Acylethyl ester polycyclic compounds and their pharmaceutical compositions, use

Abstract

The present invention relates to acylethyl ester polycyclic compounds and their pharmaceutical compositions, and their use. The acylethyl ester polycyclic compound is represented by formula I, where X is S or Se, and the compound has a prophylactic or therapeutic effect on individuals infected with a virus. TIFF2026509827000025.tif63147

Description

[Technical Field]

[0001] This application claims priority to a Chinese invention patent application filed on April 14, 2023, titled "Acylethyl ester polycyclic compounds and their pharmaceutical compositions, and use," with application number 202310402118.6, the contents of which are incorporated in their entirety by reference.

[0002] The present invention belongs to the field of pharmaceutical technology, but is not limited thereto. Specifically, it concerns acyl ethyl ester polycyclic compounds, their pharmaceutical compositions, and their uses. [Background technology]

[0003] Influenza, abbreviated as "flu," is an acute respiratory infection caused by the influenza virus. The influenza virus is the pathogen that causes influenza, belongs to the Orthomyxoviridae family, and is an RNA virus. Currently known small molecule anti-influenza virus drugs include oseltamivir, a neuraminidase inhibitor; baloxavir marboxil, a viral polymerase inhibitor; and amantadine, an M2 ion channel inhibitor. Shionogi & Co., Ltd. disclosed baloxavir, baloxavir marboxil, and compound II-5 in Chinese patent ZL201680037827.7. [ka] TIFF2026509827000003.tif59130 Baloxavir marboxil is a prodrug of baloxavir, which, after metabolism, possesses anti-influenza virus activity. In Chinese patent application (application number) CN201910030450.8, Ms. Zhao Lei disclosed deuterated baloxavir marboxyl compounds (e.g., I-20 compounds) and disclosed data on the anti-influenza virus activity of some of the compounds. Although various prodrug compounds of baroxavir are disclosed in the literature, there is still a need in this field for antiviral drugs with high bioavailability, long half-life, and high blood concentration.

Summary of the Invention

[0004] This application provides an acylethyl ester polycyclic compound and its pharmaceutical composition, which have preventive and therapeutic activities against influenza virus.

[0005] In one aspect, this application provides an acylethyl ester polycyclic compound, and the acylethyl ester polycyclic compound is a compound of formula (I)

Chemical formula

[0006] In some embodiments, the compound of formula (I) is a compound of formula (I-1),

Chemical formula

[0007] <0000-103>In some embodiments, the compound of formula (I) is a compound of formula (I-1-1),

Chemical formula

[0008] In some embodiments, the compound of formula (I) is a compound of formula (I-1-2),

Chemical formula

[0009] In some embodiments, in the compounds of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2), X is S.

[0010] In some embodiments, in the compounds of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2), X is Se.

[0011] In embodiments of the present invention, the compound of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2) is optionally in the form of a pharmaceutically acceptable salt, where "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt.

[0012] The aforementioned "pharmaceutically acceptable acid addition salts" refer to salts formed from inorganic or organic acids. Inorganic acid salts include, but are not limited to, hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, etc. Organic acid salts include, but are not limited to, formate salts, acetate salts, propionate salts, glycolate salts, gluconate salts, lactate salts, oxalate salts, maleate salts, succinate salts, fumarate salts, tartrate salts, citrate salts, glutamate salts, aspartate salts, benzoate salts, methanesulfonate salts, p-toluenesulfonate salts, and salicylate salts, etc.

[0013] In embodiments of the present invention, the compounds of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2) may be in the form of solvates, where "solvate" refers to a formulation formed from the compound of the present invention and a solvent. These react in the solvent, or precipitate or crystallize from the solvent. For example, one formulation formed with water is called a "hydrate."

[0014] In embodiments of the present invention, the compounds of the present invention contain one or more chiral centers and may exist in different optically active forms. When a compound contains one chiral center, the compound includes enantiomers. The present invention includes these two enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compounds of the present invention contain more than one chiral center, diastereomers may exist. The present invention includes mixtures of specific isomers and diastereomers of resolved optical purity. Diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.

[0015] In embodiments of the present invention, the compounds of formula (I), formula (I-1), formula (I-1-1) or formula (I-1-2) may be isotope-labeled, and the isotopes include atoms having the same atomic number but different mass numbers. Examples of isotopes that can be added to the compounds described in the present invention and their pharmaceutically acceptable salts are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. The present invention further includes labeling methods for the production of such isotope labels, and uses for metabolic pharmacokinetic studies of isotope-labeled substances and / or uses as diagnostic tools.

