added with 30mL of water, extracted twice with 40mL of ethyl acetate, the organic phase was concentrated, and the compound S-7 (1.2 g, 41%) was isolated by column chromatography as ESI-MS (+): m/z= 291.17.

S-8: boc-L-tert-leucine (1.2 g,5.0 mmol) was added to 40mL of tetrahydrofuran, HOBt (0.7 g,5.0 mmol) EDCI (1.0 g,5.0 mmol), triethylamine (1.5 g,15.0 mmol), stirred at room temperature for 1 hour, 20mL of tetrahydrofuran solution of S-7 (1.5 g,5.0 mmol) was added, the reaction was continued at room temperature for 3 hours, concentrated, 40mL of water was added, 60mL of ethyl acetate was extracted, the organic phase was added to 10mL of ethyl acetate hydrochloride solution, stirring was continued for 1 hour, the pH was adjusted to be basic with triethylamine under ice, 40mL of water was washed, the organic phase was concentrated, and the compound S-8 (0.7 g, 35%) was isolated by column chromatography, ESI-MS (+): m/z= 404.12.

S-9: 2, 2-difluoro-2-hydroxyacetic acid (0.6 g,5.0 mmol) was added to 40mL of tetrahydrofuran, HOBt (0.7 g,5.0 mmol), EDCI (1.0 g,5.0 mmol), triethylamine (1.5 g,15.0 mmol), a solution of S-8 (2.0 g,5.0 mmol) in 20mL of tetrahydrofuran was added and the reaction was continued at room temperature for 3 hours, concentrated, extracted with 40mL of ethyl acetate, the organic phase was concentrated, and the compound S-9 (0.9 g, 36%) was isolated by column chromatography as ESI-MS (+): m/z= 498.30.

Embodiment four:

s-11: s-10 (244.2 g,1.0 mol) was added to 1500mL of acetone, 30mL of sulfuric acid was added, stirred at room temperature until the reaction was complete, neutralized with saturated sodium bicarbonate solution until pH 7-8, concentrated under reduced pressure, the resulting residue was extracted with 1500mL of water, 2000mL of ethyl acetate, washed with 1000mL of saturated brine, and the organic phase was concentrated to give compound S-11 (213.2 g, 75%), ESI-MS (+): m/z= 285.09. Directly used in the next step.

S-12: s-11 (142.1 g,0.5 mol) was added to 2000mL of acetonitrile under nitrogen protection, triethylamine (202.4 g,2.0 mol) 1,2, 4-triazole (41.4 g,0.6 mol), phosphorus oxychloride (92.0 g,0.6 mol) was added, the reaction was stirred at room temperature for 6 hours, concentrated under reduced pressure, 300mL of ice water was added to slurry for 2 hours, and the obtained solid was recrystallized from acetonitrile/water to give compound S-12 (82.2 g, 49%), ESI-MS (+):m/z= 336.11.

Fifth embodiment:

s-13: 4-Nitrophenyl dichlorophosphate (2.6 g,10.0 mmol) was added to 100mL of anhydrous tetrahydrofuran under nitrogen protection, triethylamine (4.0 g,40 mmol) was added, a solution of phenol (0.9 g,10.0 mmol) in tetrahydrofuran was slowly added under ice bath for 10mL, stirring was performed at room temperature for 2 hours, S-9 (5.0 g,10.0 mmol) was added, the reaction was continued for 2 hours, S-12 (3.4 g,10.0 mmol) was added, reflux reaction was performed for 2 hours, cooling to room temperature, concentration was performed, ice water was added, stirring was performed for 2 hours, filtration was performed, and the obtained solid column was chromatographically separated to obtain compound S-13 (6.0 g, 62%) ESI-MS (+):m/z= 971.20.

S-14: s-13 (4.8 g,5.0 mmol) was added to 100mL of anhydrous tetrahydrofuran under nitrogen, 10mL of acetic acid was added, the mixture was stirred at room temperature for 5 hours, 50mL of triethylamine was added, and the mixture was concentrated, and the obtained residue was separated by column chromatography to obtain compound S-14 (2.4 g, 53%) and ESI-MS (+): m/z= 915.00.

