Deuterated nucleoside compounds and use thereof

Abstract

To provide effective drugs and methods for treating coronavirus infections.SOLUTION: Disclosed are a series of deuterated nucleoside compounds and a use thereof. Specifically provided are compounds shown in the figure, and stereoisomers thereof or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is a divisional application of Japanese Patent Application No. 2024-508580, filed on February 9, 2024, entitled "Deuterated Nucleoside Compounds and Uses Thereof." The patent application with application number CN202380009968.8 has an international filing date of May 17, 2023, and is a Chinese national phase application of the PCT application with international application number PCT / CN2023 / 094871, with a Chinese entry date of August 3, 2023. This application claims priority to a Chinese application having a filing date of May 17, 2022 and application number CN202210548373.7, a Chinese application having a filing date of June 15, 2022 and application number CN202210695557.6, a Chinese application having a filing date of August 19, 2022 and application number CN202211002496.7, and a Chinese application having a filing date of March 7, 2023 and application number CN202310213459.9. The present invention relates to the technical field of medicinal chemistry, and in particular to a series of deuterated nucleoside compounds and uses thereof, specifically to a compound represented by formula (VI-1), its stereoisomers, or pharmaceutically acceptable salts thereof: [Background technology]

[0002] Currently, seven types of coronaviruses are known to be capable of infecting humans: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (SARS), MERS-CoV (MERS), and SARS-CoV-2 (COVID-2019), which emerged at the end of 2019. The latter three can cause severe symptoms and even death in humans. Coronavirus infections, particularly the novel COVID-2019 and its variants, can spread very rapidly, and some patients may require a long recovery period, severely impacting people's work and lives. Summary of the Invention [Problem to be solved by the invention]

[0003] There is an urgent need for more effective drugs and methods for treating such infections. [Means for solving the problem]

[0004] In one aspect, the present invention provides a compound represented by formula (VI-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0005] [ka]

[0006] however, R2 and R3 are each independently hydrogen, C 1-6 Alkyl-C(=O)-, C 1-4 alkoxy-C(=O)- and phenyl-C(=O)-, wherein C 1-6 Alkyl, C 1-4 alkoxy and phenyl are each independently optionally substituted by 1, 2 or 3 R; R5 is selected from phenyl, said phenyl optionally substituted by one, two or three R; Each R is independently selected from hydroxyl, halogen, amino, and cyano. In some embodiments of the present invention, each R is independently selected from hydroxyl, and all other variables are as defined herein.

[0007] In some embodiments of the present invention, in the compound represented by the above formula (VI-1), its stereoisomer, or its pharmaceutically acceptable salt, R5 is

[0008] [ka]

[0009] and the other variables are as defined in the present invention.

[0010] In some embodiments of the present invention, R2 and R3 are each independently selected from hydrogen, isopropyl-C(=O)-, and phenyl-C(=O)-, wherein the isopropyl and phenyl are each independently optionally substituted by one, two, or three R; The variables are as defined in the present invention.

[0011] In some embodiments of the present invention, R2 and R3 are each independently selected from hydrogen, isopropyl -C(=O)-, and

[0012] [ka]

[0013] and the other variables are as defined in the present invention.

[0014] In some embodiments of the present invention, R2 and R3 are each independently selected from hydrogen and isopropyl -C(=O)-, and all other variables are as defined herein.

[0015] In some embodiments of the invention, R2 and R3 are each independently hydrogen and

[0016] [ka]

[0017] and the other variables are as defined in the present invention.

[0018] Some aspects of the present invention are further formed by any combination of the above variables.

[0019] The present invention also provides a compound selected from the formula: or a pharmaceutically acceptable salt thereof.

[0020] [ka]

[0021] In some embodiments of the present invention, there is provided the use of the above compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease associated with an RNA-dependent RNA polymerase inhibitor.

[0022] In some embodiments of the present invention, the use is characterized in that the disease associated with the RNA-dependent RNA polymerase inhibitor is a viral infection such as a viral cold or viral pneumonia.