[0016] In some embodiments, the compounds of formula (I), formula (I-1), formula (I-1-1) or formula (I-1-2) according to the present invention are selected from the following compounds or their pharmaceutically acceptable salts, solvates or isotope labels.

Chemical formula

[0017] In other embodiments, the present invention provides pharmaceutical compositions containing compounds of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2), stereoisomers thereof, pharmaceutically acceptable salts, solvates, or isotope-labeled compounds. In embodiments of the present invention, the compounds described in the present invention are present in therapeutically effective amounts in the pharmaceutical compositions.

[0018] In some embodiments, the pharmaceutical composition includes conventionally pharmaceutically acceptable carriers, such as pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, fragrances, sweeteners, etc. The pharmaceutical composition may employ any one suitable dosage form, specifically tablets, powders, capsules, granules, oral solutions, injections, powders, suppositories, pills, creams, pastes, gels, powders, inhalants, suspensions, dry suspensions, patches, lotions, nanoformulations, etc.

[0019] In some embodiments, the pharmaceutical composition may further include one or more therapeutic agents, which may be selected from neuraminidase inhibitors, nucleoside drugs, PB2 inhibitors, PB1 inhibitors, M2 inhibitors, or other anti-influenza drugs.

[0020] In another aspect, the present invention provides for the use of compounds of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2), their stereoisomers, pharmaceutically acceptable salts, solvates, or isotope-labeled products, or pharmaceutical compositions in the prevention and / or treatment of viral infections, wherein the viral infection is an influenza virus infection, for example, an influenza A virus or an influenza B virus infection.

[0021] In a further embodiment, the present invention provides applications of compounds of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2), their stereoisomers, pharmaceutically acceptable salts, solvates, or isotope-labeled products, or the pharmaceutical compositions, in the manufacture of drugs for the prevention and / or treatment of viral infections, wherein the viral infection is selectively an infection caused by an influenza virus, such as an influenza A virus or an influenza B virus.

[0022] In a further embodiment, the present invention provides a method for preventing and / or treating a viral infection, the method comprising administering to an individual having a need for the corresponding compound of formula (I), formula (I-1), formula (I-1-1), or formula (I-1-2), its stereoisomer, a pharmaceutically acceptable salt, solvate, or isotope-labeled product, or the pharmaceutical composition, wherein the viral infection is selectively an influenza virus infection, such as an influenza A virus or an influenza B virus infection. [Brief explanation of the drawing]

[0023] [Figure 1] This is the LC-MS mass spectrum of the compound of formula (I-1-1-1) in Example 2. [Figure 2] This is the LC-MS mass spectrum of the compound of formula (I-1-1-2) in Example 2. [Figure 3] This is the LC-MS mass spectrum of the compound of formula (I-20) in Comparative Example 1. [Figure 4] This is the LC-MS mass spectrum of the compound of formula (II-5) in Comparative Example 2. [Figure 5] This is the LC-MS mass spectrum of the compound of formula (I-1-1-6) in Example 3. [Figure 6] This is the single-crystal diffraction pattern of the compound of formula (I-1-1-1) in Example 2. [Figure 7] This shows the percentage change in body weight of mice after administration of the drug in each group. [Figure 8] This shows the survival rate of mice after administration of the drug in each group. [Figure 9] This is a drug-drug time curve after single oral administration of different drugs via a gastric tube to SD rats. [Figure 10] This is a drug-time curve after single oral administration of different drugs via a gastric tube to cynomolgus monkeys. [Modes for carrying out the invention]

[0024] The present invention will be further described below with reference to examples. For those skilled in the art, according to the teachings of the present invention, equivalent alternative improvements to the following examples using the prior art are still within the scope of the protection of the present invention.

[0025] Abbreviation ESI Electrospray T max Peak time C max maximum blood concentration AUC 0-t Area under the blood concentration-time (0-t) curve AUC 0-∞ Area under the blood concentration-time (0-∞) curve t 1 / 2 Half-life DMSO (Dimethyl Sulfoxide) TMS Tetramethylsilane NBS N-bromosuccinimide AIBN Azobisisobutyronitrile TsOH p-toluenesulfonic acid MsOH Methanesulfonic acid

[0026] device In the embodiments of the present invention, the mass spectrometer is an Agilent 6120 liquid chromatograph mass spectrometer. Column: KROMASIL-C18 (250 x 4.6 mm, 5 μm) Mobile phase: 0.1% formate-acetonitrile (60:40) UV detection wavelength: 254nm Flow rate: 1.0ml / min Mass Spectrum: ESI The nuclear magnetic resonance spectrometer is a Varian INOVA-400. Solvent: DMSO-d6; Internal standard: TMS Single-crystal diffractometer: Nonius CAD4 single-crystal X-ray diffraction surface detector Temperature: 20℃ Characteristics and state of the detected sample: Granules

