Polycyclic pyridone derivative and use thereof

Abstract

The present invention provides a polycyclic pyridone derivative, a composition containing same, and a use thereof. The compound of the present invention has an inhibitory effect on influenza viruses, and can be used for treating cap-dependent endonuclease-mediated diseases.

Description

Polycyclic pyridone derivatives and uses thereof Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a class of polycyclic pyridone derivatives, compositions and uses thereof. Background Art

[0002] Influenza is a highly contagious respiratory disease caused by the influenza virus. Among them, influenza A virus has the widest host range, infecting both birds and mammals, making it highly likely to cause a worldwide pandemic. Currently, vaccination is generally effective in preventing influenza infection, but the vaccine is only partially effective, with an overall efficacy of approximately 60%. Furthermore, since it typically takes about six months between antigen identification and vaccine production, the virus may mutate during this period, thereby reducing the effectiveness of the vaccine. Regarding anti-influenza drugs, there are two types of FDA-approved anti-influenza drugs: influenza neuraminidase protein inhibitors (oseltamivir, zanamivir, peramivir, and nanamivir) and M2 proton channel blockers, the amantadine class of drugs (amantadine and rimantadine). However, there are concerns about the emergence of drug-resistant strains, side effects, and the global prevalence of novel influenza viruses with high pathogenicity or lethality, leading to the development of anti-influenza drugs with novel mechanisms.

[0003] Cap-dependent endonucleases, enzymes derived from influenza viruses, are considered suitable targets for anti-influenza drugs because they are essential for viral proliferation and possess virus-specific enzymatic activity not possessed by the host. The influenza virus cap-dependent endonuclease is an endonuclease activity that generates a fragment containing 9 to 13 bases of the cap structure (the bases of the cap structure are not included in the above base count) with the host mRNA precursor as a substrate. This fragment functions as a primer for the viral RNA polymerase, used for the synthesis of mRNA encoding viral proteins. In other words, substances that inhibit cap-dependent endonucleases are believed to inhibit viral protein synthesis by inhibiting viral mRNA synthesis, thereby inhibiting viral proliferation. Mabaloxavir, a drug already marketed in multiple countries, is an innovative cap-dependent endonuclease inhibitor. With a single oral dose, it can halt viral shedding within about 24 hours, shorten the infectious period, and quickly relieve flu symptoms such as fever and body aches. Based on the fact that cap-dependent nuclease drugs have been proven to have strong anti-influenza virus effects, it is still necessary to develop new drugs with richer types and more outstanding effects. Summary of the Invention

[0004] The present invention provides a novel polycyclic pyridone derivative, a pharmaceutical composition thereof and use thereof in resisting influenza virus.

[0005] In a first aspect, the present invention provides a compound as shown in Formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof:

[0006] Wherein, R1, R2, R3, and R4 are all hydrogen or all deuterium, R5 does not exist or is an oxo group, and R6 is hydrogen or

[0007] In a preferred embodiment of the present invention, R1, R2, R3, and R4 are deuterium, R5 is absent or is an oxo group, and R6 is hydrogen or

[0008] In a preferred embodiment of the present invention, R1, R2, R3, R4 are hydrogen, R5 is oxo, R6 is hydrogen or

[0009] In a preferred embodiment of the present invention, R1, R2, R3, and R4 are deuterium, R5 is an oxo group, the configuration of the sulfur atom is S or R, and R6 is hydrogen or

[0010] In a preferred embodiment of the present invention, R1, R2, R3, and R4 are hydrogen, R5 is an oxo group, the configuration of the sulfur atom is S or R, and R6 is hydrogen or

[0011] The compound of the present invention is selected from:

[0012] and its tautomers, stereoisomers or pharmaceutically acceptable salts.

[0013] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and optionally, a pharmaceutically acceptable carrier.

[0014] In a third aspect, the present invention provides the use of a compound represented by Formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a drug for treating and / or preventing diseases or conditions mediated by cap-dependent nucleases.

[0015] The present invention also provides the use of the compound represented by Formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of drugs for treating and / or preventing diseases or conditions caused by viral infections.

[0016] In a fourth aspect, the present invention provides a method for treating and / or preventing diseases or conditions mediated by cap-dependent nucleases, comprising administering to a patient a therapeutically effective dose of a compound of formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention.

[0017] The present invention also provides a method for treating and / or preventing a disease or condition caused by a viral infection, comprising administering to a patient a therapeutically effective dose of a compound shown in Formula I, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect of the present invention. Preferably, the viral infection of the present invention is an influenza virus infection. Further, the influenza virus is selected from type A, type B, type C, or avian influenza (H5N1, H7N9); further, the disease of the present invention is selected from cold-like symptoms accompanied by fever, chills, headache, muscle pain, general fatigue, etc., or respiratory inflammation with sore throat, runny nose, nasal congestion, cough, and sputum; gastrointestinal symptoms of abdominal pain, vomiting, and diarrhea, and then accompanied by complications of acute encephalopathy, secondary pneumonia infection, or a combination thereof.

[0018] The present invention also provides the use of the compound represented by Formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention as a drug or in the preparation of a drug.

[0019] Preferably, the drug is a drug for treating and / or preventing a disease or condition mediated by a cap-dependent endonuclease. Preferably, the disease or condition is an influenza infectious disease. Preferably, the influenza infectious disease is caused by an influenza virus selected from influenza A, B, C or avian influenza (H5N1, H7N9). Preferably, the influenza infectious disease is accompanied by one or more of the following symptoms: cold-like symptoms such as fever, chills, headache, muscle pain, general fatigue, or respiratory inflammation such as sore throat, runny nose, nasal congestion, cough, and sputum; gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. Preferably, it is further accompanied by complications of acute encephalopathy, secondary pneumonia infection, or a combination thereof.

