WO2024098273A1 - Anti-influenza virus phosphate ester compound and use thereof - Google Patents

Abstract

An anti-influenza virus phosphate ester compound and a use thereof. The phosphate ester compound is a compound represented by formula (I) below or a hydrate, a solvate, an optical isomer, a polymorph, an isotope derivative or a pharmaceutically acceptable salt thereof. The compound can be used for preparing anti-influenza virus drugs.

Description

Anti-influenza virus phosphate compound and use thereof Technical Field

The present invention relates to a phosphate compound having anti-influenza virus activity or a hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt thereof, a preparation method thereof and use thereof in anti-influenza virus.

Background technique

Influenza viruses mainly include influenza A virus, influenza B virus, influenza C virus and influenza D virus. Among them, influenza A virus and influenza B virus are the main human influenza viruses. Influenza A virus is the strongest among them. It infects the most people during the influenza season and can induce severe respiratory infections, resulting in more than 300,000 deaths from influenza every year worldwide.

At present, the main anti-influenza virus drugs on the market are: Amantadine, neuraminidase inhibitors Oseltamivir or Zanamivir. The RNA polymerase of influenza virus contains cap-dependent endonuclease. Inhibiting the activity of cap-dependent endonuclease can inhibit the proliferation of the virus. Different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors.

So far, baloxavir is the first marketed drug for this target, and some other molecules have entered the clinical research stage. However, including baloxavir, these molecules all show low solubility and poor oral bioavailability, which makes them unsuitable as ideal influenza treatment agents. Especially for patients with severe influenza, intravenous administration may be required for rapid onset of action, but low solubility limits its intravenous administration.

Therefore, the development of oral and intravenous drugs for the treatment of influenza remains urgent.

Summary of the invention

Unless otherwise specified herein, the professional terms used in the present invention have the basic meanings generally understood by those skilled in the art.

The invention provides a phosphate compound with anti-influenza virus effect, and the compound can be administered orally and intravenously.

The compound of the present invention has good solubility and stability and can be administered by intravenous injection, which has good advantages in the treatment of critically ill patients.

Surprisingly, the compound of the present invention has high solubility and good oral bioavailability, so that it can be administered by injection and orally at the same time; in addition, the improvement in bioavailability is expected to reduce the oral dosage and further improve the safety of oral administration of the compound.

The present invention provides a phosphate compound represented by the following formula (I) or its hydrate, solvate, optical isomer, polymorph, isotope derivative, and pharmaceutically acceptable salt:

In formula (I), R _a is selected from hydrogen, deuterium or methyl;

R _b and R _c are each independently selected from hydrogen, deuterium or methyl, or R _b and R _c together with the carbon to which they are attached form a cyclopropyl group;

_X1 is an O atom or a S atom;

_X2 is a Se atom or a S atom;

n1 is 0, 1 or 2;

Each R ₁ or R ₂ is independently selected from hydrogen or methyl;

_R3 and _R4 are each independently selected from the following groups: hydroxyl, C1-C8 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkoxy, C6-C10 aryloxy, C7-C12 aralkyloxy, and when _X2 is an S atom, _R3 and _R4 cannot be C1-C8 alkoxy at the same time; or _R3 and _R4 together with the phosphorus atom to which they are connected form the following

wherein R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen or C1-C3 alkyl, or R ₅ and R ₆ , R ₇ and R ₈ , R ₁₀ and R ₁₁ , R ₁₁ and R ₁₂ each together with the carbon atom to which they are connected form an aromatic ring.

In some embodiments, the phosphate compound provided by the present invention or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt is as shown in formula (II):

The substituents in formula (II) are as defined in formula (I).

In some embodiments, the phosphate compound provided by the present invention or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt is as shown in formula (III):

The substituents in formula (III) are as defined in formula (I).

In some embodiments, the phosphate compound provided by the present invention or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt is as shown in formula (IV):

The substituents in formula (IV) are as defined in formula (I).

In the embodiments of the present application, the solvate refers to a complex formed by the interaction of a compound with a pharmaceutically acceptable solvent, and the pharmaceutically acceptable solvent includes water, methanol, ethanol, isopropanol, n-butanol, acetic acid, ethanolamine, and ethyl acetate.

In the embodiments of the present application, the C1-C3 alkyl group refers to a saturated aliphatic hydrocarbon group containing 1 to 3 carbon atoms in the molecule, including but not limited to methyl, ethyl, propyl, isopropyl, and cyclopropyl.

In the embodiments of the present application, the C1-C8 alkoxy group refers to a group in which an oxygen atom is inserted in any reasonable position of a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, n-butoxy, 2-ethylethoxy, and the like.

In the embodiments of the present application, the C3-C8 cycloalkoxy group refers to a monocyclic or condensed polycyclic saturated or unsaturated cyclic hydrocarbon group containing 3 to 8 carbon atoms, including but not limited to cyclopropyloxy, cyclopentyloxy, bicyclo[3.1.0]hexyloxy, bicyclo[3.2.0]heptyloxy, etc.

In the embodiments of the present application, the C3-C8 heterocycloalkoxy group refers to a group in which a C3-C8 heterocycloalkyl group is connected to oxygen, and the C3-C8 heterocycloalkyl group refers to a saturated or unsaturated cyclic group containing 3 to 8 carbon atoms and 1 to 4 heteroatoms in the molecule; the C3-C8 heterocycloalkyl group includes but is not limited to aziridine, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, hexahydropyridazinyl, dihydropyridinyl, cyclopentyl sulfide, morpholinyl and the like.

In the embodiments of the present application, the C6-C10 aryloxy group refers to a group consisting of an aromatic ring of 6 to 10 carbon atoms connected to an oxygen atom, including but not limited to phenoxy and naphthoxy.

In the embodiments of the present application, the C7-C12 aralkyloxy group refers to a group consisting of an arylalkyl group consisting of 7 to 12 carbon atoms connected to an oxygen atom, including but not limited to benzyloxy, phenethyloxy, and the like.

In some embodiments, _Ra is hydrogen; in some embodiments, _Ra is deuterium; in some embodiments, Ra _is methyl.

