Deuterated nucleoside compounds and uses thereof

Abstract

To provide effective drugs and methods for treating coronavirus infections. The present invention provides a series of deuterated nucleoside compounds and uses thereof, specifically, compounds selected from the following formulae or pharmaceutically acceptable salts thereof: JPEG2025069908000019.jpg65166

Description

[Technical field]

[0001] This application is a divisional application of the Japanese patent application number: 2024-508580, filed on February 9, 2024, with the title of "Deuterated nucleoside compounds and their uses". 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, priority to a Chinese application having a filing date of June 15, 2022 and application number CN202210695557.6, priority to a Chinese application having a filing date of August 19, 2022 and application number CN202211002496.7, and priority to 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, in particular to a series of deuterated nucleoside compounds and their uses, particularly to a compound represented by formula (VI-1), its stereoisomer or its pharma- ceutically acceptable salt: [Background technology]

[0002] Currently, there are seven known coronaviruses that can infect 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. Among them, the latter three can cause severe symptoms and even death when they infect humans. Coronavirus infections, especially the new COVID-2019 and its variants, can spread very rapidly, and some patients may require a long period of recovery, severely affecting 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 pharma- ceutically 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)-, 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 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 pharma- ceutically acceptable salt, R5 is

[0008] [ka]

[0009] and the other variables are as defined herein.

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

[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 herein.

[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 herein.

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

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

[0020] [ka]

[0021] In some embodiments of the present invention, there is provided the use of the above compound or a pharma- ceutically 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 above 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. Effect of the Invention

[0024] The compounds of the present invention have strong anti-coronavirus in vitro activity. After the compounds of the present invention are administered to mice, they are rapidly metabolized to the corresponding active metabolites in the body to exert their medicinal effects. The drug concentration of the compounds of the present invention lasts longer and is maintained at a higher concentration, which is favorable for sustained virus inhibition and medicinal effects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] [Definitions and Explanations]

[0026] Unless otherwise stated, the following terms and phrases used herein have the following meanings. A particular term or phrase, unless otherwise defined, should be understood as being of ordinary definition, not indefinite or unclear. When a trade name is mentioned in this specification, it refers to the corresponding product or its active ingredient.

[0027] As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant 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 are eliminated.

[0029] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents found in the present invention. 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 single solution or in a suitable inert solvent. 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 single solution or in a suitable inert solvent. Some specific compounds of the present invention contain basic and acidic functional groups, and therefore can be converted into any base addition salt or acid addition salt.

[0030] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. 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 specific 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 both within the scope of the present invention.

[0033] Unless otherwise stated, 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 explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.

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

[0037] [ka]

[0038] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, the number of H atoms at the site is reduced to a group with a corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is:

[0039] [ka]

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

[0041] [ka]

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

[0043] [ka]

[0044] The dotted bond in the figure means that the phenyl group can be bonded to other groups through 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 stated, 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 of tautomers if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bond electrons. Among them, 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 "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of such isomer or enantiomer 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 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0047] Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0048] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. A single enantiomer of a compound 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 resolved to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to provide the isolated enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic techniques using chiral stationary phases and any chemical derivatization techniques (e.g., carbamate formation from amines).

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

[0050] "Optional" or "optionally" means that the following event or circumstance may occur, but does not necessarily occur, and that the description includes situations where the described 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, which may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound is stable after substitution. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto group substitution does not occur on 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 composition or structure of a compound, its definition is independent in each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said 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 linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl has C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, and C5 alkyl, which 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 linked 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 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 a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments given 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, and when the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, after collecting the relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis.

[0058] All solvents used in the present 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 dimethylsulfoxide; 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 conventions in the field or ChemDraw (R) The compounds are named by the software, and commercially available compounds use the names from the manufacturer's catalogue. EXAMPLES

[0060] The present invention will be specifically described below by way of examples, but is not intended to be an adverse restriction of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious 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 system was stirred at room temperature for 14 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ISCO (R) 40g 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 addition of Dess-Martin reagent (1.19 g). The reaction was stirred at room temperature for 4 hours. The reaction solution 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 was stirred at room temperature for 1 h. The reaction solution 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 the addition of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 411.39 μL). The reaction system was stirred at room temperature for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. Compound 1-5 was obtained.

[0071] MS m / z(ESI): [M+H] + =293.2. 1H 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, and then sulfuric acid (50.34 mg) and compound acetonylidene (178.17 mg) were added in sequence. The reaction system was stirred at 45°C for 0.5 hours. Water (50 mL) was added to the reaction system, and the reaction solution was adjusted to neutral with sodium bicarbonate solution (15%), extracted with EtOAc (50 mL x 3), and the organic phases were combined and then washed with saturated saline (50 mL) and water (50 mL) in sequence. After separation, the organic phase was dried over anhydrous Na2SO4, and finally the organic phase was directly concentrated under reduced pressure to obtain 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 adding water (30 mL) and extracted with EtOAc (10 mL x 2). The organic phases were combined and then washed with saturated brine (10 mL), then dried over anhydrous Na2SO4, 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 the addition of formic acid (15 mL). The reaction system was stirred at room temperature for 4 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column type: O-Welch C18 150 x 30 mm x 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. 1H 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 study 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 intragastric administration formulations was 1% methylcellulose 4000 aqueous solution). The project used 4 male CD-1 mice, the dosage was 100mg / kg, and the drug concentration was 10mg / mL. Plasma samples were collected at 0 hours (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and centrifuged at 3200g for 10 minutes at 4℃. The supernatant was separated to obtain plasma samples. The plasma was transferred to a pre-cooled centrifuge tube and quickly frozen on dry ice, and then stored in a deep-cold refrigerator at -70±10℃ / -60℃ or below. Plasma drug concentrations were quantitatively analyzed using LC-MS / MS analytical method, and the pharmacokinetic software WinNonlin Version 6.3 or above (Pharsight) was used to process the plasma drug concentration data of 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 and exert their pharmacological effects. The drug concentrations of the compounds of the present invention last for a long time and are maintained at high concentrations, which is favorable for sustained virus inhibition and pharmacological effects.

Claims

1. A compound represented by formula (VI-1), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. 【Chemistry 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)—, 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 pharma- ceutically acceptable salt thereof, wherein each R is independently hydroxyl.

3. R ５ teeth, 【Chemistry 2】 2. The compound according to claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof,

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 optionally substituted by one, two, or three R, or a stereoisomer or a pharma- ceutically acceptable salt thereof, according to claim 1.

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

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

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

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