[0020] definition

[0021] Unless otherwise specified, D in the present invention represents deuterium ( 2 H).

[0022] Unless otherwise specified, the term "oxo" refers to a group in which two hydrogen atoms at the same substitution position are replaced by the same oxygen atom to form a double bond.

[0023] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0024] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention also include "solvates" thereof. The terms "solvate" and "solvate" refer to the physical association of a salt of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0025] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention also include "hydrates" thereof. The term "hydrate" refers to a substance formed by water molecules binding to cations or anions in the compound by coordinate bonds or covalent bonds, or refers to a substance formed by water ions not directly binding to cations or anions but existing in a certain proportion at a certain position in the solid crystal lattice.

[0026] Unless otherwise specified, the compounds of the present invention also include their "prodrugs," which refers to drugs that are converted into the parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are often related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limited to, of a prodrug is any compound of the present invention administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug is a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0027] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0028] Unless otherwise specified, the term "geometric isomers (cis / trans) isomers" may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher-order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents higher-order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers.

[0029] Unless otherwise specified, the term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.

[0030] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0031] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0032] An "effective amount," also referred to as a "therapeutically effective amount," refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to treatment of a disease or alleviation of symptoms. In some embodiments, for example, the amount is a dose that can induce a specific response in cells, or a dose that can exert a therapeutic effect on a disease in a model animal. The specific amount will vary depending on, for example, the specific compound selected, the type of subject and their age / existing health condition or risk of health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system used to carry it.

[0033] A "pharmaceutically acceptable carrier," also known as a "pharmaceutically acceptable excipient" or "pharmaceutically acceptable vehicle," refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material, that is used to transport the active ingredient from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other components of the formulation and harmless to the patient. The preparation of the pharmaceutical compositions described herein includes, but is not limited to, for example, mixing the compound of Formula I or a pharmaceutically acceptable salt thereof described in the first aspect with a pharmaceutically acceptable carrier.

[0034] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail one by one.

[0035] The beneficial effects of the present invention are:

[0036] This invention designs a class of novel compounds, offering a new direction for the development of drugs known as cap-dependent endonuclease inhibitors. Experimental studies have shown that these compounds exhibit potent inhibitory effects against influenza virus, good PK properties, and / or oral absorption, making them promising compounds for the treatment of cap-dependent endonuclease-mediated diseases. DETAILED DESCRIPTION

[0037] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0038] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker Advance 600 nuclear magnetic resonance spectrometer, LC-MS using a Waters ACQUITY UPLC I-Class Xevo TQ-S liquid chromatography-mass spectrometer, and HPLC using a Waters E2695 high-performance liquid chromatograph.

[0039] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0040] Preparation Example 1: Preparation of Intermediate 1-8

[0041] Method 1: Toluene (36 mL), compound 1-1 (5.5 g, 29.6 mmol), deuterated thiophenol (8.2 g, 35.4 mmol), and D-camphorsulfonic acid (2.32 g, 10.0 mmol) were added to a round-bottom flask and stirred at 60°C for 4 hours. The temperature was then lowered to 5°C. 2 mol / L sodium hydroxide solution (20 mL) was added and the mixture was stirred until it returned to room temperature. Toluene (20 mL) was added for extraction and phase separation. The organic phase was washed once with 2 mol / L sodium hydroxide (20 mL) and once with water (20 mL). The mixture was then concentrated under reduced pressure to yield compound 1-3 (9.2 g). MS m / z: 284.1 [M+H].

[0042] Aluminum chloride (11.1 g, 82.9 mmol) and toluene (50 mL) were added to a reaction flask, stirred, and cooled to 0°C. A solution of 1,1,3,3-tetramethyldisiloxane (11.1 g, 82.8 mmol) in toluene (20 mL) was added dropwise. After the addition was complete, the temperature was raised to 25°C, and the toluene solution of compound 1-3 was slowly added. The reaction was stirred at 25°C for 2.5 hours. 15% aqueous sulfuric acid (70 mL) was added for extraction and phase separation. The organic phase was washed twice with water (40 mL) and concentrated under reduced pressure. n-heptane (80 mL) was added and the mixture was slurried at 0°C. The mixture was filtered, and the filter cake was rinsed with n-heptane and dried to obtain compound 1-4 (14.5 g). MS m / z: 286.1 [M+H].

[0043] Polyphosphoric acid (59 g) was added to the reaction flask, and the temperature was stirred and raised to 80°C. Compound 1-4 (12 g) was added, and the temperature was raised to 120°C and stirred for 3 hours. The temperature was then lowered to 80°C, and water (30 mL) was slowly added. The temperature was lowered to 30°C, and water (120 mL) and ethyl acetate (120 mL) were added for extraction and phase separation. The organic phase was washed with 10% aqueous sodium bicarbonate solution (35 mL) and concentrated under reduced pressure. n-heptane (60 mL) was added and the mixture was slurried at room temperature. The mixture was filtered, and the filter cake was rinsed with n-heptane and dried to obtain compound 1-5 (10.2 g). MS m / z: 267.1 [M+H].