In some embodiments, R _b and R _c are both hydrogen; in some embodiments, R _b and R _c are both deuterium; in some embodiments, R _b is hydrogen and R _c is deuterium; in some embodiments, R _b and R _c are both methyl; in some embodiments, R _b and R _c together with the carbon to which they are attached form a cyclopropyl group; in some embodiments, R _b is hydrogen and R _c is methyl.

In some embodiments, n1 is 0; in some embodiments, n1 is 1; in some embodiments, n1 is 2.

In some embodiments, X ₁ is an O atom; in some embodiments, X ₁ is a S atom.

In some embodiments, X ₁ is a Se atom; in some embodiments, X ₁ is a S atom.

In an embodiment of the present invention, each R ₁ or R ₂ is independently hydrogen or methyl.

In an embodiment of the present invention, when X ₂ is an S atom, R ₃ and R ₄ may not be C1-C8 alkoxy groups at the same time;

In some embodiments, R ₃ and R ₄ are selected from the following groups: C1-C8 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkoxy; preferably, R ₃ and R ₄ are C1-C3 alkoxy;

In some embodiments, R ₃ and R ₄ are selected from the following groups: C6-C10 aryloxy, C7-C12 aralkyloxy; preferably, R ₃ and R ₄ are benzyloxy;

In some embodiments, R ₃ is selected from the following groups: C1-C8 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkoxy, C6-C10 aryloxy, C7-C12 aralkyloxy, R ₄ is hydroxyl;

In some embodiments, _R3 and _R4 together with the phosphorus atom to which they are attached form

5-7 membered ring.

In some embodiments, R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen; in some embodiments, R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each independently C1-C3 alkyl;

In some embodiments, R ₅ and R ₆ , R ₇ and R ₈ , R ₁₀ and R ₁₁ , R ₁₁ and R ₁₂ each together with the carbon atom to which they are attached form an aromatic ring, preferably a benzene ring;

In some specific embodiments, R ₅ and R ₆ together with the carbon atom to which they are attached form a benzene ring;

In some specific embodiments, R ₇ and R ₈ together with the carbon atom to which they are attached form a benzene ring;

In some specific embodiments, R ₁₀ and R ₁₁ together with the carbon atom to which they are attached form a benzene ring;

In some specific embodiments, R ₁₁ and R ₁₂ together with the carbon atom to which they are attached form a benzene ring.

In some specific embodiments, in formula (I) to (III), when _R4 is a hydroxyl group, the compound may or may not form a salt; in some specific embodiments, in formula (I) to (III), when _R4 is a hydroxyl group, the compound may form a salt with an alkali metal, an alkaline earth metal, a zinc ion, an organic amine, or a basic amino acid. Preferably, when _R4 is a hydroxyl group, the compound may form a sodium salt, a potassium salt, a magnesium salt, a zinc salt, an amine salt, or a basic amino acid salt.

The salt-forming compound of the present invention has good crystallinity and solubility.

In an embodiment of the present invention, formula (I) contains a chiral center (the carbon atom indicated by *), and the optical isomers refer to optical isomers caused by different configurations of the carbon atom indicated by *. The compounds of the present invention or their intermediates can be separated by chirality to obtain single-configuration compounds.

In some specific embodiments, the compounds of the present invention are racemates; in some specific embodiments, the compounds of the present invention are S-configuration.

In an embodiment of the present invention, after the absolute configuration of the S-configuration compound is determined by electronic circular dichroism spectroscopy, the optical rotation direction is determined by optical rotation test.

In an embodiment of the present invention, the S-configuration and R-configuration compounds are tested for optical rotation (according to the optical rotation determination method of the Chinese Pharmacopoeia 2020 Edition-Part IV-0621, with methanol as solvent), and the S-configuration compound is a levorotatory isomer.

The compounds provided by the present invention include but are not limited to the following compounds:

or a hydrate, solvate, optical isomer, polymorph, isotope derivative, or pharmaceutically acceptable salt thereof.

Another aspect of the present invention is to provide a pharmaceutical composition prepared from the above-mentioned compound or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes one or a combination of fillers, binders, diluents, lubricants, preservatives, taste masking agents or cosolvents. The pharmaceutical composition can be used to resist influenza virus.

Furthermore, the dosage form of the pharmaceutical composition is tablets, capsules, powders, granules, pills, suspensions, syrups, and injections.

In the third aspect of the present invention, the present invention provides the above-mentioned compound, including its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, or pharmaceutical composition thereof, for use against influenza virus.

The present invention provides the above-mentioned compound, including the compound, including its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt, or use of its pharmaceutical composition in preparing anti-influenza virus drugs.

The present invention provides a method for preventing or treating influenza virus infection, which comprises administering a therapeutically effective amount of the above-mentioned compound, including its hydrates, solvates, optical isomers, polymorphs, isotope derivatives, and pharmaceutically acceptable salts, to an individual in need thereof.

The compound of the present invention has good solubility and stability and is capable of being administered by injection, which is a great advantage in the treatment of critically ill patients.

Surprisingly, the study found that the compounds of the present invention have good oral bioavailability. It is generally believed that phosphate compounds have high polarity and low stability, and the molecules are highly lipid-soluble after the phosphate group is esterified, resulting in low solubility, all of which will lead to low oral bioavailability. However, the compounds of the present invention have high solubility while reducing the polarity of the compounds, so that they can meet the requirements of injection and oral administration at the same time, and have extremely high development value.

In addition, the improvement in bioavailability is expected to reduce the oral dosage and further improve the safety of oral administration of the compound.

Detailed ways

The following examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The structures of all compounds are determined by MS or ¹ H-NMR, and the configurations of all optical isomers of a single configuration are determined by optical rotation tests or electronic circular dichroism spectroscopy.

Unless otherwise specified, the solvents and reagents used in this example are all common commercial products. The starting materials are all purchased commercial raw materials.

Example 1: Synthesis of M11

Synthesis of compound 2:

At room temperature, compound 1 (100 g, 793 mmol, 1 eq) was dissolved in DMF (1.5 L), potassium carbonate (219 g, 1.59 mol, 2 eq) was added, the mixture was cooled to 0 ° C in an ice-water bath, benzyl bromide (203 g, 1.19 mol, 1.5 eq) was added dropwise, and the mixture was kept at 0 ° C for 30 minutes, and then moved to an oil bath pot and reacted at 80 ° C for 5 hours. TLC (EA/PE = 1/2, EA is ethyl acetate, PE is petroleum ether) detected that only a small amount of raw materials remained, and post-treatment was performed, the system was cooled to room temperature, poured into water (3 L), extracted with ethyl acetate (300 ml x 3), the organic phases were combined and washed with water (100 ml x 3), washed with saturated brine (200 ml x 1), dried with anhydrous sodium sulfate for 20 minutes, and the organic phase was filtered, concentrated, and purified by column chromatography (EA/PE = 1/5 to 1/1) to obtain 157 g of the product. Yellow oil, yield 91.8%.

