Anti-influenza virus derivatives and uses thereof

Abstract

This invention discloses a highly effective antiviral derivative and its use. The derivative is the compound shown below in (I-0) or its hydrate, solvate, optical isomer, polycrystalline form, isotope derivative, or pharmaceutically acceptable salt. A method for preparing this derivative is also disclosed. The compound of this invention can be used in pharmaceuticals for preventing and treating influenza viruses. JPEG2025533158000052.jpg7969

Description

[Technical Field]

[0001] This invention relates to compounds having anti-influenza virus activity, or their hydrates, solvates, optical isomers, polycrystalline forms, isotope derivatives, and pharmaceutically acceptable salts, as well as methods for producing them and their use as anti-influenza viruses. [Background technology]

[0002] There are four main types of influenza viruses: influenza A, influenza B, influenza C, and influenza D. The main anti-influenza virus drugs on the market are amantadine and the neuraminidase inhibitors oseltamivir and zanamivir. However, resistance to these compounds has emerged.

[0003] The influenza virus RNA polymerase contains a cap-dependent endonuclease, and inhibiting the activity of this enzyme can inhibit viral replication. Currently, this enzyme has become a promising target for antiviral drug development, and many companies are focusing on cap-dependent endonuclease. Furthermore, various heterocyclic compounds have already been used as cap-dependent endonuclease inhibitors. Resistance to the currently available cap-dependent endonuclease inhibitor baloxavir has been reported, and these compounds often have poor physicochemical properties, such as low solubility and bioavailability. Therefore, the development of next-generation cap-dependent endonuclease inhibitors is necessary.

[0004] Through careful research, we have found that compounds containing selenized cyclopropyl groups have a highly effective and broad-spectrum anti-influenza virus effect. Further research will clarify the specific distribution of these compounds and hopefully develop them into anti-influenza virus drugs. The compound of this invention plays a role in inhibiting influenza virus replication by inhibiting the cup-dependent endonuclease in influenza viruses. It can target an earlier stage of the viral replication cycle, which should improve the effectiveness of influenza prevention and treatment. Summary of the Invention

[0005] Unless otherwise specified in this document, the terminology used in this invention is generally understood by those skilled in the art.

[0006] This invention provides a kind of anti-influenza virus compound, its preparation method and use.

[0007] The present invention provides the compound (I-0) or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof.

[0008] JPEG2025533158000002.jpg7965

[0009] In (I-0), R a is selected from hydrogen, deuterium, a methyl group, or a deuterated methyl group.

[0010] X is S or Se, and when X is S, at least one deuterium atom is contained in (I-0).

[0011] R b and R c are each independently selected from hydrogen, deuterium, a C1-C3 alkyl group, or a deuterated C1-C3 alkyl group; or R b , R c together with the carbon atom to which they are attached constitute a cyclopropyl group or a deuterated cyclopropyl group.

[0012] R is hydrogen, JPEG2025533158000003.jpg2755, or JPEG2025533158000004.jpg2953. wherein X1 is an O atom or a S atom. n1 is 0, 1 or 2.

[0013] R1 and R2 are independently selected from hydrogen, deuterium, methyl, or deuterated methyl.

[0014] R3 is selected from the group consisting of a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, and a C1-C8 alkylamine group, in which one or more hydrogen atoms are replaced with deuterium or not replaced with deuterium.

[0015] R4 and R5 are independently a hydroxyl group, or one or more hydrogen atoms of which may or may not be replaced by deuterium, such as a C1-C8 alkoxy group, a C1-C8 alkylthio group, a C1-C8 alkylamine group, or a C6-C20 arylalkoxy group; or R4 and R5 together form a 5-7-member ring composed of the phosphorus atom to which they are bonded.

[0016] JPEG2025533158000005.jpg47129

[0017] Among them, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 Japanese R 14 independently hydrogen or a C1-C3 alkyl group, or R6 and R7, R8 and R9, R 11 and R 12 ,R 12 and R 13form an aromatic ring together with the carbon atoms to which they are bonded, and one or more of the hydrogen atoms of the 5-7 element ring and the substituents on the ring to which R4 and R5 are bonded are replaced with deuterium.

[0018] In one embodiment, the present invention provides a compound represented by the following formula (I): or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof:

[0019] JPEG2025533158000006.jpg7865

[0020] (I) with R a is selected from hydrogen, deuterium, and a methyl group.

[0021] R b and R c are independently selected from hydrogen, deuterium, and C1-C3 alkyl groups; or R b , R c together with the carbon atom to which it is attached form a cyclopropyl group.

[0022] R is hydrogen, JPEG2025533158000007.jpg2549, or JPEG2025533158000008.jpg3049. Wherein X1 is an O atom or a S atom; n1 is 0, 1 or 2;

[0023] R1 or R2 is independently selected from hydrogen or methyl.

[0024] R3 is selected from a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, and a C1-C8 alkylamine group.

[0025] R4 and R5 are independently a hydroxyl group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, or a C1-C8 alkylamine group.

[0026] In one embodiment, the present invention provides a compound shown below in (I) or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof.

[0027] JPEG2025533158000009.jpg7966

[0028] R in (I) a is selected from hydrogen, deuterium, a methyl group, or a deuterated methyl group.

[0029] R b and R c are independently selected from hydrogen, deuterium, a C1-C3 alkyl group, a deuterated C1-C3 alkyl group, or R b , R c and together with the carbon atom to which they are attached constitute a cyclopropyl or deuterated cyclopropyl group.

[0030] R is hydrogen, JPEG2025533158000010.jpg3153, or JPEG2025533158000011.jpg3153. wherein X1 is an O atom or a S atom. n1 is 0, 1 or 2.

[0031] R1 or R2 are independently selected from hydrogen, deuterium, methyl, or deuterated methyl.

[0032] R3 is selected from the group consisting of a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, and a C1-C8 alkylamine group, in which one or more hydrogen atoms are replaced with deuterium or no deuterium is replaced.

[0033] R4 and R5 are independently hydroxyl groups, or the following groups, each unsubstituted or substituted with one or more deuterium atoms: a C1-C8 alkoxy group, a C1-C8 alkylthio group, a C1-C8 alkylamine group, or a C6-C20 arylalkoxy group; or R4 and R5, together with the phosphorus atom to which they are linked, form a 5- to 7-member ring.

[0034] JPEG2025533158000012.jpg44128

[0035] Among them are R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or a C1-C3 alkyl group; or R6 and R7, R8 and R9, R 11 and R 12 ,R 12 and R 13 is an aromatic ring formed by the carbon atoms bonded together with R4 and R5, and a 5-7-member ring formed by the phosphorus atom bonded together with R4 and R5, and deuterium replacing one or more hydrogen atoms in the groups on the ring, or no hydrogen atoms are replaced.

