Cap-dependent endonuclease inhibitor, preparation method thereof and application thereof

Abstract

The present invention relates to a cap-dependent nuclease inhibitor having a structure shown in Formula I-Formula II or any one of its pharmaceutically acceptable salts, solvates or crystalline forms, wherein X is selected from any one of fluorine and deuterium, and y is an integer of 1-3.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically relates to a cap-dependent endonuclease inhibitor, a preparation method thereof and an application thereof. Background Art

[0002] The hidden and sequence- and structure-conserved region of influenza virus is the endonuclease domain of the polymerase acid protein required for transcription of the influenza virus genome. It is cap-shaped and is also called the cap-dependent endonuclease domain (CEN). Its active site contains two metal ions (Mg 2+ or Mn 2+ ) is an enzyme essential for viral replication.

[0003] WO2016175224A1 discloses a cap-dependent endonuclease (CEN) inhibitor, baloxavir marboxil, which is hydrolyzed in vivo into an active substance, baloxavir, and its keto-enol-keto structural unit can chelate two metal ions (Mg and 2+ or Mn 2+ ), inhibiting the viral replication activity of CEN and exerting antiviral activity, and targeting the viral replication cycle and earlier stages, with a faster onset of action.

[0004]

[0005] However, baloxavir dipivoxil may cause adverse reactions such as swelling of the face, eyelids or tongue, dysphonia, angioedema, rash, urticaria, erythema multiforme, gastrointestinal system diseases (such as vomiting, bloody diarrhea, melena, colitis, etc.), and nervous system diseases (such as delirium, abnormal behavior and hallucinations, etc.), and some virus strains have developed drug resistance. Therefore, it is urgent to develop safe and effective anti-influenza drugs to meet clinical needs. Summary of the invention

[0006] The object of the present invention is to provide a cap-dependent endonuclease inhibitor having a structure shown in Formula I to Formula II or any one of its pharmaceutically acceptable salts, solvates or crystalline forms.

[0007]

[0008] Wherein, X is selected from any one of fluorine and deuterium, and y is an integer of 1-3.

[0009] In the preferred technical solution of the present invention, the compound of formula I to formula II is selected from any one of compounds B01-B16:

[0010]

[0011]

[0012] In a preferred technical solution of the present invention, the salt is selected from any one of the organic acid salt or inorganic acid salt of the compound of formula I to formula II.

[0013] In a preferred technical solution of the present invention, the organic acid is selected from any one of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, p-toluenesulfonate, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid, or a combination thereof.

[0014] In a preferred technical solution of the present invention, the inorganic acid is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid, or a combination thereof.

[0015] Another object of the present invention is to provide a method for preparing a compound of formula I, comprising the steps of reacting a compound of formula II with chloromethyl methyl carbonate in a solvent in the presence of a base and a catalyst to obtain, wherein X is selected from any one of fluorine and deuterium, and y is an integer of 1-3.

[0016]

[0017] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, and disodium hydrogen phosphate, or a combination thereof.

[0018] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the catalyst is selected from potassium iodide, sodium iodide or any one or a combination thereof.

[0019] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0020] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II:catalyst is 1:0.1-1, preferably 1:0.5-1.

[0021] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II: methyl chloromethyl carbonate is 1:1-2, preferably 1:1.5-1.8.

[0022] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II: the base is 1:1-5, preferably 1:2-3.

[0023] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature is 20-100°C, preferably 50-70°C.

[0024] In the preferred technical scheme of the present invention, the compound of formula II is prepared by deprotection reaction of a compound of formula III or its salt with a lithium salt in a solvent, wherein X is selected from any one of fluorine and deuterium, and y is an integer of 1-3.

[0025]

[0026] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the lithium salt is selected from any one of lithium chloride and lithium bromide or a combination thereof.

[0027] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the solvent is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0028] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the molar ratio of the compound of formula III: lithium salt is 1:1-20, preferably 1:5-10.

[0029] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reaction temperature is 50-100°C, preferably 70-80°C.

[0030] In the preferred technical scheme of the present invention, the compound of formula III is prepared by reacting a compound of formula VI with a compound of formula V or a salt thereof and a condensing agent in a solvent, wherein X is selected from any one of fluorine and deuterium, y is an integer of 1-3,

[0031]

[0032] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the condensing agent is selected from any one or a combination of n-propylphosphonic anhydride, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, 10-camphorsulfonic acid, concentrated sulfuric acid, dichloroacetic acid, and tetramethylammonium hydrogen sulfate.

[0033] In the preferred technical scheme of the present invention, the solvent is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water, or a combination thereof.

[0034] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V or its salt: the condensing agent is 1:1-5, preferably 1:1-3.

[0035] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V: the compound of formula IV is 1:1-2, preferably 1:1-1.3.

[0036] In the preferred technical solution of the present invention, the condensing agent is composed of n-propylphosphonic anhydride and methanesulfonic acid.

[0037] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V: n-propylphosphonic anhydride is 1:1-5, preferably 1:1-3, and more preferably 1:1-1.5.

[0038] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V:methanesulfonic acid is 1:1-5, preferably 1:1-3, and more preferably 1:1-2.

[0039] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the reaction temperature is 0-100°C, preferably 50-70°C.

[0040] Another object of the present invention is to provide a method for preparing the compound of formula I, comprising the following steps:

[0041]

[0042] (1) subjecting a compound of formula IV to a condensation reaction with a compound of formula V or a salt thereof and a condensation agent in a solvent to obtain a compound of formula III or a salt thereof;

[0043] (2) subjecting the compound of formula III or its salt to a deprotection reaction with a lithium salt in a solvent to obtain a compound of formula II;

[0044] (3) The compound of formula II is reacted with methyl chloromethyl carbonate in the presence of a base and a catalyst in a solvent to obtain: wherein X is selected from any one of fluorine and deuterium, and y is an integer of 1-3.

[0045] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent in step (1) is selected from any one of n-propylphosphonic anhydride, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, 10-camphorsulfonic acid, concentrated sulfuric acid, dichloroacetic acid, tetramethylammonium hydrogen sulfate or a combination thereof.

[0046] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step (1) is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0047] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula V or its salt in step (1) to the condensing agent is 1:1-5, preferably 1:1-3.

[0048] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula V in step (1) to the compound of formula IV is 1:1-2, preferably 1:1.0-1.3.

[0049] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the condensing agent in step (1) consists of n-propylphosphonic anhydride and methanesulfonic acid.

[0050] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula V in step (1) to n-propylphosphonic anhydride is 1:1-5, preferably 1:1-3, and more preferably 1:1-1.5.

[0051] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula V in step (1): methanesulfonic acid is 1:1-5, preferably 1:1-3, and more preferably 1:1-2.

[0052] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step (1) is 0-100°C, preferably 50-70°C.

[0053] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the lithium salt in step (2) is selected from any one of lithium chloride and lithium bromide or a combination thereof.

[0054] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step (2) is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0055] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula III in step (2): the lithium salt is 1:1-20, preferably 1:5-10.

[0056] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step (2) is 50-100°C, preferably 70-80°C.

[0057] In a preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step (3) is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, and disodium hydrogen phosphate, or a combination thereof.

[0058] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the catalyst in step (3) is selected from potassium iodide, sodium iodide or any one or a combination thereof.

[0059] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step (3) is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0060] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II in step (3): the catalyst is 1:0.1-1, preferably 1:0.5-1.

[0061] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II in step (3): methyl chloromethyl carbonate is 1:1-2, preferably 1:1.5-1.8.