[0027] Example 1 500 mg of baloxavir, 180 mg of 1-bromoethyl acetate, 210 mg of potassium carbonate, and 8 ml of dichloromethane were added to a reaction flask and reacted at 25°C for 12 hours. The mixture was filtered, the filtrate was concentrated, and the solution was passed through a column with ethyl acetate / n-hexane (3 / 1) to obtain 512 mg of the pale yellow solid "compound I-1-1-3" with a yield of 87%. ESI:[M+H] + 570.2. 1 HNMR (400 MHz, DMSO-d6) δ 7.76-7.63 (m, 0.5H), 7.40 (dd, J = 14.6, 5.8 Hz, 1.5H), 7.23-7.05 (m,3H), 6.99 (dd, J = 16.9, 7.7 Hz, 1H), 6.86 (q, J = 7.8 Hz, 1H), 6.50 (q, J = 5.2 Hz, 0.5H), 6.29 (q, J = 5.3Hz, 0.5H), 5.71 (q, J = 7.3 Hz, 1.5H), 5.54 (s, 0.5H), 5.46-5.36 (m, 1H), 4.46-4.37 (m, 1.5H), 4.23 (t, J = 6.5Hz, 0.5H), 4.04 (t, J = 13.4 Hz, 1.5H), 3.97 (dd, J = 10.6, 3.0 Hz, 0.5H), 3.73-3.62 (m, 1H), 3.47 (t, J = 10.3Hz, 0.5H), 3.31-3.22 (m, 1.5H), 2.93 (q, J = 11.3, 9.1 Hz, 1H), 2.07 (s, 1.5H), 1.94 (s, 1.5H), 1.63 (dd, J = 19.6,5.3 Hz, 3H).

[0028] Example 2 [ka] 500 mg of "Compound I-1-1-3" was taken, dissolved in 3 ml of dichloromethane, and stirred with 1.5 g of silica gel. 20 g of silica gel was packed into a chromatography column using ethyl acetate / n-hexane (1 / 1), and the mixture was eluted with ethyl acetate / n-hexane (1 / 1) and passed through the column. 165 mg of "Compound I-1-1-1" and 252 mg of "Compound I-1-1-2" were obtained as pale yellow solids.

[0029] "Compound I-1-1-1": ESI:[M+H] + 570.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.36 (m, 2H), 7.16 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 6.50 (q, J = 5.2 Hz, 1H), 5.70 (d, J = 7.7 Hz, 1H), 5.54 (s, 1H), 5.46 - 5.37 (m, 1H), 4.46 - 4.38 (m, 2H), 4.06 (d, J = 14.4 Hz, 1H), 3.97 (dd, J = 10.9, 3.1 Hz, 1H), 3.66 (dd, J = 11.8, 3.2 Hz, 1H), 3.47 (t, J = 10.3 Hz, 1H), 3.30 - 3.25 (m, 1H), 3.00 - 2.88 (m, 1H), 2.06 (s, 3H), 1.61 (d, J = 5.3 Hz, 3H). The single-crystal diffraction pattern of compound I-1-1-1 is shown in Figure 6. Cu-Ka radiation, wavelength = 1.54178 Å detected. Single-crystal X-ray diffraction data analysis revealed that the molecular formula of the sample is C 28 H 25The crystal is classified as F2N3O6S, and belongs to the monoclinic system. The unit cell parameters are a=7.2738(1)Å, b=18.5103(3)Å, c=10.0095(2)Å, and the unit cell volume V=1300.94(4)Å. 3 Therefore, the density Dx = 1.454 mg / m³ 3 Z=2, F(000)=592. The molecular structure has six rings, including one 7-membered ring, three 6-membered rings, and two benzene rings, and the chiral carbon atoms in the structure match the chirality of the target substance. "Compound I-1-1-2": ESI:[M+H] + 570.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (ddd, J = 15.3, 9.4, 6.4 Hz, 2H), 7.21 - 7.12 (m, 2H), 7.12 - 7.06 (m, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.87 (t, J = 7.1 Hz, 1H), 6.29 (q, J = 5.3 Hz, 1H), 5.76 - 5.68 (m, 2H), 5.44 - 5.36 (m, 1H), 4.47 - 4.37 (m, 2H), 4.10 - 3.98 (m, 2H), 3.69 (dd, J = 11.5, 3.1 Hz, 1H), 3.35 - 3.21 (m, 2H), 2.98 - 2.86 (m, 1H), 1.93 (s, 3H), 1.66 (d, J = 5.3 Hz, 3H).