[0036] In some embodiments, the present invention provides compounds, or hydrates, solvates, optical isomers, polycrystalline forms, isotopic derivatives, and pharmaceutically acceptable salts thereof, as shown in (II).

[0037] JPEG2025533158000013.jpg7588

[0038] The definitions of the substituents in (II) are as defined in (I-0) and / or formula (I).

[0039] In one embodiment, the compound provided by this invention, or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof, is as shown in (III).

[0040] JPEG2025533158000014.jpg7588

[0041] The definitions of the substituents in (III) are as defined in (I-0) and / or (I).

[0042] In the proposed implementation, the solvate is an entanglement formed by the interaction of a compound with a pharmaceutically acceptable solvent, such as ethanol, isopropanol, acetic acid, or ethanolamine.

[0043] In the proposed implementation, the C1-C8 alkyl group refers to a linear or branched saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, and n-pentyl groups.

[0044] In the proposed implementation, C1-C8 alkoxy group and C1-C8 alkylthio group refer to a group in which an oxygen atom or a sulfur atom is inserted at any suitable position in a saturated aliphatic hydrocarbon group having 1-8 carbon atoms in the molecule, including, but not limited to, methoxy group, ethoxy group, propoxy group, isopropoxy group, isobutoxy group, 2-ethylethoxy group, methylthio group, ethylthio group, propylthio group, isopropylthio group, isobutylthio group, etc.

[0045] In this invention, the term "C1-C8 alkylamine group" refers to a group in which an -NH- or -NH2 group is inserted at any appropriate position in a saturated aliphatic hydrocarbon group having 1-8 carbon atoms in the molecule, and includes monoalkylamine groups, dialkylamine groups, and cycloalkylamine groups, including, but not limited to, methylamine groups, ethylamine groups, propylamine groups, isopropylamine groups, diisopropylamine groups, etc.

[0046] In the proposed implementation, C1-C3 alkyl groups refer to alkanes with 1-3 carbon atoms in the molecule, including methyl, ethyl, propyl, isopropyl, and cyclopropyl groups.

[0047] In the proposed implementation, the term "C6-C20 aralkoxy group" refers to an aralkyl group having 6-20 carbon atoms bound to an oxygen atom, including, but not limited to, benzyloxy group, phenylethoxy group, and naphthalmethoxy group.

[0048] In the proposed implementation, deuterium refers to a compound in which a hydrogen atom is replaced with a deuterium atom at any reasonable position in the molecule.

[0049] In one implementation plan, R a is hydrogen. In one implementation, R a is deuterium. In one implementation, R a is methyl. In one implementation, R a is a deuterated methyl group.

[0050] One implementation plan is R b and R c is hydrogen. In one implementation, R b and R c is deuterium. In one implementation, R b is hydrogen, R c is deuterium.

[0051] One implementation plan is R b and R c are independently C1-C3 alkyl groups. In some embodiments, R b is hydrogen and R c is a C1-C3 alkyl group. In some embodiments, R b is deuterium and R c is a C1-C3 alkyl group.

[0052] One implementation plan is R b and R c are independently C1-C3 alkyl groups. In some embodiments, R b is hydrogen and R c is a C1-C3 alkyl group. In some embodiments, R b is deuterium and R c is a C1-C3 alkyl group.

[0053] One implementation plan is R b is a C1-C3 alkyl group, R c is a deuterated C1-C3 alkyl group.

[0054] In one implementation plan, R b , R c and the carbon atom to which they are attached form a cyclopropyl group. b , R c together with the carbon atom to which it is attached form a deuterated cyclopropyl group.

[0055] In one embodiment, X is S. In this case, (I-0) contains at least one deuterium atom.

[0056] In some embodiments, X is Se. In some embodiments, R is hydrogen.

[0057] In one implementation, R is JPEG2025533158000015.jpg2752;

[0058] In one implementation, R is JPEG2025533158000016.jpg3052.

[0059] In some implementations, n1 is 0. In some implementations, n1 is 1. In some implementations, n1 is 2.

[0060] In some embodiments, X1 is an O atom. In some embodiments, X1 is an S atom.

[0061] In some embodiments, R1 and R2 are hydrogen. In some embodiments, R1 or R2 are deuterium. In some embodiments, R1 and R2 are methyl groups. In some embodiments, R1 and R2 are deuterated methyl groups.

[0062] In some embodiments, R1 is methyl and R2 is hydrogen. In some embodiments, R1 is deuterated methyl and R2 is hydrogen.

[0063] In one embodiment, R1 is a deuterated methyl group and R2 is deuterium.

[0064] In some embodiments, R3 is selected from the following groups: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, and C1-C18 alkylamine. R3 is preferably selected from the following groups: C1-C8 alkyl and C1-C8 alkoxy. Most preferably, R3 is a C1-C8 alkyl.

[0065] In some embodiments, R3 is selected from the following groups: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, and C1-C18 alkylamine. R3 is preferably selected from the following groups in which one or more hydrogen atoms are replaced with deuterium. Most preferably, R3 is a C1-C8 alkoxy in which one or more hydrogen atoms are replaced with deuterium.

[0066] In one specific embodiment, n1 is 1, X1 is an O atom, R1 and R2 are both hydrogen, and R3 is a C1-C8 alkoxy group or a C1-C8 alkyl group.

[0067] In one specific embodiment, n1 is 1, X1 is an O atom, R1 and R2 are both hydrogen, and R3 is a C1-C8 alkoxy group in which one or more hydrogen atoms are substituted with deuterium, or a C1-C8 alkyl group in which one or more hydrogen atoms are substituted with deuterium.

[0068] In some specific embodiments, n1 is 1, X1 is an O atom, and R3 is one or more C1-C8 alkoxy groups or C1-C8 alkyl groups.

[0069] In some specific embodiments, n1 is 1, X1 is an O atom, and R3 is a C1-C8 alkoxy group in which one or more hydrogen atoms are replaced with deuterium, or a C1-C8 alkyl group in which one or more hydrogen atoms are replaced with deuterium.

[0070] In some embodiments, R4 and R5 are both hydroxy groups. In some embodiments, R4 and R5 are the following groups: C1-C8 alkoxy groups, C1-C8 alkylthio groups, and C1-C8 alkylamine groups. In some embodiments, R4 and R5 are C6-C20 aralkoxy groups. R4 and R5 are preferably benzyloxy groups.

[0071] In some embodiments, R4 and R5 are the following groups in which one or more hydrogen atoms are replaced with deuterium: a C1-C8 alkoxy group, a C1-C8 alkylthio group, or a C1-C8 alkylamine group.