[0062] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II in step (3): the base is 1:1-5, preferably 1:2-3.

[0063] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step (3) is 20-100°C, preferably 50-70°C.

[0064] Another object of the present invention is to provide a method for preparing the compound of formula II, comprising the following steps:

[0065]

[0066] (1) subjecting a compound of formula IV to a condensation reaction with a compound of formula V or a salt thereof and a condensation agent in a solvent to obtain a compound of formula III or a salt thereof;

[0067] (2) The compound of formula III or its salt is subjected to a deprotection reaction with a lithium salt in a solvent to obtain a compound of formula II.

[0068] In the preferred technical scheme of the present invention, the condensing agent in step (1) is selected from any one of n-propylphosphonic anhydride, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, 10-camphorsulfonic acid, concentrated sulfuric acid, dichloroacetic acid, tetramethylammonium hydrogen sulfate or a combination thereof.

[0069] In the preferred technical scheme of the present invention, the solvent in step (1) is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0070] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V or its salt: the condensing agent is 1:1-5, preferably 1:1-3.

[0071] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V: the compound of formula IV is 1:1-2, preferably 1:1-1.3.

[0072] In the preferred technical solution of the present invention, the condensing agent consists of n-propylphosphonic anhydride and methanesulfonic acid.

[0073] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V: n-propylphosphonic anhydride is 1:1-5, preferably 1:1-3, and more preferably 1:1-1.5.

[0074] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V:methanesulfonic acid is 1:1-5, preferably 1:1-3, and more preferably 1:1-2.

[0075] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the reaction temperature is 0-100°C, preferably 50-70°C.

[0076] In a preferred technical solution of the present invention, the lithium salt in step (2) is selected from lithium chloride, lithium bromide or any one or a combination thereof.

[0077] In a preferred technical solution of the present invention, the solvent in step (2) is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0078] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the molar ratio of the compound of formula III: lithium salt is 1:1-20, preferably 1:5-10.

[0079] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reaction temperature is 50-100°C, preferably 70-80°C.

[0080] Another object of the present invention is to provide a compound of formula III or a salt thereof:

[0081]

[0082] In the preferred technical scheme of the present invention, the compound of formula III or its salt is any one of compounds B17-B24 or its mesylate or p-toluenesulfonate:

[0083]

[0084] Another object of the present invention is to provide a method for preparing a compound of formula III or a salt thereof, which is prepared by subjecting a compound of formula IV and a compound of formula V or a salt thereof to a condensation reaction with a condensing agent in a solvent.

[0085]

[0086] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the condensing agent is selected from any one of n-propylphosphonic anhydride, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, 10-camphorsulfonic acid, concentrated sulfuric acid, dichloroacetic acid, tetramethylammonium hydrogen sulfate or a combination thereof.

[0087] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the solvent is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

[0088] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V or its salt: the condensing agent is 1:1-5, preferably 1:1-3.

[0089] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V: the compound of formula IV is 1:1-2, preferably 1:1.0-1.3.

[0090] In the preferred technical solution of the present invention, the condensing agent consists of n-propylphosphonic anhydride and methanesulfonic acid.

[0091] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V: n-propylphosphonic anhydride is 1:1-5, preferably 1:1-3, and more preferably 1:1-1.5.

[0092] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula V:methanesulfonic acid is 1:1-5, preferably 1:1-3, and more preferably 1:1-2.

[0093] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the reaction temperature is 0-100°C, preferably 50-70°C.

[0094] Another object of the present invention is to provide a pharmaceutical composition, which is composed of a compound of Formula I to Formula II or any one of their pharmaceutically acceptable salts, solvates or crystalline forms and a pharmaceutically acceptable carrier.

[0095] In the preferred technical solution of the present invention, the amount or type of the pharmaceutically acceptable carrier in the pharmaceutical composition is determined according to factors such as the physicochemical properties and content of the active ingredient in the composition, the type of preparation, the dissolution and bioavailability of the preparation, and the like.

[0096] In a preferred technical solution of the present invention, the dosage form of the pharmaceutical composition is selected from any one of an oral preparation, an injection, and an external preparation.

[0097] In a preferred technical solution of the present invention, the oral preparation is selected from any one of oral liquid preparations, tablets, capsules, granules, syrups, powders, dews, effervescents, suspensions, pills, pellets, mixtures, pastes, emulsions, liniments, dragees, solutions, lozenges, cachets, gels, and suspensions.

[0098] In the preferred technical scheme of the present invention, the external preparation is selected from any one of a gel, a paste, a plaster, a cream, an ointment, a liniment, a lotion, a suppository, a smear, a gel, an ointment, an aerosol, a dry powder inhaler, a spray, and a nebulizer.

[0099] In the preferred technical solution of the present invention, the injection is selected from any one of a solution injection, an emulsion injection, a suspension injection, a sterile powder for injection, and a large infusion.

[0100] In the preferred technical scheme of the present invention, the pharmaceutically acceptable carrier of the present invention is a commonly used excipient or auxiliary material in the art for preparing the desired preparation, including fillers (diluents), disintegrants, binders, lubricants (glidants or anti-adhesive agents), dispersants, wetting agents, pH regulators (acid-base regulators), osmotic pressure regulators, pore-forming agents, solubilizers, antioxidants, antibacterial agents (bactericides), analgesics (anesthetics), suspending agents, emulsifiers, emulsifier aids, lyoprotectants, flavoring agents, fragrance agents, etc.

[0101] In the preferred technical scheme of the present invention, the filler is selected from any one or a combination of lactose, powdered sugar, dextrin, starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, cellulose, inorganic calcium salt, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, and hydroxypropyl methyl cellulose.

[0102] In a preferred technical solution of the present invention, the disintegrant is selected from any one or a combination of starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch or its derivatives, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose.

[0103] In the preferred technical scheme of the present invention, the adhesive is selected from any one of syrup, gum arabic, gelatin, sorbitol, tragacanth gum, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin slurry, starch slurry, polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, and corn starch, or a combination thereof.

[0104] In a preferred technical solution of the present invention, the lubricant is selected from any one of micro-powdered silica gel, magnesium stearate, talc, colloidal silicon dioxide, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, and sodium lauryl sulfate, or a combination thereof.

[0105] In a preferred technical solution of the present invention, the wetting agent is selected from any one of sodium lauryl sulfate, polysorbate (Tween), water, alcohol, ester or a combination thereof.

[0106] In the preferred technical scheme of the present invention, the antioxidant is selected from any one of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, vitamin C, vitamin E, dibutyl benzoic acid, butylated hydroxyanisole (BHA), dibutyl hydroxytoluene (BHT), propyl gallate (PG), niacinamide, acetylcysteic acid, and tert-butylhydroquinone (TBHQ) or a combination thereof.

[0107] In a preferred technical solution of the present invention, the bacteriostatic agent (bactericide) is selected from any one of phenol, cresol, chlorobutanol, benzyl alcohol or a combination thereof.

[0108] In a preferred technical solution of the present invention, the analgesic (anesthetic) is selected from any one of chlorobutanol, benzyl alcohol, lidocaine, procaine or a combination thereof.

[0109] In the preferred technical scheme of the present invention, the suspending agent is selected from any one of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, syrup, glycerin, gelatin, gum arabic, tragacanth, sodium alginate, potassium alginate, pectin or a combination thereof.