VIR-01: s-14 (4.6 g,5.0 mmol) was added to 60mL of acetonitrile, hydroxylamine hydrochloride (0.4 g,5.0 mmol) was added, and the mixture was stirred at room temperature for 3 hours, and the reaction mixture was directly separated using the preparative liquid phase to give compound VIR-01 (0.4 g, 10%), ESI-MS (+): m/z= 895.07. ¹ H NMR(DMSO)δ：10.46(s，1H)，8.31(brs，1H)，8.10(brs，2H)，7.58(d，J＝8.32Hz，1H)，7.24-7.17(m，5H)，5.83(d，J＝5.72Hz，1H)，5.59(d，J＝8.12Hz，1H)，5.06(s，1H)，4.58-4.50(m，3H)，4.42-4.40(m，1H)，4.28-4.26(m，1H)，3.95-3.89(m，3H)，3.47-3.42(m，4H)，3.12-3.09(m，2H)，2.15-2.09(m，5H)，0.99(t，J＝6.46Hz，1H)，0.91-0.87(m，9H)，0.79-0.76(m，6H)。

Example six:

s-15: s-13 (4.8 g,5.0 mmol) was added to 60mL of acetonitrile, hydroxylamine hydrochloride (0.4 g,5.0 mmol) was added, stirred at room temperature for 3 hours, triethylamine (1.0 g,10.0 mmol) was added, concentrated, the resulting solid was added to 12mL of ice water, stirred, filtered, and dried to give compound S-15 (3.0 g, 64%) ESI-MS (+):m/z= 935.01.

VIR-05: s-15 (0.9 g,1.0 mmol) was added to 25mL of anhydrous tetrahydrofuran under nitrogen protection, triethylamine (0.2 g,2.0 mmol) was added, isobutyryl chloride (0.1 g,1.0 mmol) was slowly added, stirred at room temperature for 3 hours, concentrated, the resulting solid was added to 3mL of ice water, stirred, filtered, the resulting solid was added to 10mL of acetonitrile, acetic acid was added to 1mL, stirred at room temperature for 3 hours, triethylamine 2mL was added, concentrated, and the resulting solid preparation liquid phase was separated to give compound VIR-05 (0.1 g, 11%), ESI-MS (+): m/z= 965.23. ¹ H NMR(DMSO)δ：10.23(s，1H)，8.14(brs，1H)，8.07(brs，2H)，7.61(d，J＝7.2Hz，1H)，7.25-7.17(m，5H)，5.73(d，J＝5.5Hz，1H)，5.60(d，J＝7.5Hz，1H)，5.02(s，1H)，4.62(t，J＝5.80Hz，1H)，4.53(d，J＝6.50Hz，1H)，4.44(s，1H)，4.32(s，1H)，4.27-4.25(m，1H)，4.04-4.01(m，2H)，3.83-3.80(m，1H)，3.47-3.40(m，4H)，3.02(d，J＝6.4Hz，2H)，2.11-1.84(m，10H)，1.12(d，J＝6.33Hz，1H)，0.91(t，J＝6.31Hz，1H)，0.90-0.83(m，9H)，0.72-0.70(m，6H)。

Embodiment seven:

VIR-06: VIR-05 (0.9 g,1.0 mmol) was added to 25mL of anhydrous tetrahydrofuran under nitrogen, triethylamine (0.4 g,4.0 mmol) was added slowly isobutyryl chloride (0.2 g,2.0 mmol), stirred at room temperature for 3 hours, concentrated, and the resulting solid column chromatographed to give compound VIR-06 (0.5 g, 43%) as ESI-MS (+):m/z= 1105.10. ¹ H NMR(DMSO)δ：10.18(s，1H)，8.11(brs，1H)，8.02(brs，2H)，7.57(d，J＝7.0Hz，1H)，7.22-7.15(m，5H)，5.71(d，J＝5.3Hz，1H)，5.53(d，J＝7.4Hz，1H)，5.03(s，1H)，4.60(t，J＝5.88Hz，1H)，4.50(d，J＝6.53Hz，1H)，4.40(s，1H)，4.29-4.27(m，2H)，4.03-4.00(m，2H)，3.80-3.78(m，1H)，3.45-3.39(m，4H)，3.01(d，J＝6.5Hz，2H)，2.09-1.78(m，16H)，1.11(d，J＝6.37Hz，1H)，0.92-0.84(m，11H)，0.73-0.68(m，6H)。

Example eight:

s-16: triphosgene (0.3 g,1.0 mmol) was added to 30mL of anhydrous tetrahydrofuran under nitrogen protection, triethylamine (0.4 g,4.0 mmol) was added, 10mL of tetrahydrofuran solution of S-9 (0.5 g,1.0 mmol) was slowly added under ice bath, stirring was performed at room temperature for 2 hours, 10mL of tetrahydrofuran solution of S-12 (0.3 g,1.0 mmol) was slowly added under ice bath, reflux was performed for 3 hours, cooling, concentration was performed, 3mL of ice water was added, stirring was performed for 2 hours, filtration was performed, and the obtained solid column was chromatographed to obtain compound S-16 (0.6 g, 69%), ESI-MS (+): m/z= 859.10.