[0044] Isopropanol (40 mL), water (4.5 mL), and compound 1-5 (9.2 g, 17.2 mmol) were added to a reaction flask, stirred, and heated to 40°C. Sodium borohydride (0.47 g, 12.4 mmol) was slowly added to a 0.5% aqueous sodium hydroxide solution (3.6 mL) to prepare a suspension. The suspension was slowly added to the reaction system, stirred at 40°C for 1.5 hours, cooled to room temperature, and water (65 mL) was added, followed by a 4% aqueous sulfuric acid solution (15 mL). The temperature was cooled to 5°C, filtered, and the filter cake was rinsed with water (20 mL) and dried to obtain compound 1-6 (8.7 g). MS m / z: 269.1 [M+H].

[0045] Ethyl acetate (16 mL), cyclohexane (4 mL), compound 1-6 (3.0 g, 11.2 mmol), and compound 1-7 (4.5 g, 13.4 mmol) were added to a reaction flask and stirred at room temperature. A 50% ethyl acetate solution of propylphosphonic anhydride (7.8 g, 12.3 mmol) was added, followed by methanesulfonic acid (1.5 g, 16.1 mmol). The mixture was heated to 60°C and stirred for 24 hours. After cooling to room temperature, tetrahydrofuran (20 mL) and water (12 mL) were added, followed by the slow addition of 24% aqueous sodium hydroxide solution (12 mL) for extraction and separation. The organic phase was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 1-8 (5.2 g). MS m / z: 572.2 [M+H].

[0046] Method 2: Toluene (150 mL), compound 1-1 (15 g), deuterated thiophenol (10 g), and D-camphorsulfonic acid (2.8 g) were added to a round-bottom flask and stirred at 60°C for 4 hours. The mixture was then cooled to 5°C. A 2 mol / L aqueous sodium hydroxide solution (30 mL) was added and the mixture was allowed to return to room temperature with stirring. Toluene (30 mL) was then added for extraction and phase separation. The organic phase was washed once with a 2 mol / L aqueous sodium hydroxide solution (30 mL) and once with water (30 mL). The organic phase was collected, concentrated under reduced pressure, and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 1-3 (19.7 g). MS m / z: 284.1 [M+H].

[0047] Aluminum chloride (23.7 g) and toluene (100 mL) were added to a reaction flask, stirred, and cooled to 0°C. A solution of 1,1,3,3-tetramethyldisiloxane (23.9 g) in toluene (40 mL) was added dropwise. After the addition was complete, the temperature was raised to 25°C and a solution of compound 1-3 (18 g) in toluene (60 mL) was slowly added. The mixture was stirred at 25°C for 2.5 hours. 15% aqueous sulfuric acid (140 mL) was added for extraction and phase separation. The organic phase was washed twice with water (80 mL) and concentrated under reduced pressure. The mixture was slurried with n-heptane (80 mL) at 0°C, filtered, and the filter cake was rinsed with n-heptane and dried to yield compound 1-4 (14 g). MS m / z: 286.1 [M+H].

[0048] Polyphosphoric acid (60 g) and sulfolane (120 g) were added to the reaction flask, stirred and heated to 80°C, compound 1-4 (12 g) was added, the temperature was raised to 120°C and stirred for 3 hours, the temperature was lowered to 80°C, water (30 mL) was slowly added, the temperature was lowered to 30°C, water (120 mL) and ethyl acetate (120 mL) were added for phase separation, the organic phase was washed with 10% aqueous sodium bicarbonate solution (35 mL), and the organic phase was concentrated under reduced pressure. n-heptane (60 mL) was added and the mixture was slurried at room temperature, filtered, the filter cake was rinsed with n-heptane, and dried to obtain compound 1-5 (10.6 g). MS m / z: 267.1 [M+H].

[0049] Isopropanol (40 mL), water (4.5 mL), and compound 1-5 (9.2 g) were added to a reaction flask, stirred, and heated to 40°C. Sodium borohydride (0.47 g) was slowly added to a 0.5% aqueous sodium hydroxide solution (3.6 mL) to prepare a suspension. The suspension was slowly added to the reaction system, stirred at 40°C for 1.5 hours, cooled to room temperature, and water (65 mL) was added, followed by a 4% aqueous sulfuric acid solution (15 mL). The temperature was cooled to 5°C, filtered, and the filter cake was rinsed with water (20 mL) and dried to obtain compound 1-6 (8.7 g). MS m / z: 269.1 [M+H].

[0050] Ethyl acetate (16 mL), cyclohexane (4 mL), compound 1-6 (4.0 g), and compound 1-7 (7.35 g) were added to a reaction flask and stirred at room temperature. A 50% ethyl acetate solution (19 g) of propylphosphonic anhydride was added, followed by methanesulfonic acid (2.9 g). The mixture was heated to 60°C and stirred for 24 hours. After cooling to room temperature, tetrahydrofuran (20 mL) and water (12 mL) were added, followed by the slow addition of 24% aqueous sodium hydroxide solution (12 mL). The organic phase was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 1-8 (7.2 g). MS m / z: 572.2 [M+H].

[0051] Preparation Example 2: Preparation of Intermediate 1-9

[0052] To a reaction flask, dichloromethane (20 mL), compound 1-8 (2.0 g), S-1,1'-binaphthol (0.2 g), tetraisopropyl titanate (0.2 g), and water (0.14 g) were added and stirred at room temperature for 2 hours. A 70% aqueous solution of tert-butyl peroxide (0.6 g) was added dropwise, maintaining the temperature at no more than 40°C. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 1-9 (1.6 g). MS m / z: 588.2 [M+H].

[0053] Preparation Example 3: Preparation of Intermediate 1-10

[0054] To a reaction flask, dichloromethane (20 mL), compound 1-8 (2.0 g), R-1,1'-binaphthol (0.2 g), tetraisopropyl titanate (0.2 g), and water (0.14 g) were added and stirred at room temperature for 2 hours. A 70% aqueous solution of tert-butyl peroxide (0.6 g) was added dropwise, maintaining the temperature at no more than 40°C. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 1-10 (1.6 g). MS m / z: 588.2 [M+H].