[0110] In a preferred technical scheme of the present invention, the acid-base regulator (pH regulator) is selected from any one of hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, potassium citrate, malic acid, sodium malate, potassium malate, sodium dihydrogen phosphate, disodium hydrogen phosphate, calcium hydroxide, calcium lactate, sodium lactate, sodium phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, and sodium carbonate, or a combination thereof.

[0111] In a preferred technical solution of the present invention, the osmotic pressure regulator is selected from any one of sodium chloride, potassium chloride, glucose, phosphate and citrate.

[0112] In the preferred technical scheme of the present invention, the emulsifier is selected from any one of sodium stearate, potassium stearate, triethanolamine stearate, magnesium stearate, calcium stearate, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, polysorbate (Tween), Span, benzyl alcohol, benzyl alcohol, tragacanth gum, gum arabic, Pluronic F-68, lecithin, and soybean lecithin, or a combination thereof.

[0113] In a preferred technical solution of the present invention, the auxiliary emulsifier is selected from any one of n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, and polyglycerol esters, or a combination thereof.

[0114] In a preferred technical solution of the present invention, the lyoprotectant is selected from any one of sucrose, lactose, galactose, glucose, trehalose, mannitol, and sorbitol, or a combination thereof.

[0115] In the preferred technical solution of the present invention, the solubilizing agent is selected from any one of Tween-80, Pluronic F-68, benzyl alcohol, benzyl alcohol, bile salt, deoxycholate, glycerol, propylene glycol, and polyethylene glycol, or a combination thereof.

[0116] In a preferred technical solution of the present invention, the flavoring agent is selected from any one of honey, syrup, acid, alkali, essence, sweetener, or a combination thereof.

[0117] In a preferred technical solution of the present invention, the pharmaceutical composition of the present invention is mixed with a pharmaceutically acceptable sustained-release preparation carrier or a controlled-release preparation carrier according to the preparation method of sustained-release preparation or controlled-release preparation in the art, such as adding a blocking agent coating or making a skeleton-type preparation, and any one of the compounds of formula I to formula II of the present invention or their pharmaceutically acceptable salts is microencapsulated to prepare a sustained-release preparation or a controlled-release preparation.

[0118] In the preferred technical solution of the present invention, the sustained-release preparation carrier or controlled-release preparation carrier is selected from any one of an oily admixture, a hydrophilic colloid, a water-insoluble blocker, an enteric blocker, and a biodegradable blocker or a combination thereof.

[0119] In the preferred technical solution of the present invention, the oily admixture is selected from any one of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane, dimethylsiloxane or a combination thereof.

[0120] In the preferred technical scheme of the present invention, the hydrophilic colloid is selected from any one of methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HMPC), polyvinyl pyrrolidone (PVP), gum arabic, tragacanth or carbopol, polyvinyl alcohol (PVA), pectin, alginate, chitosan, xanthan gum, guar gum, garnet, gelatin, agar, and galactomannan, or a combination thereof.

[0121] In the preferred technical solution of the present invention, the water-insoluble retarder is selected from any one of ethyl cellulose (EC), cellulose acetate (CA), polyethylene, polypropylene, polysiloxane, ethylene vinyl acetate copolymer (EVA), polymethyl methacrylate or a combination thereof.

[0122] In the preferred technical solution of the present invention, the enteric retarder is selected from any one of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HMPCP), polyvinyl alcohol phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) acrylic resin or a combination thereof.

[0123] In the preferred technical solution of the present invention, the biodegradable retarder is selected from any one of wax, fatty acid, fatty acid ester, fatty alcohol, carnauba wax, stearic acid, glyceryl monostearate, stearyl alcohol, and hexadecanol, or a combination thereof.

[0124] In a preferred technical solution of the present invention, the administration method of the pharmaceutical composition is selected from any one of oral administration, injection administration, mucosal administration, and skin administration.

[0125] Another object of the present invention is to provide a pharmaceutical composition, which consists of a first composition containing compounds of Formula I-Formula II or pharmaceutically acceptable salts, solvates or crystalline forms thereof and a second composition containing other anti-influenza drugs.

[0126] In a preferred technical solution of the present invention, the other anti-influenza drugs are selected from any one of neuraminidase inhibitors, RNA-dependent RNA polymerase inhibitors, M2 protein inhibitors, PB2 Cap binding inhibitors, anti-HA antibodies, and immune drugs, or a combination thereof.

[0127] In the preferred technical scheme of the present invention, the other anti-influenza drugs are selected from any one of Oseltamivir, Zanamivir, Peramivir, Inavir, Favipiravir, Amantadine, VX-787, MHAA4594A, Nitazoxanide or a combination thereof.

[0128] In a preferred technical solution of the present invention, the first composition and the second composition are administered simultaneously or sequentially.

[0129] In a preferred technical solution of the present invention, the administration method of the pharmaceutical composition is selected from any one of oral administration, injection administration, mucosal administration, and skin administration.

[0130] Another object of the present invention is to provide the use of compounds of formula I to formula II or any one of their pharmaceutically acceptable salts, solvates or crystalline forms or their pharmaceutical compositions for preparing drugs for preventing and treating influenza virus infection and its complications.

[0131] In a preferred technical solution of the present invention, the influenza virus includes any one of the three types A, B, and C, or a combination thereof.

[0132] The hydrogen spectrum of the compounds of the present invention ( 1 H-NMR) detection method: the instrument is a 400 MHz nuclear magnetic resonance instrument (BrukerAdvance II 400 MHz) of Bruker; tetramethylsilane (TMS) is used as the internal standard, and the data are collected at room temperature; the chemical shift (δ) is one part per million (ppm); singlets are denoted as s, doublets are denoted as d, triplet peaks are denoted as t, quartets are denoted as q, multiplets are denoted as m, and broad singlets are denoted as brs; the coupling constant is denoted as j, and the unit is Hz; the deuterated solvent is deuterated dimethyl sulfoxide (DMSO-d6).

[0133] Mass spectrometry (MS) detection method for the compounds of the present invention: the instrument is Shimadzu LCMS2010EV, in positive direction, giving the ion peak of molecular weight hydrogenation (MH+).

[0134] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage, and the rest are weight / weight percentages.

[0135] Compared with the prior art, the present invention has the following beneficial effects:

[0136] 1. The cap-dependent endonuclease (CEN) inhibitor of the present invention has significantly better antiviral activity than baloxavir, and has the advantages of a broad antiviral spectrum, excellent safety and efficacy, good stability, high bioavailability, and a wide range of applicable populations, providing a new drug option for clinical use.

[0137] 2. The preparation method of the cap-dependent endonuclease (CEN) inhibitor of the present invention has the advantages of simple operation, better cost, green environmental protection, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0138] Figure 1 The results of the study on the inhibitory activity of the cap-dependent endonuclease inhibitor B1-B08 of the present invention against IFV A / WSN / 33 (H1N1).

[0139] Figure 2 The results of the study on the inhibitory activity of the cap-dependent endonuclease inhibitor B1-B08 of the present invention on IFV B / Lee / 40.

[0140] Figure 3 The results of the study on the inhibitory activity of the cap-dependent endonuclease inhibitors B9-B16 of the present invention against IFV A / WSN / 33 (H1N1).

[0141] Figure 4 The results of the study on the inhibitory activity of the cap-dependent endonuclease inhibitors B9-B16 of the present invention against IFV B / Lee / 40.

[0142] Figure 5 Study on the in vivo antiviral activity of the cap-dependent endonuclease inhibitor of the present invention; DETAILED DESCRIPTION

[0143] The present invention will be specifically described below in conjunction with embodiments; the embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not limited to the embodiments. Any changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit, essence, and principles of the present invention shall be equivalent replacement methods and shall be included in the protection spirit and scope of the present invention.