[0030] Example 3 The reaction route for compound C-1 (compound I-1-1-6) is as follows: [ka]

[0031] Example 3-1 20 g of C-1-0, 60 mL of N,N-dimethylacetamide, 22 g of dimethyl sulfuric acid, and 18 g of sodium bicarbonate were sequentially added to a reaction flask. The mixture was heated to 40-50°C and reacted for 4 hours. After cooling to room temperature, 180 ml of water was slowly added dropwise. After the addition was complete, crystals were precipitated at room temperature for 3 hours. The mixture was filtered, and the filter cake was vacuum-dried to obtain 19.1 g of white solid C-1-1, with a yield of 88.7%.

[0032] Example 3-2 7 g of C-1-1, 6.65 g of N-bromosuccinimide (NBS), 0.77 g of azobisisobutyronitrile (AIBN), and 70 mL of chloroform were sequentially added to a reaction flask. The temperature was raised to 60-70°C and the reaction was carried out for 4 hours. The temperature was then lowered to room temperature, and the mixture was filtered by suction. 10 mL of 10% sodium sulfite aqueous solution was added to the filtrate, and the mixture was separated. The aqueous phase was extracted three times with 100 mL of dichloromethane, and the mixture was separated again to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness, yielding 8.67 g of oily substance C-1-2. The yield was 87.0%.

[0033] Example 3-3 45 mL of water, 30.5 g of sodium dihydrogen phosphate, 3 g of diphenyl diselenide, and 2.2 g of zinc powder were sequentially added to a reaction flask and stirred at room temperature for 1 hour. 4.48 g of C-1-2 was added and the mixture was reacted overnight at room temperature. The mixture was filtered by suction, and the filtrate was extracted twice with 100 mL of ethyl acetate. The filtrate was separated, the organic phase was dried over anhydrous sodium sulfate for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 5.44 g of oily substance C-1-3. The yield was 94.4%.

[0034] Examples 3-4 19.15 g of C-1-3, 140 mL of methanol, 7.5 g of sodium hydroxide, and 70 mL of water were sequentially added to a reaction flask. The temperature was raised to 60-70°C and the mixture was reacted for 2 hours. The mixture was filtered by suction, the filter cake was washed twice with 60 mL of water, the filtrate was adjusted to pH 7 with 1N hydrochloric acid, 300 mL of ethyl acetate was added and extracted three times, the mixture was separated, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 12.46 g of solid C-1-4. The yield was 67.9%.

[0035] Examples 3-5 4.7 g of C-1-4 and 98.7 g of polyphosphate were sequentially added to a reaction flask, the temperature was raised to 120°C and the reaction was carried out for 3 hours, then cooled to room temperature, the reaction solution was poured into 200 mL of water, extracted three times with 120 mL of dichloromethane, separated, the organic phases were combined, 6.8 g of activated carbon was added to the organic phase to decolorize it, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 2.84 g of oily substance C-1-5, with a yield of 63.9%.

[0036] Examples 3-6 2.84 g of C-1-5 and 56.8 g of methanol were sequentially added to a reaction flask, and 1.35 g of sodium borohydride was added in several batches. The mixture was allowed to react overnight at room temperature. The pH of the reaction solution was adjusted to 7 with 1N hydrochloric acid. The mixture was extracted twice with 80 mL of dichloromethane, separated, and the organic phases were combined. The organic phase was washed with 40 mL of saturated brine, separated, and 2 g of anhydrous sodium sulfate was added to the organic phase. The mixture was dried for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 2.36 g of solid C-1-6. The yield was 82.6%.

[0037] Examples 3-7 5 mL of ethyl acetate, 5 mL of cyclohexane, 1.88 g of C-1-7, and 1.76 g of C-1-6 were sequentially added to a reaction flask and stirred for 30 minutes. 4.68 g of 1-n-propyl phosphoric acid anhydride and 0.71 g of methanesulfonic acid were added, the temperature was raised to 60-70°C, and the reaction was maintained for 24 hours. The reaction mixture was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with 5 mL of ethyl acetate. The organic phase was dried over 2 g of anhydrous sodium sulfate for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to dryness. The concentrate was dissolved in 5 mL of ethyl acetate and 4 mL of cyclohexane, and 0.55 g of methanesulfonic acid was added dropwise. After the addition was complete, the temperature was controlled to 0-10°C and stirred for 2 hours to precipitate crystals. The mixture was filtered, and the filter cake was vacuum dried to obtain 1.58 g of white solid C-1-8. The yield was 58.4%.