Synthesis of compound 3:

Compound 2 (100 g, 115 mmol, 1 eq) was dissolved in bromobenzene (1 L) at room temperature, and SeO ₂ (152 g, 347 mmol, 3 eq) was added to react in an oil bath at 180°C for 16 hours. TLC (EA/PE=1/2) detected that the reaction was complete. The system was cooled to room temperature, diatomaceous earth was added to a Buchner funnel for suction filtration, and the diatomaceous earth was washed with dichloromethane (100 ml x 3). The organic phases were combined and concentrated with a water pump to dichloromethane, and bromobenzene was concentrated with an oil pump to obtain a crude product (100 g, red oil).

Synthesis of compound 4:

Compound 3 (100 g, 434 mmol, 1 eq) was dissolved in DMSO (1.5 L) at room temperature, cyclopropane formaldehyde (91 g, 1.3 mol, 3 eq) was added, the temperature was cooled to 0°C in an ice-water bath, pyrrolidine (31 g, 434 mmol, 1 eq) was added dropwise under nitrogen protection, the temperature was kept below 15°C for 30 minutes, and the mixture was moved to an oil bath pot at 50°C for 5 hours. TLC (DCM/MeOH=20/1) detected that the raw material reaction was complete, the system was cooled to room temperature, poured into water (3 L), extracted with ethyl acetate (250 mlx3), the organic phases were combined and washed with water (100 mlx3), washed with saturated brine (100 mlx1), dried over anhydrous sodium sulfate for 30 minutes, the organic phase was filtered and concentrated, and purified by column chromatography (EA/PE=1/10-1/1) to obtain the product (32 g, red oil, yield 24.6%). ESI-MS (+): m/z = 301.1; ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.85 (s, 1H), 7.69-7.67 (d, 1H), 7.28-7.43 (m, 5H), 6.42-6.43 (d, 1H), 5.28 (s, 2H), 4.93-4.95 (d, 1H), 2.79-2.81 (d, 1H), 1.15-1.27 (m, 4H).

Synthesis of compound 5:

Compound 4 (32 g, 107 mmol, 1 eq) was dissolved in methanol (300 ml)/water (150 ml) under ice-water bath, and trifluoroacetyl hydrazine (27.3 g, 214 mmol, 2 eq) was added. After the addition was completed, the reaction was kept in ice-water bath for 30 minutes, and then in oil bath at 50°C for 4 hours. TLC (DCM/MeOH=20/1) detected that the raw material reaction was complete. The reaction system was cooled to room temperature, the methanol in the system was concentrated, water (150 ml) was added, and ethyl acetate was extracted (100 mlx3), the organic phases were combined and washed with saturated brine (500 mlx1), dried over anhydrous sodium sulfate for 10 minutes, and the organic phase was filtered, concentrated, and purified by column chromatography (EA/PE=1/10-1/1) to obtain the product (14 g, yellow solid, yield 45%). ESI-MS(+):m/z＝297.1；1H NMR(DMSO-D6,400MHz):δ7.90-7.92(d,1H),7.31-7.43(m,5H),7.14-7.15(s,1H),6.28-6.30(d,1H),5.78-5.79(d,1H),5.27-5.30(d,1H),5.03-5.06(d,1H),4.09-4.10(m,1H),1.19-1.28(m,2H),0.85-0.90(m,1H),0.61-0.64(m,1H).

Synthesis of compound 6:

Compound 5 (14 g, 47.2 mmol, 1 eq) was dissolved in THF (150 ml) under ice-water bath, and triethylamine (9.6 g, 94.5 mmol, 2 eq) and DMAP (1.73 g, 14.2 mmol, 0.3 eq) were added. Acetic anhydride (9.6 g, 94.5 mmol, 2 eq) was added dropwise while maintaining the temperature at 0°C. After the addition was completed, the temperature was maintained at 0°C for 30 minutes, and the mixture was moved to room temperature for 2 hours. TLC (EA/PE=1/1) detected that the raw material had reacted completely. The system was poured into water (150 ml), extracted with ethyl acetate (50 ml x 3), the organic phases were combined and washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate for 10 minutes, and the organic phase was filtered, concentrated, and purified by column chromatography (EA/PE=1/10-1/1) to obtain product 6 (15 g, yellow solid, yield 94%).

Synthesis of compound 7:

Compound 6 (15 g, 44.3 mmol, 1 eq) was dissolved in THF (150 ml) and methanol (50 ml) under ice-water bath, sodium borohydride (3.35 g, 133 mmol, 3 eq) was added in batches while maintaining the temperature at 0°C, and the reaction was maintained at 0°C for 30 minutes after the addition was completed, and the reaction was moved to room temperature for 2 hours. TLC (EA/PE=1/1) detected the disappearance of the raw material, poured the system into an aqueous solution of ammonium chloride (150 ml), extracted with ethyl acetate (50 ml x 3), washed with saturated brine (50 ml x 3) and dried over anhydrous sodium sulfate for 10 minutes, the organic phase was filtered and concentrated to obtain a crude product (15 g, yellow solid), which was directly used for the next step without purification.

Synthesis of compound 8:

Under ice-water bath, compound 7 (15 g, 44 mmol, 1 eq) was dissolved in THF (150 ml), DMAP (0.54 g, 4.4 mmol, 0.1 eq) and triethylamine (8.92 g, 88 mmol, 2 eq) were added, and Boc ₂ O (19.2 g, 88 mmol, 2 eq) was added dropwise while maintaining the temperature at 0°C. After the addition was completed, the reaction was maintained at 0°C for 30 minutes, and then moved to room temperature for 2 hours. TLC (DCM/MeOH=20/1) detected the disappearance of the raw material, and the system was poured into water (150 ml), extracted with ethyl acetate (50 mlx3), the organic phases were combined and washed with saturated brine (50 mlx3), dried over anhydrous sodium sulfate for 10 minutes, and the organic phase was filtered, concentrated, and purified by column chromatography (EA/PE=1/10-1/1) to obtain the product (15 g, yellow solid, yield 78%).