[0144] Preparation Example 1Preparation of compounds of formula IV (X = F, y = 1 or 2)

[0145]

[0146] Reference 1 (Development of a Quality Controllable and Scalable Process for the Preparation of 7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol:AKey Intermediate for Baloxavir Marboxil", Zihong Zhou, et al, Organic Process Research and Development, 2019, 23, 2716-2723) method preparation: 1) 3,4-difluoro-2-methylbenzoic acid reacts with thionyl chloride in ethanol to obtain the corresponding ethyl ester, 2) reacts with NBS catalyzed by benzoyl oxide to obtain the corresponding bromide, 3) then reacts with fluorine-substituted thiophenol under the promotion of potassium carbonate to obtain a thioether intermediate, 4) then hydrolyzes the ester in ethanol-water with sodium hydroxide to obtain the corresponding carboxylic acid, 5) obtains a cyclized ketone product through polyphosphoric acid, and 6) reduces with sodium borohydride in ethanol to obtain a compound of formula IV:

[0147] 4,7,8-Trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0148] 3,7,8-Trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0149] 1,7,8-Trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0150] 2,4,7,8-Tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0151] 3,4,7,8-Tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0152] 2,3,7,8-Tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0153] 1,2,7,8-Tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol

[0154] Preparation Example 2 Preparation of compounds of formula IV (X = D, y = 2)

[0155]

[0156] Reference 2 (The Endocyclic Restriction Test: The Geometries of Nucleophilic Substitutions at Sulfur(VI)and Sulfur(II) According to the method of Stephen G.et al, Journal of Organic Chemistry, 2008, 73(24), 9627-9632), bromobenzene-d5 is prepared into thiophenol-d5; then, referring to the method of reference 3 (Specifically deuteriated intermediates for the synthesis of liquid crystals and liquid-crystalline polymers, Herbert Zimmermann, Liquid Cryatals I 1989, 4(6), 591-618), thiophenol-d5 is hydrogen-exchanged into thiophenol-d2, and then the compound of formula IV: 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazol-1,3-d2-11-ol is prepared according to the method of Preparation Example 1.

[0157] Example 1 Preparation of ({(12aR)-12-[(11S)-4,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0158]

[0159] (1) 4,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.15 g, 25.33 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept warm at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a methanesulfonate intermediate, (12aR)-12-[(11S)-4,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione methanesulfonate), as a white solid (11.9g, 86%).

[0160] (2) The mesylate intermediate (11.9 g, 17.45 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-4,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.15 g, 93%).

[0161] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (8.15 g, 16.25 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to give a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to give the target compound (8.7 g, 91%) as white crystals.

[0162] 1 H-NMR(400MHz,DMSO-d6)δ:2.86-3.01(1H,m),3.23-3.33(1H,m),3.44(1H,t,J=9.7Hz),3.68(1H, dd,J=11.5,3.2Hz),3.73(3H,s),3.99(1H,dd,J=10.8,3.1Hz),4.18(1H,d,J=14.3Hz),4.39(1H,d, J=11.8Hz),4.45(1H,dd,J=9.9,2.9Hz),5.44(1H,dd,J=14.4,1.8Hz),5.66(1H,d,J=6.6Hz),5.72 -5.88(3H,m),6.85-7.01(2H,m),7.11-7.20(1H,m),7.23(1H,d,J=7.8Hz),7.37-7.45(2H,m).LCMS ESI(+)m / z:590(M+1).

[0163] Example 2Preparation of ({(12aR)-12-[(11S)-3,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0164]

[0165] (1) 3,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.10 g, 25.15 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-3,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (11.9g, 86%).

[0166] (2) The mesylate intermediate (11.9 g, 17.45 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-3,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.15 g, 93%).

[0167] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (8.15 g, 16.25 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to give a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to give the target compound (8.8 g, 92%) as white crystals.

[0168] 1H-NMR(400MHz,DMSO-d6)δ:2.86-3.01(1H,m),3.21-3.33(1H,m),3.45(1H,t,J=9.7Hz),3.66 (1H,dd,J=11.5,3.2Hz),3.73(3H,s),3.99(1H,dd,J=10.8,3.1Hz),4.08(1H,d,J=14.3Hz),4 .33-4.50(2H,m),5.43(1H,d,J=14.5Hz),5.67(1H,d,J=6.6Hz),5.74(1H,d,J=6.6Hz),5.77- 5.88(2H,m),6.97-7.16(2H,m),7.19-7.30(1H,m),7.24(1H,d,J=7.8Hz),7.37-7.45(2H,m).

[0169] LCMS ESI (+) m / z: 590 (M+1).

[0170] Example 3 Preparation of ({(12aR)-12-[(11S)-1,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0171]

[0172] (1) 1,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.12 g, 25.22 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for separation and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-1,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (11.9g, 86%).

[0173] (2) The mesylate intermediate (11.9 g, 17.45 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-1,7,8-trifluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.15 g, 93%).

[0174] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (8.15 g, 16.25 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to give a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to give the target compound (8.7 g, 92%) as white crystals.

[0175] 1 H-NMR(400MHz,DMSO-d6)δ:2.88-3.02(1H,m),3.21-3.33(1H,m),3.46(1H,t,J=9.7Hz),3.66(1H,J=11 .5,3.2Hz),3.72(3H,s),4.01(1H,m),4.08(1H,d,J=14.3Hz),4.40(1H,d,J=13.2Hz),4.44-4.53(1H,m) ,5.41(1H,d,J=14.5Hz),5.68(1H,d,J=6.6Hz),5.74(1H,d,J=6.6Hz),5.77-5.88(2H,m),6.64-6.75(1H ,m),6.99-7.07(1H,m),6.07-7.15(1H,m),7.23(1H,d,J=7.8Hz),7.32-7.41(1H,m),7.42-7.52(1H,m).

[0176] LCMS ESI (+) m / z: 590 (M+1).

[0177] Example 4 Preparation of ({(12aR)-12-[(11S)-2,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0178]

[0179] (1) 2,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.60 g, 25.31 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly diluted with 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-2,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (12.05g, 85%).

[0180] (2) The mesylate intermediate (12.05 g, 17.22 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-2,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.32 g, 93%).

[0181] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (8.32 g, 16.02 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to give a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to give the target compound (8.85 g, 90%) as white crystals.

[0182] 1H-NMR(400MHz,DMSO-d6)δ:2.87-3.00(1H,m),3.20-3.33(1H,m),3.44(1H,t,J=9.7Hz),3.68( 1H,dd,J=11.5,3.2Hz),3.71(3H,s),4.01(1H,m),4.22(1H,d,J=14.3Hz),4.33-4.42(1H,m),4. 42-4.50(1H,m),5.38(1H,d,J=14.5Hz),5.65(1H,d,J=6.6Hz),5.74(1H,d,J=6.6Hz),5.84-5. 92(2H,m),6.90-7.00(1H,m),7.27(1H,d,J=7.8Hz),7.33-7.40(2H,m),7.41-7.51(1H,m).LCMS ESI(+)m / z:608(M+1).

[0183] Example 5 Preparation of ({(12aR)-12-[(11S)-3,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0184]

[0185] (1) 3,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.50 g, 24.98 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-3,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (12.19g, 86%).

[0186] (2) The mesylate intermediate (12.19 g, 17.42 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-3,4,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.42 g, 93%).