[0023] In some embodiments of the present invention, the use is characterized in that the disease associated with the RNA-dependent RNA polymerase inhibitor is viral pneumonia. [Effects of the Invention]

[0024] The compounds of the present invention have potent anti-coronavirus activity in vitro. After administration of the compounds of the present invention to mice, they are rapidly metabolized to the corresponding active metabolites in the body, thereby exerting their medicinal effects. The drug concentrations of the compounds of the present invention are longer-lasting and higher, which is advantageous for sustained viral inhibition and medicinal effects. DETAILED DESCRIPTION OF THE INVENTION

[0025] [Definitions and Explanations]

[0026] Unless otherwise stated, the following terms and phrases used herein have the following meanings. Unless otherwise defined, a particular term or phrase should be understood to have its ordinary definition, rather than being indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0027] As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals, without appreciable toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0028] Unless otherwise explained, the term "treatment" refers to any process that may slow, interrupt, hinder or stop the progression of a disease, but does not necessarily mean that all symptoms will disappear.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is a compound of the present invention, and which is a compound of the present invention. These compounds are prepared with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of base in a suitable inert solvent, or in a solution of the compounds themselves. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of these compounds with a sufficient amount of acid in a suitable inert solvent, or in a solution of the compounds themselves. Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base or acid addition salt.

[0030] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acidic or basic group in a conventional manner. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0031] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, enantiomers and tautomers.

[0032] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are within the scope of the present invention.

[0033] Unless otherwise specified, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.

[0034] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0035] Unless otherwise specified, the term "diastereomer" refers to stereoisomers whose molecules have two or more centers of chirality and whose molecules are not mirror-images of each other.

[0036] Unless otherwise stated, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0037] [ka]

[0038] Unless otherwise specified, if a group has one or more available bonding sites, any one or more of the sites on the group can be bonded to another group by a chemical bond. When the system is delocalized and there are H atoms at the bondable sites, when a chemical bond is formed, the number of H atoms at the site is reduced to a group with a corresponding valence according to the number of chemical bonds formed.

[0039] [ka]

[0040] For example, the straight solid bond in -OCH3 means that the group is bonded to another group through the oxygen atom of that group.

[0041] [ka]

[0042] A straight dashed bond within a group means that both ends of the nitrogen atom within the group are bonded to other groups.

[0043] [ka]

[0044] The dotted bond in the figure means that the phenyl group can be bonded to another group by one chemical bond through any available site on the phenyl group.

[0045] The compounds of the present invention may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can be rapidly interconverted. Tautomers can reach chemical equilibrium if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions mediated by the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bond electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0046] Unless otherwise explained, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomerically enriched" mean a product that is less than 100% rich in one isomer or enantiomer, and that is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99% or more. This means that the accuracy is 0.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0047] Unless otherwise stated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0048] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared using asymmetric synthesis, chiral reagents, or other conventional techniques. Single enantiomers of certain compounds of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers by conventional methods known in the art and subsequent recovery to provide the isolated enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic methods using chiral stationary phases and optionally chemical derivatization (e.g., carbamate formation from an amine).

[0049] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms constituting the compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioactive isotopes such as C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs offer the advantages of reduced toxic side effects, increased drug stability, improved therapeutic efficacy, and a longer biological half-life. Conversion of the isotopic composition of the compounds of the present invention, whether radioactive or not, is within the scope of the present invention.

[0050] "Optional" or "optionally" means that the following event or circumstance may occur, but does not necessarily occur, and that the description includes the case where the described event or circumstance occurs but the event or circumstance does not occur.

[0051] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, and may include deuterium and hydrogen variants, provided that the particular valence state is correct and the resulting compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto group substitution does not occur in aromatic groups. The term "optionally substituted" refers to either substituted or unsubstituted, and unless otherwise defined, the type and number of substituents are any that are chemically stable and feasible.

[0052] When any variable (e.g., R) occurs more than once in a compound composition or structure, its definition is independent at each occurrence. So, for example, if a group is substituted with 0 to 2 R, then that group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0053] Unless otherwise defined, the term "C 1―6 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 6 carbon atoms, either straight or branched. 1-6 C for alkyl 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, and C5 alkyl, and It may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). 1-6 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), hexyl, and the like.

[0054] Unless otherwise defined, the term "C 1―4"Alkoxy" refers to an alkyl group containing 1 to 4 carbon atoms connected to the remainder of the molecule through an oxygen atom. 1-4 Alkoxy has C 1-3 , C 1-2 , C 2-4 , C4 and C3 alkoxy, etc. 1-6 Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0055] Unless otherwise defined, the terms "halogen" or "halo," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0056] The compounds of the present invention can be prepared by various synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0057] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. When the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means known to those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting the relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis.