[0055] Preparation Example 4: Preparation of Intermediate 2-6

[0056] Method 1: Toluene (36 mL), compound 1-1 (5.0 g), thiophenol (7.2 g), and D-camphorsulfonic acid (2.1 g) were added to a round-bottom flask and stirred at 60°C for 4 hours. The temperature was then lowered to 5°C. 2 mol / L sodium hydroxide solution (18 mL) was added and the mixture was stirred until it returned to room temperature. Toluene (20 mL) was added for extraction and phase separation. The organic phase was washed once with 2 mol / L sodium hydroxide (20 mL) and once with water (20 mL). The mixture was then concentrated under reduced pressure to yield compound 2-1 (7.8 g). MS m / z: 279.0 [M+H].

[0057] Aluminum chloride (10.0 g) and toluene (50 mL) were added to a reaction flask, stirred, and cooled to 0°C. A solution of 1,1,3,3-tetramethyldisiloxane (10.0 g) in toluene (20 mL) was added dropwise. After the addition was complete, the temperature was raised to 25°C, and the toluene solution of compound 2-1 was slowly added. The mixture was stirred at 25°C for 2.5 hours. 15% aqueous sulfuric acid (70 mL) was added for extraction and phase separation. The organic phase was washed twice with water (40 mL) and concentrated under reduced pressure. n-heptane (80 mL) was added and the mixture was slurried at 0°C. The mixture was filtered, and the filter cake was rinsed with n-heptane and dried to obtain compound 2-2 (13.0 g). MS m / z: 281.0 [M+H].

[0058] Polyphosphoric acid (45 g) was added to the reaction flask, and the temperature was raised to 80°C with stirring. Compound 2-2 (9.0 g) was added, and the temperature was raised to 120°C with stirring for 3 hours. The temperature was then lowered to 80°C, and water (25 mL) was slowly added. The temperature was lowered to 30°C, and water (90 mL) and ethyl acetate (90 mL) were added for extraction and phase separation. The organic phase was washed with 10% aqueous sodium bicarbonate solution (30 mL) and concentrated under reduced pressure. n-heptane (50 mL) was added and the mixture was slurried at room temperature. The mixture was filtered, and the filter cake was rinsed with n-heptane and dried to obtain compound 2-3 (7.5 g). MS m / z: 263.0 [M+H].

[0059] Isopropanol (25 mL), water (3 mL), and compound 2-3 (6.0 g) were added to a reaction flask, stirred, and heated to 40°C. Sodium borohydride (0.3 g) was slowly added to a 0.5% aqueous sodium hydroxide solution (2.0 mL) to prepare a suspension. The suspension was slowly added to the reaction system, stirred at 40°C for 1.5 hours, cooled to room temperature, and water (45 mL) was added, followed by a 4% aqueous sulfuric acid solution (10 mL). The temperature was cooled to 5°C, filtered, and the filter cake was rinsed with water (15 mL) and dried to obtain compound 2-4 (10.0 g). MS m / z: 265.0 [M+H].

[0060] Ethyl acetate (10 mL), cyclohexane (2 mL), compound 2-4 (2.0 g), and compound 1-7 (3.0 g) were added to a reaction flask and stirred at room temperature. A 50% ethyl acetate solution (5.1 g) of propylphosphonic anhydride was added, followed by methanesulfonic acid (1.0 g). The mixture was heated to 60°C and stirred for 24 hours. After cooling to room temperature, tetrahydrofuran (15 mL) and water (10 mL) were added, followed by the slow addition of 24% aqueous sodium hydroxide solution (10 mL). The organic phase was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 2-5 (3.5 g). MS m / z: 568.2 [M+H].

[0061] To a reaction flask, dichloromethane (20 mL), compound 2-5 (2.0 g), S-1,1'-binaphthol (0.2 g), tetraisopropyl titanate (0.2 g), and water (0.14 g) were added and stirred at room temperature for 2 hours. A 70% aqueous solution of tert-butyl peroxide (0.6 g) was added dropwise, maintaining the temperature at no more than 40°C. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 2-6 (1.6 g). MS m / z: 584.2 [M+H].

[0062] Method 2: Toluene (100 mL), compound 1-1 (15.0 g), thiophenol (21.6 g), and D-camphorsulfonic acid (6.3 g) were added to a round-bottom flask and stirred at 60°C for 4 hours. The mixture was then cooled to 5°C. 2 mol / L sodium hydroxide solution (54 mL) was added and the mixture was stirred until it returned to room temperature. Toluene (60 mL) was added for extraction and phase separation. The organic phase was washed once with 2 mol / L sodium hydroxide (60 mL) and once with water (60 mL). The mixture was then concentrated under reduced pressure to yield compound 2-1 (20.4 g). MS m / z: 279.0 [M+H].

[0063] Aluminum chloride (30.0 g) and toluene (150 mL) were added to a reaction flask, stirred, and cooled to 0°C. A solution of 1,1,3,3-tetramethyldisiloxane (30.0 g) in toluene (60 mL) was added dropwise. After the addition was complete, the temperature was raised to 25°C, and a solution of compound 2-1 (22.8 g) in toluene (90 mL) was slowly added. The mixture was stirred at 25°C for 2.5 hours. 15% aqueous sulfuric acid (210 mL) was added for extraction and phase separation. The organic phase was washed twice with water (120 mL) and concentrated under reduced pressure. The mixture was slurried in n-heptane (240 mL) at 0°C, filtered, and the filter cake was rinsed with n-heptane and dried to yield compound 2-2 (18.0 g). MS m / z: 281.0 [M+H].