VIR-07: s-16 (0.8 g,1.0 mmol) was added to 20mL of acetonitrile, hydroxylamine hydrochloride (0.1 g,1.0 mmol) was added, the reaction was carried out at room temperature for 5 hours, triethylamine (5 mL) was added, the obtained solid was concentrated, ice water (3 mL) was added, filtration was carried out, the obtained solid was added to 20mL of acetonitrile, acetic acid (2 mL) was added, the reaction was carried out at room temperature for 5 hours with stirring, triethylamine (5 mL) was added, and the residue obtained after concentration was separated by column chromatography to give the compound VIR-07 (0.1 g, 13%), ESI-MS (+): m/z= 783.03. ¹ H NMR(DMSO)δ：10.45(s，1H)，8.03(brs，3H)，7.64(d，J＝8.1Hz，1H)，5.78(d，J＝5.5Hz，1H)，5.67(d，J＝8.3Hz，1H)，5.11(s，1H)，4.64(t，J＝5.65Hz，1H)，4.53(d，J＝6.63Hz，1H)，4.52(s，1H)，4.47(s，1H)，4.33-4.31(m，1H)，3.82-3.79(m，3H)，3.52-3.47(m，4H)，3.11(d，J＝6.3Hz，2H)，2.16-2.11(m，5H)，1.13(d，J＝6.59Hz，1H)，0.92(t，J＝6.2Hz，1H)，0.93-0.88(m，9H)，0.74-0.70(m，6H)。

Example nine:

s-17: 4-Nitrophenyl dichlorophosphate (2.6 g,10.0 mmol) was added to 100mL of anhydrous tetrahydrofuran under nitrogen protection, triethylamine (4.0 g,40 mmol) was added, a solution of L-alanine isopropyl ester (1.3 g,10.0 mmol) in tetrahydrofuran was slowly added under ice bath, stirring was performed at room temperature for 2 hours, S-9 (5.0 g,10.0 mmol) was added, the reaction was continued for 2 hours, S-12 (3.4 g,10.0 mmol) was added, reflux reaction was performed for 2 hours, cooling to room temperature, concentration was performed, ice water was added, stirring was performed for 2 hours, and filtration was performed to obtain a solid column chromatography to obtain compound S-17 (5.6 g, 56%) ESI-MS (+): m/z= 1008.21.

S-18: s-17 (5.0 g,5.0 mmol) was added to 100mL of anhydrous tetrahydrofuran under nitrogen, 10mL of acetic acid was added, the reaction was stirred at room temperature for 5 hours, 50mL of triethylamine was added, and the obtained residue was concentrated and separated by column chromatography to give compound S-18 (2.4 g, 51%) and ESI-MS (+): m/z= 968.08.

VIR-31: s-18 (4.8 g,5.0 mmol) was added to 60mL of acetonitrile, hydroxylamine hydrochloride (0.4 g,5.0 mmol) was added, stirred at room temperature for 3 hours, triethylamine 50mL was added, and the reaction mixture was directly separated by using the preparative liquid phase to obtain compound VIR-31 (0.6 g, 13%), ESI-MS (+): m/z= 932.27. 10.40 (s, 1H), 8.32 (brs, 1H), 8.17 (brs, 2H), 7.62 (d, j=8.3 hz, 1H), 5.85 (d, j=5.3 hz, 1H), 5.64 (d, j=7.6 hz, 1H), 5.06 (s, 1H), 4.63 (t, j=5.80 hz, 1H), 4.53 (d, j=6.59 hz, 1H), 4.45 (s, 1H), 4.38 (s, 1H), 4.33 (m, 1H), 4.02-3.98 (m, 2H), 3.82-3.79 (m, 2H), 3.51-3.46 (m, 4H), 3.12-3.03 (m, 7H), 2.15-2.10 (m, 5H), 1.18-1.10 (m, 7H), 0.97 (t, j=6.89 (m, 1H), 4.02-3.98 (m, 2H), 3.82-3.79 (m, 2H), 3.51-3.46 (m, 4H), 0.9-0.94 (m, 7H).