[0072] In one embodiment, R4 and R5 together form a 5-7 member ring with the phosphorus atom to which they are attached.

[0073] JPEG2025533158000017.jpg45130

[0074] Among them are R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or a C1-C3 alkyl group; or R6 and R7, R8 and R9, R 11 and R 12 ,R 12 and R 13 together with the carbon atom to which they are bonded form an aromatic ring.

[0075] In one embodiment, R4 and R5 together form a 5-7 member ring with the phosphorus atom to which they are bonded.

[0076] JPEG2025533158000018.jpg45130

[0077] One or more hydrogen atoms of the phosphorus atom to which R4 and R5 are jointly bonded, the 5-7 ring, and the substituents on the ring are replaced with deuterium.

[0078] In some specific embodiments, n1 is 1, X1 is an O atom, R1 and R2 are hydrogen, R4 and R5 are hydroxyl groups. In some specific embodiments, n1 is 0, X1 is an O atom, and R4 and R5 are hydroxyl groups.

[0079] In one embodiment, when R is hydrogen, the pharmaceutically acceptable salts of the compound can be alkali metal salts, alkaline earth metal salts, amine salts, and amino acid salts. Preferential pharmaceutically acceptable salts include sodium salts, potassium salts, magnesium salts, zinc salts, amine salts, basic amino acid salts, etc.

[0080] In some embodiments, when R4 and R5 are both hydroxyl groups, the pharmaceutically acceptable salts of the compound can be alkali metal salts, alkaline earth metal salts, amine salts and amino acid salts, and preferably include sodium salts, potassium salts, magnesium salts, zinc salts, amine salts, basic amino acid salts, etc.

[0081] In the embodiments of the present invention, the pharmaceutically acceptable salts are obtained by conventional salt-making methods.

[0082] In the embodiments of this invention, the structures of the pharmaceutically acceptable salts are confirmed by nuclear magnetic, mass spectrometry, atomic absorption spectroscopy, elemental analysis, melting point detection, and other means.

[0083] In the embodiments of this invention, (I-0) and / or (I) contain two chiral centers. The compounds of this invention or their intermediates can be separated to obtain single-component compounds.

[0084] In a specific embodiment, the compound of the present invention is a single optical isomer represented by (I-0) or / and (I).

[0085] In the embodiment of the present invention, the absolute configuration of the single optical isomer is determined by electronic circular dichroism spectroscopy.

[0086] In the embodiment of this invention, the racemite and single-component optical isomers are subjected to optical rotation test according to the Chinese Pharmacopoeia 2020 Edition-Part 4-0621 Optical Rotation Measurement Method.

[0087] The comparative compounds synthesized by referring to the literature, patents and synthetic methods of the examples of this invention can be used in relevant biological tests if the detected purity is 98% or more.

[0088] Compounds provided by this invention include, but are not limited to, the following compounds:

[0089] JPEG2025533158000019.jpg237144

[0090] or a hydrate, solvate, optical isomer, polycrystal, isotope derivative, or pharmaceutically acceptable salt thereof.

[0091] Metal salts of compounds provided by this invention include, but are not limited to, the following compounds:

[0092] JPEG2025533158000020.jpg106152

[0093] Another aspect of this invention provides a pharmaceutical composition comprising the above compound or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include one or more of a filler, binder, diluent, lubricant, preservative, flavor-reducing agent, or auxiliary agent. This pharmaceutical combination can be used for anti-influenza virus.

[0094] The above pharmaceutical combinations may be in various forms such as tablets, capsules, powders, granules, pills, suspensions, syrups, injections or inhalants.

[0095] In a third aspect, the present invention includes the above-mentioned compound, its hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt, or pharmaceutical composition thereof, for use as an anti-influenza virus drug.

[0096] This invention provides a method for producing a drug against influenza virus.

[0097] This includes the above compounds, their hydrates, solvates, optical isomers, polycrystalline forms, isotopic derivatives, and pharmaceutically acceptable salts.

[0098] This invention provides a method for preventing or treating influenza virus infection, comprising administering to an individual in need thereof a therapeutically effective amount of the above-described compound, including its hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt.

[0099] The compounds of the present invention have stronger antiviral activity in vivo or in vitro and exhibit a better safety margin.

[0100] The compounds of the present invention are effective against multiple strains of influenza viruses, including avian influenza viruses, and are also effective against oseltamivir-resistant influenza viruses and other resistant strains, and have superior activity compared to other compounds with similar structures, particularly in inhibiting influenza B.

[0101] The in vivo anti-influenza virus activity of the compound of the present invention was significantly improved, the pulmonary virus titer was reduced, and the histopathological results showed that the lesions in the lung tissues were milder after treatment with the compound of the present invention.

[0102] Further research has shown that the compound of the present invention has good lung tissue distribution in animal tests, which is consistent with the results of low lung virus titers and milder lung tissue lesions in in vivo anti-influenza virus tests, which is advantageous for anti-influenza virus and is expected to have great clinical value and therapeutic advantages.

[0103] Pharmacokinetic studies of the compound of the present invention have shown that it has a shorter mean absorption time, is rapidly absorbed after oral administration, and exhibits a faster onset of drug efficacy. [Brief explanation of the drawings]

[0104] [Figure 1] Figure 1 shows the lung tissue viral titer in a drug efficacy test using an influenza virus mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0105] The following examples will enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention. The structures of all compounds were determined by MS or 1H-NMR, and the configuration of single optical isomers involved was determined by optical rotation studies or electronic circular dichroism spectroscopy.

[0106] All solvents and reagents used in the examples are commercial products unless otherwise stated. All starting materials are sourced materials.

[0107] Example 1: Synthesis of 9a

[0108] JPEG2025533158000021.jpg48131

[0109] Synthesis of compound 3a 5 g of compound 1a, 2.95 g of compound 2a, and 7 ml of triethylamine were added to a mixed solvent of 40 ml of DMF (N,N-dimethylformamide) and 40 ml of toluene, and the mixture was heated to 130°C and reacted for 8 hours. Water was added and the mixture was stirred to precipitate a solid. 7.03 g of compound 3a, a white solid, was obtained by filtration. This was used directly in the next reaction without separation.

[0110] Synthesis of compound 4a Add 5.84g of 2-bromo-1,1-dimethoxyethane and 5g of compound 3a to 40ml of DCM, and slowly add 3.9g of potassium tert-butoxide to the mixture at room temperature. After the addition, heat the mixture to 40°C and react for 5 hours. After warming the mixture to room temperature, add water and stir for 15 minutes. After separating the liquid, concentrate the organic phase to dryness and purify it on a silica gel column to obtain 5.2g of compound 4a. The shrinkage is 74%. 1 H NMR (CDCl3,400MHz): δ7.83-7.88(m,2H),7.68-7.70(m,2H),4.46(t,1H),3.81(s,2H),3.55(d,2H),3.31(s, 6H),0.47-0.95(m,4H).