Synthesis of compound 9:

Compound 8 (15 g, 34 mmol, 1 eq) was dissolved in methanol (150 ml) under ice-water bath, and potassium carbonate (4.7 g, 34 mmol, 1 eq) was added in batches. After the addition was completed, the reaction was maintained at 0°C for 30 minutes and at room temperature for 6 hours. TLC (DCM/MeOH=20/1) detected that the raw material reaction was complete, and the system was poured into water (150 ml), extracted with ethyl acetate (50 ml x 3), the organic phases were combined, washed with saturated brine (30 ml x 3), dried over anhydrous sodium sulfate for 10 minutes, and the organic phase was filtered and concentrated to obtain a crude product (10 g, yellow solid).

Synthesis of compound 10:

Compound 9 (10 g, 25 mmol, 1 eq) was dissolved in DCM (100 ml) under ice-water bath, and Dess-Martin oxidant (16 g, 37.6 mmol, 1.5 eq) was added in batches at 0 °C. After the addition was completed, the reaction was maintained at 0 °C for 30 minutes and at room temperature for 5 hours. TLC (DCM/MeOH=15/1) detected that the raw material reaction was complete, and the system was poured into an aqueous solution of sodium bicarbonate (100 ml), extracted with DCM (30 mlx3), and the organic phase was combined and washed with saturated brine (30 mlx1). Drying with anhydrous sodium sulfate for 10 minutes, the organic phase was filtered, concentrated, and purified by column chromatography (EA/PE=1/10-1/0) to obtain 10 g of crude product, and the crude product was slurried with ethyl acetate to obtain 5.4 g of pure product, and the mother liquor was concentrated to obtain 4.6 g of crude product. ESI-MS (+): m/z = 397.3; ¹ H NMR (DMSO-D6, 400 MHz): δ 7.84-7.86 (d, 1H), 7.28-7.46 (m, 5H), 6.30-6.32 (d, 1H), 5.07-5.20 (m, 2H), 3.85-4.20 (dd, 2H), 1.43 (s, 9H), 1.35-1.37 (m, 1H), 1.18-1.28 (m, 2H), 1.08-1.12 (m, 1H).

Synthesis of compound 12

After replacing nitrogen in the three-necked flask, add 226 ml of phenylmagnesium bromide (2.8 mol/L), cool down to below 10°C in an ice-water bath, add 49.9 g of selenium powder in batches, control the reaction temperature not to exceed 30°C, and react for 2 hours after the addition of selenium powder. Add 2 mol/L hydrochloric acid in an ice-water bath, the reaction is obviously exothermic, add EA for extraction, separate the liquids, and spin-dry the organic phase to obtain product 12 as a brown oil with a strong odor. Proceed directly to the next step.

Synthesis of compound 14

After replacing nitrogen in the three-necked flask, 81.18g of LDA (diisopropyl lithium amide) was added, cooled to -30°C in a dry ice-ethanol solution, and 50g of compound 3,4-difluorobenzoic acid THF solution was added dropwise. During the addition, heat release was obvious, and the temperature of the reaction system was controlled to be lower than -20 degrees Celsius. The reaction was performed for 2 hours, and DMF was added. Heat release was obvious, and the temperature of the reaction system was controlled to be lower than -20 degrees Celsius. No temperature control was required, and the reaction was gradually transferred to room temperature. The reaction was overnight, and the reaction was terminated by sampling and detection. HCl was added to the reaction system, and heat release was obvious. EA was added for extraction, and the organic phase was spin-dried to obtain 72g of a crude product of compound 14. The product was directly used in the next step of the reaction. The crude product was a yellow solid with a yield of 122% (DMF was not spin-dried in the material).

Synthesis of compound 15

After replacing nitrogen in the three-necked flask, 58.81g of compound 12, 49.6g of compound 14, 300ml of toluene, and 17.6g of camphorsulfonic acid were added, and the temperature was raised to 70°C, and the reaction was allowed to proceed overnight. The reaction system was cooled to room temperature, and NaOH solution was added, and the liquid was separated. After the aqueous phase was extracted with EA, the organic phase was combined, and the organic phase was washed with saturated NaCl and then spin-dried. The crude product was 123.08g. The obtained crude product was pulped with PE and then filtered to obtain 34.4g of the product. The pulping filtrate recovered 14.83g of the product. Compound 15 was an orange solid with a yield of 47.9%.

Synthesis of compound 16

16.9g _AlCl3 and 250ml toluene were added to a three-necked flask, the system was cooled in an ice-water bath, 17.1g tetramethyldisiloxane was added, stirred evenly, 150ml toluene solution of compound 15 (34.4g) was added, the reaction was slightly exothermic, _AlCl3 was gradually dissolved, heated to 80°C, reacted for 1 hour; the reaction was stopped, sulfuric acid solution (16.2mL+240mL water) was added, the liquids were separated, the aqueous phase was extracted with EA, the organic phase was spin-dried, the crude product was pulped with PE and filtered, 22g of solid was obtained, the obtained solid was a yellow powdery solid, the theoretical amount of the product was: 34.68g, and a total of 22g of solid product compound 16 was obtained, with a yield of: 63.4%. It was directly used for the next step reaction.

Synthesis of compound 17:

429 g of polyphosphoric acid was added to a three-necked flask, heated to 80°C, 42 g of compound 16 was added, and the temperature was raised to 120°C. The reaction system became viscous and the color changed from yellow to dark purple. The reaction was carried out for 1 hour, and a sample was taken. Water was added and the mixture was treated with EA. The reaction temperature was lowered to below 100°C, water was added and stirred evenly, EA was added for extraction, the organic phase was separated, and the mixture was spin-dried. The crude product was pulped with PE and filtered to obtain 3.4 g of the product. The filtrate was separated by column chromatography to obtain 10 g of the product. Compound 17 was a colorless to light yellow flocculent solid. The theoretical yield was 39.69 g, the actual output was 13.4 g, and the yield was 33.76%.