[0058] All solvents used in this invention can be obtained from commercial sources. The present invention uses the following abbreviations: aq stands for water; eq stands for equivalent; M stands for mol / L; DCM stands for dichloromethane; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; THF stands for tetrahydrofuran; HCOOH stands for formic acid; TFA stands for trifluoroacetic acid; Py stands for pyridine; DIPEA stands for diisopropylethylamine; DMP stands for Dess-Martin reagent; NaBD₄ stands for sodium borodeuteride; MeOD stands for deuterated methanol; TBAF stands for tetrabutylammonium fluoride; ACN stands for acetonitrile; mp stands for melting point; RdRp stands for RNA-dependent RNA polymerase, and room temperature stands for 25°C.

[0059] Compounds are named according to the usual naming principles of the field or ChemDraw (R) Names are assigned by the software, and commercially available compounds use the names from the manufacturer's catalog. [Example]

[0060] The present invention will be specifically described below by way of examples, but is not intended to be an adverse limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0061] Example 1

[0062] Synthesis scheme:

[0063] [ka]

[0064] Step 1: Synthesis of Compound 1-2 Compound 1-1 (3.0 g) and dichloromethane (20 mL) were added to a reaction flask, followed by pyridine (29.40 g) and compound 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (3.90 g). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ISCO). (R) 40g of SepaFlash (R) Compound 1-2 (purity: 84.0%) was obtained by separation using a Silica Flash Column (mobile phase: 0-50% EtOAc / PE, flow rate: 50 mL / min).

[0065] MS m / z(ESI): [M+H] + =534.6.

[0066] Step 2: Synthesis of Compounds 1-3 Compound 1-2 (1.0 g, purity: 84%) and dichloromethane (50 mL) were added to a reaction flask, followed by the Dess-Martin reagent (1.19 g). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and then directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ISCO). (R) 12g SepaFlash (R) Compounds 1-3 were obtained by separation using a Silica Flash Column (mobile phase: 0-33% EtOAc / PE, flow rate: 35 mL / min).

[0067] MS m / z(ESI): [M+H] + =532.2.

[0068] Step 3: Synthesis of Compounds 1-4 Compound 1-3 (200 mg) and deuterated methanol (10 mL) were added to a reaction flask, followed by sodium borodeuteride (28.46 mg). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ISCO). (R) 12g SepaFlash (R)Compounds 1-4 were obtained by separation using a Silica Flash Column (mobile phase: 0-30% EtOAc / PE, flow rate: 30 mL / min).

[0069] MS m / z(ESI): [M+H] + =535.2.

[0070] Step 4: Synthesis of Compounds 1-5 Compound 1-4 (110 mg) and tetrahydrofuran (4 mL) were added to a reaction flask, followed by a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 411.39 μL). The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was directly concentrated under reduced pressure to give the crude product. Compound 1-5 was obtained.

[0071] MS m / z(ESI): [M+H] + =293.2. 1 H NMR (400MHz, DMSO-d6) δ =7.88 (s, 1H), 6.91-6.94 (m, 2H) ,3.95 (d, J=5.3 Hz, 1H), 3.65 (br d, J=3.5 Hz, 1H), 3.62 (br d, J=3.3 Hz, 2H), 3.52 (br d, J=4.5 Hz, 2H).

[0072] Step 5: Synthesis of Compounds 1-6 Compound 1-5 (100 mg) and acetone (40 mL) were added to a reaction flask, followed by the addition of sulfuric acid (50.34 mg) and compound acetonylidene (178.17 mg). The reaction mixture was stirred at 45 °C for 0.5 hours. Water (50 mL) was added to the reaction mixture, and the reaction solution was adjusted to neutral with sodium bicarbonate solution (15%). The mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL) and water (50 mL), and the organic phase was dried over anhydrous Na2SO4. Finally, the organic phase was directly concentrated under reduced pressure to give compound 1-6.

[0073] MS m / z(ESI): [M+H]+ =333.2.