[0111] Synthesis of compound 5a 5 g of compound 4a was added to 15 ml of ethanol and 15 ml of water, respectively, and the mixture was heated to 60°C. 1.5 g of hydrazine hydrate (80%) was added and the mixture was reacted at 60°C for 5 hours. The mixture was concentrated to dryness, cooled to room temperature, and then 40 ml of DCM and 40 ml of 1N NaOH aqueous solution were added. The organic phase was separated, and the aqueous phase was subsequently extracted twice with DCM to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness to obtain 2.75 g of crude compound 5a, which was used directly in the next step without further separation.

[0112] Synthesis of compound 7a 5 g of compound 6a was added to 10 ml of DMA, and 1.62 g of sodium hydride (60%) and 3.2 g of iodine methane were added. The mixture was stirred at 25 °C for 12 hours, 100 ml of water was added, and the mixture was stirred for 0.5 hours and extracted with EA. The organic phase was synthesized, washed sequentially with 0.5 N dilute hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate to obtain 4.65 g of an oil. 30 ml of DMA, 3.54 g of Boc hydrazine, and 13.47 g of pyridine p-toluenesulfonate were added to this oil. The mixture was heated to 60 °C and reacted for 18 hours. After the reaction was complete, the mixture was extracted with water and EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. Purification using a silica gel column gave 4.68 g of compound 7a. The shrinkage was 61.65%. The product was a yellow oil with ESI-MS(+): m / z=375.2.

[0113] Synthesis of compound 8a Add 4.5 g of compound 7a to 30 ml of ethanol and then add it to 24 ml of 1N NaOH solution. The mixture is reacted at 60 °C for 15 hours, and the pH is adjusted with dilute hydrochloric acid. The mixture is extracted with DCM (dichloromethane), and the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a gray-white solid. The resulting gray-white solid is added to DCM. Add 2.53 g of compound 5a, 4 ml of triethylamine, and 6.85 g of HATU at 25 °C. The mixture is stirred at 25 °C for 11 hours, diluted with water, and extracted with DCM. The combined organic phase is washed with saturated brine. After drying over anhydrous sodium sulfate, 4.1 g of compound 8a is obtained by silica gel column chromatography. The shrinkage is 66%. The product is a white solid with ESI-MS (+): m / z = 518.3.

[0114] Synthesis of compound 9a To 3 g of compound 8a, add 20 ml of acetonitrile and 4 ml of water. Heat the mixture to 60°C, add 1.7 g of methanesulfonic acid dropwise, and continue the reaction at this temperature for 5 hours. After the reaction is complete, cool the mixture to room temperature and add aqueous sodium bicarbonate solution to adjust the pH to a weak alkaline. Concentrate the mixture, add DCM and water, extract, separate the organic phase, dry it over anhydrous sodium sulfate, and purify it on a silica gel column to obtain 1.21 g of compound 9a, a white solid. Shrinkage: 59%. ESI-MS (+): m / z = 354.2.

[0115] Example 2: Synthesis of 21a

[0116] JPEG2025533158000022.jpg41170

[0117] Synthesis of compound 15a After purging the atmosphere with nitrogen gas, a three-neck flask was filled with 226 ml (2.8 mol / L) of phenylmagnesium bromide. The temperature was lowered to below 10°C in an ice-water bath, and 49.9 g of selenium powder was added in batches. The reaction temperature was lowered to below 30°C, and the reaction was allowed to proceed for 2 hours. 2 mol / L hydrochloric acid was added in an ice-water bath, and the reaction became exothermic. EA was added for extraction, and the organic phase was spin-dried. Product 15a was a brown oil with a strong odor. The reaction proceeded directly to the next step.

[0118] Synthesis of compound 17a After purging with nitrogen gas, a three-neck flask was charged with 81.18 g of LDA (diisopropylaminolithium). The temperature was lowered to -30°C under a dry ice-ethanol solution, and 50 g of a THF solution of 3,4-difluorobenzoic acid was added dropwise. A noticeable exotherm was observed during the addition, and the reaction temperature was controlled below -20°C. The reaction was allowed to proceed for 2 hours. DMF was then added, and the exotherm became noticeable. The reaction was then completed. HCl was added to the reaction mixture, and the exotherm became noticeable. EA was added for extraction, and the liquid was separated. The organic phase was dried to obtain 72 g of crude compound 17a. This product was used directly in the next reaction. The crude product was a yellow solid with a shrinkage of 122% (there was undried DMF in the material).

[0119] Synthesis of compound 18a After replacing the atmosphere with nitrogen gas, a three-neck flask was charged with 58.81 g of compound 15a, 49.6 g of compound 17a, 300 ml of toluene, and 17.6 g of camphorsulfonic acid. The mixture was heated to 70°C and reacted overnight. The reaction mixture was cooled to room temperature, NaOH solution was added, and the liquid was separated. The aqueous phase was extracted with EA, and the organic phase was combined. The organic phase was washed with saturated NaCl and dried. Crude product: 123.08 g. The resulting crude product was slurried with PE and filtered to obtain 34.4 g of product. 14.83 g of product was recovered from the filtrate. Compound 18a was an orange solid with a shrinkage of 47.9%.

[0120] Synthesis of compound 19a A three-neck flask was charged with 16.9 g of AlCl3 and 250 ml of toluene. The mixture was cooled in an ice-water bath, and 17.1 g of tetramethyldisiloxane was added. Stirring was continued until uniform. 150 ml of a toluene solution of compound 18a (34.4 g) was added. The reaction was slightly exothermic, and the AlCl3 gradually dissolved. The mixture was heated to 80°C and reacted for 1 hour. The reaction was then quenched by adding sulfuric acid solution (16.2 mL + 240 mL of water). The aqueous phase was extracted with EA, the organic phase was spin-dried, and the crude product was slurried with PE and filtered to obtain 22 g of a yellow powdery solid, 19a. The theoretical product yield was 34.68 g, and the shrinkage rate was 63.4%. This was used directly in the next reaction.