Synthesis of compound 18:

Add 2.12g of compound 17 and 20ml of ethanol to a three-necked flask and stir the system. Add sodium borohydride (0.26g) ethanol solution dropwise in an ice-water bath. The reaction system has a slight temperature rise. After the addition is completed, it is transferred to room temperature for reaction. The materials gradually dissolve. After the reaction liquid is clear, sampling is performed for testing. After the reaction is completed, treatment is performed; 2mol/L hydrochloric acid is added until no bubbles are generated, pH = 4-6, a large amount of solid precipitates, and solids are obtained by suction filtration. The filtrate is extracted with EA, and the organic phase is separated. The organic phase is spin-dried to obtain product 18 as a brown solid, which is directly used in the next step reaction.

Synthesis of compound 19

To a single-mouth bottle, 2.5 g of compound 10, 2.13 g of compound 18, 5.44 g of compound T3P (propylphosphonic anhydride), 1.1 g of methanesulfonic acid and 30 ml of EA were added, the temperature was raised to reflux, the reaction was allowed to proceed overnight, sampling was performed for detection, and treatment was performed after the reaction was completed; post-treatment: saturated aqueous sodium bicarbonate solution was added until no bubbles were released, the liquids were separated, the aqueous phase was extracted with EA, the organic phases were combined, and the crude product was slurried with PE to obtain product 19, which was a light brown powdery solid. The theoretical yield was 3.36 g, the actual output was 2.2 g, and the yield was 65.48%.

Synthesis of compound M01:

Add 2.6g of compound 19, 0.94g of compound LiCl and 20ml of DMA (N,N-dimethylacetamide) to a single-mouth bottle, heat to 100°C, the reaction liquid is yellow and turbid, react for 2 hours, take samples for detection, and treat after the reaction is completed; add saturated sodium bicarbonate aqueous solution, solid precipitates, filter, extract the filtrate with EA, spin dry the organic phase, and beat the crude product with PE to obtain 2.28g of compound M01, the product is a brown solid powder, and the yield is 104% (the yield is slightly higher than the theoretical yield, and the reason is the residual solvent DMA). Use it directly for the next step reaction. ESI-MS (+): m/z = 501.1.

Synthesis of compound M11:

Add 1.1g of compound M01, 0.61g of K ₂ CO ₃ , 0.55g of KI and 0.55g of dimethyl chloromethyl carbonate to a single-mouth bottle. Add 20mL of DMA to the system, heat to 60°C, react overnight, take samples for testing, and treat after the reaction is completed. Cool the reaction system to room temperature, add 2N HCl, add water, solid precipitates, filter, extract the filtrate with EA, separate the organic phase, dissolve the filter cake with EA, mix with the organic phase, dry the organic phase with anhydrous sodium sulfate, spin dry, and separate by column chromatography to obtain 0.766g of brown solid powder of compound M11, yield: 58.9%. ESI-MS (+): m/z=589.5; ¹ H NMR (DMSO-D6, 400 MHz): δ7.26-7.41 (m, 5H), 7.10-7.13 (m, 1H), 6.92-6.98 (m, 2H), 5.90-5.92 (d, 1H), 5.74-5.86 (d, 1H), 5.56-5.58 (d, 1H), 5.38-5.42 (m, 2H), 4.12-4.16 (m, 2H), 4.01-4.07 (m, 1H), 3.74 (s, 3H), 2.79 (s, 1H), 1.73-1.75 (m, 1H), 1.16-1.24 (m, 2H), 0.87-0.90 (m, 1H), 0.72-0.74 (m, 1H).

Example 2: Splitting of M19

Compound M11 was prepared and separated to obtain M19 and enantiomer M19-1, both of which were white solids. Preparation conditions: using a supercritical liquid chromatograph; chromatographic column: CHIRALPAK IB-N 4.6*100mm, 3μm; the solvent was methanol, the carrier was liquid CO ₂ ; the pressure was 1500psi, the flow rate was set to 2.0ml/min, the column temperature was 25°C, and the gradient elution was performed. The retention time of M19 was 2.86min, and the optical rotation was measured with methanol as the solvent, and the result showed that it was a left-handed isomer. The retention time of M19-1 was 2.55min, and the optical rotation was measured with methanol as the solvent, and the result showed that it was a right-handed isomer. M19 and M19-1 adopt the method currently widely used internationally to determine the absolute configuration of chiral compounds. The theoretical electron circular dichroism (ECD, usually referred to as circular dichroism) spectrum is quantitatively calculated and predicted, and compared with the experimental ECD spectrum. The experimental ECD signal is consistent with the theoretical calculation results, thus finally determining the absolute configuration. M19 is S configuration and M19-1 is R configuration.

Example 3: Synthesis of M02

Compound M01 was prepared and separated to obtain M02 and its enantiomer, both of which were white solids. Preparation conditions: using a supercritical liquid chromatograph; chromatographic column: CHIRALPAK IB-N 4.6*100mm, 3μm; the solvent was methanol, the carrier was liquid CO ₂ ; the pressure was 1500psi, the flow rate was set to 2.0ml/min, the column temperature was 25℃, and the gradient elution was performed. The optical rotation was measured with methanol as the solvent, and M02 was shown as a levorotatory isomer, and the M02 enantiomer was shown as a dextrorotatory isomer. By comparison with M19 and M19-1, it can be seen that the absolute configuration of M02 is S configuration.

Example 4: Synthesis of M03 and M04

Synthesis of compound 23

Under nitrogen protection, 1g of compound 17 was dissolved in 15ml of THF. At 0°C, 140mg of lithium aluminum hydride-D4 was slowly added. The system was heated to 25°C and reacted for 8 hours. The system was cooled to 0°C and water was added to quench the reaction. The system was extracted with 2N hydrochloric acid and EA. The organic phase was concentrated to dryness. Column chromatography gave 0.58g of compound 23, with a yield of 57%. ESI-MS (+): m/z = 314.0.

Synthesis of compound 24

Referring to the synthesis method of compound 19, 0.94 g of compound 24 was synthesized, ESI-MS (+): m/z = 592.1.

Synthesis of compound M03

Referring to the synthesis method of compound M01, 0.51 g of compound M03 was synthesized, ESI-MS (+): m/z = 502.1.