[0187] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (8.42 g, 16.21 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to obtain a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to obtain the target compound (8.96 g, 91%) as white crystals.

[0188] 1 H-NMR (400MHz, DMSO-d6)δ:2.85-2.98(1H,m),3.22-3.33(1H,m),3.45(1H,t,J=9.7H z),3.67(1H,dd,J=11.5,3.2Hz),3.72(3H,s),3.94-4.04(1H,m),4.25(1H,d,J=14.3H z),4.33-4.48(2H,m),5.38-5.50(1H,m),5.69(1H,d,J=6.6Hz),5.75(1H,d,J=6.6Hz) ,5.82-5.92(2H,m),6.91-7.06(2H,m),7.25(1H,d,J=7.8Hz),7.35-7.51(2H,m).LCMS ESI(+)m / z:608(M+1).

[0189] Example 6Preparation of ({(12aR)-12-[(11S)-2,3,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0190]

[0191] (1) 2,3,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.55 g, 25.14 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-2,3,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (12.16g, 86%).

[0192] (2) The mesylate intermediate (12.16 g, 17.38 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-2,3,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.40 g, 93%).

[0193] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (8.40 g, 16.17 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to give a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to give the target compound (8.94 g, 91%) as white crystals.

[0194] 1H-NMR(400MHz,DMSO-d6)δ:2.86-3.00(1H,m),3.23-3.33(1H,m),3.46(1H,t,J=9.7 Hz), 3.68 (1H, dd, J = 11.5, 3.2 Hz), 3.72 (3H, s), 3.94-4.05 (1H, m), 4.11 (1H, d, J = 14. 3Hz),4.35-4.51(2H,m),5.38-5.50(1H,m),5.69(1H,d,J=6.6Hz),5.75(1H,d,J=6.6 Hz),5.82-5.92(2H,m),7.18-7.38(3H,m),7.28(1H,d,J=7.8Hz),7.38-7.51(1H,m).

[0195] LCMS ESI (+) m / z: 608 (M+1).

[0196] Example 7 Preparation of ({(12aR)-12-[(11S)-1,2,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0197]

[0198] (1) 1,2,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-ol (7.60 g, 25.31 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept warm at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-1,2,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (12.21g, 86%).

[0199] (2) The mesylate intermediate (12.21 g, 17.45 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then continued to stir at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to obtain the deprotected intermediate, (12aR)-12-[(11S)-1,2,7,8-tetrafluoro-6,11-dihydrodibenzo[b,e]thiazol-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (8.43 g, 93%).

[0200] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol), potassium iodide (1.5 g, 9.04 mmol), the intermediate obtained in the previous step (8.43 g, 16.23 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid (1 .6g), isopropanol (6g), water (39g) and THF (3g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80g) was slowly added, and then water (3g) was added; the resulting slurry was cooled to 0°C, and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to obtain a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to obtain the target compound (8.96 g, 91%) as white crystals.

[0201] 1 H-NMR(400MHz,DMSO-d6)δ:2.87-2.99(1H,m),3.22-3.33(1H,m),3.46(1H,t,J=9.7Hz),3.68(1H,dd,J=1 1.5,3.2Hz),3.70(3H,s),3.97-4.06(1H,m),4.10(1H,d,J=14.3Hz),4.39(1H,d,J=13.2Hz),4.43-4.50(1 H,m),5.33(1H,d,J=14.5Hz),5.66(1H,d,J=6.6Hz),5.74(1H,d,J=6.6Hz),5.81(1H,s),5.85-5.93(1H,m ),7.08-7.17(1H,m),7.28(1H,d,J=7.8Hz),7.30-7.38(1H,m),7.48-7.60(1H,m),7.60-7.72(1H,m).LCMS ESI(+)m / z:608(M+1).

[0202] Example 8 Preparation of ({(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazol-1,3-d2-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl carbonate

[0203]

[0204] (1) 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazol-1,3-d2-11-ol (6.70 g, 25.16 mmol), (R)-7-hexyloxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione p-toluenesulfonate (10.0 g, 20.26 mmol), ethyl acetate (40 g) and cyclohexane (12 g) were stirred and dissolved at room temperature, and then 50% (w / w) T3P-ethyl acetate solution (17.4 g, 27.34 mmol) and methanesulfonic acid (3 g, 31.21 mmol) were added in sequence; the reaction mixture was stirred and kept at 60° C. for 25 hours, then cooled to room temperature, tetrahydrofuran (26 g) and water (2 0g), and then slowly added 24% sodium hydroxide aqueous solution (25.5g); allowed to stand for stratification, and the aqueous phase was discarded; the organic layer was washed twice with 7% brine (50g); cyclohexane (8g), ethyl acetate (26g) and methanesulfonic acid (2.3g) were added to the obtained organic layer; the mixture was stirred at 25°C for 5 hours and filtered; the filter cake was washed with ethyl acetate (35g) and dried to obtain a mesylate intermediate, (12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazol-1,3-d2-11-yl]-3,4,12,12a-tetrahydro-7-hexyloxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione mesylate, as a white solid (11.60g, 86%).

[0205] (2) The mesylate intermediate (11.60 g, 17.42 mmol), lithium chloride (7 g, 165.13 mmol) and N-methylpyrrolidone (37 g) obtained in the previous step were stirred and mixed at room temperature, heated to 75°C and stirred for 20 hours; then cooled to 40°C, acetonitrile (15 g) and water (2 g) were added in sequence; after cooling to 30°C, water (7 g) was slowly added; after continuing to stir at 30°C for 1.5 hours, water (110 g) was slowly added; then stirring was continued at 30°C After stirring for 2 hours, the mixture was filtered; the filter cake was washed with isopropanol (45 g) and dried to give the deprotected intermediate, (12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazol-1,3-d2-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, as a white solid (7.86 g, 93%).

[0206] (3) Methyl chloromethyl carbonate (3.5 g, 28.11 mmol), potassium carbonate (5 g, 36.18 mmol) and potassium iodide (1.5 g, 9.04 mmol), the deprotected intermediate obtained in the previous step (7.86 g, 16.19 mmol), tetrahydrofuran (THF, 65 g), N,N-dimethylacetamide (DMA, 7 g) and water (0.5 g) were mixed at room temperature; the mixture was stirred at 60° C. for 8 hours and then cooled to room temperature, and acetic acid was added. (1.6 g), isopropanol (6 g), water (39 g) and THF (3 g), stirring was continued for 30 minutes, and then the layers were separated; the aqueous phase was extracted with THF (15 g); the combined organic phases were concentrated under reduced pressure to remove low-boiling volatiles; isopropanol (3.5 g) was dropped into the concentrate at 45°C; the resulting mixture was cooled to 20°C, 0.75% aqueous sodium acetate solution (80 g) was slowly added, and then water (3 g) was added; the resulting slurry was cooled to 0°C and the crystalline solid was collected by filtration. The solid was washed with isopropanol-water (21 g, v / v=1:1) and then with isopropanol (12 g) to give a crude product; the crude product was dissolved in dimethyl sulfoxide (60 g) at 60°C; a mixed solvent of dimethyl sulfoxide (5 g) and water (9 g) was added to the solution of the crude product; the resulting slurry was stirred at 60°C for 30 minutes, and then an additional mixed solvent of dimethyl sulfoxide (38 g) and purified water (55 g) was added; after the mixture was cooled to 20°C, the precipitate was collected by filtration; the obtained solid was washed with dimethyl sulfoxide-aqueous solution (25 g, v / v=3:2) and purified water (70 g), and then dried to give the target compound (8.45 g, 91%) as white crystals.