[0074] Example 2

[0075] [ka]

[0076] Synthesis scheme:

[0077] [ka]

[0078] Step 1: Synthesis of compound 2-2 Compound 1-6 (300 mg), salicylic acid (311.71 mg), and dichloromethane (3 mL) were added to a reaction flask, followed by the addition of 4-dimethylaminopyridine (275.71 mg) and N,N'-dicyclohexylcarbodiimide (465.63 mg). The reaction was stirred at 35°C for 12 hours. The reaction was quenched by the addition of water (30 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, and the organic phase was filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ISCO). (R) ;4g SepaFlash (R) Compound 2-2 was obtained by separation using a Silica Flash Column (mobile phase: 0-80% ethyl acetate / petroleum ether, flow rate: 18 mL / min).

[0079] MS m / z(ESI): [M+H] + =453.0.

[0080] Step 2: Synthesis of Compound 2 Compound 2-2 (275 mg) and water (3 mL) were added to a reaction flask, followed by formic acid (15 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column type: O-Welch C18 150 × 30 mm × 5 μm; mobile phase: [HO(FA)-ACN]; ACN%: 18% to 58%, 10 min) to obtain compound 2.

[0081] MS m / z(ESI): [M+H] + =413.3. 1 H NMR: (400MHz, DMSO-d6) δ = 10.43 (s, 1H), 7.98 - 7.81 (m, 2H), 7.64 (d, J=6.8 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.91 (t, J=7.7 Hz, 1H), 6.87 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.34 (s, 1H), 5.46 (br s, 1H), 4.63 (dd, J=2.6, 12.2 Hz, 1H), 4.48 - 4.43 (m, 1H), 4.41 - 4.36 (m, 1H), 4.13 (br d, J=6.3 Hz, 1H).

[0082] Biological testing: Test Example 1: Pharmacokinetic evaluation of compounds Experimental objective: To test the pharmacokinetics of the compound in CD-1 mice. Experimental materials: CD-1 mice (male, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0083] Experimental procedure: Standard protocols were used to test the pharmacokinetic properties of compounds after intragastric administration in rodents. In the experiment, the candidate compounds were prepared into a clear solution (the solvent for the intragastric administration formulation was 1% methylcellulose 4000 aqueous solution). Four male CD-1 mice were used in this project. The dose was 100 mg / kg, and the drug concentration was 10 mg / mL. Plasma samples were collected at time 0 (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The samples were centrifuged at 3200 g for 10 minutes at 4°C and the supernatant was separated to obtain plasma samples. The plasma was transferred to pre-cooled centrifuge tubes and rapidly frozen on dry ice before being stored in an ultra-low temperature refrigerator at -70±10°C / -60°C or below. Plasma drug concentrations were quantitatively analyzed using an LC-MS / MS analytical method, and the pharmacokinetic software WinNonlin Version 6.3 or higher (Pharsight) was used to process the plasma drug concentration data of the metabolites of the compounds of the present invention using a non-compartmental model. Peak concentrations (C max ), half-life (T 1 / 2 ), area under the drug-time curve (AUC 0-inf ) and other pharmacokinetic parameters were calculated, and the experimental results are shown in Tables 3 and 4.

[0084] [Table 1]

[0085] [Table 2]

[0086] Conclusion: After administration of the compounds of the present invention to mice, they are rapidly metabolized in the body to the corresponding active metabolites, exerting their medicinal effects. The drug concentrations of the compounds of the present invention are long-lasting and maintained at high concentrations, which is advantageous for sustained viral inhibition and medicinal effects.

Claims

1. A compound represented by formula (VI-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (however, R ２ and R ３ are each independently hydrogen, C １－６ Alkyl-C(=O)-, C １－４ alkoxy-C(=O)- and phenyl-C(=O)-, wherein C １－６ Alkyl, C １－４ alkoxy and phenyl are each independently optionally substituted with 1, 2, or 3 R; R ５ is selected from phenyl, said phenyl optionally substituted by one, two or three R; Each R is independently selected from hydroxyl, halogen, amino, and cyano.

2. 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently hydroxyl.

3. R ５ teeth, 【Chemistry 2】 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

4. R ２ and R ３ are each independently selected from hydrogen, isopropyl-C(=O)-, and phenyl-C(=O)-, wherein said isopropyl and phenyl are each independently one of 2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, optionally substituted with two or three R.

5. R ２ and R ３ are each independently hydrogen, isopropyl -C(=O)-, and 【Chemistry 3】 5. The compound of claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, selected from:

6. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

7. Use of the compound according to any one of claims 1 to 6, its stereoisomer or its pharmaceutically acceptable salt in the manufacture of a medicament for treating a disease associated with an RNA-dependent RNA polymerase inhibitor.

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