[0121] Synthesis of compound 20a: Add 429g of polyphosphoric acid to a three-neck flask and heat to 80°C. Add 42g of compound 19a and heat to 120°C. The reaction system becomes viscous. The color changes from yellow to dark purple. After 1 hour of reaction, a sample is taken. Add water and treat with EA. Reduce the reaction temperature to below 100°C, add water and stir evenly. Add EA to extract. Separate the organic phase, spun dry, and slurried the crude product with PE. Filter to obtain 3.4g of product. The filtrate is purified by column chromatography to obtain 10g of product. Compound 20a is a colorless to pale yellow, flocculent solid. The theoretical yield is 39.69g, the actual yield is 13.4g, and the shrinkage is 33.76%. 1H NMR (DMSO-D6,400MHz): δ 7.95-8.09(d.1H), 7.54-7.67(d,1H), 731-7.52(m,3H), 7.20-7.29(m,1H), 4.21-4.27(s,2H).

[0122] Synthesis of compound 21a: Add 2.12 g of compound 20a and 20 ml of ethanol to a three-neck flask and stir. Add sodium borohydride (0·26 g) in an ethanol solution dropwise under ice-water bath. The reaction mixture will warm slightly. After the addition is complete, transfer to room temperature and allow the material to gradually dissolve. Once the reaction mixture is clear, take a sample for testing and dispose of it after the reaction is complete. Add 2 mol / L hydrochloric acid until no bubbles are generated and the pH is 4-6, and a large amount of solid precipitates. Filter to obtain the solid. Extract the filtrate with EA, separate the organic phase, spin-dry the organic phase, and refine the solid to obtain product 21a as a brown solid, which can be used directly in the next reaction.

[0123] Example 3: Synthesis of DS1491 and DS1494

[0124] JPEG2025533158000023.jpg39169

[0125] Synthesis of compound 22a: Add 0.8 g of compound 9a, 0.77 g of compound 21a, 1.8 g of compound T3P (propyl phosphate anhydride, 50% EA solution), 0.33 g of methanesulfonic acid, and 10 ml of EA to a single-neck flask, heat to reflux, and react overnight. Take a sample and test it. After completion of the reaction, process it. Workup: Add saturated aqueous sodium bicarbonate solution until no more bubbles appear. Separate the liquid. Extract the aqueous phase with EA. The organic phase is combined, spin-dried, and purified on a silica gel column. Then, separate the mixture on a chiral column to obtain 0.52 g of compound 22a. Shrinkage: 37%.

[0126] Synthesis of compound DS1491: A single-neck flask was charged with 0.5 g of compound 22a, 0.17 g of LiCl, and 5 ml of DMA (N,N-dimethylacetamide). The mixture was heated to 100°C, and the reaction mixture became yellow and cloudy. After 2 hours of reaction, a sample was taken and analyzed. After completion of the reaction, the solid was precipitated by adding saturated aqueous sodium bicarbonate. The solid was filtered under suction, extracted with EA, and the organic phase was spin-dried and purified on a silica gel column to obtain 0.34 g of compound DS1491. The shrinkage was 77%. ESI-MS (+): m / z = 558.1.

[0127] Synthesis of compound DS1494: Add 0.3g of compound DS1491, 150mg of K2CO3, 10mg of KI, and 110mg of chloromethyl dimethyl carbonate to a single-neck flask. Add 5mL of DMA, heat to 60°C, and react overnight. Take a sample for testing and dispose of after the reaction is complete. Cool the reaction mixture to room temperature, add 2N HCl, and add water to precipitate a solid. Extract with EA and water. Separate the organic phase, dry it over anhydrous sodium sulfate, spin-dry, and separate it by column chromatography to obtain 0.21g of compound DS1494. Shrinkage: 61%. ESI-MS(+): m / z=646.1.

[0128] Example 4: Synthesis of compounds DS1492 and DS1495

[0129] JPEG2025533158000024.jpg39169

[0130] Synthesis of compound 1b Under nitrogen gas protection, 1 g of compound 20a was dissolved in 15 ml of THF, and 140 mg of lithium aluminum hydride-D4 was slowly added at 0°C. The mixture was then heated to 25°C and reacted for 8 hours. The temperature of the mixture was then lowered to 0°C, and water was added to quench the reaction. The mixture was extracted with 2N hydrochloric acid and EA. The organic phase was dried and subjected to column chromatography to obtain a total of 0.58 g of compound 1b. The shrinkage was 57%, and ESI-MS (+): m / z = 314.0.

[0131] Synthesis of compound 2b Following the synthesis method for compound 22a, compound 9a and compound 1b were synthesized, yielding a total of 0.36 g. The shrinkage rate was 35%. ESI-MS(+): m / z=649.2.

[0132] Synthesis of compound DS1492 Refer to the synthesis method of compound DS1491 to obtain a total of 0.21 g of compound DS1492. The shrinkage rate is 79%. ESI-MS(+): m / z=559.1.

[0133] Synthesis of compound DS1495 Refer to the synthesis method of compound DS1494 to obtain a total of 0.13 g of compound DS1495. The shrinkage rate is 63%. ESI-MS(+): m / z=647.1.

[0134] Example 5: Synthesis of compounds DS1493 and DS1496

[0135] JPEG2025533158000025.jpg39169

[0136] Synthesis of compound 1c: Under nitrogen gas protection, 1 g of compound 20a was dissolved in 15 ml of THF, and 4 ml of methyllithium reagent (1.6 M solution in diethyl ether) was slowly added dropwise at -20°C. The mixture was allowed to warm naturally to 25°C and reacted for 8 hours. The mixture was cooled to 0°C and water was added to quench the reaction. The mixture was dried and extracted with EA and water. The organic phase was separated and dried. A total of 0.77 g of compound 1c was obtained by column chromatography. The shrinkage was 73%, and ESI-MS (+): m / z = 327.1.

[0137] Synthesis of compound 2c Following the synthesis method for compound 22a, a total of 0.33 g of compound 9a and compound 1c was obtained. The shrinkage rate was 23%. ESI-MS(+): m / z=662.1.

[0138] Synthesis of compound DS1493 Refer to the synthesis method of compound DS1491 to obtain a total of 0.19 g of compound DS1493. The shrinkage rate is 73%. ESI-MS(+): m / z=571.1.

[0139] Synthesis of compound DS1496 Following the synthesis method for compound DS1494, a total of 95 mg of compound DS1496 was obtained. The shrinkage rate was 55%. ESI-MS(+): m / z=660.1.

[0140] Example 6: Synthesis of DS1497

[0141] JPEG2025533158000026.jpg45128

[0142] Synthesis of compound 1d: A reaction flask was charged with 1 g of compound DS1491, 0.7 g of tert-butyl chloromethyl phosphate, 1 ml of triethylamine, and 10 ml of DMF (N,N-dimethylformamide), followed by a reaction at 45°C for 8 hours. Water was added, and the mixture was crystallized and filtered to obtain approximately 0.59 g of crude compound 1d. The shrinkage was 42%. ESI-MS (+): m / z = 779.5. The product was used directly in the next step without further purification.