[0064] Polyphosphoric acid (45 g) and sulfolane (70 mL) were added to the reaction flask, stirred and heated to 80°C, compound 2-2 (9.0 g) was added, the temperature was raised to 120°C and stirred for 3 hours, the temperature was lowered to 80°C, water (25 mL) was slowly added, the temperature was lowered to 30°C, water (90 mL) and ethyl acetate (90 mL) were added for phase separation, the organic phase was washed with 10% aqueous sodium bicarbonate solution (30 mL), and the organic phase was concentrated under reduced pressure. n-heptane (50 mL) was added and the mixture was slurried at room temperature, filtered, the filter cake was rinsed with n-heptane, and dried to obtain compound 2-3 (7.5 g). MS m / z: 263.0 [M+H].

[0065] Isopropanol (25 mL), water (3 mL), and compound 2-3 (6.0 g) were added to a reaction flask, stirred, and heated to 40°C. Sodium borohydride (0.3 g) was slowly added to a 0.5% aqueous sodium hydroxide solution (2.0 mL) to prepare a suspension. The suspension was slowly added to the reaction system, stirred at 40°C for 1.5 hours, cooled to room temperature, and water (45 mL) was added, followed by a 4% aqueous sulfuric acid solution (10 mL). The temperature was cooled to 5°C, filtered, and the filter cake was rinsed with water (15 mL) and dried to obtain compound 2-4 (4.0 g). MS m / z: 265.0 [M+H].

[0066] Ethyl acetate (10 mL), cyclohexane (2 mL), compound 2-4 (2.4 g), and compound 1-7 (3.0 g) were added to a reaction flask and stirred at room temperature. A 50% ethyl acetate solution of propylphosphonic anhydride (7.7 g) was added, followed by methanesulfonic acid (1.0 g). The mixture was heated to 60°C and stirred for 24 hours. After cooling to room temperature, tetrahydrofuran (15 mL) and water (10 mL) were added, followed by the slow addition of 24% aqueous sodium hydroxide solution (10 mL). The organic phase was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 2-5 (4.1 g). MS m / z: 568.2 [M+H].

[0067] To a reaction flask, dichloromethane (20 mL), compound 2-5 (2.0 g), S-1,1'-binaphthol (0.2 g), tetraisopropyl titanate (0.2 g), and water (0.14 g) were added and stirred at room temperature for 2 hours. A 70% aqueous solution of tert-butyl peroxide (0.6 g) was added dropwise, maintaining the temperature at no more than 40°C. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 2-6 (1.6 g). MS m / z: 584.2 [M+H].

[0068] Preparation Example 5, Preparation of Intermediate 2-7

[0069] To a reaction flask, dichloromethane (20 mL), compound 2-5 (2.0 g), R-1,1'-bi-2-naphthol (0.2 g), tetraisopropyl titanate (0.2 g), and water (0.14 g) were added and stirred at room temperature for 2 hours. A 70% aqueous solution of tert-butyl peroxide (0.6 g) was added dropwise, maintaining the temperature at no more than 40°C. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 2-7 (1.8 g). MS m / z: 584.2 [M+H].

[0070] Example 1: Preparation of Compound 6

[0071] N-methylpyrrolidone (5 mL), intermediate compound 1-8 (1 g), and lithium chloride (0.57 g) were added to a reaction flask. The temperature was raised to 75°C, and methanesulfonic acid (70 mg) was added. The reaction was maintained at 75°C for 20 h. The temperature was lowered to 45°C, and acetonitrile (1.5 mL) and water 1 (10 mL) were added. The mixture was stirred at 45°C for 1 hour, then lowered to 15°C, stirred at this temperature for 1 hour, and filtered. The filter cake was slurried with isopropanol (10 mL) at room temperature for 2 hours, filtered, rinsed with isopropanol (5 mL), and dried to yield compound 6 (0.7 g). MS m / z: 488.1 [M+H]. 1H NMR (600MHz, CDCl3) δ11.52(s,1H),7.10(dd,J=16.8,8.5Hz,1H),7.06–6.97(m,2H),5.77(d,J=7.7Hz,1H),5.29 -2.27(m,2H),4.67(d,J=13.5Hz,1H),4.58(dd,J=10.0,2.8Hz,1H),4.07(d,J=13.9Hz,1H),3.96(dd,J=11.1,2. 8Hz,1H),3.81(dd,J=12.0,3.2Hz,1H),3.62(t,J=10.6Hz,1H),3.47(td,J=11.8,2.1Hz,1H),3.06–2.95(m,1H).

[0072] Example 2-5: The following compounds of Example 2-5 were prepared by referring to the preparation method of Example 1