Synthesis of compound M04

Referring to the preparation and separation method of compound M01, compound M04 was obtained. It was confirmed that M04 was still a levorotatory isomer and its absolute configuration was S configuration.

Example 5: Synthesis of M05 and M06

Synthesis of compound 25:

Under nitrogen protection, 1g of compound 17 was dissolved in 15ml of THF. At -20°C, 4ml of methyl lithium reagent (1.6M ether solution) was slowly added dropwise. The system was naturally heated to 25°C for 8 hours. The system was cooled to 0°C and water was added to quench the reaction. Concentrated to dryness, extracted with EA and water. The organic phase was separated and concentrated to dryness. Column chromatography gave 0.77g of compound 25, with a yield of 73%. ESI-MS (+): m/z = 327.1.

Synthesis of compound 26

Referring to the synthesis method of compound 19, 0.94 g of compound 26 was synthesized, ESI-MS (+): m/z = 605.2.

Synthesis of compound M05

Referring to the synthesis method of compound M01, 0.51 g of compound M05 was synthesized, ESI-MS (+): m/z = 515.1.

Synthesis of Compound M06

Referring to the preparation and separation method of compound M01, compound M06 was obtained. It was confirmed that M06 was still a levorotatory isomer and its absolute configuration was S configuration.

Example 6: Synthesis of B-1

Synthesis of compound B-1:

At room temperature, 100 mg of compound M02, 130 mg of DIPEA (diisopropylethylamine), 73 mg of DMAP (4-dimethylaminopyridine) and 2 ml of anhydrous dichloromethane were added to the reaction flask, and then 104 mg of diethyl chlorophosphate was added. The system was reacted at room temperature overnight, and dichloromethane and water were added. The organic phase was separated by extraction, dried over anhydrous sodium sulfate, and then concentrated to dryness. 77.6 mg of compound B-1 was obtained by column chromatography purification, with a yield of 61%, and ESI-MS (+): m/z = 637.1.

Example 7: Synthesis of Compound B-5:

Synthesis of compound 30

Compound 30 was synthesized according to the synthesis method in the literature (Chem. Eur. J. 2011, 17, 1649-1659).

A solution of 4.45 g of phosphorus oxychloride in THF (35 ml) was cooled to -78°C, and then a solution of 3 g of compound 29 and 3.14 g of triethylamine in THF (tetrahydrofuran, 45 ml) was added dropwise to the system. After the addition, the system was heated to -50°C for 1 h, and then heated to 25°C for 4 h. The system was filtered to remove the triethylamine salt, and then 5 ml of water was added dropwise to the solution, and then the reaction was continued for 2 h. The system was concentrated to dryness and purified by column chromatography to obtain 3.06 g of compound 30, with a yield of 68%, and ESI-MS (+): m/z = 187.0.

Synthesis of compound 31

Compound 31 was synthesized according to the synthetic method in the literature (Journal of Medicinal Chemistry, 2020, vol. 63, #24, p. 15785–15801).

Compound 30 was dissolved in water at 0°C, and tetrabutylammonium hydrogen sulfate and sodium bicarbonate were added. After reacting for 15 minutes, a DCM solution of chloromethyl chlorosulfonate was added to the system. The system was reacted at 25°C for 18 hours. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. 0.6 g of compound 31 was obtained by column chromatography with a yield of 16%.

Synthesis of compound B-5

Referring to the synthesis of compound B-1, 160 mg of compound B-5 was obtained with a yield of 54%. ESI-MS (+): m/z = 699.0.

Example 8: Synthesis of B-6, L-1 and L-2

Synthesis of compound B-6

Under nitrogen protection, 100 mg of compound M02 and 10 mL of dry acetonitrile were added to the reaction flask, stirred and dissolved, cooled to -25°C, 60 mg of dry carbon tetrachloride, 52 mg of diisopropylethylamine and 2.5 mg of 4-dimethylaminopyridine were added in sequence, and a mixed solution of 58 mg of dibenzyl phosphite and 5 ml of dry acetonitrile was slowly added dropwise, and the temperature was controlled below -10°C. After the dropwise addition, the reaction was continued for 3.5 h, and the temperature was naturally raised to 20-25°C. 0.5 mol/L of potassium dihydrogen phosphate was added to terminate the reaction, and the reaction was extracted with ethyl acetate. The organic layers were combined, washed with distilled water and brine in sequence, and the organic phase was concentrated to dryness. 97.35 mg of compound B-6 was obtained by column chromatography with a yield of 64%. ESI-MS (+): m/z = 761.1.

Synthesis of compounds L-1 and L-2

40 mg of compound B-6, 16 mg of sodium iodide and 2 ml of anhydrous acetonitrile were added to the reaction flask, and the system was heated to 82°C for 3 hours. Solid precipitated and the system was filtered to obtain 30 mg of solid compound L-1 with a yield of 85%, ESI-MS (-): m/z = 669.1. Compound L-1 was dissolved in water, and an acidic ion exchange resin was added. After stirring for 10 minutes and filtering, it was concentrated to dryness to obtain compound L-2, ESI-MS (-): m/z = 669.1.

Example 9: Synthesis of B-7

70 mg of compound M02, 91.34 mg of Cs ₂ CO ₃ , 28 mg of KI, 224 mg of dibenzyl chloromethyl phosphate and 2 mL of DMA were added to a single-mouth bottle. The system was heated to 50°C and reacted for 2.5 hours. The reaction was completed. The reaction system was cooled to room temperature, extracted with EA and water, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 68.6 mg of solid compound B-7, with a yield of 62%. ESI-MS (+): m/z = 791.2

Example 10: Synthesis of L-3

Add 70 mg of compound M02, 91.34 mg of Cs ₂ CO ₃ , 28 mg of KI, 224 mg of dibenzyl chloromethyl phosphate and 2 mL of DMA to a single-mouth bottle. Heat the system to 50°C and react for 2.5 hours until the reaction is complete. Add 1 ml of methanol to the reaction system and stir for 10 minutes. Evaporate the methanol and DMA reaction solution, and perform c18 column chromatography to obtain 60 mg of monobenzyl ester compound L-3, with a yield of 50%. ESI-MS (-): m/z = 699.1

Example 11: Synthesis of L-3

Compound L-5-0 was synthesized according to the method of patent (CN110300753B) and obtained by chiral column preparation and separation. Referring to the synthesis method of compound L-3, compound L-5 was obtained, ESI-MS (-): m/z = 651.1.