[0038] Examples 3-8 1.58 g of C-1-8, 0.61 g of lithium chloride, and 5 mL of N-methylpyrrolidone were sequentially added to a reaction flask, and the mixture was stirred to raise the temperature to 75-80°C. 0.08 g of methanesulfonic acid was added, and the mixture was incubated for 17 hours to allow the reaction to proceed. The temperature was then lowered to 20-30°C, incubated, and 10 mL of water was added dropwise. After the addition was complete, the temperature was lowered to 5-10°C, incubated for 2 hours, stirred, filtered, and the filter cake was vacuum-dried to obtain 0.84 g of the yellowish-brown compound C-1-9, with a yield of 71.23%.

[0039] Examples 3-9 0.8 g of compound C-1-9, 0.4 g of 1-bromoethyl acetate, 0.41 g of potassium carbonate, and 16 mL of acetonitrile were sequentially added to a reaction flask. The mixture was stirred, and the temperature was controlled to 40-50°C for 5 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with dichloromethane. The resulting filtrate was passed through a column with ethyl acetate / n-hexane = 1 / 1, and the eluate was concentrated to dryness. After slurrying with 10 mL of n-hexane, the mixture was filtered to obtain 0.35 g of compound C-1 (compound I-1-1-6). ESI:[M+H] + The value is 618.05; see Figure 5. 1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.32 (m, 4H), 7.28 - 7.19 (m, 4H), 7.14 - 7.05 (m, 4H), 6.94 - 6.87 (m, 2H), 6.25- 6.50 (m, 2H), 5.85 - 5.62 (m, 3H), 5.59 (s, 1H), 5.28 (ddd, J = 12.2, 9.2, 2.5 Hz, 2H), 4.50 (dt, J = 10.0, 2.9 Hz, 2H), 4.40 (dd, J = 13.7, 3.0 Hz, 2H), 4.10 (d, J = 12.6 Hz, 2H), 4.05 - 4.01 (m, 2H), 3.71-3.64 (m, 2H), 3.51 (d, J = 10.3 Hz, 1H), 3.36 - 3.21 (m, 3H), 2.99 - 2.92 (m, 2H), 2.03 (d, 6H), 1.62 (dd, J = 5.3Hz, 6H)

[0040] Comparative Example 1 [ka] 5 mL of phosphorus tribromide was added to the reaction flask, cooled to 0°C, and 10 g of acetic acid-D4 was added dropwise. After the addition was complete, the temperature was raised to 45-50°C and the mixture was kept warm for 1 hour to allow the reaction to proceed. The temperature was then raised to 75-80°C and distillation was performed at atmospheric pressure to obtain 12.53 g of oily deuterated acetyl bromide, with a yield of 63.74%. 12.5 g of deuterated acetyl bromide and 0.01 g of zinc chloride were sequentially added to a reaction flask. The temperature was lowered to -15 to -10°C, and 4.36 g of paraaldehyde was added dropwise while controlling the temperature. After the addition was complete, the temperature was raised to 0 to 10°C and the reaction was allowed to proceed for 5 hours. 80 mL of water was added dropwise, and after the addition was complete, 50 mL of dichloromethane was added for extraction. The mixture was then separated, the organic phase was washed with 80 mL of water, separated again, 2 g of anhydrous sodium sulfate was added to the organic phase, and it was dried for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure at a controlled temperature of 20 to 30°C to obtain 10.45 g of the oily substance 1-bromoethyl deuterated acetate. The yield was 61.47%. 1.5 g of baloxavir, 0.85 g of 1-bromoethyl deuterate, 0.86 g of potassium carbonate, and 30 mL of acetonitrile were sequentially added to a reaction flask. The mixture was stirred, and the temperature was controlled to 40-50°C for 15 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with dichloromethane. The resulting filtrate was passed through a column with ethyl acetate / n-hexane = 1 / 1. The eluate was concentrated to dryness, then slurryed with 30 mL of n-hexane, filtered, and 1.2 g of compound I-20 was obtained. ESI:[M+H] + The value is 573.2; see Figure 3. 1 H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.37 (m, 4H), 7.18 - 7.08 (m, 6H), 7.00 (ddd, J = 15.3, 7.8, 1.5 Hz, 2H), 6.86 (dtd, J = 10.3, 7.2, 1.4 Hz, 2H), 6.50 (q, J = 5.2 Hz, 1H), 6.28 (q, J = 5.2 Hz, 1H), 5.74 - 5.69 (m, 3H), 5.54 (s, 1H), 5.41 (ddd, J = 14.6, 7.4, 2.4 Hz, 2H), 4.42 (ddt, J = 12.0, 6.4, 2.7 Hz, 4H), 4.08 - 3.95 (m, 4H), 3.68 (ddd, J = 14.3, 11.5, 3.2 Hz, 2H), 3.47 (t, J = 10.3 Hz, 1H), 3.30 - 3.22 (m, 3H), 2.98 - 2.89 (m, 2H), 1.63 (dd, J = 20.1, 5.3 Hz, 6H).