[0073] Example 6: Preparation of Compound 1

[0074] To a reaction flask were added tetrahydrofuran (5 mL), N,N-dimethylacetamide (0.5 mL), compound 6 (0.5 g), anhydrous potassium carbonate (0.19 g), potassium iodide (70 mg), isopropyl alcohol (30 mL), and purified water (15 mL). The mixture was stirred and heated to 60°C. Chloromethyl methyl carbonate (0.22 g) was then added. The reaction was allowed to proceed at 60°C for 10 hours. The mixture was cooled to room temperature, glacial acetic acid (0.1 g) was added, and the mixture was stirred for 15 minutes. Water (2.5 mL) was added and stirred for 30 minutes. The mixture was extracted and separated. The organic phase was concentrated and separated by column chromatography using a mixed solvent of ethyl acetate and n-hexane to afford compound 1 (0.47 g). MS m / z: 576.2 [M+H]. 1H NMR (600MHz, CDCl3) δ7.14(d,J=7.6Hz,1H),7.10(dd,J=16.8,8.4Hz,1H),7.01(dd,J=8.2,4.3Hz,1 H),5.93(d,J=7.7Hz,1H),5.90(s,2H),5.33(s,1H),5.27(d,J=14.3Hz,1H),4.64(d,J=13.2Hz,1H), 4.52(dd,J=9.9,2.6Hz,1H),4.07(d,J=13.9Hz,1H),3.94(dd,J=10.9,2.4Hz,1H),3.86(s,3H),3.7 6(dd,J=11.8,2.9Hz,1H), 3.56(t,J=10.5Hz,1H), 3.44(dd,J=11.7,10.0Hz,1H), 2.98–2.90(m,1H).

[0075] Example 7-35: The following compound of Example 7-35 was prepared by referring to the preparation method of Example 6

[0076] Biological testing

[0077] The following test examples further illustrate the present invention, but these examples are not intended to limit the scope of the present invention.

[0078] Test Example 1: Pharmacokinetics experiment in rats

[0079] 1. Purpose:

[0080] The pharmacokinetic characteristics of the compounds of the present invention after intravenous and oral administration were investigated.

[0081] 2. Reagents and experimental animals:

[0082] Reagents: dimethyl sulfoxide (DMSO), polyethylene glycol 400 (PEG400), methylcellulose (MC).

[0083] Experimental animals: SD rats, male.

[0084] 3. Comparative Pharmacokinetic Experimental Methods in Rats

[0085] (1) Drug preparation

[0086] The control compound (mabaloxavir) and the compounds 1-5 and 11-35 of the present invention were prepared respectively using the following formulations.

[0087] Intravenous administration: Dosage: 1 mg / kg, volume: 5 ml / kg, concentration: 0.2 mg / ml; 5% DMSO + 10% PEG400 + 85% aqueous solution;

[0088] Oral administration: Dosage: 5 mg / kg, Dosage volume: 10 ml / kg, Dosage concentration: 0.5 mg / ml; 0.5% methylcellulose (MC) suspension.

[0089] (2) Dosage regimen

[0090] Healthy adult Sprague-Dawley rats (3 animals per group) were fasted overnight (with free access to water) and then administered with either 1 mg / kg via tail vein injection (iv) or 5 mg / kg via gavage (po). For the iv group, 0.2 mL of blood was collected from the jugular vein in EDTA-K2 tubes at 5, 15, 0.5, 1, 2, 4, 8, and 24 hours after dosing. After collection, the blood samples were placed on wet ice and centrifuged within 1 hour (3500 g, 4°C, 5 minutes) to separate plasma. Plasma was placed in labeled 1.5 mL EP tubes and stored at -80°C until analysis. For the po group, 0.2 mL of blood was collected from the jugular vein before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Blood was processed as for the iv group. Plasma concentrations of unchanged drug were determined by LC / MS / MS. Concentration-time curves were plotted, and key pharmacokinetic parameters were calculated using WinNonlin 7.2 software.

[0091] Exemplary test results are shown in the table below:

[0092] Table 1 Pharmacokinetic results in rats

[0093] The experimental results show that the compounds of the present invention have good PK properties and / or oral absorption properties.

[0094] Test Example 2: Detection of virus inhibition activity (EC50) and cytotoxicity (CC50) of compounds 1

[0095] Cell plating: MDCK cells were seeded at a certain density in a 96-well plate, and then the cells were cultured in a 37°C, 5% CO2 incubator overnight.

[0096] Compound Treatment: Test compounds (control compound baloxavir and compounds 6-10 of the present invention) were serially diluted with DMSO to a final DMSO concentration of 0.5% and added to the cell culture plates. CC50 determinations were performed using a 3-fold dilution from 50 μM for 10 concentrations. EC50 determinations were performed using a 3-fold dilution from 100 nM for 10 concentrations.

[0097] Virus Inoculation: Add diluted influenza virus (A / WSN / 33 (H1N1) or A / PR / 8 / 34 (H1N1)) to the antiviral activity test wells; add only the compound, without virus, to the cytotoxicity test wells. Incubate the cells in a 37°C, 5% CO2 incubator for 3-5 days until the cytopathic effect (CPE) rate in the virus control wells (no compound) reaches 80-95%.

[0098] Cell viability assay: Cell viability assay reagent (CCK-8 assay reagent) was added to each well. After culturing the cells in a 37°C, 5% CO2 incubator for 3-4 hours, the signal value was detected by a microplate reader. The raw data was used to calculate the anti-influenza virus activity and cytotoxicity of the compound.

[0099] GraphPad Prism software was used to analyze the compound dose-response curves and their EC50 and CC50 values, and the therapeutic index was calculated (therapeutic index = CC50 / EC50).

[0100] The experimental results show that the compound of the present invention has good influenza virus inhibitory activity and low cytotoxicity.

[0101] Test Example 3: Detection of virus inhibition activity (EC50) and cytotoxicity (CC50) of compounds 2

[0102] 1. Purpose:

[0103] The in vitro anti-influenza virus activity of the compounds of the present invention was investigated using an indirect immunofluorescence virus quantitative assay (FFA) method.