[0143] Synthesis of compound DS1497: Under nitrogen gas protection, 0.5 g of compound 1d and 5 ml of anhydrous dichloromethane were added to a reaction flask, and 1 ml of trifluoroacetic acid was added dropwise with stirring at room temperature. The mixture was then stirred at 25°C for 3 hours. The mixture was concentrated to dryness, and crystallized from isopropyl alcohol and water to obtain 0.29 g of compound DS1497. The shrinkage was 69%. ESI-MS (+): m / z = 668.1, ESI-MS (-): m / z = 606.2.

[0144] Example 7: Synthesis of compound DS1831:

[0145] JPEG2025533158000027.jpg67134

[0146] A single-neck flask was charged with 70 mg of compound DS1491, 82 mg of Cs2CO3, 2.1 mg of KI, 30 mg of compound diethyl chloromethylphosphate, and 10 mL of DMA. The mixture was heated to 50°C and reacted for 2.5 hours to complete the reaction. The reaction mixture was cooled to room temperature, extracted with EA and water, and the organic phase was separated, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 55.45 mg of compound DS1831. The shrinkage was 61%. ESI-MS (+): m / z = 724.1.

[0147] Example 8: Synthesis of compound DS1833:

[0148] JPEG2025533158000028.jpg44133

[0149] Synthesis of compound DS1833-1 Add 1.1g of deuterated methanol, 5.2ml of triethylamine, and 30ml of dichloromethane to a reaction flask, cool the system to 0°C, and then slowly add 4g of chloromethyl chloroformate. After the addition, allow the system to warm to room temperature and react for 3 hours. Add water to quench the reaction. Extract with dichloromethane, separate the organic phase, dry it over anhydrous sodium sulfate, and concentrate to dryness to obtain 3.28g of liquid compound DS1833-1. The shrinkage rate is 83%.

[0150] Synthesis of compound DS1833 Using the synthesis method of compound DS1494 as a reference, compounds DS1491 and DS1833-1 were used as materials to obtain 78 mg of compound DS1833. The shrinkage rate was 55%, and ESI-MS (+): m / z = 649.1.

[0151] Example 9: Synthesis of compound DS14914:

[0152] JPEG2025533158000029.jpg59136

[0153] 1 g of compound DS1497 was added to 10 ml of absolute ethanol, the mixture was heated to 30°C, 120 mg of sodium hydroxide was added, and the mixture was stirred for 2 hours. The mixture was then cooled to -10°C, filtered, and dried under reduced pressure to give DS14914, with a shrinkage of 90% and a content of 99.7%. ESI-MS(+): m / z=734.1 (M+Na). Elemental analysis: Found: Na, 6.33%; Se, 11.02%; Theoretical: Na, 6.47%; Se, 11.12%.

[0154] Example 10: Synthesis of compound DS14915:

[0155] JPEG2025533158000030.jpg59138

[0156] 0.6 g of compound DS14914 was dissolved in 25 ml of deionized water, and a solution of 185 mg of zinc acetate dihydrate in 5 ml of deionized water was added. The mixture was stirred at room temperature for 2 hours, filtered, and the resulting product was dried under reduced pressure to give DS14915. The shrinkage was 84%, the purity was 99.4%, and the ESI-MS (+): m / z = 729.9 (M + H). Elemental analysis: Found: Se, 10.66%; Zn, 8.81%; Theoretical: Se, 10.82%; Zn, 8.96%.

[0157] Example 11: Synthesis of compound DS1836:

[0158] JPEG2025533158000031.jpg59107

[0159] 1 g of compound DS1491 was added to 10 ml of absolute ethanol, the mixture was heated to 50°C, 100 mg of potassium hydroxide was added, and the mixture was stirred for 2 hours. The mixture was then cooled to 0°C, filtered, and dried under reduced pressure to obtain DS1836, with a shrinkage of 95% and a content of 99.1%. ESI-MS(+): m / z = 617.9 (M + Na). Elemental analysis: Found: K 6.65%; Se 13.15%; Theoretical: K 6.58%; Se 13.28%.

[0160] The following example compounds are synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0161] JPEG2025533158000032.jpg146129

[0162] The following example compounds are obtained by referring to the synthesis methods of metal salts in this invention and in the literature.

[0163] JPEG2025533158000033.jpg114169

[0164] Comparative Example 1: Synthesis of M41 and M42

[0165] JPEG2025533158000034.jpg65166

[0166] The above two comparative compounds M41 and M42 are synthesized with reference to the synthesis methods of compounds DS1491 and DS1494.

[0167] Compound M43 was synthesized according to the synthetic method described in the literature (CN113226327B).

[0168] Example 12: Anti-influenza virus cellular activity experiment

[0169] MDCK cells were seeded into 96-well culture plates and cultured in a 5% CO2, 37°C incubator. During the exponential growth phase, cell culture medium containing different dilutions of sample and positive control drugs was added. Three composite wells were set up for each concentration, along with a normal cell control well. After sample addition, the cells were cultured for 72 hours, and the cytotoxicity of the samples was tested using the CPE method. MDCK cells were seeded into 96-well culture plates and cultured in a 5% CO2, 37°C incubator. After 24 hours of culture, they were infected with influenza virus (A / Hanban / 359 / 95(H3N2)). After 2 hours of virus adsorption, the virus solution was discarded, and cell culture medium containing different dilutions of sample and positive control drugs was added. Three composite wells were set up for each concentration, with both cell control and virus control wells set up simultaneously. These were then cultured in a 5% CO2, 37°C incubator.

[0170] Table 1: Cytotoxicity and inhibitory activity of compounds against influenza virus JPEG2025533158000035.jpg83163Note: IAV in Table 1 refers to the A / Hanfang / 359 / 95 (H3N2) virus strain.

[0171] Experiments have shown that the compounds of the present invention have very good in vitro anti-influenza virus activity and a relatively large therapeutic index (TC50 / EC50).Compared to the comparative compounds M41 and baloxavir, the compounds DS1491-DS1493 (active ingredients) of the present invention have significantly better in vitro anti-influenza virus activity and a larger therapeutic index.In addition, the prodrug compounds in the compounds of the present invention have better in vitro activity against influenza virus and a larger therapeutic index than the comparative compounds M42 and baloxavir dipisol.