[0041] Comparative Example 2 [ka] 1.5 g of baloxavir, 0.77 g of bromomethyl acetate, 0.86 g of potassium carbonate, and 30 mL of acetonitrile were sequentially added to a reaction flask. The mixture was stirred, and the temperature was controlled to 40-50°C for 10 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with dichloromethane. The resulting filtrate was passed through a column with ethyl acetate / n-hexane = 1 / 1. The eluate was concentrated to dryness, then slurryed with 30 mL of n-hexane, filtered, and 1.1 g of compound II-5 was obtained. ESI:[M+H] + The value is 556.2; see Figure 4. 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.40(m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.16 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.09 (dd, J = 8.0, 1.4 Hz, 1H), 7.01 (dd, J = 7.9, 1.5 Hz, 1H), 6.86 (td, J = 7.4, 1.4 Hz, 1H), 5.74 - 5.65 (m, 4H), 5.43 (dd, J = 14.3, 2.4 Hz, 1H), 4.43 (td, J = 11.2, 10.6, 2.7Hz, 2H), 4.06 (d, J = 14.4 Hz, 1H), 3.99 (dd, J = 10.8, 3.1 Hz, 1H), 3.68 (dd, J = 11.5, 3.2 Hz, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.32-3.26(m, 1H), 2.94 (ddd, J = 14.6, 11.7, 3.4 Hz, 1H), 2.04 (s, 3H).

[0042] In vitro and in vivo testing of anti-influenza virus activity 1. In vitro anti-influenza virus activity Good quality MDCK cells in the logarithmic growth phase were inoculated into 96-well plates at a rate of 2.5 × 10⁴ cells / well. Excluding the normal control group, 100 TCID50 infectious doses of H1N1 influenza A virus strain A / FM / 1 / 47 were added to each of the other wells. The incubators were then incubated in a constant temperature CO₂ incubator for 1 hour. Subsequently, sequentially diluted compounds I-1-1-1, I-1-1-2, I-1-1-3, I-1-1-6, I-20, II-5, and baloxavir marboxil were added. The drug-treated cell culture plates were incubated at 35°C for 72 hours. The viral replication inhibitory effect of the test drugs was determined based on the virus detection results in the supernatant. Finally, the viral replication inhibitory effect of the drugs was evaluated using the Reed-Muench method. 50 The result was calculated. The results showed that compounds I-1-1-6, II-5, I-20, I-1-1-1, I-1-1-2, I-1-1-3, and baloxavir marboxil inhibited H1N1 (FM1) influenza virus replication in vitro. 50 The concentrations (μg / mL) were 0.32, 0.32, 0.32, 0.32, 0.032, 0.32, and 0.32, respectively. Of these, compound I-1-1-2 showed strong inhibitory activity against H1N1 influenza virus replication.

[0043] 2. In vivo anti-influenza virus activity Female SPF-grade ICR mice weighing 19-21g were randomly divided into five groups of 10 mice each. Each group consisted of a blank solvent group, compound I-1-1-2 (1 mg / kg in the low-dose group and 5 mg / kg in the high-dose group), and baloxavir marboxil (1 mg / kg in the low-dose group and 5 mg / kg in the high-dose group). An appropriate amount of FM1 mouse lung-acclimatized H1N1 influenza A virus strain (A / FM / 1 / 47) was aspirated using a pipette and administered intranasally. Administration began 2 hours after infection and was given twice daily for 6 days. The blank solvent was an aqueous solution of 1% DMSO / 4% PEG300 / 2% Tween 80 (v / v). During the trial period, the animals' condition was observed daily, and the percentage change in mouse weight and the number of deaths were recorded. The observation period was a total of 15 days, and the survival rate was calculated. Survival rate (%) = Number of animals surviving at the end of the trial / Number of animals participating in the trial × 100%. The results of the study showed that (1) the high-dose group of 5 mg / kg of the compound of formula I-1-1-2 and the high-dose group of 5 mg / kg of baloxavir marboxil had a significant protective effect against lethal infection by H1N1 mouse lung acclimatized strains, and all mice survived throughout the study, with no significant difference in body weight change between the two groups. (2) Compared to the low-dose group of 1 mg / kg of baloxavir marboxil, the low-dose group of 1 mg / kg of the compound of formula I-1-1-2 showed a higher mouse survival rate and less weight loss in the mice, demonstrating superior protective effect. The results are shown in Figures 7 and 8.