[0104] 2. Key reagents, strains and cells:

[0105] Key reagents: Influenza Anti-HA Serum (strain-specific serum), Alexa Fluor 488 donkey anti-sheep IgG

[0106] Strain: Type A (H1N1) A / Victoria / 2570 / 2019 & A / Victoria / 4897 / 2022

[0107] Type A (H3N2)A / Cambodia / E0826360 / 2020&A / Darwin / 9 / 2021

[0108] Cell plating: MDCK cells

[0109] 3. Detection method:

[0110] Cell preparation: Observe the cell status and ensure the confluence is 85% to 95% and the viability is ≥ 90%. Digest the cells and inoculate them into 96-well cell culture plates at 2.5 to 3.0 × 105 cells / mL, 100 μL / well, incubated at 37°C in a CO2 incubator for about 24 h;

[0111] Virus dilution: Take the virus solution and dilute it with MEM medium according to the virus titer of each strain to 8000 PFU / mL as the virus working solution. Place it on ice or at 2-8°C until ready for use.

[0112] Compound Dilution: Test compounds (control compound 1: baloxavir, control compound 2: Example compound 1A in CN108440564A, and compounds of the present invention) were serially diluted with DMSO to a final DMSO concentration of 0.5% and added to the cell culture plate. EC50 determination dilution factor: 20 concentrations, starting from 100 nM, with 3-fold dilutions.

[0113] Compound Dosing and Virus Inoculation: Remove the pre-seeded cell plate from the 37°C CO2 incubator, spin off the culture supernatant, add 100 μL / well MEM medium, and wash twice. Spin off any remaining liquid. According to the designed plate layout, pipette the compound serial dilutions and compound blank dilutions at a rate of 50 μL / well onto the antiviral assay plate using a multichannel pipette. Except for wells CC (cell control), add 50 μL of the corresponding virus working solution to each well. Gently shake the assay plate to mix thoroughly. Incubate the plate in a 37°C, 5% CO2 incubator for 18–24 hours.

[0114] GraphPad Prism software was used to analyze the compound dose-response curves and their EC50 values.

[0115] Table 2 In vitro anti-influenza virus activity of compounds

[0116] The experimental results show that the compound of the present invention is significantly superior to the control compound and has good influenza virus inhibitory activity.

[0117] Test Example 4: Pharmacokinetics experiment in mice

[0118] 1. Purpose:

[0119] The distribution levels of the compounds of the present invention in the lungs and plasma were investigated after oral administration to mice.

[0120] 2. Reagents and experimental animals:

[0121] Reagents: methylcellulose (MC);

[0122] Experimental animals: Balb / c mice, male.

[0123] 3. Comparative Pharmacokinetic Experimental Methods in Mice

[0124] (1) Drug preparation

[0125] Oral administration: The dosage is 10 mg / kg, the administration volume is 10 ml / kg, and 0.5% methylcellulose (MC) is used to prepare a uniform suspension with a dosage concentration of 1.0 mg / ml.

[0126] (2) Dosage regimen

[0127] 6-8 week old Balb / c mice (3 animals at each time point) were fasted overnight (with free access to water) and then orally administered with 10 mg / kg of compound (such as compound 1 of the present invention); blood samples were collected at 0.5, 1, 2, 4, and 8 hours after the drug administration for each compound group, and the mice were immediately killed and lung tissue was collected. The blood samples were collected into test tubes with stabilizers added in advance, mixed by inversion, and centrifuged within 30 minutes (4°C, 3000g, 10 minutes). The plasma was separated and frozen for testing. After the lung tissue was collected, it was immediately placed in an ice water bath, weighed within 20 minutes, and glacial acetonitrile was quickly added according to 1g:3mL. The homogenate was completed within 1 hour for testing. The metabolite compounds (such as compound 6 of the present invention) in the plasma were determined by LC / MS / MS method, and the results are as follows:

[0128] The experimental results show that the exposure levels of the compound of the present invention in mouse plasma and lungs, as well as the ratio of lung blood exposure, are both good.

[0129] Experimental Example 5: Pharmacokinetic Experiment in Cynomolgus Monkeys

[0130] 1. Purpose:

[0131] The pharmacokinetic characteristics of the compounds of the present invention were investigated after intravenous and oral administration to cynomolgus monkeys.

[0132] 2. Reagents and experimental animals:

[0133] Reagents: dimethyl sulfoxide (DMSO), polyethylene glycol 400 (PEG400), methylcellulose (MC).

[0134] Experimental animals: Cynomolgus monkeys, male.

[0135] 3. Comparative Pharmacokinetic Experimental Methods in Cynomolgus Monkeys

[0136] (1) Drug preparation

[0137] Intravenous administration: Dosage: 1 mg / kg, dosing volume: 2 ml / kg, dosing concentration: 0.5 mg / ml; 5% DMSO + 30% PEG400 + 65% aqueous solution;

[0138] Oral administration: Dosage: 10 mg / kg, administration volume: 2 ml / kg, administration concentration: 0.5 mg / ml; 0.5% methylcellulose (MC) suspension.

[0139] (2) Dosage regimen

[0140] Healthy eluted cynomolgus monkeys (n=4 per oral group and n=2 per intravenous group) were fasted overnight (with free access to water) and then administered 1 mg / kg via tail vein injection (iv) or oral administration (po). For the iv group, 0.3 mL of blood was collected from each limb vein at 2, 5, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration. Blood was collected into EDTA-K2 anticoagulant tubes (pre-prepared with 5 μL PMSF solution (300 mM PMSF in methanol)). The tubes were gently shaken several times, placed in an ice-water bath, and centrifuged within 30 minutes (4°C, 3000g, 10 minutes). Plasma was separated and quickly frozen at -70°C for analysis. For the po group, blood samples were collected before administration and at 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration and processed in the same manner as the intravenous group. Metabolites (such as compound 6, a metabolite of the inventive compound) in plasma were determined by LC / MS / MS, and blood drug concentration-time curves were drawn. The main pharmacokinetic parameters were calculated using WinNonlin 8.0 software.