According to the above synthesis scheme, the intermediate is obtained by reasonably adding a protecting group and removing the protecting group, and the following compounds are obtained by adopting similar synthesis means:

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Example ten: toxicity study of Compounds on Normal cells

At 5X 10 ⁴ MDCK (Madin-Darby Canine Kidney, canine kidney epithelial cells) cell suspensions were inoculated into 96-well plates at a concentration of/mL, incubated in an incubator for 24h, medium was removed, washed three times with PBS solution, DMEM medium was added, compound or ribavirin was formulated as a 0.1M stock solution (containing 0.02% DMSO to aid solubilization), then diluted with DMEM medium, added to the corresponding wells, final drug solution concentration per well was controlled to 20.0. Mu.M, three compound wells were placed per compound, incubation was continued for 72h after drug addition, OD (Optical Density) values at 490nm were tested using standard MTT (tetramethyl azo salt trace enzyme reaction colorimetric) method under light-shielding conditions, and cell viability (%) = (dosing group OD/normal group OD). Times.100%). The final results were calculated using SPSS 20 software as in table 1:

table 1: toxicity of Compounds against MDCK cells

Compounds of formula (I)	Survival (%)	Compounds of formula (I)	Survival (%)	Compounds of formula (I)	Survival (%)	Compounds of formula (I)	Survival (%)
								VIR-01	68.3	VIR-11	54.7	VIR-21	56.6	VIR-31	58.5
VIR-02	50.2	VIR-12	51.2	VIR-22	55.5	VIR-32	56.0
								VIR-03	55.3	VIR-13	62.8	VIR-23	57.1	VIR-33	52.1
VIR-04	56.7	VIR-14	49.3	VIR-24	53.0	VIR-34	57.3
								VIR-05	49.7	VIR-15	59.1	VIR-25	52.6	VIR-35	57.4
VIR-06	49.9	VIR-16	55.3	VIR-26	58.0	VIR-36	53.5
								VIR-07	51.6	VIR-17	51.4	VIR-27	53.3	VIR-37	57.6
VIR-08	59.0	VIR-18	58.8	VIR-28	63.6	VIR-38	49.7
								VIR-09	54.4	VIR-19	52.0	VIR-29	55.7	VIR-39	50.8
VIR-10	50.0	VIR-20	64.2	VIR-30	62.4	Ribavirin	30.3

The data show that the synthesized compounds have lower toxicity to MDCK cells than ribavirin at the concentration of 20.0 mu M, and especially the compounds VIR-01, VIR-13, VIR-20, VIR-28 and VIR-30 have the survival rate of more than 60% at the concentration of 20.0 mu M, and the compounds of the invention are expected to have lower cytotoxicity and higher safety as medicines.

Example eleven: compounds in vitro anti-H1N 1 and H3N2 viral Activity

The experimental method comprises the following steps: will be 1X 10 ⁵ The uniform suspension of MDCK cells was added to a 96-well plate at a rate of 5 per wellAfter culturing for 24 hours, cells were attached, the culture solution was discarded, and virus culture solution with a multiplicity of infection (MOI) of 0.1 by H1N1 or H3N2 virus was inoculated, and no virus solution was added to the blank wells, and only the corresponding volume of the culture solution was added, and after incubation for 2 hours, fresh culture solution was replaced, and culture solution diluted compounds VIR-01, VIR-13, VIR-20, VIR-28, VIR-30, ribavirin (positive control group) were added, and the final concentrations of each compound were set as follows: 0.1. Mu.M, 0.5. Mu.M, 2.5. Mu.M, 5.0. Mu.M, 10.0. Mu.M, 20.0. Mu.M, no compound solution was added to the virus control wells, only the corresponding volume of culture solution was added, 3 wells were set for each concentration of each compound, then incubation was continued for 48 hours, and absorbance at 570nm wavelength (OD value) was measured after fixation and staining, cytopathic inhibition (%) = [ (drug treatment well OD value-virus control well OD value)]Blank control well OD value-virus control well OD value]Inhibition was calculated by x 100% and then EC of compound to H1N1, or H3N2 virus was calculated using GraphPad Prism 5.0 software ₅₀ Values, calculated as shown in table 2:

table 2: compounds against H1N1, H3N2 Virus Activity

From the results, the compounds VIR-01, VIR-13, VIR-20, VIR-28 and VIR-30 have better anti-H1N 1 and H3N2 virus activities, can exert obvious anti-H1N 1 and H3N2 virus activities in a lower concentration range, have more obvious antiviral activities in vitro compared with ribavirin, and are expected to achieve obvious treatment effects by clinical administration of the compounds of the invention at lower doses.