[0172] Example 13: Activity against other influenza viruses

[0173] The antiviral effects of compounds against five true virus strains, influenza A virus (IAV) A / WSN / 33 (H1N1), A / PR / 8 / 34 (H1N1) (PR8), A / Weiss / 43 (H1N1) oseltamivir-resistant strain, and influenza B virus B / Beijing-Haidian / 1386 / 2013 (BV), and B / Massachusetts / 2 / 2012 (BY-3), were measured using the following method. The specific experimental procedure was as follows: MDCK cells were inoculated into a 24-well plate at 1 × 105 cells per well and cultured in a 5% CO2, 37°C incubator. After 24 hours of cell culture, gradient dilutions of the test compound were added to each well. One hour after compound addition, the cells were infected with different strains of influenza virus. Normal cell control wells and virus control wells were set up. The antiviral test of the test samples was performed using the CPE method. When the CPE score of the virus control group reached 4+, the CPE score of each group was observed. The EC50 of each sample was calculated using the Reed-Muench method. The experiment was repeated three times, and the results are shown in Table 2.

[0174] Table 2: Inhibitory activity against other influenza viruses JPEG2025533158000036.jpg49132Note: A / WSN / 33 = A / WSN / 33 (H1N1); PR8 = A / Puerto Rico / 8 / 1934 (H1N1); OSE-R = A / Weiss / 43 (H1N1) oseltamivir-resistant strain; HD = B / Beijing-Haidian / 1386 / 2013 (BV); BY-3 = BY / Massachusetts / 02 / 2012

[0175] Experiments have shown that the compound of the present invention has good activity against oseltamivir-resistant strains and influenza B virus. The activity of the compound of the present invention is significantly improved compared to the comparative compound M42 and is significantly higher than that of Ribavirin. In addition, the inhibitory activity of the compound of the present invention against influenza B virus is superior to that of the comparative compound M43.

[0176] Example 14: Viral titer test and histopathological examination

[0177] Fifteen female C57BL / 6J mice (8 weeks old, 18-20 g) were divided into five groups (Group A, Group B, Group C, Group D, and Group E), each consisting of three mice. After nasal inoculation with a median lethal dose of A / PR / 8 / 34 (H1N1) virus, Groups A, B, and C received the test drug (Group A: DS1494; Group B: DS1833; Group C: M42, all suspended in 1% methylcellulose solution, at a dose of 2 mg / kg for each group). Group D received an equal volume of 1% methylcellulose solution orally and intragastrically. Group E received the test drug DS1835 (1.4 mg / kg, dissolved in saline) intraperitoneally. All groups received the test drug once daily. Five days after infection, lung tissue samples were collected, and the left lung was examined for pathological examination, while TCID50 measurements were performed on the right lung homogenate. The viral titer results are shown in Figure 1.

[0178] Lung virus titer test results: Compared with the vehicle group, the lung tissue virus titers of the other groups were lower. In addition, the lung tissue virus titers of the DS1494 and DS1833 groups of this invention were lower than those of the comparative compound M42 at the same dose, demonstrating superior anti-influenza virus efficacy. DS1835 was administered intraperitoneally at a relatively low dose and showed the lowest lung tissue virus titer.

[0179] Lung histopathological examination results showed that the lung tissue structure of group D (model) mice was obviously damaged, the alveolar structure was unclear, localized parenchyma was formed, and epithelial cells were degenerated and necrotic. The lung tissue of group E (intraperitoneal injection DS1835) mice had a clear bronchial structure, complete epithelial cell morphology, and an orderly arrangement. The lung tissue of group A (DS1494), group B (DS1833), and group C (M42) mice had a clear bronchial structure, orderly arrangement of epithelial cells, and a small amount of inflammatory cell infiltration. The lung tissue of group C mice showed a small amount of epithelial cell necrosis. The lung lesions of mice treated with this compound were milder than those of the comparative compound M42, indicating that this compound can ameliorate the pathological damage of lung tissue caused by influenza virus.

[0180] The above results indicate that the compound of the present invention has a superior anti-influenza virus effect.

[0181] Example 15: Mouse tissue distribution test

[0182] Eighteen female DBA / 1J mice (6-8 weeks old) were weighed the day before administration and the dose was calculated. They were randomly divided into two groups (nine mice per group) and orally administered DS1494 or M42 (2 mg / kg each, suspended in 1% methylcellulose). Mice were sampled at three time points: 2, 4, and 8 hours (three mice per time point). Mice were euthanized by CO2 at each time point. Organs (lungs, liver, kidneys, spleen, and heart) were collected from the euthanized mice, washed with saline to remove blood, then aspirated with filter paper, weighed, and homogenized in three volumes of saline in glass homogenite tubes to obtain tissue homogenates. The homogenates were stored at -80°C. After processing, the samples were analyzed by LC-MS / MS (DS1491 for the DS1494 group and M41 for the M42 group).

[0183] The results showed that both compounds reached their highest concentrations in the above tissues 2 hours after administration. In lung tissue, DS1491 concentrations in the DS1494 group were higher than those in the M42 group. Furthermore, at 4 and 8 hours after administration, the rate of decline in DS1491 concentrations in the DS1494 group was much slower than that of M41 in the M42 group. By 8 hours after administration, DS1491 concentrations in the DS1494 group were approximately four times higher than those in the M42 group.

[0184] Example 16: PK study in cynodont monkeys

[0185] Twenty-four normal-sized cynomolgus monkeys, half male and half female, aged 3-6 years, weighing 2.5-4 kg, were randomly divided into eight groups designated as groups A1, B1, C1, D1, and A2, B2, C2, and D2. Groups A1, B1, C1, and D1 were administered orally (po) and fasted overnight without water before administration. Groups A2, B2, C2, and D2 were administered intravenously (iv) and fasted overnight without water before administration.

[0186] Oral administration samples were prepared as suspensions using 0.5% CMC-Na aqueous solution and administered at a dose of 2 mg / kg. Group A1 was M42, Group B1 was DS1494, Group C1 was DS1833, and Group D1 was DS1837. Intravenous injection samples were dissolved in a mixed solvent (5% DMSO + 35% PEG400 + 60% injection water) to prepare a solution, and the dose was 0.5 mg / kg. Group A2 was M42, Group B2 was DS1494, Group C2 was DS1833, and Group D2 was DS1837.

[0187] For the oral administration group, blood samples were collected via the femoral vein before administration (0 h) and at 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after administration. For the intravenous administration group, blood samples were collected via the femoral vein before administration (0 h) and at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, and 24 h after administration. Approximately 1.5 mL of blood was collected and placed in heparin-containing anticoagulant tubes. The samples were refrigerated and centrifuged at 2-8°C for 10 minutes. The target compounds in the plasma were detected by LC / MS / MS (compound M41 was detected in the M42 and DS1837 groups, and compound DS1491 was detected in the DS1833 and DS1494 groups). Pharmacokinetic parameters were calculated using DAS from the blood concentration data at different time points, and the results are shown in Table 3.