[0044] Biology Test 1 - Rat PK Study 1. Research Objectives SD rats were administered a single oral dose of different drugs via a gastric tube, including compounds I-1-1-2, I-1-1-3, I-1-1-6, I-20, II-5, and baloxavir marboxil. Plasma samples were collected at different time points after administration, and drug content was measured. The pharmacokinetic parameters of the different drug groups in SD rats were then calculated and compared.

[0045] 2. Information on the test substance, control substance, and other solvents and media. 2.1 Test substance 2.1.1 Name: Compound I-1-1-2 Lot number: 20230504-1 2.1.2 Name: Compound I-1-1-3 Lot number: 20231227-1 2.1.3 Name: Compound I-1-1-6 Lot number: 20240203-1 2.1.4 Name: Compound I-20 Lot number: 20231205-1 2.1.5 Name: Compound II-5 Lot number: 20231201-1 2.1.6 Name: Baloxavir marboxil Lot number: BLX-705-220505 2.2 Solvent 2.2.1 Name: Sodium Lauryl Sulfate (SDS) Lot Number: 20210426 2.2.2 Name: Ethanol

[0046] 3. Experimental System 3.1 Classification of Animals Forty-eight SD rats were selected, divided into six groups of 8 rats each, based on weight (180g-220g), with an equal number of males and females. The grouping information for the animals is as follows:

[0047] [Table 1]

[0048] 3.2 Administration and Sample Collection SD rats were randomly divided into groups. They were prohibited from eating or drinking for at least 12 hours before administration, but were allowed to drink water freely. They were prohibited from drinking water for 1 hour before to 1 hour after administration. They were fed 4 hours after administration. Each group received a single oral dose of 3.0 mg / kg via a gastric tube. Approximately 0.2 mL of blood was collected from the jugular vein of each animal group at 0h before administration and at 5min, 10min, 15min, 30min, 1, 2, 4, 6, 10, 24, and 30h after administration, and placed in EDTA-K2 anticoagulation tubes.

[0049] 3.3 Analysis of Biological Samples After whole blood collection, plasma was obtained by centrifugation at 4°C and 4000 rpm for 10 minutes. The plasma was then frozen and stored in a -80°C freezer for detection. Drug concentrations in the plasma of each group's samples were measured by LC-MS / MS. Non-compartmental model analysis was performed using Phoenix winnonlin8.0, and PK parameters were calculated. Data analysis was performed using C. max , T max AUC 0-t AUC 0-∞ t 1 / 2 This includes pharmacokinetic parameters such as those listed above.

[0050] 4. Test results 4.1 Cage-side observation No significant abnormalities were observed in any of the animals during cage-side observation after administration.

[0051] 4.2 Detection Results The main pharmacokinetic parameters after single oral administration of the same dose of each compound to SD rats via a gastric tube are shown in Table 2, and the drug-time curve is shown in Figure 9.

[0052] [Table 2]

[0053] Research results (1) After administering the same dose of each compound from each group to SD rats via a single gastric tube orally, the bioavailability of the rats in each group (C max and AUC 0-t The order of highest to lowest is: Compound I-1-1-2 > Compound I-1-1-3 > Compound I-1-1-6 > Baloxavir marboxyl > Compound I-20 > Compound II-5. (2) Compared with compound group I-20 and compound group II-5, the bioavailability of rats of compound group I-1-1-2, compound group I-1-1-3 and baloxavir marboxil (C max and AUC 0-t The results showed a significant improvement, with statistically significant differences (P<0.001, P<0.01, and P<0.05, respectively). (3) Compared to the baloxavir marboxil group, the Cmax and AUC of the bioavailability of rats in the compound I-1-1-2 group and the compound I-1-1-3 group were compared. 0-t The results showed a significant improvement and exhibited statistically significant differences (P<0.01 and P<0.05, respectively). (4) Compounds in group I-1-1-2 have the longest half-life (t 1 / 2 Next are the compounds in groups I-1-1-3, baloxavir marboxil, and I-1-1-6. These compounds demonstrate the potential to maintain their therapeutic effects for a relatively long period of time.

[0054] Biology Exam 2 - Cynomolgus Monkey PK Study 1. Research Objectives Cynomolgus monkeys were administered a single oral dose of different drugs via a gastric tube, containing compounds I-1-1-2, I-1-1-3, and baloxavir marboxil. Plasma samples were collected at different time points after administration, and drug content was measured. The pharmacokinetic parameters of the different drug groups in cynomolgus monkeys were then calculated and compared.