Embodiment twelve: anti-H1N 1 viral Activity in Compounds

80 BALB/c mice of 18.0+/-1.0 g are randomly divided into 8 groups of 10 mice each, wherein the groups are respectively: blank, model, VIR-01, VIR-13, VIR-20, VIR-28, VIR-30, ribavirin groups, mice of each group were infected with 25 μl of H1N1 virus solution in the nose, and blank was not treated. After 36 hours of H1N1 virus infection, the compound was dissolved in a 1.0% methylcellulose solution, the corresponding compound solution was administered by gavage at a dose of 30mg/kg, neither the blank nor the model control group was administered with the compound solution, only the corresponding volume of 1.0% methylcellulose solution was administered once daily, and the administration was continued for 12 days, during which the physiological condition of each BALB/c mouse was observed, while the death was recorded. The surviving mice were weighed the last day and dissected, lung tissue was removed, the water was blotted with water absorbing paper, weighed, and lung index calculated using formula 1:

Formula 1: lung index= [ mouse lung tissue mass (g)/mouse body weight (g) ]×100%

Simultaneously, calculating the lung index inhibition rate by adopting a method of 2:

formula 2: lung index inhibition ratio = [ (average lung index of model control group-average lung index of administration group)/average lung index of model control group ] ×100%

The experimental results are shown in table 3:

table 3: in vivo Activity of Compounds

Group of	Dosage (mg/kg)	Lung index (x±sd)	Pulmonary index inhibition (%)
				Blank control group	-	0.83±0.12	-
Model control group	-	2.00±0.15	0
				Ribavirin group	30	1.47±0.16	26.5
VIR-01 group	30	0.89±0.13	55.5
				VIR-13 group	30	1.05±0.10	47.5
VIR-20 group	30	0.95±0.12	52.5
				VIR-28 group	30	1.02±0.08	49.0
VIR-30 group	30	0.87±0.15	56.5

The data show that the lung index of the mice in the model control group is obviously increased, which indicates that the lung of the BALB/c mice is obviously swollen after being infected by the H1N1 virus, the lung index of the compounds VIR-01, VIR-13, VIR-20, VIR-28, VIR-30 and ribavirin can reduce the lung index of the mice infected by the H1N1 virus, and compared with ribavirin, the lung index of the mice infected by the BALB/c mice is obviously reduced by the compounds VIR-01, VIR-13, VIR-20, VIR-28 and VIR-30, and particularly, the lung index inhibition rate of the compounds VIR-01, VIR-20 and VIR-30 on the BALB/c mice is more than 50 percent, which indicates that the compounds have obvious anti-H1N 1 virus activity in vivo, and unexpected effects are achieved.

Mice were observed and recorded for 12 consecutive days for mortality, and the number of deaths was recorded, and mortality was calculated using formula 3:

formula 3: mortality (%) = (total number of mice dead/total number of mice in group) ×100%

The calculation results are shown in Table 4:

table 4: mortality rate of mice

Group of	Dosage (mg/kg)	Mortality (%)	Group of	Dosage (mg/kg)	Mortality (%)
						Blank control group	-	0	VIR-13 group	30	20
Model control group	-	80	VIR-20 group	30	10
						Ribavirin group	30	50	VIR-28 group	30	20
VIR-01 group	30	20	VIR-30 group	30	10

The data shows that the mortality rate of BALB/c mice in ribavirin groups is 50% after 12 days of continuous administration of the corresponding compound solutions, while the mortality rate of BALB/c mice in VIR-01 group, VIR-13 group, VIR-20 group, VIR-28 group, VIR-30 group and BALB/c group is within 20%, which is significantly lower than that of BALB/c mice in ribavirin groups, indicating that the compound of the invention has more remarkable anti-H1N 1 virus activity than ribavirin in vivo.

The model control group mice show poor appetite after two days from the beginning of the experiment, and gradually show listlessness, mattness of hair, emaciation, slow action, obvious weight loss along with the prolonged experimental time, part of individuals show death, the death number is gradually increased, the mental state is good after the administration of the mice in the anti-observation administration group BALB/c, the weight is not obviously reduced, and the compounds VIR-01, VIR-13, VIR-20, VIR-28 and VIR-30 show no obvious toxicity in vivo and the compounds are expected to have smaller toxic and side effects in vivo.