[0207] 1H-NMR(400MHz,DMSO-d6)δ:2.87-2.99(1H,m),3.22-3.33(1H,m),3.46(1H,t,J=9.7Hz),3.68(1H ,dd,J=11.5,3.2Hz),3.70(3H,s),3.97-4.06(1H,m),4.10(1H,d,J=14.3Hz),4.39(1H,d,J=13.2 Hz),4.43-4.50(1H,m),5.33(1H,d,J=14.5Hz),5.66(1H,d,J=6.6Hz),5.74(1H,d,J=6.6Hz),5.8 1(1H,s),5.85-5.93(1H,m),6.85(1H,s),7.09(1H,s),7.22(1H,d,J=7.8Hz),7.35-7.50(2H,m).

[0208] LCMS ESI(+)m / z:574(M+1).

[0209] Test Example 1 Study on the anti-influenza virus activity of the cap-dependent endonuclease inhibitor of the present invention

[0210] The influenza virus cytopathic effect assay was used to evaluate the antiviral activity of the test compounds.

[0211] Test virus strains: influenza A virus IFV A / WSN / 33 (H1N1); influenza B virus IFV B / Lee / 40.

[0212] Test cell line: canine kidney cells (MDCK), purchased from the American Type Culture Collection (ATCC). They were cultured in EMEM medium containing 10% fetal bovine serum, 2 mM glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin. OptiPRO SFM medium supplemented with 2 mM glutamine, 100 U / ml penicillin, 100 μg / ml streptomycin and 2.5 μg / ml pancreatin was used as the test medium.

[0213] Test compounds: B01-B16, prepared into 20 mM stock solution in 100% DMSO;

[0214] Positive controls: Baloxavir and Baloxavir marboxil, prepared as 20 mM stock solutions in 100% DMSO.

[0215] Six concentrations were tested, 5-fold dilutions, duplicate wells. The starting test concentrations are shown in Table 1.

[0216] Table 1

[0217] Compound Name Stock solution concentration (mM) Antiviral activity concentration Cytotoxicity test concentration B01-B08 20 500nM 100μM Baloxavir marboxil 20 500nM 100μM B09-B16 20 100nM 100μM Baloxavir 20 100nM 100μM

[0218] The anti-influenza virus activity of the compounds was determined by the cytopathic effect (CPE) assay induced by virus infection.

[0219] Table 2

[0220]

[0221] MDCK cells were inoculated into 96-well cell culture plates at a cell density of 15,000 cells / well and 100 μl / well, and cultured overnight at 5% CO2 and 37°C. The next day, graded dilutions of compounds and viruses (MOI shown in Table 2) were added at 200 μl / well, with a final DMSO concentration of 0.5%. The cells were cultured for 5 days at 5% CO2 and 37°C until obvious cytopathic effects were shown in the virus-infected control wells without the compound. The cell viability of each well was detected using CCK-8. If the cell viability of the wells containing the compound is higher than that of the virus-infected control wells, that is, the CPE is weakened, it indicates that the compound has an inhibitory effect on the tested virus. The cell viability test is the same as the antiviral experiment, but without virus infection. The antiviral activity and cytotoxicity of the compound are represented by the inhibition rate (%) and cell viability (%) of the compound on the cell viral effect caused by the virus, respectively.

[0222] Inhibition rate (%) = (test well reading - virus control average) / (cell control average - virus control average) × 100 Cell viability (%) = (test well reading - medium control average) / (cell control average - medium control average) × 100

[0223] EC 50 and CC 50 The values ​​were calculated using Prism software, and the inhibition curve fitting method was: log(inhibitor) vs.response--Variable slope of GraphPad Prism. Selectivity index (SI) = CC 50 / EC 50 The results are shown in Table 3. Figure 1-4 .

[0224] Table 3

[0225]

[0226] Test Example 2 Study on the anti-influenza virus activity of the cap-dependent endonuclease inhibitor of the present invention

[0227] Female BALB / c mice aged 6-8 weeks and weighing 18-20 g were selected for the experiment after at least 3 days of environmental adaptation.

[0228] Preparation solvent: 5% DMSO + 10% Solutol + 85% Saline;

[0229] Positive control: Baloxavir ester, dissolved in a preparation solvent (5% DMSO + 10% Solutol + 85% Saline) to prepare a 0.5 mg / mL solution, and stored at 4°C for later use.

[0230] Test group: B08 was dissolved in a preparation solvent (5% DMSO + 10% Solutol + 85% Saline) to prepare a 0.5 mg / mL solution, which was stored at 4°C for later use.

[0231] Test virus: influenza A virus, A / PR / 8 / 34 (H1N1), titer: 7.15E+07 PFU / ml.

[0232] The day of virus inoculation was defined as day 0 of the experiment, the day before that as day -1, the day after that as day 1, and so on.

[0233] Virus inoculation: On day 0, mice were deeply anesthetized by intraperitoneal injection of Zotal 50 (30 mg / kg) / xylazine hydrochloride (6 mg / kg) (injection volume 6 mL / kg), and the virus was inoculated by nasal drops. The inoculation dose for each mouse was 500 PFU in a volume of 50 μL.

[0234] The animals were randomly divided into 3 groups, 5-8 animals in each group, to ensure that there was no statistical difference in the average weight of the animals between the groups. The drug was administered by gavage twice a day for 7 consecutive days, with an interval of 8-16 hours between the two doses per day. The first dose was 48 hours after virus inoculation, and the scheme is shown in Table 4.

[0235] Table 4

[0236]

[0237] The data were statistically analyzed using Prism, the weight changes of mice were analyzed using Two-way ANOVA, and the survival status of mice was analyzed using Log-rank (Mantel-cox) test; the concentration of the test compound in plasma was analyzed using WinNonlin Version 8.3 pharmacokinetic software.

[0238] The weight on day 0 was used as the baseline weight to calculate the percentage of daily weight change of mice + standard error. A weight loss of -35% was considered a humane endpoint and euthanasia was performed. The results of the experiment were analyzed using Two Way ANOVA. Figure 5 , Table 5-Table 6.

[0239] Figure 5There were significant differences between the positive control group and the blank group (*, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001); there were significant differences between the experimental group and the blank group (*, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001); there were significant differences between the experimental group and the positive control group (#, P<0.05; ##, P<0.01; ###, P<0.001; ####, P<0.0001).

[0240] Compared with the blank group, the experimental group could significantly alleviate the weight loss of mice caused by viral infection on days 4-8, and the difference was statistically significant (P<0.05). Compared with the positive control, B08 could further alleviate the weight loss of mice on days 6-8, and the difference was statistically significant (P<0.05).

[0241] After virus inoculation, the survival status of mice in each group is shown in Table 5. All mice in the blank group died on the 8th day, with a median survival period of 8 days and a final survival rate of 0%; no mice in the positive control group and the test group died during the experiment, and the final survival rates were both 100%.

[0242] Table 5

[0243]

[0244] Table 6

[0245] analyze Positive control group Group B08 Matrix plasma plasma Dosage (mg / kg) 5.00 5.00 <![CDATA[C max (mol / L)]]> 18.68 261.67 <![CDATA[T 1 / 2 (h)]]> 5.71 5.04 <![CDATA[AUC 0-last (ng.h / ml)]]> 89.76 811.55

[0246] The compound B08 of the present invention has a bioavailability significantly superior to that of baloxavir dipyramide.