[0055] 2. Information on the test substance, control substance, and other solvents and media. 2.1 Test substance 2.1.1 Name: Compound I-1-1-2 Lot number: 20230504-1 2.1.2 Name: Compound I-1-1-3 Lot number: 20231227-1 2.1.3 Name: Baloxavir marboxil Lot number: BLX-705-220505 2.2 Solvent 2.2.1 Name: Sodium Lauryl Sulfate (SDS) Lot Number: 20210426 2.2.2 Name: Ethanol

[0056] 3. Experimental System 3.1 Classification of Animals Twenty-four crab-eating macaques were selected, aged 3-5 years, weighing 3-7 kg, with an equal number of males and females, and randomly divided into three groups of eight based on weight. The grouping information for the animals is as follows:

[0057] [Table 3]

[0058] 3.2 Administration and Sample Collection After randomly dividing the cynomolgus monkeys into groups, they were prohibited from eating or drinking for at least 12 hours before administration, but were allowed to drink water freely. They were prohibited from drinking water for 1 hour before administration and 1 hour after administration. They were fed 4 hours after administration. Each group received a single oral dose of 5.0 mg / kg via a gastric tube. Approximately 1.0 mL of blood was collected from the jugular vein of each animal group at 0 hours before administration and at 5 min, 10 min, 15 min, 30 min, 1, 2, 4, 6, 8, 12, 24, and 48 hours (D2) after administration, and placed in an EDTA-K2 anticoagulation tube.

[0059] 3.3 Analysis of Biological Samples After whole blood collection, plasma was obtained by centrifugation at 4°C and 4000 rpm for 10 minutes. The plasma was then frozen and stored in a -80°C freezer for detection. Drug concentrations in the plasma of each group's samples were measured by LC-MS / MS. Non-compartmental model analysis was performed using Phoenix winnonlin8.0, and PK parameters were calculated. Data analysis was performed using C. max , T max AUC 0-t AUC 0-∞ t 1 / 2 This includes pharmacokinetic parameters such as those listed above.

[0060] 4. Test results 4.1 Cage-side observation No significant abnormalities were observed in any of the animals during cage-side observation after administration.

[0061] 4.2 Detection Results The main pharmacokinetic parameters after single oral administration of the same dose of each compound to cynomolgus monkeys via a gastric tube are shown in Table 4, and the drug-time curve is shown in Figure 10.

[0062] [Table 4]

[0063] Research results (1) After administering the same dose of each compound from each group to cynomolgus monkeys via a single gastric tube, the bioavailability of each group of cynomolgus monkeys (Cmax and AUC 0-t The order of highest to lowest is compound I-1-1-2 > compound I-1-1-3 > baloxavir marboxil. (2) Bioavailability of compound I-1-1-2 and compound I-1-1-3 compared to the baloxavir marboxil group (C max and AUC 0-t ) showed a significant improvement and exhibited statistically significant differences (P<0.01 and P<0.05, respectively). (3) Compound I-1-1-2 has the highest exposure levels and the longest half-life in cynomolgus monkeys. It can maintain a long-lasting drug therapeutic effect.

Claims

1. The acylethyl ester polycyclic compound is of formula (I) 【Chemistry 1】 A compound of formula (I), or an isomer of a compound of formula (I), a pharmaceutically acceptable salt, solvate, or isotope-labeled compound, The acylethyl ester polycyclic compound, wherein X is S (sulfur) or Se (selenium) in formula (I).

2. The compound of formula (I) is given by formula (I-1). 【Chemistry 2】 The acylethyl ester polycyclic compound according to claim 1, which is a compound of the above.

3. The compound of formula (I) is given by formula (I-1-1). 【Transformation 3】 The acylethyl ester polycyclic compound according to claim 2, which is a compound of the above.

4. The compound of formula (I) is given by formula (I-1-2). 【Chemistry 4】 The acylethyl ester polycyclic compound according to claim 2, which is a compound of the above.

5. The acylethyl ester polycyclic compound according to any one of claims 1 to 4, wherein X is S.

6. The acylethyl ester polycyclic compound according to any one of claims 1 to 4, wherein X is Se. 【Request Item 7】 【Chemistry 5】 【change】 A compound selected from the compound or its pharmaceutically acceptable salt, solvate, or isotope-labeled product.

8. A pharmaceutical composition containing the compound described in any one of claims 1 to 7.

9. An application of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the manufacture of a drug for preventing and / or treating a viral infection, wherein the viral infection is selectively an infection caused by influenza A virus or influenza B virus.

10. The use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the prevention and / or treatment of a viral infection, wherein the viral infection is selectively an infection caused by influenza A virus or influenza B virus.

11. A method for preventing and / or treating a viral infection, the method comprising administering to an individual having a need for treatment a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8, wherein the viral infection is an infection caused by influenza A virus or influenza B virus.

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