The present application describes a number of embodiments, but the description is exemplary rather than limiting and many more embodiments and implementations are possible within the scope of the embodiments described herein.

Claims

1. A compound of the structure of formula I:

w is O or S;

n is 1, 2, 3, or 4;

Ra、R _b Each independently hydrogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C3-C8 cycloalkyl, 3-to 6-membered-ring monocyclic or bicyclic heterocyclyl may independently be optionally substituted with one or more of the following groups: methyl, ethyl, halogenA member selected from the group consisting of a cyano group, an amino group, a hydroxy group, a carboxy group, a trifluoromethyl group, a mercapto group mercaptomethyl, mercaptoethyl, methoxy, ethoxy, acetyl; and Ra, R _b Are not hydrogen at the same time;

R ₅ is hydrogen, hydroxy,

Q ₁ 、Q ₂ Each independently O, S;

R ₆ is hydrogen,

Or by reasonable means with R ₅ Are connected into a ring;

C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8Linear or branched alkylamino, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 linear or branched alkyl) C6-C15 aryl, 3-to 6-membered-ring monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered-ring monocyclic or bicyclic heteroaryl can independently optionally be substituted with one or more of R ₉ Substitution;

R ₉ is hydrogen, halogen, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercapto, mercaptomethyl, mercaptoethyl, methoxy, ethoxy, acetyl,

l is

X ₁ 、X ₂ Each independently O, S, or NH;

R ₁₀ is that

R ₁₁ Is hydrogen, deuterium, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic mono-cyclicThe cyclic or bicyclic heteroaryl groups may be independently optionally substituted with one or more of R ₁₈ Substitution;

R ₁₄ hydrogen, methyl, ethyl;

(C1-C8 linear or branched alkyl) enamino, (C1-C8 linear or branched alkoxy) enamino, C1-C8 linear or branched alkyl)Branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C2-C8 linear or branched alkenyl, C2-C8 linear or branched alkynyl, C3-C8 cycloalkyl, C6-C15 aryl, (C1-C8 linear or branched alkyl) C6-C15 aryl, 3-to 6-membered monocyclic or bicyclic heterocyclyl, 5-and/or 6-membered monocyclic or bicyclic heteroaryl of the ring may be independently optionally substituted with one or more of R ₁₉ Substitution;

R ₁₉ is hydrogen, deuterium, halogen, methyl, ethyl, cyano, amino, hydroxy, carboxyl, nitro, trifluoromethyl, mercapto methyl, mercapto ethyl, methoxy, ethoxy, acetyl,

R ₂₁ Is hydrogen, C1-C8 linear or branched alkyl, C1-C8 linear or branched alkoxy, C1-C8 linear or branched alkylamino, C3-C8 cycloalkyl, a 3-to 6-membered ring of mono-or mono-cyclicThe cyclic or bicyclic heterocyclyl, the 5-and/or 6-membered cyclic mono-or bicyclic heteroaryl, the C6-C15 aryl may be independently optionally substituted with one or more of R ₂₃ Substitution;

R ₂₂ is that

m is 1, or 2;

2. A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant and a compound of formula II:

3. A pharmaceutical composition comprising a pharmaceutically acceptable adjuvant and a compound of formula III:

4. A pharmaceutical composition comprising pharmaceutically acceptable excipients and the following compounds:

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5. the compound of claims 1-4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, enantiomer, diastereomer thereof, having an anti-orthomyxoviridae, paramyxoviridae, coronaviridae, or filoviridae effect in a human or other animal body.

6. An antiviral agent pharmaceutical composition comprising a compound as claimed in claims 1 to 4 and a pharmaceutically acceptable adjuvant.

7. A method for treating an individual infected with an orthomyxoviridae virus, a paramyxoviridae virus, a coronavirus, a filoviridae virus comprising administering to the infected individual a therapeutically effective amount of a compound as described in claims 1-4 or a combination thereof.

8. The use according to claims 5-7, wherein the dosage form for treating said individual with viral infection is an injectable dosage form, a respiratory tract dosage form, a skin dosage form, a mucosal dosage form, a luminal dosage form, an oral dosage form.

9. The compounds of claims 1 to 4 and their pharmaceutical compositions can be used alone and/or in combination with other drugs to enhance the ability of another antiviral drug to exert an antiviral effect in humans or other mammals.

10. The pharmaceutical composition according to claim 8, comprising the compounds of claims 1 to 6 in the following ranges: 0.01% -75% (W/W%).