[0247] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A cap-dependent endonuclease inhibitor compound having a structure represented by formula B08 or formula B16, or a pharmaceutically acceptable salt thereof, or any one of its crystalline forms, 、 。 2. The compound according to claim 1, wherein the salt is selected from any one of an organic acid salt and an inorganic acid salt.

3. The compound of claim 2, wherein the organic acid is selected from any one of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid, or a combination thereof.

4. The compound according to claim 2, wherein the inorganic acid is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or a combination thereof.

5. A method for preparing compound B08, comprising the following steps: ； (1) reacting a compound of formula IV with a compound of formula V and a condensing agent in a solvent to obtain a compound of formula III; (2) subjecting the compound of formula III to a deprotection reaction with a lithium salt in a solvent to obtain a compound of formula II; (3) The compound of formula II is reacted with methyl chloromethyl carbonate in the presence of a base and a catalyst in a solvent to obtain the compound.

6. The preparation method according to claim 5, wherein the condensing agent in step (1) consists of n-propylphosphonic anhydride and methanesulfonic acid.

7. The preparation method as claimed in claim 5, wherein the solvent in step (1) is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water, or a combination thereof.

8. The preparation method according to claim 5, wherein the molar ratio of the compound of formula V to the condensing agent in step (1) is 1:1-5.

9. The preparation method according to claim 8, wherein the molar ratio of the compound of formula V to the condensing agent is 1:1-3.

10. The preparation method according to claim 5, wherein the molar ratio of the compound of formula V to the compound of formula IV in step (1) is 1:1-2.

11. The preparation method according to claim 10, wherein the molar ratio of the compound of formula V to the compound of formula IV is 1:1.0-1.

3.

12. The preparation method according to claim 6, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-5.

13. The preparation method according to claim 12, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-3.

14. The preparation method according to claim 13, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-1.

5.

15. The preparation method according to claim 6, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-5.

16. The preparation method according to claim 15, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-3.

17. The preparation method according to claim 16, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-2.

18. The preparation method according to claim 5, wherein the reaction temperature in step (1) is 0-100°C.

19. The preparation method according to claim 18, wherein the reaction temperature is 50-70°C.

20. The preparation method according to claim 5, wherein the lithium salt in step (2) is selected from lithium chloride, lithium bromide or any one or a combination thereof.

21. The preparation method according to claim 5, wherein the solvent in step (2) is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

22. The preparation method according to claim 5, wherein the molar ratio of the compound of formula III: lithium salt in step (2) is 1:1-20.

23. The preparation method according to claim 22, wherein the molar ratio of the compound of formula III: lithium salt is 1:5-10.

24. The preparation method according to claim 5, wherein the reaction temperature in step (2) is 50-100°C.

25. The preparation method according to claim 24, wherein the reaction temperature is 70-80°C.

26. The preparation method according to claim 5, wherein the base in step (3) is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, and disodium hydrogen phosphate, or a combination thereof.

27. The preparation method according to claim 5, wherein the catalyst in step (3) is selected from potassium iodide, sodium iodide or a combination thereof.

28. The preparation method according to claim 5, wherein the solvent in step (3) is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

29. The preparation method as claimed in claim 5, wherein the molar ratio of the compound of formula II in step (3) to the catalyst is 1:0.1-1.

30. The preparation method according to claim 29, wherein the molar ratio of the compound of formula II:catalyst is 1:0.5-1.

31. The preparation method as claimed in claim 5, wherein the molar ratio of the compound of formula II in step (3) to methyl chloromethyl carbonate is 1:1-2.

32. The preparation method according to claim 31, wherein the molar ratio of the compound of formula II to methyl chloromethyl carbonate is 1:1.5-1.

8.

33. The preparation method as claimed in claim 5, wherein the molar ratio of the compound of formula II: the base in step (3) is 1:1-5.

34. The preparation method according to claim 33, wherein the molar ratio of the compound of formula II: the base is 1:2-3.

35. The preparation method according to claim 5, wherein the reaction temperature in step (3) is 20-100°C.

36. The preparation method according to claim 35, wherein the reaction temperature is 50-70°C.

37. A method for preparing compound B16, comprising the following steps: ； (1) reacting a compound of formula IV with a compound of formula V and a condensing agent in a solvent to obtain a compound of formula III; (2) The compound of formula III is subjected to a deprotection reaction with a lithium salt in a solvent to obtain the compound.

38. The preparation method as claimed in claim 37, wherein the condensing agent in step (1) consists of n-propylphosphonic anhydride and methanesulfonic acid.

39. The preparation method as claimed in claim 37, wherein the solvent in step (1) is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water, or a combination thereof.

40. The preparation method as claimed in claim 37, wherein the molar ratio of the compound of formula V to the condensing agent is 1:1-5.

41. The preparation method according to claim 40, wherein the molar ratio of the compound of formula V to the condensing agent is 1:1-3.

42. The preparation method according to claim 37, wherein the molar ratio of the compound of formula V to the compound of formula IV is 1:1-2.

43. The preparation method according to claim 42, wherein the molar ratio of the compound of formula V to the compound of formula IV is 1:1-1.

3.

44. The preparation method as claimed in claim 38, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-5.

45. The preparation method according to claim 44, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-3.

46. ​​The preparation method according to claim 45, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-1.

5.

47. The preparation method as claimed in claim 38, wherein the molar ratio of the compound of formula V:methanesulfonic acid is 1:1-5.

48. The preparation method according to claim 47, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-3.

49. The preparation method according to claim 48, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-2.

50. The preparation method according to claim 37, wherein the reaction temperature in step (1) is 0-100°C. The preparation method according to claim 50 , wherein the reaction temperature is 50-70° C.

52. The preparation method as claimed in claim 37, wherein the lithium salt in step (2) is selected from any one of lithium chloride and lithium bromide or a combination thereof.

53. The preparation method as claimed in claim 37, wherein the solvent in step (2) is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, water, or a combination thereof.

54. The preparation method as claimed in claim 37, wherein the molar ratio of the compound of formula III: lithium salt is 1:1-20.

55. The preparation method according to claim 54, wherein the molar ratio of the compound of formula III: lithium salt is 1:5-10.

56. The preparation method as claimed in claim 37, wherein the reaction temperature in step (2) is 50-100°C.

57. The preparation method according to claim 56, wherein the reaction temperature is 70-80°C.

58. A compound represented by formula B24 or any one of its mesylate and p-toluenesulfonate: 。 59. A method for preparing a compound represented by formula III, comprising subjecting a compound represented by formula IV and a compound represented by formula V to a condensation reaction with a condensing agent in a solvent to obtain the compound. 。 60. The preparation method as claimed in claim 59, wherein the condensing agent consists of n-propylphosphonic anhydride and methanesulfonic acid.

61. The preparation method as claimed in claim 59, wherein the reaction solvent is selected from any one of toluene, hexane, cyclohexane, heptane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate, toluene, tetrahydrofuran, 1,4-dicyclohexane, N-methylpyrrolidone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water, or a combination thereof.

62. The preparation method as claimed in claim 59, wherein the molar ratio of the compound of formula V to the condensing agent is 1:1-5.

63. The preparation method according to claim 62, wherein the molar ratio of the compound of formula V to the condensing agent is 1:1-3.

64. The preparation method as claimed in claim 59, wherein the molar ratio of the compound of formula V to the compound of formula IV is 1:1-2.

65. The preparation method according to claim 64, wherein the molar ratio of the compound of formula V to the compound of formula IV is 1:1.0-1.