Comparative Example 1: Synthesis of DB-1

Referring to the synthesis method of compound M19, compound DB-1 was synthesized in one step using L-5-0 as the raw material. The optical rotation of DB-1 was tested and compared with that of M19, confirming that DB-1 was levorotatory, S configuration.

The following example compounds were synthesized by the same method as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds or other intermediates synthesized in the present invention as materials:

or a hydrate, solvate, optical isomer, polymorph, isotope derivative, or pharmaceutically acceptable salt thereof.

Example 12: Solubility test in water

The solubility of the compound of the present invention in water was tested according to the solubility determination method in the 2020 edition of the Chinese Pharmacopoeia: 0.1000 g of the test sample ground into fine powder was weighed, added to a certain amount of water at 25°C ± 2°C, and vigorously shaken for 30 seconds every 5 minutes. The dissolution within 30 minutes was observed. If no solute particles were visible, it was considered to be completely dissolved. The results are shown in Table 1:

Table 1: Solubility test results

Compound	Dissolution	Compound	Dissolution	Compound	Dissolution
B-1	Slightly soluble	B-3	Slightly soluble	B-5	Slightly soluble
L-1	Dissolve	L-2	Dissolve	L-3	Dissolve
L-4	Dissolve	L-5	Dissolve	L-7	Dissolve
L-8	Dissolve	M-19 **	Almost insoluble	DB-1 *	Almost insoluble

**Compound M-19 was used as a comparative example compound;

*Compound DB-1 is compound 45 in patent CN 110300753 B, used as a comparative compound;

The test results show that the comparative compound is almost insoluble, while the solubility of the compound of the present invention is significantly improved, especially the water solubility of compounds L-1 to L-8 is better. Solubility is a key factor affecting the utilization of drugs, and the improvement of solubility is more conducive to the dissolution of drug molecules in the gastrointestinal tract; at the same time, due to the significant improvement of solubility, it is suitable for the development of true solution preparations.

Example 13: Stability Study

Preparation of simulated gastric fluid: Accurately measure 4.5 ml of 36% hydrochloric acid into a 1L volumetric flask, add water to the mark, shake well for later use, and mark as stock solution. Accurately measure 10 ml of the stock solution into a 50 ml volumetric flask, then accurately weigh 500.0 mg of pepsin into the volumetric flask, add water to the mark, sonicate until dissolved, filter to obtain a clear solution, and mark as simulated gastric fluid.

Weigh 1.0 mg of sample into a 5 ml volumetric flask, add 2.5 ml of isopropanol to the flask, shake to dissolve, and then add simulated gastric fluid (pH 2.0) to the mark. Shake well, filter and use for stability study of simulated gastric fluid.

Weigh 1.0 mg of sample accurately into a 5 ml volumetric flask, add 2.5 ml of isopropanol to the flask, shake to dissolve, and then add water to the mark. Shake well, filter and use for solution stability test.

After the samples were sealed and protected from light, they were placed at 25°C ± 2°C for 6 hours. The solution stability and the stability in simulated gastric fluid were tested by HPLC. The results are shown in Table 2:

Table 2: Solution stability of samples and stability in simulated gastric fluid

The results show that the compound of the present invention has good stability in solution and in simulated gastric fluid, and can meet the requirements of drug administration.

Example 14: Determination of cytopathic effect (CPE)

MDCK cells were inoculated in 96-well culture plates and cultured at 5% CO ₂ and 37°C. During the cell exponential growth phase, maintenance solutions containing samples of different dilutions and positive control drugs were added, with 3 replicates for each concentration, and normal cell control wells were set at the same time. After adding the sample, the cells were cultured for 72 hours, and the cytotoxicity test of the samples was performed by the CPE method. MDCK cells were inoculated in 96-well culture plates and cultured at 5% CO ₂ and 37°C. After 24 hours, influenza virus (A/Hanfang/359/95 (H3N2)) was infected, adsorbed for 2 hours, the virus solution was discarded, and maintenance solutions containing samples of different dilutions and positive control drugs were added, with 3 replicates for each concentration, and cell control wells and virus control wells were set at the same time, 5% CO ₂ , 37°C. The antiviral test of the test samples was performed by the CPE method, and the cytopathic degree (CPE) of each group was observed when the cytopathic degree (CPE) of the virus control group reached 4+. The Reed-Muench method was used to calculate the half toxic concentration (TC ₅₀ ) of the sample to cells and the effective concentration (EC ₅₀ ) of the drug that inhibited 50% of the cytopathic effect. The therapeutic index (TI) was calculated as TC ₅₀ /EC ₅₀ .

Table 3: Anti-influenza virus cellular activity/toxicity data

The experiments show that the compounds of the present invention have good safety and anti-influenza virus activity. Compared with the positive controls baloxavir and baloxavir disoproxil, the compounds of the present invention have better anti-influenza virus cell activity.

Example 15: Oral pharmacokinetic study in rats

12 SD rats, male, 180g-220g, before the experiment, the SD rats were cannulated in the jugular vein, and the experiment was started after three days of adaptation (free access to food and water, room temperature: 20-26℃; humidity: 40-70%; light illumination: dark = 12h: 12h). The experimental animals were divided into 4 groups A/B/C/D, with 3 rats in each group. Each group was given a suspension of the test article by oral gavage (the test articles were B-3, L-3, M19 and DB-1, all suspended with 0.5% sodium carboxymethyl cellulose), the dosage was 2.25mg/kg based on M19, and each group was given equimolar administration. Fasting but not water was started at 5 pm the day before administration, and fasting for 16-17h. The animals were fed 4h after administration, and water was not allowed during the whole process.