[0141] The experimental results show that the compound of the present invention has good PK properties and oral absorption properties after oral administration.

[0142] Test Example 6: Stability test of compound in human liver S9 in vitro

[0143] Test samples: 1 μM baloxavir and compound 1 of the present invention

[0144] Reagents: Phosphate buffer: 200mM, 200μL, final concentration 100mM; Ultrapure water: 138μL, MgCl2 solution: 50mM, 40μL, final concentration 5mM; S9 component: 20mg / mL, 20μL, final concentration 1mg / mL

[0145] Procedure: Add 2 μL of a 200 μM test compound or control compound solution to the above reagent system. Verapamil was used as a positive control, and the final concentration of the test compound and control compound was 1 μM. After 0, 5, 15, 30, 45, and 60 minutes, the reaction solution was mixed on a vortex mixer for 10 seconds, and then 50 μL was transferred to 400 μL of acetonitrile, sealed, and placed on ice. After further mixing for 10 minutes, the solution was centrifuged at 4°C and 3,220 g for 50 minutes. The concentrations of mabaloxavir and compound 1 were analyzed by LC-MS / MS. The measured concentrations were used to calculate the remaining percentage at each time point using Microsoft Excel, and the half-life T was calculated based on the slope. 1 / 2 and in vitro intrinsic clearance CL int .

[0146] Table 3 In vitro stability results of compound human liver S9

[0147] The experimental results show that the compound of the present invention is metabolized faster in human liver S9 than Yangshen, and is more likely to release the original drug molecule.

[0148] Test Example 7: Stability test of compound in human intestinal S9 in vitro

[0149] Test samples: 1 μM baloxavir and compound 1 of the present invention

[0150] Reagents: Phosphate buffer: 200mM, 200μL, final concentration 100mM; Ultrapure water: 138μL, MgCl2 solution: 50mM, 40μL, final concentration 5mM; S9 component: 20mg / mL, 20μL, final concentration 1mg / mL

[0151] Procedure: Add 2 μL of a 200 μM test compound or control compound solution to the above reagent system. Verapamil was used as a positive control, and the final concentration of the test compound and control compound was 1 μM. After 0, 5, 15, 30, 45, and 60 minutes, the reaction solution was mixed on a vortex mixer for 10 seconds, and then 50 μL was transferred to 400 μL of acetonitrile, sealed, and placed on ice. After further mixing for 10 minutes, the solution was centrifuged at 4°C and 3,220 g for 50 minutes. The concentrations of mabaloxavir and compound 1 were analyzed by LC-MS / MS. The measured concentrations were used to calculate the remaining percentage at each time point using Microsoft Excel, and the half-life T was calculated based on the slope. 1 / 2 and in vitro intrinsic clearance CL int .

[0152] Table 4 In vitro stability results of compound human intestinal S9

[0153] The experimental results show that the compounds of the present invention are metabolized faster in human intestinal S9 than the Yangshen compounds and are more likely to release the original drug molecules.

[0154] Test Example 8: Stability test of compound in human plasma

[0155] Test samples: Yangshenmabaloxavir and compound 1 of the present invention

[0156] Procedure: 50 μL of a 400 ng / mL solution of test compound or control compound was added to human plasma. The final concentration of the test compound and control compound was 20 ng / mL. After incubation at 37°C for 0, 5, 15, 30, and 60 minutes, the stable plasma was pooled and 30 μL was transferred to 270 μL of acetonitrile. After mixing, the mixture was quickly centrifuged at 10,000 g for 5 minutes at 4°C. The concentrations of mabaloxavir and compound 1 were analyzed by LC-MS / MS. The measured concentrations were used to calculate the percentage remaining at each time point using Microsoft Excel.

[0157] Table 5 In vitro stability results of compounds in human plasma

[0158] Experimental results show that the compound of the present invention is metabolized faster in human plasma than the Yangshen compound and is more likely to release the original drug molecules.

Claims

1. A compound of formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof: in, R1, R2, R3, and R4 are all hydrogen or all deuterium, R5 does not exist or is an oxo group, and R6 is hydrogen or 2. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3, and R4 are deuterium, R5 is absent or is an oxo group, and R6 is hydrogen or 3. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3, R4 are hydrogen, R5 is oxo, R6 is hydrogen or 4. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3, and R4 are deuterium, R5 is an oxo group, the configuration of the sulfur atom is S or R, and R6 is hydrogen or 5. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1, R2, R3, R4 are hydrogen, R5 is an oxo group, the configuration of the sulfur atom is S or R, R6 is hydrogen or 6. A compound selected from: and its tautomers, stereoisomers or pharmaceutically acceptable salts.

7. A pharmaceutical composition, characterized in that It comprises the compound according to any one of claims 1 to 6, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, and optionally further comprises a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by a cap-dependent endonuclease.

9. Use of the compound according to any one of claims 1 to 6, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing a disease or condition caused by viral infection.

10. The use according to claim 9, characterized in that The viral infection is an influenza virus infection; further, the influenza virus is selected from type A, type B, type C or avian influenza (H5N1, H7N9); further, the symptoms are selected from cold-like symptoms accompanied by fever, chills, headache, muscle pain, general fatigue, etc., or respiratory tract inflammation with sore throat, runny nose, nasal congestion, cough, and sputum; gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea, and further accompanied by complications of acute encephalopathy, secondary pneumonia infection, or a combination thereof.

Images