3.

66. The preparation method as claimed in claim 60, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-5.

67. The preparation method according to claim 66, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-3.

68. The preparation method as claimed in claim 67, wherein the molar ratio of the compound of formula V to n-propylphosphonic anhydride is 1:1-1.

5.

69. The preparation method as claimed in claim 60, wherein the molar ratio of the compound of formula V:methanesulfonic acid is 1:1-5.

70. The preparation method according to claim 69, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-3.

71. The preparation method of claim 70, wherein the molar ratio of the compound of formula V to methanesulfonic acid is 1:1-2.

72. The preparation method according to claim 59, wherein the reaction temperature is 0-100°C.

73. The preparation method according to claim 72, wherein the reaction temperature is 50-70°C.

74. A pharmaceutical composition, comprising the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

75. The pharmaceutical composition of claim 74, wherein the amount or type of the pharmaceutically acceptable carrier in the pharmaceutical composition is determined according to the physicochemical properties and content of the active ingredient in the composition, the type of preparation, the dissolution of the preparation, and the bioavailability factors.

76. The pharmaceutical composition of claim 74, wherein the dosage form of the pharmaceutical composition is selected from any one of an oral preparation, an injection, and an external preparation.

77. The pharmaceutical composition of claim 76, wherein the oral formulation is selected from any one of tablets, capsules, granules, syrups, powders, dews, effervescents, pills, mixtures, pastes, emulsions, solutions, lozenges, cachets, gels, and suspensions.

78. The pharmaceutical composition of claim 76, wherein the external preparation is selected from any one of a gel, an ointment, a cream, a liniment, a lotion, a suppository, an ointment, an aerosol, a dry powder inhaler, and a spray.

79. The pharmaceutical composition of claim 76, wherein the injection is selected from any one of a solution injection, an emulsion injection, a suspension injection, a sterile powder for injection, and a large infusion.

80. The pharmaceutical composition of claim 74, wherein the pharmaceutically acceptable carrier is selected from any one of a filler, a disintegrant, a binder, a lubricant, a dispersant, a wetting agent, a pore-forming agent, a solubilizing agent, a suspending agent, an emulsifier, an emulsifier aid, and a lyoprotectant, or a combination thereof.

81. The pharmaceutical composition of claim 80, wherein the filler is selected from any one of lactose, dextrin, starch, modified starch, cellulose, inorganic calcium salt, sorbitol, mannitol, or a combination thereof.

82. The pharmaceutical composition of claim 80, wherein the disintegrant is selected from any one of starch, modified starch, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose, or a combination thereof.

83. The pharmaceutical composition of claim 80, wherein the binder is selected from any one of syrup, gum arabic, gelatin, sorbitol, gum tragacanth, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin slurry, starch slurry, polyvinyl pyrrolidone, sodium carboxymethyl starch, and sodium starch glycolate, or a combination thereof.

84. The pharmaceutical composition of claim 80, wherein the lubricant is selected from any one of micropowdered silica gel, magnesium stearate, talc, colloidal silicon dioxide, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, and sodium lauryl sulfate, or a combination thereof.

85. The pharmaceutical composition of claim 80, wherein the wetting agent is selected from any one of sodium lauryl sulfate, polysorbate, water, alcohol, or a combination thereof.

86. The pharmaceutical composition of claim 80, wherein the suspending agent is selected from any one of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, syrup, glycerin, gelatin, gum arabic, gum tragacanth, sodium alginate, potassium alginate, pectin, or a combination thereof.

87. The pharmaceutical composition of claim 80, wherein the emulsifier is selected from any one of sodium stearate, potassium stearate, triethanolamine stearate, magnesium stearate, calcium stearate, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, polysorbate, Span, benzyl alcohol, gum tragacanth, gum arabic, Pluronic F-68, lecithin, and soybean lecithin, or a combination thereof.

88. The pharmaceutical composition of claim 80, wherein the co-emulsifier is selected from any one of n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, and polyglycerol esters, or a combination thereof.

89. The pharmaceutical composition of claim 80, wherein the lyoprotectant is selected from any one of sucrose, lactose, galactose, glucose, trehalose, mannitol, sorbitol, or a combination thereof.

90. The pharmaceutical composition of claim 80, wherein the solubilizing agent is selected from any one of Tween-80, Pluronic F-68, benzyl alcohol, benzyl alcohol, cholate, deoxycholate, glycerol, propylene glycol, and polyethylene glycol, or a combination thereof.

91. The pharmaceutical composition according to any one of claims 80 to 90, wherein the pharmaceutical composition is mixed with a pharmaceutically acceptable sustained-release formulation carrier or a controlled-release formulation carrier according to a method for preparing a sustained-release formulation or a controlled-release formulation.

92. The pharmaceutical composition of claim 91, wherein the sustained-release preparation carrier or the controlled-release preparation carrier is selected from any one of an oily admixture, a hydrophilic colloid, a water-insoluble retarder, an enteric retarder, and a biodegradable retarder or a combination thereof.

93. The pharmaceutical composition of claim 92, wherein the grease admixture is selected from any one of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane, dimethylsiloxane, or a combination thereof.

94. The pharmaceutical composition of claim 92, wherein the hydrophilic colloid is selected from any one of methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic, tragacanth or carbopol, polyvinyl alcohol, pectin, alginate, chitosan, xanthan gum, guar gum, carrageenan, gelatin, agar, and galactomannan, or a combination thereof.

95. The pharmaceutical composition of claim 92, wherein the water-insoluble retarder is selected from any one of ethyl cellulose, cellulose acetate, polyethylene, polypropylene, polysiloxane, ethylene vinyl acetate copolymer, polymethyl methacrylate, or a combination thereof.

96. The pharmaceutical composition according to claim 92, wherein the enteric retardant is selected from any one of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, hydroxypropylmethylcellulose acetate succinate, acrylic resin, or a combination thereof.

97. The pharmaceutical composition of claim 92, wherein the biodegradable retarder is selected from any one of waxes, fatty acids, fatty acid esters, fatty alcohols, or a combination thereof.

98. A pharmaceutical composition as described in any one of claims 80-90, wherein the mode of administration of the pharmaceutical composition is selected from any one of oral administration, injection, mucosal administration, and skin administration.

99. A pharmaceutical composition, which consists of a first composition comprising the compound according to any one of claims 1 to 4 and a second composition comprising other anti-influenza drugs.

100. The pharmaceutical composition of claim 99, wherein the other anti-influenza drugs are selected from any one of neuraminidase inhibitors, RNA-dependent RNA polymerase inhibitors, M2 protein inhibitors, and PB2 Cap binding inhibitors, or a combination thereof.

101. The pharmaceutical composition of claim 99, wherein the other anti-influenza drugs are selected from any one of Oseltamivir, Zanamivir, Peramivir, Inavir, Favipiravir, Amantadine, Nitazoxanide or a combination thereof.

102. The pharmaceutical composition of any one of claims 99-101, wherein the first composition and the second composition are administered simultaneously or sequentially.

103. A pharmaceutical composition as described in any one of claims 99-101, wherein the administration method of the pharmaceutical composition is selected from any one of oral administration, injection, mucosal administration, and skin administration.

104. Use of the compound according to any one of claims 1 to 4 or the pharmaceutical composition according to claims 74 to 103 for preparing a medicament for preventing and treating influenza virus infection and its complications.

105. The use according to claim 104, wherein the influenza virus comprises any one of types A, B, and C, or a combination thereof.

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