[0188] Table 3: PK parameters in caniclus monkeys JPEG2025533158000037.jpg23167 *Oral tube stomach data

[0189] As a result, the peak time Tmax and mean absorption time MAT (MAT = MRT(po) - MRT(iv)) of the compound of the present invention were both small, indicating that it was rapidly absorbed after administration compared to the control group M42. Other compounds in this invention also exhibit this characteristic.

[0190] Although multiple embodiments are described in this application, within the scope of the embodiments described in this application, they are exemplary and not limiting, and many more embodiments and configurations are possible.

Claims

1. It is a compound such as that shown in (I-0), or a hydrate, solvate, optical isomer, polycrystal, isotopic derivative, or pharmaceutically acceptable salt thereof. In (I-0), Ra is selected from hydrogen, deuterium, a methyl group, or a deuterated methyl group. X is S or Se. When X is S, at least one deuterium atom is contained in (I-0). R b and R c are each independently hydrogen, deuterium, a C1-C3 alkyl group or a deuterated C1-C3 alkyl group, or a cyclopropyl group or a deuterated cyclopropyl group formed by combining Rb, Rc and the carbon atom bonded thereto. R is hydrogen, 、 or 。 In this, X1 is an O atom or a S atom. n1 is 0, 1 or 2. R 1 or R 2 are each independently selected from hydrogen, deuterium, methyl, or deuterated methyl. R 3 is a group in which one or more hydrogen atoms are replaced with deuterium or not replaced with deuterium, such as a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, or a C1-C8 alkylamine group. R 4 and R 5 are each independently a hydroxyl group, or the following groups in which one or more hydrogen atoms are replaced with or without deuterium: a C1-C8 alkoxy group, a C1-C8 alkylthio group, a C1-C8 alkylamine group, or a C6-C20 arylalkoxy group; or R 4 and R 5 It is a 5-7 member ring formed with the phosphorus atoms bonded together. Among them, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 and each independently is hydrogen or a C1-C3 alkyl group; or R 6 and R 7 , R 8 and R 9 , R 11 and R 12 , R 12 and R 13 Each of these forms an aromatic ring together with the carbon atoms to which it is bonded, and R 4 and R 5 is a 5-7 member ring consisting of a phosphorus atom bonded together and one or more deuterium atoms replacing hydrogen atoms on the ring, which may or may not be substituted.

2. The compound according to claim 1, or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof. (I-0) in R a was selected from hydrogen, deuterium, or a methyl group. X is Se. R b and R c are each independently selected from hydrogen, deuterium, a C1-C3 alkyl group, or a deuterated C1-C3 alkyl group; or R b , R c are each a cyclopropyl group or a deuterated cyclopropyl group formed together with the associated carbon atom. R is hydrogen, 、 or 。 wherein X1 is an O atom or a S atom. n1 is 0, 1 or 2. R 1 Or R 2 are each independently selected from hydrogen or methyl. R 3 is selected from the following groups: a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 alkylthio group, and a C1-C8 alkylamine group. R 4 and R 5 are each independently a hydroxyl group or the following groups: a C1-C8 alkoxy group, a C1-C8 alkylthio group, or a C1-C8 alkylamine group.

3. It is a compound such as that shown in (I), or a hydrate, solvate, optical isomer, polycrystal, isotopic derivative, or pharmaceutically acceptable salt thereof. (I) to R a is selected from hydrogen, deuterium, a methyl group, or a deuterated methyl group. R b and Rc are each independently selected from hydrogen, deuterium, a C1-C3 alkyl group, and a deuterated C1-C3 alkyl group, or R b , Rc and the carbon atom bonded thereto form a cyclopropyl group or a deuterated cyclopropyl group. R is hydrogen, 、 or ； Among them, X 1 is an O atom or a S atom. n1 is 0, 1 or 2. R 1 Alternatively, each R2 is independently selected from the group consisting of hydrogen, deuterium, methyl, or deuterated methyl. R 3 is selected from the following C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 alkylthio group, and C1-C8 alkylamine group, in which one or more hydrogen atoms are replaced with deuterium or are not replaced with deuterium. R 4 and R 5 are each independently a hydroxyl group, one or more hydrogen atoms of which may or may not be replaced by deuterium, a C1-C8 alkoxy group, a C1-C8 alkylthio group, a C1-C8 alkylamine group, or a C6-C20 arylalkoxy group; or R 4 and R 5 It is a 5-7 element ring formed by the phosphorus atom to which it is bonded. Among them is R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or a C1-C3 alkyl group, or R 6 and R 7 , R 8 and R 9 , R 11 and R 12 , R 12 and R 13 Together with the carbon atoms bonded together, they form an aromatic ring, R 4 and R 5 A 5-7-member ring consisting of a phosphorus atom bonded together with one or more hydrogen atoms of the substituents on the ring not being replaced with deuterium.

4. It is a compound, for example, as represented by formula (II), or a hydrate, solvate, optical isomer, polycrystalline form, isotopic derivative, or pharmaceutically acceptable salt thereof. The definition of the substituents in (II) is the same as that in claim 1.

5. It is a compound such as that shown in (III), or a hydrate, solvate, optical isomer, polycrystal, isotopic derivative, or pharmaceutically acceptable salt thereof. The definition of the substituents in (III) is the same as that in claim 1.

6. Any one of the compounds in claims 1 to 5 is selected from the following structures: or a hydrate, solvate, optical isomer, polycrystal, isotope derivative, or pharmaceutically acceptable salt thereof.

7. It is a drug containing multiple ingredients. The compound according to any one of claims 1 to 6, or a hydrate, solvate, optical isomer, polycrystal, isotopic derivative, pharmaceutically acceptable salt, or pharmaceutically acceptable carrier thereof.

8. A multi-component drug as recited in claim 7. The drug may be in the form of a tablet, capsule, powder, granule, pill, suspension, syrup, injection or inhalant.

9. Any one of the compounds of claims 1 to 6, including hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts thereof. Alternatively, it is a drug having multiple components as set forth in claim 7 or claim 8. Used against influenza viruses.

10. Any one of the compounds of claims 1 to 6, including hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, and pharmaceutically acceptable salts thereof. Alternatively, it is a drug having multiple components as set forth in claim 7 or claim 8. Used as an anti-influenza drug.

11. A method for preventing and treating influenza virus infection, comprising any one of the compounds set forth in claims 1 to 6, including hydrates, solvates, optical isomers, polycrystalline forms, isotopic derivatives, and pharmaceutically acceptable salts thereof. Or a combination of drugs as set forth in claims 7-8.

12. Any one of the compounds of claims 1 to 6, including hydrates, solvates, optical isomers, polycrystalline forms, isotopic derivatives, and pharmaceutically acceptable salts thereof. Or a combination of drugs as set forth in claim 7 or claim 8. Used against influenza viruses.

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