Before administration and 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, and 24h after administration. About 0.25mL of whole blood was collected from the jugular vein in a sodium heparin anticoagulant tube. After blood collection, the anticoagulant tube containing the blood sample was immediately inverted 5 to 10 times and temporarily stored in an ice bath. Within 1 hour after blood sample collection, centrifuge at 3000rpm for 5 minutes at 4°C. The plasma collected by centrifugation was transferred to a new labeled centrifuge tube and temporarily stored in a -20°C refrigerator. After all samples were collected, they were handed over to the biological sample manager and stored in a -80°C refrigerator. After processing, the biological samples were tested by LC-MS/MS for the analyte (the analyte for the B-3, L-3 and M19 groups was M02, and the analyte for the DB-1 group was L-5-0). WinNonlin 7.0 was used to calculate the main pharmacokinetic parameters according to the non-compartmental model method. The main pharmacokinetic parameters of each group of samples after oral administration are shown in Table 4:

Table 4: Main pharmacokinetic parameters in rats after equimolar oral administration of the test article

parameter	T1/2	Tmax	Cmax	AUC 0-∞
unit	h	h	ng/ml	h*ng/ml
B-3	3.89	1	38.8	347.236
L-3	4.13	0.5	43.1	373.641
M19	4.33	1	34.5	289.914
DB-1	4.73	0.5	20.3	212.359

The results of the pharmacokinetic study of oral administration to rats showed that: compared with M19 and DB-1, the in vivo exposure (AUC) of the compound of the present invention was significantly increased after oral administration to rats, which indicates that the compound of the present invention has a higher bioavailability.

Example 16: Pharmacokinetic study in cynomolgus monkeys

Twelve male cynomolgus monkeys, 3-6 kg, were randomly divided into 4 groups (A/B/C/D groups) after 3 days of adaptive feeding. Group A was intravenously injected with 0.2 mg/kg of saline solution of compound L-2, and group B was orally gavaged with 2 mg/kg of saline solution of compound L-2; group C was intravenously injected with 0.2 mg/kg of saline solution of compound L-4, and group D was orally gavaged with 2 mg/kg of saline solution of compound L-4; during the experiment, animals in the intravenous injection group were free to eat and drink, and animals in the oral gavage group were fasted for more than 12 hours before administration but were not forbidden to drink.

For the intravenous administration group, about 0.5 mL of whole blood was collected from the jugular vein before and after administration at 0.033, 0.083, 0.17, 0.25, 0.5, 1, 2, 4, 8, and 24 h, respectively; for the oral gavage administration group, about 0.5 mL of whole blood was collected from the jugular vein before and after administration at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, respectively; the whole blood samples were placed in sodium heparin anticoagulant tubes, immediately inverted 5 to 10 times, and temporarily stored in an ice bath. Within 1 hour after blood sample collection, centrifuge at 3000 rpm for 5 minutes at 4 ° C. The plasma collected by centrifugation was transferred to a new labeled centrifuge tube and temporarily stored in a -20 ° C refrigerator. After all samples were collected, they were handed over to the biological sample manager and stored in a -80 ° C refrigerator. After processing, the biological samples were detected by LC-MS/MS for compound M02. WinNonlin 7.0 was used to calculate the main pharmacokinetic parameters and bioavailability according to the non-compartmental model method. The results are shown in Table 5:

Table 5: Pharmacokinetic parameters of cynomolgus monkeys

parameter	T1/2	Tmax	Cmax	AUC 0-∞	F
unit	h	h	ng/ml	h*ng/ml	%
L-2(IV) Group	11.55h	/	/	174	/
L-2(PO) group	11.13	2.0	101	955	54.88%
L-4(IV) group	11.08h	/	/	156	/
L-4(PO) group	10.87	2.0	93	891	57.11%

As can be seen from the table above, when the cynomolgus monkeys were orally and injected, the compounds L-2 and L-4 of the present invention had good in vivo exposure, and the absolute bioavailability reached 54.88% and 57.11%, respectively. This shows that the compounds of the present invention can meet the requirements of injection and oral administration at the same time, and have a high oral bioavailability.

The present application describes multiple embodiments, but the description is exemplary rather than restrictive, and there may be more embodiments and implementations within the scope of the embodiments described in the present application.

Claims (11)

1. A phosphate compound, as shown in formula (I), or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt:

   

   In formula (I), R _a is selected from hydrogen, deuterium or methyl;

   R _b and R _c are each independently selected from hydrogen, deuterium or methyl, or R _b and R _c together with the carbon to which they are attached form a cyclopropyl group;

   _X1 is an O atom or a S atom;

   _X2 is a Se atom or a S atom;

   n1 is 0, 1 or 2;

   Each R ₁ or R ₂ is independently selected from hydrogen or methyl;

   _R3 and _R4 are each independently selected from the following groups: hydroxyl, C1-C8 alkoxy, C3-C8 cycloalkoxy, C3-C8 heterocycloalkoxy, C6-C10 aryloxy, C7-C12 aralkyloxy, and when _X2 is an S atom, _R3 and _R4 cannot be C1-C8 alkoxy at the same time; or _R3 and _R4 together with the phosphorus atom to which they are connected form the following

   

   wherein R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen or C1-C3 alkyl, or R ₅ and R ₆ , R ₇ and R ₈ , R ₁₀ and R ₁₁ , R ₁₁ and R ₁₂ each together with the carbon atom to which they are connected form an aromatic ring.
2. The phosphate compound according to claim 1, as shown in formula (II):

   

   The substituents in formula (II) are as defined in claim 1.
3. The phosphate compound according to claim 1 or 2, as shown in formula (III):

   

   The substituents in formula (III) are as defined in claim 1.
4. The phosphate compound according to any one of claims 1 or 2, as shown in formula (IV):

   

   The substituents in formula (IV) are as defined in claim 1.
5. The sodium salt, potassium salt, magnesium salt, zinc salt, amine salt, or basic amino acid salt of the phosphate compound as claimed in claim 3.
6. The phosphate compound according to any one of claims 1 to 5, selected from the following structures:

   

   or a hydrate, solvate, optical isomer, polymorph, isotope derivative, or pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or its hydrate, solvate, optical isomer, polymorph, isotope derivative, pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition is tablets, capsules, powders, granules, pills, suspensions, syrups, or injections.
9. The compound according to any one of claims 1 to 6, including its hydrates, solvates, optical isomers, polymorphs, isotope derivatives, pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 7, for use against influenza virus.
10. Use of the compound according to any one of claims 1 to 6, including its hydrates, solvates, optical isomers, polymorphs, isotope derivatives, pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 7 in the preparation of an anti-influenza virus drug.
11. A method for preventing or treating influenza virus infection, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 6, including its hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 7.